Emmanuel Mignot, MD, PhD

All Publications

• HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease. Brain : a journal of neurology Yogeshwar, S. M., Muñiz-Castrillo, S., Sabater, L., Peris-Sempere, V., Mallajosyula, V., Luo, G., Yan, H., Yu, E., Zhang, J., Lin, L., Fagundes Bueno, F., Ji, X., Picard, G., Rogemond, V., Pinto, A. L., Heidbreder, A., Höftberger, R., Graus, F., Dalmau, J., Santamaria, J., Iranzo, A., Schreiner, B., Giannoccaro, M. P., Liguori, R., Shimohata, T., Kimura, A., Ono, Y., Binks, S., Mariotto, S., Dinoto, A., Bonello, M., Hartmann, C. J., Tambasco, N., Nigro, P., Prüss, H., McKeon, A., Davis, M. M., Irani, S. R., Honnorat, J., Gaig, C., Finke, C., Mignot, E. 2024

  Abstract

  Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

  View details for DOI 10.1093/brain/awae048

  View details for PubMedID 38425314

• Circadian protein expression patterns in healthy young adults. Sleep health Specht, A., Kolosov, G., Cederberg, K. L., Bueno, F., Arrona-Palacios, A., Pardilla-Delgado, E., Ruiz-Herrera, N., Zitting, K. M., Kramer, A., Zeitzer, J. M., Czeisler, C. A., Duffy, J. F., Mignot, E. 2023

  Abstract

  To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity.Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform. We used differential rhythmicity analysis based on a cosinor model with mixed effects to identify a subset of proteins that showed circadian rhythmicity in their abundance.One thousand and sixty-three (15%) proteins exhibited significant daily rhythmicity. Of those, 431 (6.2%) proteins displayed consistent endogenous circadian rhythms on both a sleep-wake schedule and under controlled conditions: it included both known and novel proteins. When models were fitted with two harmonics, an additional 259 (3.7%) proteins exhibited significant endogenous circadian rhythmicity, indicating that some rhythmic proteins cannot be solely captured by a simple sinusoidal model. Overall, we found that the largest number of proteins had their peak levels in the late afternoon/evening, with another smaller group peaking in the early morning.This study reveals that hundreds of plasma proteins exhibit endogenous circadian rhythmicity in humans. Future analyses will likely reveal novel physiological pathways regulated by circadian clocks and pave the way for improved diagnosis and treatment for patients with circadian disorders and other pathologies. It will also advance efforts to include knowledge about time-of-day, thereby incorporating circadian medicine into personalized medicine.

  View details for DOI 10.1016/j.sleh.2023.10.005

  View details for PubMedID 38087675

• Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences of the United States of America Le Guen, Y., Luo, G., Ambati, A., Damotte, V., Jansen, I., Yu, E., Nicolas, A., de Rojas, I., Peixoto Leal, T., Miyashita, A., Bellenguez, C., Lian, M. M., Parveen, K., Morizono, T., Park, H., Grenier-Boley, B., Naito, T., Küçükali, F., Talyansky, S. D., Yogeshwar, S. M., Sempere, V., Satake, W., Alvarez, V., Arosio, B., Belloy, M. E., Benussi, L., Boland, A., Borroni, B., Bullido, M. J., Caffarra, P., Clarimon, J., Daniele, A., Darling, D., Debette, S., Deleuze, J. F., Dichgans, M., Dufouil, C., During, E., Düzel, E., Galimberti, D., Garcia-Ribas, G., García-Alberca, J. M., García-González, P., Giedraitis, V., Goldhardt, O., Graff, C., Grünblatt, E., Hanon, O., Hausner, L., Heilmann-Heimbach, S., Holstege, H., Hort, J., Jung, Y. J., Jürgen, D., Kern, S., Kuulasmaa, T., Lee, K. H., Lin, L., Masullo, C., Mecocci, P., Mehrabian, S., de Mendonça, A., Boada, M., Mir, P., Moebus, S., Moreno, F., Nacmias, B., Nicolas, G., Niida, S., Nordestgaard, B. G., Papenberg, G., Papma, J., Parnetti, L., Pasquier, F., Pastor, P., Peters, O., Pijnenburg, Y. A., Piñol-Ripoll, G., Popp, J., Porcel, L. M., Puerta, R., Pérez-Tur, J., Rainero, I., Ramakers, I., Real, L. M., Riedel-Heller, S., Rodriguez-Rodriguez, E., Ross, O. A., Luís Royo, J., Rujescu, D., Scarmeas, N., Scheltens, P., Scherbaum, N., Schneider, A., Seripa, D., Skoog, I., Solfrizzi, V., Spalletta, G., Squassina, A., van Swieten, J., Sánchez-Valle, R., Tan, E. K., Tegos, T., Teunissen, C., Thomassen, J. Q., Tremolizzo, L., Vyhnalek, M., Verhey, F., Waern, M., Wiltfang, J., Zhang, J., Zetterberg, H., Blennow, K., He, Z., Williams, J., Amouyel, P., Jessen, F., Kehoe, P. G., Andreassen, O. A., Van Duin, C., Tsolaki, M., Sánchez-Juan, P., Frikke-Schmidt, R., Sleegers, K., Toda, T., Zettergren, A., Ingelsson, M., Okada, Y., Rossi, G., Hiltunen, M., Gim, J., Ozaki, K., Sims, R., Foo, J. N., van der Flier, W., Ikeuchi, T., Ramirez, A., Mata, I., Ruiz, A., Gan-Or, Z., Lambert, J. C., Greicius, M. D., Mignot, E. 2023; 120 (36): e2302720120

  Abstract

  Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

  View details for DOI 10.1073/pnas.2302720120

  View details for PubMedID 37643212

• Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1. The New England journal of medicine Dauvilliers, Y., Mignot, E., Del Rio Villegas, R., Du, Y., Hanson, E., Inoue, Y., Kadali, H., Koundourakis, E., Meyer, S., Rogers, R., Scammell, T. E., Sheikh, S. I., Swick, T., Szakacs, Z., von Rosenstiel, P., Wu, J., Zeitz, H., Murthy, N. V., Plazzi, G., von Hehn, C. 2023; 389 (4): 309-321

  Abstract

  BACKGROUND: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.METHODS: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.RESULTS: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients.CONCLUSIONS: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

  View details for DOI 10.1056/NEJMoa2301940

  View details for PubMedID 37494485

• The immunopathogenesis of narcolepsy type 1. Nature reviews. Immunology Liblau, R. S., Latorre, D., Kornum, B. R., Dauvilliers, Y., Mignot, E. J. 2023

  Abstract

  Narcolepsy type 1 (NT1) is a chronic sleep disorder resulting from the loss of a small population of hypothalamic neurons that produce wake-promoting hypocretin (HCRT; also known as orexin) peptides. An immune-mediated pathology for NT1 has long been suspected given its exceptionally tight association with the MHC class II allele HLA-DQB1*06:02, as well as recent genetic evidence showing associations with polymorphisms of T cell receptor genes and other immune-relevant loci and the increased incidence of NT1 that has been observed after vaccination with the influenza vaccine Pandemrix. The search for both self-antigens and foreign antigens recognized by the pathogenic T cell response in NT1 is ongoing. Increased T cell reactivity against HCRT has been consistently reported in patients with NT1, but data demonstrating a primary role for T cells in neuronal destruction are currently lacking. Animal models are providing clues regarding the roles of autoreactive CD4+ and CD8+ T cells in the disease. Elucidation of the pathogenesis of NT1 will allow for the development of targeted immunotherapies at disease onset and could serve as a model for other immune-mediated neurological diseases.

  View details for DOI 10.1038/s41577-023-00902-9

  View details for PubMedID 37400646

• Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature communications Ollila, H. M., Sharon, E., Lin, L., Sinnott-Armstrong, N., Ambati, A., Yogeshwar, S. M., Hillary, R. P., Jolanki, O., Faraco, J., Einen, M., Luo, G., Zhang, J., Han, F., Yan, H., Dong, X. S., Li, J., Zhang, J., Hong, S. C., Kim, T. W., Dauvilliers, Y., Barateau, L., Lammers, G. J., Fronczek, R., Mayer, G., Santamaria, J., Arnulf, I., Knudsen-Heier, S., Bredahl, M. K., Thorsby, P. M., Plazzi, G., Pizza, F., Moresco, M., Crowe, C., Van den Eeden, S. K., Lecendreux, M., Bourgin, P., Kanbayashi, T., Martínez-Orozco, F. J., Peraita-Adrados, R., Benetó, A., Montplaisir, J., Desautels, A., Huang, Y. S., Jennum, P., Nevsimalova, S., Kemlink, D., Iranzo, A., Overeem, S., Wierzbicka, A., Geisler, P., Sonka, K., Honda, M., Högl, B., Stefani, A., Coelho, F. M., Mantovani, V., Feketeova, E., Wadelius, M., Eriksson, N., Smedje, H., Hallberg, P., Hesla, P. E., Rye, D., Pelin, Z., Ferini-Strambi, L., Bassetti, C. L., Mathis, J., Khatami, R., Aran, A., Nampoothiri, S., Olsson, T., Kockum, I., Partinen, M., Perola, M., Kornum, B. R., Rueger, S., Winkelmann, J., Miyagawa, T., Toyoda, H., Khor, S. S., Shimada, M., Tokunaga, K., Rivas, M., Pritchard, J. K., Risch, N., Kutalik, Z., O'Hara, R., Hallmayer, J., Ye, C. J., Mignot, E. J. 2023; 14 (1): 2709

  Abstract

  Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

  View details for DOI 10.1038/s41467-023-36120-z

  View details for PubMedID 37188663

  View details for PubMedCentralID PMC10185546

• What Is Narcolepsy? JAMA Sum-Ping, O., Mignot, E. 2023

  View details for DOI 10.1001/jama.2023.5149

  View details for PubMedID 37145499

• Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients. Proceedings of the National Academy of Sciences of the United States of America Evans, R., Kimura, H., Alexander, R., Davies, C. H., Faessel, H., Hartman, D. S., Ishikawa, T., Ratti, E., Shimizu, K., Suzuki, M., Tanaka, S., Yukitake, H., Dauvilliers, Y., Mignot, E. 2022; 119 (35): e2207531119

  Abstract

  Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.

  View details for DOI 10.1073/pnas.2207531119

  View details for PubMedID 35994639

• Genetics of circadian rhythms and sleep in human health and disease. Nature reviews. Genetics Lane, J. M., Qian, J., Mignot, E., Redline, S., Scheer, F. A., Saxena, R. 2022

  Abstract

  Circadian rhythms and sleep are fundamental biological processes integral to human health. Their disruption is associated with detrimental physiological consequences, including cognitive, metabolic, cardiovascular and immunological dysfunctions. Yet many of the molecular underpinnings of sleep regulation in health and disease have remained elusive. Given the moderate heritability of circadian and sleep traits, genetics offers an opportunity that complements insights from model organism studies to advance our fundamental molecular understanding of human circadian and sleep physiology and linked chronic disease biology. Here, we review recent discoveries of the genetics of circadian and sleep physiology and disorders with a focus on those that reveal causal contributions to complex diseases.

  View details for DOI 10.1038/s41576-022-00519-z

  View details for PubMedID 36028773

• Characterization of T cell receptors reactive to HCRTNH2, pHA273-287, and NP17-31 in control and narcolepsy patients. Proceedings of the National Academy of Sciences of the United States of America Luo, G., Zhang, J., Lin, L., Mignot, E. J. 2022; 119 (32): e2205797119

  Abstract

  Narcolepsy type 1 (NT1), a disorder caused by hypocretin/orexin (HCRT) cell loss, is associated with human leukocyte antigen (HLA)-DQ0602 (98%) and T cell receptor (TCR) polymorphisms. Increased CD4+ T cell reactivity to HCRT, especially DQ0602-presented amidated C-terminal HCRT (HCRTNH2), has been reported, and homology with pHA273-287 flu antigens from pandemic 2009 H1N1, an established trigger of the disease, suggests molecular mimicry. In this work, we extended DQ0602 tetramer and dextramer data to 77 cases and 44 controls, replicating our prior finding and testing 709 TCRs in Jurkat 76 T cells for functional activation. We found that fewer TCRs isolated with HCRTNH2 (11%) versus pHA273-287 or NP17-31 antigens (50%) were activated by their ligand. Single-cell characterization did not reveal phenotype differences in influenza versus HCRTNH2-reactive T cells, and analysis of TCR CDR3alphabeta sequences showed TCR clustering by responses to antigens but no cross-peptide class reactivity. Our results do not support the existence of molecular mimicry between HCRT and pHA273-287 or NP17-31.

  View details for DOI 10.1073/pnas.2205797119

  View details for PubMedID 35914171

• Age estimation from sleep studies using deep learning predicts life expectancy. NPJ digital medicine Brink-Kjaer, A., Leary, E. B., Sun, H., Westover, M. B., Stone, K. L., Peppard, P. E., Lane, N. E., Cawthon, P. M., Redline, S., Jennum, P., Sorensen, H. B., Mignot, E. 2022; 5 (1): 103

  Abstract

  Sleep disturbances increase with age and are predictors of mortality. Here, we present deep neural networks that estimate age and mortality risk through polysomnograms (PSGs). Aging was modeled using 2500 PSGs and tested in 10,699 PSGs from men and women in seven different cohorts aged between 20 and 90. Ages were estimated with a mean absolute error of 5.8±1.6years, while basic sleep scoring measures had an error of 14.9±6.29years. After controlling for demographics, sleep, and health covariates, each 10-year increment in age estimate error (AEE) was associated with increased all-cause mortality rate of 29% (95% confidence interval: 20-39%). An increase from -10 to +10years in AEE translates to an estimated decreased life expectancy of 8.7years (95% confidence interval: 6.1-11.4years). Greater AEE was mostly reflected in increased sleep fragmentation, suggesting this is an important biomarker of future health independent of sleep apnea.

  View details for DOI 10.1038/s41746-022-00630-9

  View details for PubMedID 35869169

• Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response. International journal of molecular sciences Cederberg, K. L., Hanif, U., Peris Sempere, V., Hedou, J., Leary, E. B., Schneider, L. D., Lin, L., Zhang, J., Morse, A. M., Blackman, A., Schweitzer, P. K., Kotagal, S., Bogan, R., Kushida, C. A., Ju, Y. S., Petousi, N., Turnbull, C. D., Mignot, E., The Stages Cohort Investigator Group 2022; 23 (14)

  Abstract

  Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea-hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

  View details for DOI 10.3390/ijms23147983

  View details for PubMedID 35887329

• The Genetic Etiology of Periodic Leg Movement in Sleep. Sleep Edelson, J. L., Schneider, L. D., Amar, D., Brink-Kjaer, A., Cederberg, K. L., Kutalik, Z., Hagen, E. W., Peppard, P. E., Tempaku, P. F., Tufik, S., Evans, D. S., Stone, K., Tranah, G., Cade, B., Redline, S., Haba-Rubio, J., Heinzer, R., Marques-Vidal, P., Vollenweider, P., Winkelmann, J., Zou, J., Mignot, E. 2022

  Abstract

  STUDY OBJECTIVES: Periodic Limb Movement in Sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a Genome-Wide Association Study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of 4 cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6,843 total subjects..METHODS: The MrOS study and Wisconsin Sleep Cohort Study (N=1,745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1,002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using mendelian randomization.RESULTS: We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 x 10 -12, beta=0.486), a SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 x10 -22, beta=0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS.CONCLUSIONS: Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.

  View details for DOI 10.1093/sleep/zsac121

  View details for PubMedID 35670608

• Automatic detection of cortical arousals in sleep and their contribution to daytime sleepiness. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Brink-Kjaer, A. n., Olesen, A. N., Peppard, P. E., Stone, K. L., Jennum, P. n., Mignot, E. n., Sorensen, H. B. 2020; 131 (6): 1187–1203

  Abstract

  Significant interscorer variability is found in manual scoring of arousals in polysomnographic recordings (PSGs). We propose a fully automatic method, the Multimodal Arousal Detector (MAD), for detecting arousals.A deep neural network was trained on 2,889 PSGs to detect cortical arousals and wakefulness in 1-second intervals. Furthermore, the relationship between MAD-predicted labels on PSGs and next day mean sleep latency (MSL) on a multiple sleep latency test (MSLT), a reflection of daytime sleepiness, was analyzed in 1447 MSLT instances in 873 subjects.In a dataset of 1,026 PSGs, the MAD achieved an F1 score of 0.76 for arousal detection, while wakefulness was predicted with an accuracy of 0.95. In 60 PSGs scored by nine expert technicians, the MAD performed comparable to four and significantly outperformed five expert technicians for arousal detection. After controlling for known covariates, a doubling of the arousal index was associated with an average decrease in MSL of 40 seconds (p = 0.0075).The MAD performed better or comparable to human expert scorers. The MAD-predicted arousals were shown to be significant predictors of MSL.This study validates a fully automatic method for scoring arousals in PSGs.

  View details for DOI 10.1016/j.clinph.2020.02.027

  View details for PubMedID 32299002

• Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy. Nature communications Stephansen, J. B., Olesen, A. N., Olsen, M. n., Ambati, A. n., Leary, E. B., Moore, H. E., Carrillo, O. n., Lin, L. n., Han, F. n., Yan, H. n., Sun, Y. L., Dauvilliers, Y. n., Scholz, S. n., Barateau, L. n., Hogl, B. n., Stefani, A. n., Hong, S. C., Kim, T. W., Pizza, F. n., Plazzi, G. n., Vandi, S. n., Antelmi, E. n., Perrin, D. n., Kuna, S. T., Schweitzer, P. K., Kushida, C. n., Peppard, P. E., Sorensen, H. B., Jennum, P. n., Mignot, E. n. 2018; 9 (1): 5229

  Abstract

  Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.

  View details for PubMedID 30523329

• HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy. American journal of human genetics Ollila, H. M., Ravel, J., Han, F., Faraco, J., Lin, L., Zheng, X., Plazzi, G., Dauvilliers, Y., Pizza, F., Hong, S., Jennum, P., Knudsen, S., Kornum, B. R., Dong, X. S., Yan, H., Hong, H., Coquillard, C., Mahlios, J., Jolanki, O., Einen, M., Lavault, S., Högl, B., Frauscher, B., Crowe, C., Partinen, M., Huang, Y. S., Bourgin, P., Vaarala, O., Désautels, A., Montplaisir, J., Mack, S. J., Mindrinos, M., Fernandez-Vina, M., Mignot, E. 2015; 96 (1): 136-146

  Abstract

  Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

  View details for DOI 10.1016/j.ajhg.2014.12.010

  View details for PubMedID 25574827

  View details for PubMedCentralID PMC4289679

• Sleep-spindle detection: crowdsourcing and evaluating performance of experts, non-experts and automated methods. Nature methods Warby, S. C., Wendt, S. L., Welinder, P., Munk, E. G., Carrillo, O., Sorensen, H. B., Jennum, P., Peppard, P. E., Perona, P., Mignot, E. 2014; 11 (4): 385-392

  Abstract

  Sleep spindles are discrete, intermittent patterns of brain activity observed in human electroencephalographic data. Increasingly, these oscillations are of biological and clinical interest because of their role in development, learning and neurological disorders. We used an Internet interface to crowdsource spindle identification by human experts and non-experts, and we compared their performance with that of automated detection algorithms in data from middle- to older-aged subjects from the general population. We also refined methods for forming group consensus and evaluating the performance of event detectors in physiological data such as electroencephalographic recordings from polysomnography. Compared to the expert group consensus gold standard, the highest performance was by individual experts and the non-expert group consensus, followed by automated spindle detectors. This analysis showed that crowdsourcing the scoring of sleep data is an efficient method to collect large data sets, even for difficult tasks such as spindle identification. Further refinements to spindle detection algorithms are needed for middle- to older-aged subjects.

  View details for DOI 10.1038/nmeth.2855

  View details for PubMedID 24562424

  View details for PubMedCentralID PMC3972193

• Narcolepsy and Predictors of Positive MSLTs in the Wisconsin Sleep Cohort. Sleep Goldbart, A., Peppard, P., Finn, L., Ruoff, C. M., Barnet, J., Young, T., Mignot, E. 2014; 37 (6): 1043-1051

  Abstract

  To study whether positive multiple sleep latency tests (MSLTs, mean sleep latency [MSL] ≤ 8 minutes, ≥ 2 sleep onset REM sleep periods [SOREMPs]) and/or nocturnal SOREMP (REM sleep latency ≤ 15 minutes during nocturnal polysomonography [NPSG]) are stable traits and can reflect incipient narcolepsy.Cross-sectional and longitudinal investigation of the Wisconsin Sleep Cohort Study.Adults (44% females, 30-81 years) underwent NPSG (n = 4,866 in 1,518 subjects), and clinical MSLT (n = 1,135), with 823 having a repeat NPSG-MSLT at 4-year intervals, totaling 1725 NPSG with MSLT studies. Data were analyzed using linear mixed-effects models, and the stability of positive MSLTs was explored using κ statistics.Prevalence of a nocturnal SOREMP on a NPSG, of ≥ 2 SOREMPs on the MSLT, of MSL ≤ 8 minutes on the MSLT, and of a positive MSLT (MSL ≤ 8 minutes plus ≥ 2 SOREMPs) were 0.35%, 7.0%, 22%, and 3.4%, respectively. Correlates of a positive MSLT were shift work (OR = 7.8, P = 0.0001) and short sleep (OR = 1.51/h, P = 0.04). Test-retest for these parameters was poor, with κ < 0.2 (n.s.) after excluding shift workers and short sleepers. Excluding shift-work, short sleep, and subjects with negative MSLTs, we found one undiagnosed subject with possible cataplexy (≥ 1/month) and a NPSG SOREMPs; one subject previously diagnosed with narcolepsy without cataplexy with 2 NPSG SOREMPs and a positive MSLT, and two subjects with 2 independently positive MSLTs (66% human leukocyte antigen [HLA] positive). The proportions for narcolepsy with and without cataplexy were 0.07% (95% CI: 0.02-0.37%) and 0.20% (95% CI: 0.07-0.58%), respectively.The diagnostic value of multiple sleep latency tests is strongly altered by shift work and to a lesser extent by chronic sleep deprivation. The prevalence of narcolepsy without cataplexy may be 3-fold higher than that of narcolepsy-cataplexy.Goldbart A, Peppard P, Finn L, Ruoff CM, Barnet J, Young T, Mignot E. Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort. SLEEP 2014;37(6):1043-1051.

  View details for DOI 10.5665/sleep.3758

  View details for PubMedID 24882899

  View details for PubMedCentralID PMC4015378

• Design and validation of a periodic leg movement detector. PloS one Moore, H., Leary, E., Lee, S., Carrillo, O., Stubbs, R., Peppard, P., Young, T., Widrow, B., Mignot, E. 2014; 9 (12)

  Abstract

  Periodic Limb Movements (PLMs) are episodic, involuntary movements caused by fairly specific muscle contractions that occur during sleep and can be scored during nocturnal polysomnography (NPSG). Because leg movements (LM) may be accompanied by an arousal or sleep fragmentation, a high PLM index (i.e. average number of PLMs per hour) may have an effect on an individual's overall health and wellbeing. This study presents the design and validation of the Stanford PLM automatic detector (S-PLMAD), a robust, automated leg movement detector to score PLM. NPSG studies from adult participants of the Wisconsin Sleep Cohort (WSC, n = 1,073, 2000-2004) and successive Stanford Sleep Cohort (SSC) patients (n = 760, 1999-2007) undergoing baseline NPSG were used in the design and validation of this study. The scoring algorithm of the S-PLMAD was initially based on the 2007 American Association of Sleep Medicine clinical scoring rules. It was first tested against other published algorithms using manually scored LM in the WSC. Rules were then modified to accommodate baseline noise and electrocardiography interference and to better exclude LM adjacent to respiratory events. The S-PLMAD incorporates adaptive noise cancelling of cardiac interference and noise-floor adjustable detection thresholds, removes LM secondary to sleep disordered breathing within 5 sec of respiratory events, and is robust to transient artifacts. Furthermore, it provides PLM indices for sleep (PLMS) and wake plus periodicity index and other metrics. To validate the final S-PLMAD, experts visually scored 78 studies in normal sleepers and patients with restless legs syndrome, sleep disordered breathing, rapid eye movement sleep behavior disorder, narcolepsy-cataplexy, insomnia, and delayed sleep phase syndrome. PLM indices were highly correlated between expert, visually scored PLMS and automatic scorings (r2 = 0.94 in WSC and r2 = 0.94 in SSC). In conclusion, The S-PLMAD is a robust and high throughput PLM detector that functions well in controls and sleep disorder patients.

  View details for DOI 10.1371/journal.pone.0114565

  View details for PubMedID 25489744

  View details for PubMedCentralID PMC4260847

• Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS genetics Han, F., Faraco, J., Dong, X. S., Ollila, H. M., Lin, L., Li, J., An, P., Wang, S., Jiang, K. W., Gao, Z. C., Zhao, L., Yan, H., Liu, Y. N., Li, Q. H., Zhang, X. Z., Hu, Y., Wang, J. Y., Lu, Y. H., Lu, C. J., Zhou, W., Hallmayer, J., Huang, Y. S., Strohl, K. P., Pollmächer, T., Mignot, E. 2013; 9 (10)

  Abstract

  Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10(-9) beta -1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8 × 10(-10) OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

  View details for DOI 10.1371/journal.pgen.1003880

  View details for PubMedID 24204295

  View details for PubMedCentralID PMC3814311

• Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA neurology Andlauer, O., Moore, H., Jouhier, L., Drake, C., Peppard, P. E., Han, F., Hong, S., Poli, F., Plazzi, G., O'Hara, R., Haffen, E., Roth, T., Young, T., Mignot, E. 2013; 70 (7): 891-902

  Abstract

  Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically.To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency.Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels.Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level.Short REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%).Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.

  View details for DOI 10.1001/jamaneurol.2013.1589

  View details for PubMedID 23649748

• Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic ANNALS OF NEUROLOGY Han, F., Lin, L., Li, J., Dong, X. S., Mignot, E. 2013; 73 (4): 560-560

  View details for DOI 10.1002/ana.23799

  View details for Web of Science ID 000319523800018

  View details for PubMedCentralID PMC4403642

• ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS genetics Faraco, J., Lin, L., Kornum, B. R., Kenny, E. E., Trynka, G., Einen, M., Rico, T. J., Lichtner, P., Dauvilliers, Y., Arnulf, I., Lecendreux, M., Javidi, S., Geisler, P., Mayer, G., Pizza, F., Poli, F., Plazzi, G., Overeem, S., Lammers, G. J., Kemlink, D., Sonka, K., Nevsimalova, S., Rouleau, G., Desautels, A., Montplaisir, J., Frauscher, B., Ehrmann, L., Högl, B., Jennum, P., Bourgin, P., Peraita-Adrados, R., Iranzo, A., Bassetti, C., Chen, W., Concannon, P., Thompson, S. D., Damotte, V., Fontaine, B., Breban, M., Gieger, C., Klopp, N., Deloukas, P., Wijmenga, C., Hallmayer, J., Onengut-Gumuscu, S., Rich, S. S., Winkelmann, J., Mignot, E. 2013; 9 (2)

  Abstract

  Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

  View details for DOI 10.1371/journal.pgen.1003270

  View details for PubMedID 23459209

  View details for PubMedCentralID PMC3573113

• HLA-DQ association and allele competition in Chinese narcolepsy TISSUE ANTIGENS Han, F., Lin, L., Li, J., Dong, S. X., An, P., Zhao, L., Liu, N. Y., Li, Q. Y., Yan, H., Gao, Z. C., Faraco, J., Strohl, K. P., Liu, X., Miyadera, H., Mignot, E. 2012; 80 (4): 328-335

  Abstract

  In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility.

  View details for DOI 10.1111/j.1399-0039.2012.01948.x

  View details for Web of Science ID 000308938000005

  View details for PubMedID 22862152

• Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy SLEEP Andlauer, O., Moore, H., Hong, S., Dauvilliers, Y., Kanbayashi, T., Nishino, S., Han, F., Silber, M. H., Rico, T., Einen, M., Kornum, B. R., Jennum, P., Knudsen, S., Nevsimalova, S., Poli, F., Plazzi, G., Mignot, E. 2012; 35 (9): 1247-1255

  Abstract

  To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1.University-based sleep clinics and laboratories.Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1.Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis.The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (≤ 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status.Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy.

  View details for DOI 10.5665/sleep.2080

  View details for Web of Science ID 000308360100012

  View details for PubMedID 22942503

  View details for PubMedCentralID PMC3413802

• Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy HUMAN MOLECULAR GENETICS Winkelmann, J., Lin, L., Schormair, B., Kornum, B. R., Faraco, J., Plazzi, G., Melberg, A., Cornelio, F., Urban, A. E., Pizza, F., Poli, F., Grubert, F., Wieland, T., Graf, E., Hallmayer, J., Strom, T. M., Mignot, E. 2012; 21 (10): 2205-2210

  Abstract

  Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

  View details for DOI 10.1093/hmg/dds035

  View details for Web of Science ID 000303333700006

  View details for PubMedID 22328086

  View details for PubMedCentralID PMC3465691

• Narcolepsy Onset Is Seasonal and Increased following the 2009 H1N1 Pandemic in China ANNALS OF NEUROLOGY Han, F., Lin, L., Warby, S. C., Faraco, J., Li, J., Dong, S. X., An, P., Zhao, L., Wang, L. H., Li, Q. Y., Yan, H., Gao, Z. C., Yuan, Y., Strohl, K. P., Mignot, E. 2011; 70 (3): 410-417

  Abstract

  Narcolepsy is caused by the loss of hypocretin/orexin neurons in the hypothalamus, which is likely the result of an autoimmune process. Recently, concern has been raised over reports of narcolepsy in northern Europe following H1N1 vaccination.The study is a retrospective analysis of narcolepsy onset in subjects diagnosed in Beijing, China (1998-2010). Self-reported month and year of onset were collected from 629 patients (86% children). Graphical presentation, autocorrelations, chi-square, and Fourier analysis were used to assess monthly variation in onset. Finally, 182 patients having developed narcolepsy after October 2009 were asked for vaccination history.The occurrence of narcolepsy onset was seasonal, significantly influenced by month and calendar year. Onset was least frequent in November and most frequent in April, with a 6.7-fold increase from trough to peak. Studying year-to-year variation, we found a 3-fold increase in narcolepsy onset following the 2009 H1N1 winter influenza pandemic. The increase is unlikely to be explained by increased vaccination, as only 8 of 142 (5.6%) patients recalled receiving an H1N1 vaccination. Cross-correlation indicated a significant 5- to 7-month delay between the seasonal peak in influenza/cold or H1N1 infections and peak in narcolepsy onset occurrences.In China, narcolepsy onset is highly correlated with seasonal and annual patterns of upper airway infections, including H1N1 influenza. In 2010, the peak seasonal onset of narcolepsy was phase delayed by 6 months relative to winter H1N1 infections, and the correlation was independent of H1N1 vaccination in the majority of the sample.

  View details for DOI 10.1002/ana.22587

  View details for Web of Science ID 000294816800014

  View details for PubMedID 21866560

• Common variants in P2RY11 are associated with narcolepsy NATURE GENETICS Kornum, B. R., Kawashima, M., Faraco, J., Lin, L., Rico, T. J., Hesselson, S., Axtell, R. C., Kuipers, H., Weiner, K., Hamacher, A., Kassack, M. U., Han, F., Knudsen, S., Li, J., Dong, X., Winkelmann, J., Plazzi, G., Nevsimalova, S., Hong, S., Honda, Y., Honda, M., Hogl, B., Ton, T. G., Montplaisir, J., Bourgin, P., Kemlink, D., Huang, Y., Warby, S., Einen, M., Eshragh, J. L., Miyagawa, T., Desautels, A., Ruppert, E., Hesla, P. E., Poli, F., Pizza, F., Frauscher, B., Jeong, J., Lee, S., Strohl, K. P., Longstreth, W. T., Kvale, M., Dobrovolna, M., Ohayon, M. M., Nepom, G. T., Wichmann, H., Rouleau, G. A., Gieger, C., Levinson, D. F., Gejman, P. V., Meitinger, T., Peppard, P., Young, T., Jennum, P., Steinman, L., Tokunaga, K., Kwok, P., Risch, N., Hallmayer, J., Mignot, E. 2011; 43 (1): 66-U90

  Abstract

  Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

  View details for DOI 10.1038/ng.734

  View details for PubMedID 21170044

• Narcolepsy is strongly associated with the T-cell receptor alpha locus NATURE GENETICS Hallmayer, J., Faraco, J., Lin, L., Hesselson, S., Winkelmann, J., Kawashima, M., Mayer, G., Plazzi, G., Nevsimalova, S., Bourgin, P., Hong, S. S., Honda, Y., Honda, M., Hoegl, B., Longstreth, W. T., Montplaisir, J., Kemlink, D., Einen, M., Chen, J., Musone, S. L., Akana, M., Miyagawa, T., Duan, J., Desautels, A., Erhardt, C., Hesla, P. E., Poli, F., Frauscher, B., Jeong, J., Lee, S., Ton, T. G., Kvale, M., Kolesar, L., Dobrovolna, M., Nepom, G. T., Salomon, D., Wichmann, H., Rouleau, G. A., Gieger, C., Levinson, D. F., Gejman, P. V., Meitinger, T., Young, T., Peppard, P., Tokunaga, K., Kwok, P., Risch, N., Mignot, E. 2009; 41 (6): 708-711

  Abstract

  Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

  View details for DOI 10.1038/ng.372

  View details for PubMedID 19412176

• IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin) PLOS ONE Honda, M., Eriksson, K. S., Zhang, S., Tanaka, S., Lin, L., Salehi, A., Hesla, P. E., Maehlen, J., Gaus, S. E., Yanagisawa, M., Sakurai, T., Taheri, S., Tsuchiya, K., Honda, Y., Mignot, E. 2009; 4 (1)

  Abstract

  The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression.We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals.Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

  View details for DOI 10.1371/journal.pone.0004254

  View details for Web of Science ID 000265482200010

  View details for PubMedID 19158946

  View details for PubMedCentralID PMC2617764

• Cataplexy features in childhood narcolepsy MOVEMENT DISORDERS Serra, L., Montagna, P., Mignot, E., Lugaresi, E., Plazzi, G. 2008; 23 (6): 858-865

  Abstract

  Cataplexy, the hallmark of narcolepsy, has been well characterized in adults but not in children. This study systematically used structured clinical assessments and video-recordings (49 episodes in eight cases) to evaluate cataplexy in 23 patients diagnosed before the age of 18 years. Forty-three percent of patients had falls as part of their attacks. During cataplexy knees, head, and jaw were the most frequently compromised body segments; eyelids, arms, and trunk being less commonly involved. More rarely, blurred vision, slurred speech, irregular breathing, or a sudden loss of smiling mimics were reported. One-third of the sample presented with a previously unrecognized description of cataplexy that we coined "cataplectic facies," consisting of a state of semipermanent eyelid and jaw weakness, on which partial or complete cataplectic attacks were superimposed. The usual triggering emotions, such as laughter, joking, or anger, were not always present, especially when close to an abrupt onset, hampering diagnosis. Video-recordings of cataplectic attacks may be useful to document the attack, allowing a comparison with archived presentations.

  View details for DOI 10.1002/mds.21965

  View details for Web of Science ID 000255600200013

  View details for PubMedID 18307264

• Kleine-Levin syndrome: A systematic study of 108 patients ANNALS OF NEUROLOGY Arnulf, I., Lin, L., Gadoth, N., File, J., Lecendreux, M., Franco, P., Zeitzer, J., Lo, B., Faraco, J. H., Mignot, E. 2008; 63 (4): 482-493

  Abstract

  Kleine-Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality.We collected detailed clinical data and blood samples on 108 patients, 79 parent pairs, and 108 matched control subjects. We measured biological markers and typed human leukocyte antigen genes DR and DQ.Novel predisposing factors were identified including increased birth and developmental problems (odds ratio, 6.5). Jewish heritage was overrepresented, and five multiplex families were identified. Human leukocyte antigen typing was unremarkable. Patients were 78% male (mean age at onset, 15.7 +/- 6.0 years), averaged 19 episodes of 13 days, and were incapacitated 8 months over 14 years. The disease course was longer in men, in patients with hypersexuality, and when onset was after age 20. During episodes, all patients had hypersomnia, cognitive impairment, and derealization; 66% had megaphagia; 53% reported hypersexuality (principally men); and 53% reported a depressed mood (predominantly women). Patients were remarkably similar to control subjects between episodes regarding sleep, mood, and eating attitude, but had increased body mass index. We found marginal efficacy for amantadine and mood stabilizers, but found no increased family history for neuropsychiatric disorders.The similarity of the clinical and demographic features across studies strongly suggests that Kleine-Levin syndrome is a genuine disease entity. Familial clustering and increased prevalence in the Jewish population support a role for a major genetic susceptibility factor. Considering the inefficacy of available treatments, we propose that disease management should primarily be supportive and educational.

  View details for DOI 10.1002/ana.21333

  View details for Web of Science ID 000255454400011

  View details for PubMedID 18438947

• Why we sleep: The temporal organization of recovery PLOS BIOLOGY Mignot, E. 2008; 6 (4): 661-669

  View details for DOI 10.1371/journal.pbio.0060106

  View details for Web of Science ID 000255368600002

  View details for PubMedID 18447584

  View details for PubMedCentralID PMC2689703

• Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index PLOS MEDICINE Taheri, S., Lin, L., Austin, D., Young, T., Mignot, E. 2004; 1 (3): 210-217

  Abstract

  Sleep duration may be an important regulator of body weight and metabolism. An association between short habitual sleep time and increased body mass index (BMI) has been reported in large population samples. The potential role of metabolic hormones in this association is unknown.Study participants were 1,024 volunteers from the Wisconsin Sleep Cohort Study, a population-based longitudinal study of sleep disorders. Participants underwent nocturnal polysomnography and reported on their sleep habits through questionnaires and sleep diaries. Following polysomnography, morning, fasted blood samples were evaluated for serum leptin and ghrelin (two key opposing hormones in appetite regulation), adiponectin, insulin, glucose, and lipid profile. Relationships among these measures, BMI, and sleep duration (habitual and immediately prior to blood sampling) were examined using multiple variable regressions with control for confounding factors. A U-shaped curvilinear association between sleep duration and BMI was observed. In persons sleeping less than 8 h (74.4% of the sample), increased BMI was proportional to decreased sleep. Short sleep was associated with low leptin (p for slope = 0.01), with a predicted 15.5% lower leptin for habitual sleep of 5 h versus 8 h, and high ghrelin (p for slope = 0.008), with a predicted 14.9% higher ghrelin for nocturnal (polysomnographic) sleep of 5 h versus 8 h, independent of BMI.Participants with short sleep had reduced leptin and elevated ghrelin. These differences in leptin and ghrelin are likely to increase appetite, possibly explaining the increased BMI observed with short sleep duration. In Western societies, where chronic sleep restriction is common and food is widely available, changes in appetite regulatory hormones with sleep curtailment may contribute to obesity.

  View details for DOI 10.1371/journal.pmed.0010062

  View details for PubMedID 15602591

• The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias ARCHIVES OF NEUROLOGY Mignot, E., Lammers, G. J., Ripley, B., Okun, M., Nevsimalova, S., Overeem, S., Vankova, J., Black, J., Harsh, J., Bassetti, C., Schrader, H., Nishino, S. 2002; 59 (10): 1553-1562

  Abstract

  Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels.To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy.Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels.Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif.There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders).Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies.Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features.HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions.Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

  View details for Web of Science ID 000178560100005

  View details for PubMedID 12374492

• A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains NATURE MEDICINE Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., Li, R., Hungs, M., Pedrazzoli, M., Padigaru, M., Kucherlapati, M., Fan, J., Maki, R., Lammers, G. J., Bouras, C., Kucherlapati, R., Nishino, S., Mignot, E. 2000; 6 (9): 991-997

  Abstract

  We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

  View details for Web of Science ID 000089190500030

  View details for PubMedID 10973318

• The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene CELL Lin, L., Faraco, J., Li, R., KADOTANI, H., Rogers, W., Lin, X. Y., Qiu, X. H., de Jong, P. J., Nishino, S., Mignot, E. 1999; 98 (3): 365-376

  Abstract

  Narcolepsy is a disabling sleep disorder affecting humans and animals. It is characterized by daytime sleepiness, cataplexy, and striking transitions from wakefulness into rapid eye movement (REM) sleep. In this study, we used positional cloning to identify an autosomal recessive mutation responsible for this sleep disorder in a well-established canine model. We have determined that canine narcolepsy is caused by disruption of the hypocretin (orexin) receptor 2 gene (Hcrtr2). This result identifies hypocretins as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients.

  View details for Web of Science ID 000081950300011

  View details for PubMedID 10458611

• Validation of a cataplexy questionnaire in 983 sleep-disorders patients SLEEP Anic-Labat, S., Guilleminault, C., Kraemer, H. C., Meehan, J., Arrigoni, J., Mignot, E. 1999; 22 (1): 77-87

  Abstract

  Our goal was to validate a self-administered narcolepsy questionnaire focusing on cataplexy. Nine hundred and eight three consecutive subjects entering the Stanford Sleep Disorder Clinic completed the questionnaire. Clinic physicians reported on the presence or absence of "clear-cut" cataplexy. Responses to 51 cataplexy-related questionnaire items were compared between subjects with clear-cut cataplexy (n = 63) and all other patients (n = 920). As previously reported, a large portion of the non-narcoleptic population was found to experience muscle weakness with various intense emotions (1.8% to 18.0%) or athletic activities (26.2% to 28.8%). Factor analysis and Receiver Operating Characteristic Curve (ROC) analysis were used to determine the most predictive items for clear-cut cataplexy. Most strikingly, cataplexy was best differentiated from other types of muscle weakness when triggered by only three typical situations: "when hearing and telling a joke," "while laughing," or "when angry." Face or neck, rather than limbs, were also more specifically involved in clear-cut cataplexy. Other items, such as length of attacks, bilaterality, and alteration in consciousness, were poorly predictive. A simple decision tree was constructed to isolate high-(91.7%) and low-(0.6%) risk groups for cataplexy. This questionnaire will be used to increase diagnostic consistency across clinical centers, thus providing more homogenous subject pools for clinical and basic research studies.

  View details for Web of Science ID 000081155300010

  View details for PubMedID 9989368

• Pharmacological aspects of human and canine narcolepsy PROGRESS IN NEUROBIOLOGY Nishino, S., Mignot, E. 1997; 52 (1): 27-78

  Abstract

  Narcolepsy-cataplexy is a disabling neurological disorder that affects 1/2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafmil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming.

  View details for Web of Science ID A1997XC57300002

  View details for PubMedID 9185233

• CANINE CATAPLEXY IS PREFERENTIALLY CONTROLLED BY ADRENERGIC-MECHANISMS - EVIDENCE USING MONOAMINE SELECTIVE UPTAKE INHIBITORS AND RELEASE ENHANCERS PSYCHOPHARMACOLOGY Mignot, E., RENAUD, A., Nishino, S., Arrigoni, J., Guilleminault, C., Dement, W. C. 1993; 113 (1): 76-82

  Abstract

  Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.

  View details for Web of Science ID A1993MG37200013

  View details for PubMedID 7862832

• HETEROZYGOSITY AT THE CANARC-1 LOCUS CAN CONFER SUSCEPTIBILITY FOR NARCOLEPSY - INDUCTION OF CATAPLEXY IN HETEROZYGOUS ASYMPTOMATIC DOGS AFTER ADMINISTRATION OF A COMBINATION OF DRUGS ACTING ON MONOAMINERGIC AND CHOLINERGIC SYSTEMS JOURNAL OF NEUROSCIENCE Mignot, E., Nishino, S., Sharp, L. H., Arrigoni, J., Siegel, J. M., Reid, M. S., Edgar, D. M., CIARANELLO, R. D., Dement, W. C. 1993; 13 (3): 1057-1064

  Abstract

  Narcolepsy is a genetically determined disorder of sleep characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep that affects both humans and animals. Although its exact pathophysiologic mechanisms remain undetermined, recent experiments have demonstrated that in both humans and canines, susceptibility genes are linked with immune-related genes. A striking difference, however, is that the genes thought to be involved in the human pathology are autosomal dominant, whereas canine narcolepsy in Dobermans is transmitted as a single autosomal recessive gene with full penetrance (canarc-1). In this study, we have examined the development of narcoleptic symptoms in homozygous narcoleptic, heterozygous, and control Dobermans. Animals were behaviorally observed until 5 months of age and then treated at weekly intervals with cataplexy-inducing compounds that act on cholinergic or monoaminergic systems (alone and in combination). Our data indicate that cataplexy can be induced in 6-month-old asymptomatic heterozygous animals, but not in control canines, with a combination of drugs that act on the monoaminergic and cholinergic systems. This demonstrates that disease susceptibility may be carried by heterozygosity at the canarc-1 locus. Our data further suggest that cataplexy, a model of REM sleep atonia, is centrally regulated by a balance of activity between cholinergic and monoaminergic neurons.

  View details for Web of Science ID A1993KP71100016

  View details for PubMedID 8095066

• RESTORE: Once-nightly oxybate dosing preference and nocturnal experience with twice-nightly oxybates. Sleep medicine: X Roy, A., Stern, T., Harsh, J., Hudson, J. D., Ajayi, A. O., Corser, B. C., Mignot, E., Santamaria, A., Morse, A. M., Abaluck, B., Ibrahim, S., Schweitzer, P. K., Lancaster, K., Dubow, J., Gudeman, J. 2024; 8: 100122

  Abstract

  Preference for extended-release, once-nightly sodium oxybate (ON-SXB, FT218) vs twice-nightly immediate-release (IR) oxybate was assessed in participants switching from IR oxybate to ON-SXB in an open-label/switch study, RESTORE (NCT04451668).Participants aged ≥16 years with narcolepsy who completed the phase 3 REST-ON trial, were oxybate-naive, or were on a stable IR oxybate dose (≥1 month) were eligible for RESTORE. For participants who switched from twice-nightly dosing to ON-SXB, initial doses were closest or equivalent to their previous nightly IR oxybate dose. These participants completed a questionnaire at baseline about nocturnal adverse events associated with the middle-of-the-night IR oxybate dose in the preceding 3 months, a preference questionnaire after 3 months of stable-dose ON-SXB, and an end-of-study (EOS) questionnaire.There were 130 switch participants; 92/98 (93.9 %) who completed the preference questionnaire preferred ON-SXB. At baseline, 69.2 % reported missing their second IR oxybate dose at least once; in these cases, 80 % felt worse the next day. Approximately 39 % reported taking a second nightly IR oxybate dose >4 h after the first dose, 51 % of whom felt somewhat to extremely groggy/unsteady the next morning; 120 participants (92 %) reported getting out of bed after their second oxybate dose. Of those, 9 (8 %) reported falls and 5 (4 %) reported injuries. Of the switch participants who completed the EOS questionnaire, 91.2 % felt better able to follow the recommended ON-SXB dosing schedule.The second nightly IR oxybate dose presents significant treatment burdens and adherence concerns. Participants overwhelmingly preferred the once-nightly dosing regimen of ON-SXB.

  View details for DOI 10.1016/j.sleepx.2024.100122

  View details for PubMedID 39263597

  View details for PubMedCentralID PMC11388664

• Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts. Brain : a journal of neurology Binks, S. N., Elliott, K. S., Muñiz-Castrillo, S., Gilbert, E., Kawasaki de Araujo, T., Harper, A. R., Brown, A. C., Chong, A. Y., Band, G., Peris Sempere, V., Pinto, A. L., Costantino, F., Rayner, N. W., Mentzer, A. J., Delanty, N., Rogemond, V., Picard, G., Handel, A. E., Melzer, N., Titulaer, M. J., Lee, S. T., Leypoldt, F., Kuhlenbaeumer, G., Honnorat, J., Mignot, E., Cavelleri, G. L., Knight, J. C., Irani, S. R. 2024

  Abstract

  Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

  View details for DOI 10.1093/brain/awae349

  View details for PubMedID 39454566

• Probabilistic Sleep Staging in MSLTs across Hypersomnia Disorders. Sleep Hjuler Andersen, L., Brink-Kjaer, A., Sum-Ping, O., Pizza, F., Biscarini, F., Haubjerg Østerby, N. C., Mignot, E., Plazzi, G., Jennum, P. J. 2024

  Abstract

  This study aimed to identify novel markers of narcolepsy type 1 (NT1) using between-nap opportunity periods ('Lights On') and in-nap opportunity periods ('Lights Off') features of Multiple Sleep Latency Test (MSLT) recordings. We hypothesized that NT1 could be identified both from sleep-wake instability and patterns of sleepiness during wakefulness. Further, we explored if MSLTs from NT1 and narcolepsy type 2 (NT2) patients could be distinguished despite having the same diagnostic thresholds.We analyzed 'Lights On' and 'Lights Off' periods of the MSLT, extracting 163 features describing sleepiness, microsleep, and sleep stage mixing using data from 177 patients with NT1, NT2, Idiopathic Hypersomnia (IH), and Subjective Hypersomnia (sH) from three sleep centers. These features were based on automated probabilistic sleep staging, also denoted as hypnodensities, using U-Sleep. Hypersomnias were differentiated using either or both features from 'Lights On' and 'Lights Off'.Patients with NT1 could be distinguished from NT2, IH, and sH using features solely from 'Lights On' periods with a sensitivity of 0.76 and specificity of 0.71. When using features from all periods of the MSLT, NT1 was distinguished from NT2 alone with a sensitivity of 0.77 and a specificity of 0.84.The findings of this study demonstrate microsleeps and sleep stage mixing as potential markers of the sleep attacks and unstable sleep-wake states common in NT1. Further, NT1 and NT2 could be frequently distinguished using 'Lights Off' features.

  View details for DOI 10.1093/sleep/zsae241

  View details for PubMedID 39392922

• Mortality Risk Assessment Using Deep Learning-Based Frequency Analysis of EEG and EOG in Sleep. Sleep Kristjánsson, T. Ó., Stone, K. L., Sorensen, H. B., Brink-Kjaer, A., Mignot, E., Jennum, P. 2024

  Abstract

  To assess whether the frequency content of electroencephalography (EEG) and electrooculography (EOG) during nocturnal polysomnography (PSG) can predict all-cause mortality.Power spectra from PSGs of 8,716 participants, included from the MrOS Sleep Study and the Sleep Heart Health Study (SHHS), were analyzed in deep learning-based survival models. The best-performing model was further examined using SHapley Additive Explanation (SHAP) for data-driven sleep-stage specific definitions of power bands, which were evaluated in predicting mortality using Cox Proportional Hazards models.Survival analyses, adjusted for known covariates, identified multiple EEG frequency bands across all sleep stages predicting all-cause mortality. For EEG, we found an all-cause mortality hazard ratio (HR) of 0.90 (CI95% 0.85-0.96) for 12-15 Hz in N2, 0.86 (CI95% 0.82-0.91) for 0.75-1.5 Hz in N3, and 0.87 (CI95% 0.83-0.92) for 14.75-33.5 Hz in REM sleep. For EOG, we found several low-frequency effects including an all-cause mortality HR of 1.19 (CI95% 1.11-1.28) for 0.25 Hz in N3, 1.11 (CI95% 1.03-1.21) for 0.75 Hz in N1, and 1.11 (CI95% 1.03-1.20) for 1.25-1.75 Hz in Wake. The gain in the concordance index (C-index) for all-cause mortality is minimal, with only a 0.24% increase: The best single mortality predictor was EEG N3 (0-0.5 Hz) with C-index of 77.78% compared to 77.54% for confounders alone.Spectral power features, possibly reflecting abnormal sleep microstructure, are associated with mortality risk. These findings add to a growing literature suggesting that sleep contains incipient predictors of health and mortality.

  View details for DOI 10.1093/sleep/zsae219

  View details for PubMedID 39301948

• Lifestyle Profiling Using Wearables and Prediction of Glucose Metabolism in Individuals with Normoglycemia or Prediabetes. medRxiv : the preprint server for health sciences Park, H., Metwally, A. A., Delfarah, A., Wu, Y., Perelman, D., Rodgar, M., Mayer, C., Celli, A., McLaughlin, T., Mignot, E., Snyder, M. 2024

  Abstract

  This study examined the relationship between lifestyles (diet, sleep, and physical activity) and glucose responses at a personal level. 36 healthy adults in the Bay Area were monitored for their lifestyles and glucose levels using wearables and continuous glucose monitoring (NCT03919877). Gold-standard metabolic tests were conducted to phenotype metabolic characteristics. Through the lifestyle data (2,307 meals, 1,809 nights, and 2,447 days) and 231,206 CGM readings from metabolically-phenotyped individuals with normoglycemia or prediabetes, we found: 1) eating timing was associated with hyperglycemia, muscle insulin resistance (IR), and incretin dysfunction, whereas nutrient intakes were not; 2) timing of increased activity in muscle IS and IR participants was associated with differential benefits of glucose control; 3) Integrated ML models using lifestyle factors predicted distinct metabolic characteristics (muscle, adipose IR or incretin dysfunction). Our data indicate the differential impact of lifestyles on glucose regulation among individuals with different metabolic phenotypes, highlighting the value of personalized lifestyle modifications.

  View details for DOI 10.1101/2024.09.05.24312545

  View details for PubMedID 39281757

  View details for PubMedCentralID PMC11398605

• TAK-861 improves cognitive impairments in patients with narcolepsy type 1 Plazzi, G., Lammers, G., Mignot, E., Pizza, F., Dauvilliers, Y., Barateau, L., Maruff, P., Stukalin, E., Tanaka, S., Naylor, M., Olsson, T., Latzman, R., Harel, B. WILEY. 2024

  View details for Web of Science ID 001319389400086

• Efficacy and safety of TAK-861, an oral orexin receptor 2 agonist, in individuals with narcolepsy type 2: Results from phase 2 studies Mignot, E., Bogan, R., Del Rio, R., Arnulf, I., Kadali, H., Yao, B., Abraham, A., von Rosenstiel, P., Lamberton, M., Tanaka, S., Olsson, T., Naylor, M. WILEY. 2024

  View details for Web of Science ID 001319389400085

• Associations between self-reported parasomnias and psychiatric illness in 370,000 patients with sleep disorders. Psychiatry and clinical neurosciences Hanif, U., Cairns, A., Mysliwiec, V., Bettinardi, R. G., Elbaz, M., Gimenez, U., Mignot, E. J. 2024

  Abstract

  To assess self-reported parasomnias in patients with sleep disorders and explore relationships with psychiatric illness, comorbidities, subjective sleep assessments, and polysomnographic study results.Results from intake questionnaires and polysomnographic assessments, collected from 240 sleep centers across 30 US states between 2004 and 2019, were analyzed retrospectively. Of 540,000 total patients, 371,889 who answered parasomnia-specific questions were included. Patients responding "often" or "always" to parasomnia-specific questions were considered "symptom-positive," whereas a "few times" or "never" were considered "symptom-negative" (controls).The study sample was 54.5% male with mean age 54 years (range, 2-107 years). Frequencies for the different parasomnias were 16.0% for any parasomnia, 8.8% for somniloquy, 6.0% for hypnagogic hallucinations, 4.8% for sleep-related eating disorder, 2.1% for sleep paralysis, and 1.7% for somnambulism. Frequent parasomnias were highly associated with diagnosed depression (odds ratio = 2.72). All parasomnias were associated with being younger and female and with symptoms of depression, anxiety, insomnia, restless legs, pain, medical conditions, fatigue, and sleepiness. Associations with objective sleep metrics showed characteristics of consolidated sleep and differentiated weakly between nonrapid eye movement sleep and rapid eye movement sleep parasomnias. Machine learning accurately classified patients with parasomnia versus controls (balanced accuracies between 71% and 79%). Benzodiazepines, antipsychotics, and opioids increased the odds of experiencing parasomnias, while antihistamines and melatonin reduced the odds. Z-drugs were found to increase the likelihood of a sleep-related eating disorder.Our findings suggest that parasomnias may be clinically relevant, yet understudied, symptoms of depression and anxiety. Further investigation is needed to quantify the nature of multimorbidity, including causality and implications for diagnosis and treatment.

  View details for DOI 10.1111/pcn.13723

  View details for PubMedID 39210704

• A Deep Transfer Learning Approach for Sleep Stage Classification and Sleep Apnea Detection Using Wrist-Worn Consumer Sleep Technologies. IEEE transactions on bio-medical engineering Olsen, M., Zeitzer, J. M., Nakase-Richardson, R., Musgrave, V. H., Sorensen, H. B., Mignot, E., Jennum, P. J. 2024; 71 (8): 2506-2517

  Abstract

  Obstructive sleep apnea (OSA) is a common, underdiagnosed sleep-related breathing disorder with serious health implications Objective - We propose a deep transfer learning approach for sleep stage classification and sleep apnea (SA) detection using wrist-worn consumer sleep technologies (CST). Methods - Our model is based on a deep convolutional neural network (DNN) utilizing accelerometers and photo-plethysmography signals from nocturnal recordings. The DNN was trained and tested on internal datasets that include raw data from clinical and wrist-worn devices; external validation was performed on a hold-out test dataset containing raw data from a wrist-worn CST. Results - Training on clinical data improves performance significantly, and feature enrichment through a sleep stage stream gives only minor improvements. Raw data input outperforms feature-based input in CST datasets. The system generalizes well but performs slightly worse on wearable device data compared to clinical data. However, it excels in detecting events during REM sleep and is associated with arousal and oxygen desaturation. We found; cases that were significantly underestimated were characterized by fewer of such event associations. Conclusion - This study showcases the potential of using CSTs as alternate screening solution for undiagnosed cases of OSA. Significance - This work is significant for its development of a deep transfer learning approach using wrist-worn consumer sleep technologies, offering comprehensive validation for data utilization, and learning techniques, ultimately improving sleep apnea detection across diverse devices.

  View details for DOI 10.1109/TBME.2024.3378480

  View details for PubMedID 38498753

• From sleep patterns to heart rhythm: Predicting atrial fibrillation from overnight polysomnograms. Journal of electrocardiology Koscova, Z., Rad, A. B., Nasiri, S., Reyna, M. A., Sameni, R., Trotti, L. M., Sun, H., Turley, N., Stone, K. L., Thomas, R. J., Mignot, E., Westover, B., Clifford, G. D. 2024; 86: 153759

  Abstract

  Atrial fibrillation (AF) is often asymptomatic and thus under-observed. Given the high risks of stroke and heart failure among patients with AF, early prediction and effective management are crucial. Given the prevalence of obstructive sleep apnea among AF patients, electrocardiogram (ECG) analysis from polysomnography (PSG) offers a unique opportunity for early AF prediction. Our aim is to identify individuals at high risk of AF development from single‑lead ECGs during standard PSG.We analyzed 18,782 single‑lead ECG recordings from 13,609 subjects undergoing PSG at the Massachusetts General Hospital sleep laboratory. AF presence was identified using ICD-9/10 codes. The dataset included 15,913 recordings without AF history and 2054 recordings from patients diagnosed with AF between one month to fifteen years post-PSG. Data were partitioned into training, validation, and test cohorts ensuring that individual patients remained exclusive to each cohort. The test set was held out during the training process. We employed two different methods for feature extraction to build a final model for AF prediction: Extraction of hand-crafted ECG features and a deep learning method. For extraction of ECG-hand-crafted features, recordings were split into 30-s windows, and those with a signal quality index (SQI) below 0.95 were discarded. From each remaining window, 150 features were extracted from the time, frequency, time-frequency domains, and phase-space reconstructions of the ECG. A compilation of 12 statistical features summarized these window-specific features per recording, resulting in 1800 features (12 × 150). A pre-trained deep neural network from the PhysioNet Challenge 2021 was updated using transfer learning to discriminate recordings with and without AF. The model processed PSG ECGs in 16-s windows to generate AF probabilities, from which 13 statistical features were extracted. Combining 1800 features from feature extraction with 13 from the deep learning model, we performed a feature selection and subsequently trained a shallow neural network to predict future AF and evaluated its performance on the test cohort.On the test set, our model exhibited sensitivity, specificity, and precision of 0.67, 0.81, and 0.3, respectively, for AF prediction. Survival analysis revealed a hazard ratio of 8.36 (p-value: 1.93 × 10-52) for AF outcomes using the log-rank test.Our proposed ECG analysis method, utilizing overnight PSG data, shows promise in AF prediction despite modest precision, suggesting false positives. This approach could enable low-cost screening and proactive treatment for high-risk patients. Refinements, including additional physiological parameters, may reduce false positives, enhancing clinical utility and accuracy.

  View details for DOI 10.1016/j.jelectrocard.2024.153759

  View details for PubMedID 39067281

• HLA-DR3 ~ DQ2 associates with sensory neuropathy in paraneoplastic neurological syndromes with Hu antibodies. Journal of neurology Muñiz-Castrillo, S., Villagrán-García, M., Peris Sempere, V., Farina, A., Pinto, A. L., Picard, G., Rogemond, V., Honnorat, J., Mignot, E. 2024

  Abstract

  To investigate the association between human leukocyte antigen (HLA) and paraneoplastic neurological syndromes (PNS) with Hu antibodies, and potential specificities according to clinical presentation and cancer status.HLA genotypes at four-digit resolution were imputed from available genome-wide association data. Allele carrier frequencies were compared between patients (whole cohort, n = 100, and according to clinical presentation and cancer status) and matched healthy controls (n = 508) using logistic regression controlled by the three main principal components.The clinical presentation of 100 anti-Hu patients involved the central nervous system (28, 28%), the peripheral nervous system (36, 36%) or both combined (36, 36%). Cancer diagnosis was certain in 75 (75%). HLA association analyses revealed that anti-Hu PNS patients were more frequently carriers of DQA1*05:01 (39% vs. 19%, OR = 2.8 [1.74-4.49]), DQB1*02:01 (39% vs. 18%, OR = 2.88 [1.79-4.64]) and DRB1*03:01 (41% vs. 19%, OR = 2.92 [1.80-4.73]) than healthy controls. Remarkably, such DR3 ~ DQ2 association was absent in patients with pure central involvement, but more specific to those manifesting with peripheral involvement: DQA1*05:01 (OR = 3.12 [1.48-6.60]), DQB1*02:01 (OR = 3.35 [1.57-7.15]) and DRB1*03:01 (OR = 3.62 [1.64-7.97]); being even stronger in cases with sensory neuropathy, DQA1*05:01 (OR = 4.41 [1.89-10.33]), DQB1*02:01 (OR = 4.85 [2.04-11.53]) and DRB1*03:01 (OR = 5.79 [2.28-14.74]). Similarly, DR3 ~ DQ2 association was only observed in patients with cancer.Patients with anti-Hu PNS show different HLA profiles according to clinical presentation and, probably, cancer status, suggesting pathophysiological differences.

  View details for DOI 10.1007/s00415-024-12534-7

  View details for PubMedID 38990347

  View details for PubMedCentralID 8815287

• Digital Measures Development: Lessons Learned from an Expert Workshop Addressing Cross-Therapeutic Area Measures of Sleep. Digital biomarkers Fromy, P., Kremliovsky, M., Mignot, E., Aloia, M., Berent, J., Hasan, F., Hwang, D., Poon, J. L., Malcolm, R., Miller, C., Nawa, W., Bakker, J. 2024; 8 (1): 132-139

  Abstract

  The Digital Measures Development: Core Measures of Sleep project, led by the Digital Medicine Society (DiMe), emphasizes the importance of sleep as a cornerstone of health and the need for standardized measurements of sleep and its disturbances outside the laboratory. This initiative recognizes the complex relationship between sleep and overall health, addressing it as both a symptom of underlying conditions and a consequence of therapeutic interventions. It aims to fill a crucial gap in healthcare by promoting the development of accessible, nonintrusive, and cost-effective digital tools for sleep assessment, focusing on factors important to patients, caregivers, and clinicians.A central feature of this project was an expert workshop conducted on April 19th, 2023. The workshop convened stakeholders from diverse backgrounds, including regulatory, payer, industry, academic, and patient groups, to deliberate on the project's direction. This gathering focused on discussing the challenges and necessities of measuring sleep across various therapeutic areas, aiming to identify broad areas for initial focus while considering the feasibility of generalizing these measures where applicable. The methodological emphasis was on leveraging expert consensus to guide the project's approach to digital sleep measurement.The workshop resulted in the identification of seven key themes that will direct the DiMe Core Digital Measures of Sleep project and the broader field of sleep research moving forward. These themes underscore the project's innovative approach to sleep health, highlighting the complexity of omni-therapeutic sleep measurement and identifying potential areas for targeted research and development. The discussions and outcomes of the workshop serve as a roadmap for enhancing digital sleep measurement tools, ensuring they are relevant, accurate, and capable of addressing the nuanced needs of diverse patient populations.The Digital Medicine Society's Core Measures of Sleep project represents a pivotal effort to advance sleep health through digital innovation. By focusing on the development of standardized, patient-centric, and clinically relevant digital sleep assessment tools, the project addresses a significant need in healthcare. The expert workshop's outcomes underscore the importance of collaborative, multi-stakeholder engagement in identifying and overcoming the challenges of sleep measurement. This initiative sets a new precedent for the integration of digital tools into sleep health research and practice, promising to improve outcomes for patients worldwide by enhancing our understanding and measurement of sleep.

  View details for DOI 10.1159/000539253

  View details for PubMedID 39015515

  View details for PubMedCentralID PMC11250246

• Novel biomarkers derived from the Maintenance of Wakefulness Test as predictors of sleepiness and response to treatment. Sleep Tracey, B., Culp, M., Fabregas, S., Mignot, E., Buhl, D. L., Volfson, D. 2024

  Abstract

  The Maintenance of Wakefulness Test (MWT) is a widely accepted objective test used to evaluate daytime somnolence and is commonly used in clinical studies evaluating novel therapeutics for excessive daytime sleepiness. In the latter, sleep onset latency (SOL) is typically the sole MWT endpoint. Here, we explored microsleeps, sleep probability measures derived from automated sleep scoring, and quantitative electroencephalography (qEEG) features as additional MWT biomarkers of daytime sleepiness, using data from a phase 1B trial of the selective orexin receptor 2 agonist danavorexton (TAK-925) in people with narcolepsy type 1 (NT1) or type 2 (NT2). Danavorexton treatment reduced the rate and duration of microsleeps during the MWT in NT1 (days 1 and 7; p ≤ 0.005) and microsleep rate in NT2 (days 1 and 7; p < 0.0001). Use of an EEG-sleep-staging-derived measure to determine the probability of wakefulness for each minute revealed a novel metric to track changes in daytime sleepiness, which were consistent with the theta/alpha ratio, a known biomarker of drowsiness. The slopes of line-fits to both the log-transformed sleepiness score or log-transformed theta/alpha ratio correlated well to (inverse) MWT SOL for NT1 (R = 0.93 and R = 0.83, respectively) and NT2 (R = 0.97 and R = 0.84, respectively), suggesting that individuals with narcolepsy have increased sleepiness immediately after lights-off. These analyses demonstrate that novel EEG-based biomarkers can augment SOL as predictors of sleepiness and its response to treatment and provide a novel framework for the analysis of wake EEG in hypersomnia disorders.

  View details for DOI 10.1093/sleep/zsae148

  View details for PubMedID 38954525

• CIRCADIAN PROTEINS AND CIRCADIAN PHASE ESTIMATION IN HEALTHY ADULTS Specht, A., Saha, P., Cederberg, K., Bueno, F., Arrona-Palacios, A., Pardilla-Delgado, E., Ruiz-Herrera, N., Zitting, K., Kramer, A., Zeitzer, J., Czeisler, C., Duffy, J., Mignot, E. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/sleep/zsae067.0009

  View details for Web of Science ID 001262172000010

• IN AND BETWEEN NAP MSLT FEATURES IN HYPERSOMNIA Andersen, L., Brink-Kjaer, A., Sum-Ping, O., Mignot, E. OXFORD UNIV PRESS INC. 2024

  View details for Web of Science ID 001262172001183

• VALIDITY AND RELIABILITY OF THE PEDIATRIC NARCOLEPSY PATIENT-REPORTED OUTCOMES SCALE (PN-PROS) Maski, K., Mignot, E., Narang, I., Marie, M., Meltzer, L. OXFORD UNIV PRESS INC. 2024

  View details for Web of Science ID 001262172001181

• PATIENT PREFERENCES OF SODIUM OXYBATE TREATMENT FOR NARCOLEPSY: RESTORE END-OF-STUDY SURVEY DATA Ajayi, A., Mignot, E., Roy, A., Corser, B., Stern, T., Hudson, J., Santamaria, A., Abaluck, B., Gudeman, J. OXFORD UNIV PRESS INC. 2024: A275

  View details for Web of Science ID 001262172001166

• VALIDATION OF THE SITUATIONAL SLEEPINESS SCALE Lomba, S., Sum-Ping, O., Mignot, E. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/sleep/zsae067.01026

  View details for Web of Science ID 001262172000129

• PERCEIVED EXERCISE RESPONSE HETEROGENEITY IN ADULTS WITH RESTLESS LEGS SYNDROME Cederberg, K., Sikes, E., Mejia, G., Mignot, E. OXFORD UNIV PRESS INC. 2024: A300

  View details for Web of Science ID 001262172001224

• INFLUENZA HA ANTIBODY TITERS IN RECENT ONSET TYPE-1 NARCOLEPSY Yan, H., Lin, L., Zhang, J., Mignot, E. OXFORD UNIV PRESS INC. 2024: A268

  View details for Web of Science ID 001262172001150

• A MASS SPECTROMETRY METHOD EVALUATING OREXIN METABOLITES SUGGEST ABNORMALITIES IN HYPERSOMNIAS OF CENTRAL ORIGIN Horie, K., Steger, C., Koppisetti, R., Mignot, E., Lucey, B. OXFORD UNIV PRESS INC. 2024: A267

  View details for Web of Science ID 001262172001147

• ABED: AUTOMATIC SLEEP-DISORDERED BREATHING EVENT DETECTION Kjaer, M., Hanif, U., Brink-Kjaer, A., Mignot, E. OXFORD UNIV PRESS INC. 2024: A220

  View details for Web of Science ID 001262172001035

• Validation of the RBD Symptom Severity Scale in the North American Prodromal Synucleinopathy Consortium. Neurology Choudhury, P., Lee-Iannotti, J. K., Busicescu, A. O., Rangan, P., Fantini, M. L., Avidan, A. Y., Bliwise, D. L., Criswell, S. R., During, E. H., Elliott, J. E., Fields, J. A., Gagnon, J. F., Howell, M. J., Huddleston, D. E., McLeland, J., Mignot, E., Miglis, M. G., Lim, M. M., Pelletier, A., Schenck, C. H., Shprecher, D., St Louis, E. K., Videnovic, A., Ju, Y. S., Boeve, B. F., Postuma, R. 2024; 102 (3): e208008

  Abstract

  REM sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment. The International RBD Study Group developed the RBD Symptom Severity Scale (RBDSSS) to assess symptom severity for clinical or research use. We assessed the psychometric and clinimetric properties of the RBDSSS in participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium for RBD.NAPS participants, who have polysomnogram-confirmed RBD, and their bedpartners completed the RBDSSS (participant and bedpartner versions). The RBDSSS contains 8 questions to assess the frequency and severity/impact of (1) dream content, (2) vocalizations, (3) movements, and (4) injuries associated with RBD. Total scores for participant (maximum score = 54) and bedpartner (maximum score = 38) questionnaires were derived by multiplying frequency and severity scores for each question. The Clinical Global Impression Scale of Severity (CGI-S) and RBD symptom frequency were assessed by a physician during a semistructured clinical interview with participants and, if available, bedpartners. Descriptive analyses, correlations between overall scores, and subitems were assessed, and item response analysis was performed to determine the scale's validity.Among 261 study participants, the median (interquartile range) score for the RBDSSS-PT (participant) was 10 (4-18) and that for the RBDSSS-BP (bedpartner) was 8 (4-15). The median CGI-S was 3 (3-4), indicating moderate severity. RBDSSS-BP scores were significantly lower in women with RBD (6 vs 9, p = 0.02), while there were no sex differences in RBDSSS-PT scores (8 vs 10.5, p = 0.615). Positive correlations were found between RBDSSS-PT vs RBDSSS-BP (Spearman rs = 0.561), RBDSSS-PT vs CGI-S (rs = 0.556), and RBDSSS-BP vs CGI-S (rs = 0.491, all p < 0.0001). Item response analysis showed a high discriminatory value (range 1.40-2.12) for the RBDSSS-PT and RBDSSS-BP (1.29-3.47).We describe the RBDSSS with adequate psychometric and clinimetric properties to quantify RBD symptom severity and good concordance between participant and bedpartner questionnaires and between RBDSSS scores and clinician-assessed global severity.

  View details for DOI 10.1212/WNL.0000000000208008

  View details for PubMedID 38181331

• Fatigued but not sleepy? An empirical investigation of the differentiation between fatigue and sleepiness in sleep disorder patients in a cross-sectional study. Journal of psychosomatic research Suh, S., Lok, R., Weed, L., Cho, A., Mignot, E., Leary, E. B., Zeitzer, J. M. 2024; 178: 111606

  Abstract

  Sleepiness and fatigue are common complaints among individuals with sleep disorders. The two concepts are often used interchangeably, causing difficulty with differential diagnosis and treatment decisions. The current study investigated sleep disorder patients to determine which factors best differentiated sleepiness from fatigue.The study used a subset of participants from a multi-site study (n = 606), using a cross-sectional study design. We selected 60 variables associated with either sleepiness or fatigue, including demographic, mental health, and lifestyle factors, medical history, sleep questionnaires, rest-activity rhythms (actigraphy), polysomnographic (PSG) variables, and sleep diaries. Fatigue was measured with the Fatigue Severity Scale and sleepiness was measured with the Epworth Sleepiness Scale. A Random Forest machine learning approach was utilized for analysis.Participants' average age was 47.5 years (SD 14.0), 54.6% female, and the most common sleep disorder diagnosis was obstructive sleep apnea (67.4%). Sleepiness and fatigue were moderately correlated (r = 0.334). The model for fatigue (explained variance 49.5%) indicated depression was the strongest predictor (relative explained variance 42.7%), followed by insomnia severity (12.3%). The model for sleepiness (explained variance 17.9%), indicated insomnia symptoms was the strongest predictor (relative explained variance 17.6%). A post hoc receiver operating characteristic analysis indicated depression could be used to discriminate fatigue (AUC = 0.856) but not sleepiness (AUC = 0.643).The moderate correlation between fatigue and sleepiness supports previous literature that the two concepts are overlapping yet distinct. Importantly, depression played a more prominent role in characterizing fatigue than sleepiness, suggesting depression could be used to differentiate the two concepts.

  View details for DOI 10.1016/j.jpsychores.2024.111606

  View details for PubMedID 38359639

• Prevalence and Course of Idiopathic Hypersomnia in the Wisconsin Sleep Cohort Study. Neurology Plante, D. T., Hagen, E. W., Barnet, J. H., Mignot, E., Peppard, P. E. 2024; 102 (2): e207994

  Abstract

  BACKGROUND AND OBJECTIVES: Idiopathic hypersomnia (IH) is a CNS disorder of hypersomnolence of unknown etiology. Due to the requirement for objective sleep testing to diagnose the disorder, there are currently no population-based estimates of the prevalence of IH nor data regarding the longitudinal course of IH in naturalistic settings.METHODS: Subjective and objective data from the Wisconsin Sleep Cohort study were used to identify cases with probable IH from participants with polysomnography and multiple sleep latency test data. Demographic, polysomnographic, and symptom-level data were compared between those with and without IH. Longitudinal trajectories of daytime sleepiness among those with IH were assessed to evaluate symptom persistence or remission over time.RESULTS: From 792 cohort study participants with available polysomnography and multiple sleep latency test data, 12 cases with probable IH were identified resulting in an estimated prevalence of IH of 1.5% (95% CI 0.7-2.5, p < 0.0001). Consistent with inclusion/exclusion criteria, cases with IH had more severe sleepiness and sleep propensity, despite similar or longer sleep times. Longitudinal data (spanning 12.1 ± 4.3 years) demonstrated a chronic course of sleepiness for most of the cases with IH, though pathologic somnolence remitted in roughly 40% of cases.DISCUSSION: These results demonstrate IH is more common in the working population than generally assumed with a prevalence on par with other common neurologic and psychiatric conditions. Further efforts to identify and diagnose those impaired by unexplained daytime somnolence may help clarify the causes of IH and the mechanisms underlying symptomatic remission.

  View details for DOI 10.1212/WNL.0000000000207994

  View details for PubMedID 38165322

• Stability and Volatility of Human Rest-Activity Rhythms: Insights from Very Long Actograms (VLAs). medRxiv : the preprint server for health sciences Adhyapak, N., Abboud, M. A., Rao, P. S., Kar, A., Mignot, E., Delucca, G., Smagula, S. F., Krishnan, V. 2024

  Abstract

  Importance: Wrist-worn activity monitors provide biomarkers of health by non-obtrusively measuring the timing and amount of rest and physical activity (rest-activity rhythms, RARs). The morphology and robustness of RARs vary by age, gender, and sociodemographic factors, and are perturbed in various chronic illnesses. However, these are cross-sectionally derived associations from recordings lasting 4-10 days, providing little insights into how RARs vary with time.Objective: To describe how RAR parameters can vary or evolve with time (~months).Design Setting and Participants: 48 very long actograms ("VLAs", ≥90 days in duration) were identified from subjects enrolled in the STAGES (Stanford Technology, Analytics and Genomics in Sleep) study, a prospective cross-sectional, multi-site assessment of individuals > 13 years of age that required diagnostic polysomnography to address a sleep complaint. A single 3-year long VLA (author GD) is also described.Exposures/Intervention: None planned.Main Outcomes and Measures: For each VLA, we assessed the following parameters in 14-day windows: circadian/ultradian spectrum, pseudo-F statistic ("F"), cosinor amplitude, intradaily variability, interdaily stability, acrophase and estimates of "sleep" and non-wearing.Results: Included STAGES subjects (n = 48, 30 female) had a median age of 51, BMI of 29.4kg/m2, Epworth Sleepiness Scale score (ESS) of 10/24 and a median recording duration of 120 days. We observed marked within-subject undulations in all six RAR parameters, with many subjects displaying ultradian rhythms of activity that waxed and waned in intensity. When appraised at the group level (nomothetic), averaged RAR parameters remained remarkably stable over a ~4 month recording period. Cohort-level deficits in average RAR robustness associated with unemployment or high BMI (>29.4) also remained stable over time.Conclusions and Relevance: Through an exemplary set of months-long wrist actigraphy recordings, this study quantitatively depicts the longitudinal stability and dynamic range of human rest-activity rhythms. We propose that continuous and long-term actigraphy may have broad potential as a holistic, transdiagnostic and ecologically valid monitoring biomarker of changes in chronobiological health. Prospective recordings from willing subjects will be necessary to precisely define contexts of use.

  View details for DOI 10.1101/2024.01.22.24301243

  View details for PubMedID 38370763

• Role of Daytime Continuous Polysomnography in the Diagnosis of Pediatric Narcolepsy Type 1. Neurology Pizza, F., Vignatelli, L., Vandi, S., Zenesini, C., Biscarini, F., Franceschini, C., Antelmi, E., Ingravallo, F., Mignot, E., Bruni, O., Nobili, L., Veggiotti, P., Ferri, R., Plazzi, G. 2024; 102 (1): e207815

  Abstract

  BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is still largely underdiagnosed or diagnosed too late in children. Difficulties in obtaining rapid and reliable diagnostic evaluations of the condition in clinical practice partially explain this problem. Predictors of NT1 include cataplexy and sleep-onset REM periods (SOREMPs), documented during nocturnal polysomnography (N-PSG) or through the multiple sleep latency test (MSLT), although low CSF hypocretin-1 (CSF hcrt-1) is the definitive biological disease marker. Obtaining reliable MSLT results is not always feasible in children; therefore, this study aimed to validate daytime continuous polysomnography (D-PSG) as an alternative diagnostic tool.METHODS: Two hundred consecutive patients aged younger than 18 years (112 with NT1; 25 with other hypersomnias, including narcolepsy type 2 and idiopathic hypersomnia; and 63 with subjective excessive daytime sleepiness) were randomly split into 2 groups: group 1 (n = 133) for the identification of diagnostic markers and group 2 (n = 67) for the validation of the detected markers. The D-PSG data collected included the number of spontaneous naps, total sleep time, and the number of daytime SOREMPs (d-SOREMP). D-PSG data were tested against CSF hcrt-1 deficiency (NT1 diagnosis) as the gold standard using receiver operating characteristic (ROC) curve analysis in group 1. ROC diagnostic performances of single and combined D-PSG parameters were tested in group 1 and validated in group 2.RESULTS: In group 1, the areas under the ROC curve (AUCs) were 0.91 (95% CI 0.86-0.96) for d-SOREMPs, 0.81 (95% CI 0.74-0.89) for the number of spontaneous naps, and 0.70 (95% CI 0.60-0.79) for total sleep time. A d-SOREMP count ≥1 (sensitivity of 95% and specificity of 72%), coupled with a diurnal total sleep time above 60 minutes (sensitivity of 89% and specificity of 91%), identified NT1 in group 1 with high reliability (area under the ROC curve of 0.93, 95% CI 0.88-0.97). These results were confirmed in the validation group with an AUC of 0.88 (95% CI 0.79-0.97).DISCUSSION: D-PSG recording is an easily performed, cost-effective, and reliable tool for identifying NT1 in children. Further studies should confirm its validity with home D-PSG monitoring. These alternative procedures could be used to confirm NT1 diagnosis and curtail diagnostic delay.

  View details for DOI 10.1212/WNL.0000000000207815

  View details for PubMedID 38165365

• Comorbid neurotrauma increases neurodegenerative-relevant cognitive, motor, and autonomic dysfunction in patients with REM sleep behavior disorder: A substudy of the North American Prodromal Synucleinopathy Consortium. Sleep Elliott, J. E., Ligman, B. R., Bryant-Ekstrand, M. D., Keil, A. T., Powers, K., Olivo, C., Neilson, L., Postuma, R. B., Pelletier, A., Gagnon, J. F., Gan-Or, Z., Yu, E., Liu, L., St Louis, E. K., Forsberg, L. K., Fields, J. A., Ross, O. A., Huddleston, D. E., Bliwise, D. L., Avidan, A. Y., Howell, M. J., Schenck, C. H., McLeland, J., Criswell, S. R., Videnovic, A., During, E. H., Miglis, M. G., Shprecher, D. R., Lee-Iannotti, J. K., Boeve, B. F., Ju, Y. S., Lim, M. M. 2024

  Abstract

  Rapid eye movement (REM) sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g., Parkinson's disease (PD), Lewy Body Dementia (LBD), and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) - henceforth "neurotrauma" (NT) - increase the odds of RBD by ~2.5-fold and is associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD.Participants ≥18 years with overnight-polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy (NAPS) Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory and autonomic function were completed. This cross-sectional analysis compared cases (n=24; RBD+NT) to controls (n=96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years).RBD+NT reported earlier RBD symptom onset (37.5±11.9 vs. 52.2±15.1 years of age) and a more severe RBD phenotype. Similarly, RBD+NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed.This cross-sectional, matched case:control study shows individuals with RBD+NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD+NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.

  View details for DOI 10.1093/sleep/zsae007

  View details for PubMedID 38181205

• HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis. Frontiers in immunology Peris Sempere, V., Luo, G., Muniz-Castrillo, S., Pinto, A., Picard, G., Rogemond, V., Titulaer, M. J., Finke, C., Leypoldt, F., Kuhlenbaumer, G., GENERATE study group, Jones, H. F., Dale, R. C., Binks, S., Irani, S. R., Bastiaansen, A. E., de Vries, J. M., de Bruijn, M. A., Roelen, D. L., Kim, T., Chu, K., Lee, S., Kanbayashi, T., Pollock, N. R., Kichula, K. M., Mumme-Monheit, A., Honnorat, J., Norman, P. J., Mignot, E. 2024; 15: 1423149

  Abstract

  Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

  View details for DOI 10.3389/fimmu.2024.1423149

  View details for PubMedID 39050850

• Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Dominguez, D., Rudock, R., Tomko, S., Pathak, S., Mignot, E., Licis, A. 2023

  Abstract

  Kleine-Levin syndrome (KLS) is a rare disorder characterized by episodic bouts of severe hypersomnia associated with cognitive and behavioral abnormalities, and normal alertness and functioning in between episodes. The pathophysiology is unclear but may involve neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, viral/autoimmune etiology, or circadian abnormalities. No single treatment has been shown to be reliably efficacious; lithium has demonstrated the most consistent efficacy, although many do not respond and its use is limited by side effects. Due to the evidence of circadian involvement, we hypothesized that strengthening circadian signals may ameliorate symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, two patients with KLS are described with apparent resolution of hypersomnia episodes following ramelteon initiation.

  View details for DOI 10.5664/jcsm.10968

  View details for PubMedID 38156412

• Stakeholder involvement in the optimization of a patient-centered exercise intervention for people with restless legs syndrome. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Cederberg, K. L., Sikes, E. M., Mignot, E. 2023

  Abstract

  STUDY OBJECTIVES: Previous research supports exercise as a behavioral approach to manage symptoms of restless legs syndrome (RLS); however, completion rates in exercise studies are low. This study obtained key stakeholder feedback from people with RLS to modify and optimize a 12-week, evidence-based exercise program for RLS.METHODS: Participants with RLS(N=513) completed a nationwide survey to provide feedback on the necessity, interest, feasibility, and efficacy of the program as well as perceived barriers and proposed modifications to improve the exercise program.RESULTS: Most respondents(67%) expressed the need for an exercise program designed specifically for people with RLS and 64% were interested in the program. Only 6% of participants thought the program wouldn't be well tolerated and 6% responded that it would likely exacerbate symptoms. However, only 58% said they would be likely to participate in the program if it was available to them locally. Key barriers to participation were (1)accessibility; (2)personal factors; (3)trustworthiness; and (4)fear of injury, illness, or symptom exacerbations. Respondents highlighted modification considerations for the individualization of exercise features, adaptations for specific impairments/personal factors, inclusion of flexibility and balance exercises, and flexibility for more home-based activities.CONCLUSIONS: Interest in the program was driven by the desire to reduce medications and improve overall quality of life. Appropriately educated and trained exercise providers knowledgeable about RLS are integral to buy-in from stakeholders. This study provides an imperative step in clinical research that can increase the success of subsequent implementation efforts and may accelerate the adoption of exercise programs into practice.

  View details for DOI 10.5664/jcsm.10928

  View details for PubMedID 38059333

• Excessive daytime sleepiness in primary care - Authors' reply. Lancet (London, England) Perez-Carbonell, L., Mignot, E., Leschziner, G., Dauvilliers, Y. 2023; 402 (10411): 1420-1421

  View details for DOI 10.1016/S0140-6736(23)01505-2

  View details for PubMedID 37865465

• RRWaveNet: A Compact End-to-End Multiscale Residual CNN for Robust PPG Respiratory Rate Estimation IEEE INTERNET OF THINGS JOURNAL Osathitporn, P., Sawadwuthikul, G., Thuwajit, P., Ueafuea, K., Mateepithaktham, T., Kunaseth, N., Choksatchawathi, T., Punyabukkana, P., Mignot, E., Wilaiprasitporn, T. 2023; 10 (18): 15943-15952

  View details for DOI 10.1109/JIOT.2023.3265980

  View details for Web of Science ID 001085214200018

• Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment. Human molecular genetics Davis, K. N., Qu, P. P., Ma, S., Lin, L., Plastini, M., Dahl, N., Plazzi, G., Pizza, F., O'Hara, R., Wong, W. H., Hallmayer, J., Mignot, E., Zhang, X., Urban, A. E. 2023

  Abstract

  DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell-type specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia, and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.

  View details for DOI 10.1093/hmg/ddad123

  View details for PubMedID 37584462

• Proteomic insights into the pathophysiology of periodic limb movements and restless legs syndrome. Sleep health Cederberg, K. L., Peris Sempere, V., Lin, L., Zhang, J., Leary, E. B., Moore, H., Morse, A. M., Blackman, A., Schweitzer, P. K., Kotagal, S., Bogan, R., Kushida, C. A., STAGES cohort investigator group, Mignot, E. 2023

  Abstract

  OBJECTIVES: We used a high-throughput assay of 5000 plasma proteins to identify biomarkers associated with periodic limb movements (PLM) and restless legs syndrome (RLS) in adults.METHODS: Participants (n=1410) of the Stanford Technology Analytics and Genomics in Sleep (STAGES) study had blood collected, completed a sleep questionnaire, and underwent overnight polysomnography with the scoring of PLMs. An aptamer-based array (SomaScan) was used to quantify 5000 proteins in plasma. A second cohort (n=697) that had serum assayed using a previous iteration of SomaScan (1300 proteins) was used for replication and in a combined analysis (n=2107). A 5% false discovery rate was used to assess significance.RESULTS: Multivariate analyses in STAGES identified 68 proteins associated with the PLM index after correction for multiple testing (ie, base model). Most significantly decreased proteins were iron-related and included Hepcidin (LEAP-1), Ferritin, and Ferritin light chain. Most significantly increased proteins included RANTES, Cathepsin A, and SULT 1A3. Of 68 proteins significant in the base model, 17 were present in the 1300 panel, and 15 of 17 were replicated. The most significant proteins in the combined model were Hepcidin (LEAP-1), Cathepsin A, Ferritin, and RANTES. Exploration of proteins in RLS versus non-RLS identified Cathepsin Z, Heme oxygenase 2 (HO-2), Interleukin-17A (upregulated in the combined cohort), and Megalin (upregulated in STAGES only) although results were less significant than for proteins associated with PLM index.CONCLUSIONS: These results confirm the association of PLM with low iron status and suggest the involvement of catabolic enzymes in PLM/RLS.

  View details for DOI 10.1016/j.sleh.2023.06.008

  View details for PubMedID 37563071

• Repeated polysomnography and multiple sleep latency test in narcolepsy type 1 and other hypersomnolence disorders. Sleep medicine Torstensen, E. W., Haubjerg Osterby, N. C., Kornum, B. R., Wanscher, B., Mignot, E., Barlose, M., Jennum, P. J. 2023; 110: 91-98

  Abstract

  BACKGROUND: The diagnosis of narcolepsy is based on clinical information, combined with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). PSG and the MSLT are moderately reliable at diagnosing narcolepsy type 1 (NT1) but unreliable for diagnosing narcolepsy type 2 (NT2). This is a problem, especially given the increased risk of a false-positive MSLT in the context of circadian misalignment or sleep deprivation, both of which commonly occur in the general population.AIM: We aimed to clarify the accuracy of PSG/MSLT testing in diagnosing NT1 versus controls without sleep disorders. Repeatability and reliability of PSG/MSLT testing and temporal changes in clinical findings of patients with NT1 versus patients with hypersomnolence with normal hypocretin-1 were compared.METHOD: 84 patients with NT1 and 100 patients with non-NT1-hypersomnolence disorders, all with congruent cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) levels, were included. Twenty-five of the 84 NT1 patients and all the hypersomnolence disorder patients underwent a follow-up evaluation consisting of clinical assessment, PSG, and a modified MSLT. An additional 68 controls with no sleep disorders were assessed at baseline.CONCLUSION: Confirming results from previous studies, we found that PSG and our modified MSLT accurately and reliably diagnosed hypocretin-deficient NT1 (accuracy=0.88, reliability=0.80). Patients with NT1 had stable clinical and electrophysiological presentations over time that suggested a stable phenotype. In contrast, the PSG/MSLT results of patients with hypersomnolence, and normal CSF-hcrt-1 had poor reliability (0.32) and low repeatability.

  View details for DOI 10.1016/j.sleep.2023.07.029

  View details for PubMedID 37544279

• Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies. Brain : a journal of neurology Armangue, T., Olivé-Cirera, G., Martínez-Hernandez, E., Rodes, M., Peris-Sempere, V., Guasp, M., Ruiz, R., Palou, E., González, A., Marcos, M. Á., Erro, M. E., Bataller, L., Corral-Corral, Í., Planagumà, J., Caballero, E., Vlagea, A., Chen, J., Bastard, P., Materna, M., Marchal, A., Abel, L., Cobat, A., Alsina, L., Fortuny, C., Saiz, A., Mignot, E., Vanderver, A., Casanova, J. L., Zhang, S. Y., Dalmau, J. 2023

  Abstract

  Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, HLA haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between January 1st, 2014 and December 31st, 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurologic syndromes; HLA haplotypes; blood type I-IFN signature (RNA quantification of 6 or 28 IFN- response genes [IRG]), and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in B. 39/93(42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis, and behavioral-psychiatric) showed a high (≥95% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A*02 (4/21, 19%) than those who did not develop AE (42/65, 65%, p = 0.0003) or the Spanish general population (2005/4335, 46%, p = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19/21 (91%) and 18/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE (median Zs-6-IRG 1.4 [0.6; 2.0] vs 0.2 [-0.4; 0.8], p = 0.03). However, a very high median Zs-6-IRG (>4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE (3/37[8%] vs 2/57[4%], p = 0.379). Multivariate logistic regression showed that a moderate increase of the blood IFN signature at day 21 (median Zs-6-IRG >1.5 but <4) was the most important predictor of AE post-HSE (OR 34.8 IQR [1.7-691.9]). Altogether, these findings show that most AE post-HSE manifest with 3 distinct syndromes, and HLA-A*02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.

  View details for DOI 10.1093/brain/awad238

  View details for PubMedID 37453099

• Perceptions of exercise and restless legs syndrome: Results from a nationwide survey. Journal of sleep research Cederberg, K. L., Sikes, E. M., Mignot, E. 2023: e13980

  Abstract

  Restless legs syndrome is a prevalent, sensorimotor sleep disorder temporarily relieved by movement, with evidence of symptomatic improvement with regular exercise. The present study describes perceptions of the effects of exercise on symptoms of restless legs syndrome. Participants (N = 528) completed a mixed-methods (i.e. numerical and narrative), nationwide survey including items assessing personal experiences with exercise and restless legs syndrome (both positive and negative), as well as restless legs syndrome diagnosis, restless legs syndrome severity, and demographic and clinical characteristics. Responses varied widely on specific experiences with exercise, but a higher percentage of participants indicated positive experiences with exercise than those who reported negative experiences (72%-40%, respectively) with exercise. Further, 54% of respondents reported that exercise only improves restless legs syndrome, while 24% reported exercise only worsens symptoms. Participants described that any abrupt change in exercise routine would almost always elicit restless legs syndrome symptoms (e.g. hiking for a long time, stopping an exercise routine), and that a consistent pattern of exercise improved restless legs syndrome symptoms with an overall beneficial effect on the frequency of symptomatic bouts. Participants further described time of day as impactful for their exercise experience, with > 50% indicating morning exercise improves symptoms and evening exercise worsens symptoms. Participants described several questions that they wanted answered regarding the evidence for exercise in restless legs syndrome and specific exercise prescription recommendations. The present study describes information crucial to the creation of stakeholder-informed health promotion programs for individuals with restless legs syndrome to optimize personalized treatment plans that could prevent and manage symptoms.

  View details for DOI 10.1111/jsr.13980

  View details for PubMedID 37353978

• Key results from two phase 3 clinical trials on the efficacy and safety of daridorexant in patients with chronic insomnia disorder: a plain language summary FUTURE NEUROLOGY Mignot, E., Mayleben, D., Fietze, I., Leger, D., Zammit, G., Bassetti, C. L., Kinter, D., Roth, T. 2023

  View details for DOI 10.2217/fnl-2022-0014

  View details for Web of Science ID 000981957300001

• ARTIFICIAL INTELLIGENCE TO AID IN DIAGNOSIS OF TYPE I NARCOLEPSY Nygate, Y., Rusk, S., Fernandez, C., Winzurk, Z., Wickwire, E., Mignot, E., Watson, N. F. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001008232900572

• PERCEPTIONS OF PEOPLE WITH RESTLESS LEGS SYNDROME ON THE EFFECT OF EXERCISE ON SYMPTOMS: RESULTS OF A NATIONWIDE SURVEY Cederberg, K., Sikes, E., Mignot, E. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001008232900698

• Continued Validation of the RBD Symptom Severity Scale (RBDSSS) in Participants of the North American Prodromal Synucleinopathy (NAPS) Consortium Busicescu, A., Choudhury, P., Lee-Iannotti, J., Rangan, P., Fantini, M., Shprecher, D., Lim, M., Elliott, J., Avidan, A., Huddleston, D., Bliwise, D., Howell, M., Schenck, C., Criswell, S., Xiong, C., McLeland, J., During, E., Mignot, E., Pelletier, A., Gagnon, J., Forsberg, L., Fields, J., St Louis, E., Videnovic, A., Ju, Y., Boeve, B., Postuma, R. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000203116

  View details for Web of Science ID 001053672105018

• Sodium Oxybate in Treatment-Resistant REM Sleep Behavior Disorder. Sleep During, E. H., Hernandez, B., Miglis, M. G., Sum-Ping, O., Hekmat, A., Cahuas, A., Ekelmans, A., Yoshino, F., Mignot, E., Kushida, C. A. 2023

  Abstract

  Symptomatic therapies for REM sleep behavior disorder (RBD) are limited. Sodium oxybate (SXB), a gamma-aminobutyric acid (GABA)-B agonist, could be effective but has not been evaluated against placebo.This double-blind, parallel-group, randomized, placebo-controlled trial in 24 participants was conducted at the Stanford Sleep Center. Patients were adults with definite iRBD or Parkinson's disease and probable RBD (PD-RBD), and persistence of ≥ 2 weekly episodes despite standard therapy. Patients were randomized 1:1 to receive SXB during a 4-week titration followed by a 4-week stable dosing period. Primary outcome was number of monthly RBD episodes according to a diary filled by patients and partners. Secondary outcomes were severity, number of severe RBD episodes, and objective RBD activity on video-polysomnography.12 iRBD and 12 PD-RBD participated (mean 65.8 years), and 22 (n = 10 SXB, 12 placebo) completed the study. Although no significant between-group difference was found, SXB showed reduction of monthly RBD episodes by 23.1 (95% CI -36.0, -10.2; P=0.001) versus 10.5 with placebo (95% CI, -22.6, 1.6; P=0.087). Improvement from baseline was similarly observed for RBD overall severity burden (each episode weighted for severity), number of severe episodes, and objective RBD activity per video-polysomnography. Two participants receiving SXB withdrew due to anxiety and dizziness. The majority of adverse events otherwise resolved with dose adjustment.SXB could reduce RBD symptoms; however, response was inconsistent and a large placebo effect was observed across patient-reported outcomes. Larger studies using objective endpoints are needed.

  View details for DOI 10.1093/sleep/zsad103

  View details for PubMedID 37052688

• Safety and pharmacodynamics of a single infusion of danavorexton in adults with idiopathic hypersomnia. Sleep Mignot, E., Bogan, R. K., Emsellem, H., Foldvary-Schaefer, N., Naylor, M., Neuwirth, R., Faessel, H., Swick, T., Olsson, T. 2023

  Abstract

  STUDY OBJECTIVES: Idiopathic hypersomnia (IH) is a chronic disorder characterized by excessive daytime sleepiness unexplained by another disorder or drug/medication use. Although the orexinergic system plays a role in sleep-wake regulation, orexin A levels in the cerebrospinal fluid are normal in people with IH. This phase 1b, randomized, placebo-controlled, crossover study aimed to investigate the safety, pharmacokinetics, and pharmacodynamics of danavorexton, a small-molecule orexin-2 receptor agonist, in adults with IH.METHODS: Adults with IH aged 18-75 years were randomized to one of two treatment sequences of single intravenous infusions of danavorexton 112mg and placebo. Pharmacodynamic endpoints included the maintenance of wakefulness test (MWT), the Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance task (PVT). Adverse events were monitored throughout the study period.RESULTS: Of 28 randomized participants, 12 (44.4%) had a treatment-emergent adverse event (TEAE) and 10 (37.0%) had a TEAE considered related to study drug, most of which were mild or moderate. Four participants (18.2%) had urinary TEAEs while receiving danavorexton, all of which were mild in severity. There were no deaths or TEAEs leading to discontinuation. Improvements in MWT, KSS, and PVT scores were observed with danavorexton compared to placebo. Following drug administration, a mean sleep latency of 40 minutes (maximum value) was observed during the MWT within 2 hours of danavorexton infusion in most participants.CONCLUSIONS: A single infusion of danavorexton improves subjective and objective excessive daytime sleepiness in people with IH with no serious TEAEs, indicating orexin-2 receptor agonists are promising treatments for IH.

  View details for DOI 10.1093/sleep/zsad049

  View details for PubMedID 36883238

• Baseline characteristics of the North American prodromal Synucleinopathy cohort. Annals of clinical and translational neurology Elliott, J. E., Lim, M. M., Keil, A. T., Postuma, R. B., Pelletier, A., Gagnon, J., St Louis, E. K., Forsberg, L. K., Fields, J. A., Huddleston, D. E., Bliwise, D. L., Avidan, A. Y., Howell, M. J., Schenck, C. H., McLeland, J., Criswell, S. R., Videnovic, A., During, E. H., Miglis, M. G., Shprecher, D. R., Lee-Iannotti, J. K., Boeve, B. F., Ju, Y. S., North American Prodromal Synucleinopathy (NAPS) Consortium, Ju, Y. S., Boeve, B. F., Avidan, A. Y., Bliwise, D. L., Choudhury, P., Criswell, S. R., During, E. H., Elliott, J. E., Fields, J. A., Forsberg, L. K., Gagnon, J., Howell, M. J., Huddleston, D. E., Lee-Iannotti, J. K., Lim, M. M., Miglis, M. G., Postuma, R. B., Shprecher, D. R., St Louis, E. K., Videnovic, A., McLeland, J., Amudson-Huffmaster, S., Brushaber, N., Chung, J. W., De Kam, J., Ekelmans, A., Keane, M., Keil, A. T., Kraft, R., Ligman, B. R., MacKinnon, C., Miner-Rose, D., Murphy, S., Pelletier, A., Powers, K. L., Stauder, M., Rivera, A., Sanchez, S., Summers, R., Tiegan, L., Timm, P., Tucker, K. A., Tran, P., Galasko, D., Mignot, E., Schenck, C. 2023

  Abstract

  OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment.METHODS: Participants ≥18years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function.RESULTS: Outcomes are primarily reported based on sex (361 total: n=295 male, n=66 female), and secondarily based on history of antidepressant use (n=200 with, n=154 without; with correction for sex differences) and based on extent of synucleinopathy burden (n=56 defined as isolated RBD, n=305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ-9; 39.3% and 31%, respectively).INTERPRETATION: These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

  View details for DOI 10.1002/acn3.51738

  View details for PubMedID 36751940

• The sleep and wake electroencephalogram over the lifespan. Neurobiology of aging Sun, H., Ye, E., Paixao, L., Ganglberger, W., Chu, C. J., Zhang, C., Rosand, J., Mignot, E., Cash, S. S., Gozal, D., Thomas, R. J., Westover, M. B. 2023; 124: 60-70

  Abstract

  Both sleep and wake encephalograms (EEG) change over the lifespan. While prior studies have characterized age-related changes in the EEG, the datasets span a particular age group, or focused on sleep and wake macrostructure rather than the microstructure. Here, we present sex-stratified data from 3372 community-based or clinic-based otherwise neurologically and psychiatrically healthy participants ranging from 11 days to 80 years of age. We estimate age norms for key sleep and wake EEG parameters including absolute and relative powers in delta, theta, alpha, and sigma bands, as well as sleep spindle density, amplitude, duration, and frequency. To illustrate the potential use of the reference measures developed herein, we compare them to sleep EEG recordings from age-matched participants with Alzheimer's disease, severe sleep apnea, depression, osteoarthritis, and osteoporosis. Although the partially clinical nature of the datasets may bias the findings towards less normal and hence may underestimate pathology in practice, age-based EEG reference values enable objective screening of deviations from healthy aging among individuals with a variety of disorders that affect brain health.

  View details for DOI 10.1016/j.neurobiolaging.2023.01.006

  View details for PubMedID 36739622

• Changed epidemiology of narcolepsy before, during, and after the 2009 H1N1 pandemic: a nationwide narcolepsy surveillance network study in mainland China, 1990-2017. Sleep Wang, X., Xiao, F., Wang, Y., Deng, X., Chen, Z., Dong, X., Wang, W., Li, C., Xu, Z., Wu, H., Yu, H., Su, C., Wang, Z., Tang, X., Lv, Y., Li, Y., Sun, S., Huang, J., Hao, L., Wei, X., Deng, L., Huang, Y., Zhang, J., Wing, Y., Zhang, J., Mignot, E., Han, F., Yu, H. 2023

  Abstract

  STUDY OBJECTIVES: Increased incidence of narcolepsy was reported in children during the 2009 H1N1 pandemic following Pandemrix, a H1N1 flu vaccine. A link with A(H1N1)pdm09 infections remains controversial. Using nationwide surveillance data from China (1990 to 2017), the epidemiology of narcolepsy was analyzed.METHODS: Individual records of narcolepsy patients were collected from 15 of 42 hospitals across China known to diagnose cases. Incidence was estimated assuming representativeness of these hospitals. Age-specific incidence, epidemiological and clinical characteristics of patients were evaluated before, during, and after the 2009 H1N1 pandemic. Sensitivity analyses were conducted by including NT1 cases only and to exclude the effect of 2009 H1N1 vaccination.RESULTS: Average annual incidence was 0.79 per 100,000 person-years (PY) from 1990 to 2017 and 1.08 per 100,000 PY from 2003 to 2017. Incidence increased 4.17 (95%CI 4.12, 4.22) and 1.42 (95%CI 1.41, 1.44) fold during and after the 2009 H1N1 pandemic when compared to baseline. These results were robust in sensitivity analyses. Patients with onset of narcolepsy during the pandemic period were younger (notably in 5-9-year-old strata), and age shift toward younger children reversed to baseline following the pandemic.CONCLUSIONS: Increased incidence of narcolepsy was observed during the 2009 H1N1 pandemic period. This is likely to be associated with the circulation of the wild-type A(H1N1)pdm09 virus. This observation should be considered for future influenza pandemic preparedness plans.

  View details for DOI 10.1093/sleep/zsac325

  View details for PubMedID 36595587

• A Flexible Deep Learning Architecture for Temporal Sleep Stage Classification Using Accelerometry and Photoplethysmography IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Olsen, M., Zeitzer, J. M., Richardson, R. N., Davidenko, P., Jennum, P. J., Sorensen, H. D., Mignot, E. 2023; 70 (1): 228-237

  Abstract

  Wrist-worn consumer sleep technologies (CST) that contain accelerometers (ACC) and photoplethysmography (PPG) are increasingly common and hold great potential to function as out-of-clinic (OOC) sleep monitoring systems. However, very few validation studies exist because raw data from CSTs are rarely made accessible for external use. We present a deep neural network (DNN) with a strong temporal core, inspired by U-Net, that can process multivariate time series inputs with different dimensionality to predict sleep stages (wake, light-, deep-, and REM sleep) using ACC and PPG signals from nocturnal recordings. The DNN was trained and tested on 3 internal datasets, comprising raw data both from clinical and wrist-worn devices from 301 recordings (PSG-PPG: 266, Wrist-worn PPG: 35). External validation was performed on a hold-out test dataset containing 35 recordings comprising only raw data from a wrist-worn CST. An accuracy = 0.71±0.09, 0.76±0.07, 0.73±0.06, and κ = 0.58±0.13, 0.64±0.09, 0.59±0.09 was achieved on the internal test sets. Our experiments show that spectral preprocessing yields superior performance when compared to surrogate-, feature-, raw data-based preparation. Combining both modalities produce the overall best performance, although PPG proved to be the most impactful and was the only modality capable of detecting REM sleep well. Including ACC improved model precision to wake and sleep metric estimation. Increasing input segment size improved performance consistently; the best performance was achieved using 1024 epochs (∼8.5 hrs.). An accuracy = 0.69±0.13 and κ = 0.58±0.18 was achieved on the hold-out test dataset, proving the generalizability and robustness of our approach to raw data collected with a wrist-worn CST.

  View details for DOI 10.1109/TBME.2022.3187945

  View details for Web of Science ID 000936179400023

  View details for PubMedID 35786544

• Automatic Detection of Chronic Insomnia from Polysomnographic and Clinical Variables Using Machine Learning. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Hanif, U., Gimenez, U., Cairns, A., Lewin, D., Ashraf, N., Mignot, E. 2023; 2023: 1-5

  Abstract

  Insomnia is defined subjectively by the presence and frequency of specific clinical symptoms and an association with distress. Although sleep study data has shown some weak associations, no objective test can currently be used to predict insomnia. The purpose of this study was to use previously reported and relatively crafted insomnia-related polysomnographic variables in machine learning models to classify groups with and without insomnia. Demographics, diagnosed depression, Epworth Sleepiness Scale (ESS), and features derived from electroencephalography (EEG), arousals, and sleep stages from 3,407 sleep clinic patients (2,617 without insomnia and 790 insomnia patients based on responses to a set of questions) were included in this analysis. The number of features were reduced using pair-wise correlation and recursive feature elimination. Predictive value of three machine learning models (logistic regression, neural network, and support vector machine) was investigated, and the best performance was achieved with logistic regression, yielding a balanced accuracy of 71%. The most important features in predicting insomnia were depression, age, sex, duration of longest arousal, ESS score, and EEG power in theta and sigma bands across all sleep stages. Results indicate potential of machine learning-based screening for insomnia using clinical variables and EEG.

  View details for DOI 10.1109/EMBC40787.2023.10340587

  View details for PubMedID 38083711

• Fully Automated Detection of Isolated Rapid-Eye-Movement Sleep Behavior Disorder Using Actigraphy. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Brink-Kjaer, A., Winer, J., Zeitzer, J. M., Sorensen, H. B., Jennum, P., Mignot, E., During, E. 2023; 2023: 1-5

  Abstract

  Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is caused by motor disinhibition during REM sleep and is a strong early predictor of Parkinson's disease. However, screening questionnaires for iRBD lack specificity due to other sleep disorders that mimic the symptoms. Nocturnal wrist actigraphy has shown promise in detecting iRBD by measuring sleep-related motor activity, but it relies on sleep diary-defined sleep periods, which are not always available. Our aim was to precisely detect iRBD using actigraphy alone by combining two actigraphy-based markers of iRBD - abnormal nighttime activity and 24-hour rhythm disruption. In a sample of 42 iRBD patients and 42 controls (21 clinical controls with other sleep disorders and 21 community controls) from the Stanford Sleep Clinic, the nighttime actigraphy model was optimized using automated detection of sleep periods. Using a subset of 38 iRBD patients with daytime data and 110 age-, sex-, and body-mass-index-matched controls from the UK Biobank, the 24-hour rhythm actigraphy model was optimized. Both nighttime and 24-hour rhythm features were found to distinguish iRBD from controls. To improve the accuracy of iRBD detection, we fused the nighttime and 24-hour rhythm disruption classifiers using logistic regression, which achieved a sensitivity of 78.9%, a specificity of 96.4%, and an AUC of 0.954. This study preliminarily validates a fully automated method for detecting iRBD using actigraphy in a general population.Clinical relevance- Actigraphy-based iRBD detection has potential for large-scale screening of iRBD in the general population.

  View details for DOI 10.1109/EMBC40787.2023.10341133

  View details for PubMedID 38083699

• MSED: A Multi-Modal Sleep Event Detection Model for Clinical Sleep Analysis. IEEE transactions on bio-medical engineering Zahid, A. N., Jennum, P., Mignot, E., Sorensen, H. B. 2023; 70 (9): 2508-2518

  Abstract

  Clinical sleep analysis require manual analysis of sleep patterns for correct diagnosis of sleep disorders. However, several studies have shown significant variability in manual scoring of clinically relevant discrete sleep events, such as arousals, leg movements, and sleep disordered breathing (apneas and hypopneas). We investigated whether an automatic method could be used for event detection and if a model trained on all events (joint model) performed better than corresponding event-specific models (single-event models). We trained a deep neural network event detection model on 1653 individual recordings and tested the optimized model on 1000 separate hold-out recordings. F1 scores for the optimized joint detection model were 0.70, 0.63, and 0.62 for arousals, leg movements, and sleep disordered breathing, respectively, compared to 0.65, 0.61, and 0.60 for the optimized single-event models. Index values computed from detected events correlated positively with manual annotations (r2 = 0.73, r2 = 0.77, r2 = 0.78, respectively). We furthermore quantified model accuracy based on temporal difference metrics, which improved overall by using the joint model compared to single-event models. Our automatic model jointly detects arousals, leg movements and sleep disordered breathing events with high correlation with human annotations. Finally, we benchmark against previous state-of-the-art multi-event detection models and found an overall increase in F1 score with our proposed model despite a 97.5% reduction in model size.

  View details for DOI 10.1109/TBME.2023.3252368

  View details for PubMedID 37028083

• SViT: A Spectral Vision Transformer for the Detection of REM Sleep Behavior Disorder. IEEE journal of biomedical and health informatics Gunter, K. M., Brink-Kjaer, A., Mignot, E., Sorensen, H. B., During, E., Jennum, P. 2023; 27 (9): 4285-4292

  Abstract

  REM sleep behavior disorder (RBD) is a parasomnia with dream enactment and presence of REM sleep without atonia (RSWA). RBD diagnosed manually via polysomnography (PSG) scoring, which is time intensive. Isolated RBD (iRBD) is also associated with a high probability of conversion to Parkinson's disease. Diagnosis of iRBD is largely based on clinical evaluation and subjective PSG ratings of REM sleep without atonia. Here we show the first application of a novel spectral vision transformer (SViT) to PSG signals for detection of RBD and compare the results to the more conventional convolutional neural network architecture. The vision-based deep learning models were applied to scalograms (30 or 300 s windows) of the PSG data (EEG, EMG and EOG) and the predictions interpreted. A total of 153 RBD (96 iRBD and 57 RBD with PD) and 190 controls were included in the study and 5-fold bagged ensemble was used. Model outputs were analyzed per-patient (averaged), with regards to sleep stage, and the SViT was interpreted using integrated gradients. Models had a similar per-epoch test F1 score. However, the vision transformer had the best per-patient performance, with an F1 score 0.87. Training the SViT on channel subsets, it achieved an F1 score of 0.93 on a combination of EEG and EOG. EMG is thought to have the highest diagnostic yield, but interpretation of our model showed that high relevance was placed on EEG and EOG, indicating these channels could be included for diagnosing RBD.

  View details for DOI 10.1109/JBHI.2023.3292231

  View details for PubMedID 37402190

• Automatic scoring of drug-induced sleep endoscopy for obstructive sleep apnea using deep learning. Sleep medicine Hanif, U., Kiaer, E. K., Capasso, R., Liu, S. Y., Mignot, E. J., Sorensen, H. B., Jennum, P. 2022; 102: 19-29

  Abstract

  Treatment of obstructive sleep apnea is crucial for long term health and reduced economic burden. For those considered for surgery, drug-induced sleep endoscopy (DISE) is a method to characterize location and pattern of sleep-related upper airway collapse. According to the VOTE classification system, four upper airway sites of collapse are characterized: velum (V), oropharynx (O), tongue (T), and epiglottis (E). The degree of obstruction per site is classified as 0 (no obstruction), 1 (partial obstruction), or 2 (complete obstruction). Here we propose a deep learning approach for automatic scoring of VOTE obstruction degrees from DISE videos.We included 281 DISE videos with varying durations (6 s-16 min) from two sleep clinics: Copenhagen University Hospital and Stanford University Hospital. Examinations were split into 5-s clips, each receiving annotations of 0, 1, 2, or X (site not visible) for each site (V, O, T, and E), which was used to train a deep learning model. Predicted VOTE obstruction degrees per examination was obtained by taking the highest predicted degree per site across 5-s clips, which was evaluated against VOTE degrees annotated by surgeons.Mean F1 score of 70% was obtained across all DISE examinations (V: 85%, O: 72%, T: 57%, E: 65%). For each site, sensitivity was highest for degree 2 and lowest for degree 0. No bias in performance was observed between videos from different clinicians/hospitals.This study demonstrates that automating scoring of DISE examinations show high validity and feasibility in degree of upper airway collapse.

  View details for DOI 10.1016/j.sleep.2022.12.015

  View details for PubMedID 36587544

• DAYTIME SLEEPINESS AND WEIGHT CHANGE AMONG ADULTS: FINDINGS FROM THE WISCONSIN SLEEP COHORT STUDY Liu, Y., Barnet, J., Hagen, E., Peppard, P., Reither, E., Mignot, E., Plante, D. OXFORD UNIV PRESS. 2022: 364

  View details for Web of Science ID 000913044001649

• Ambulatory Detection of Isolated Rapid-Eye-Movement Sleep Behavior Disorder Combining Actigraphy and Questionnaire. Movement disorders : official journal of the Movement Disorder Society Brink-Kjaer, A., Gupta, N., Marin, E., Zitser, J., Sum-Ping, O., Hekmat, A., Bueno, F., Cahuas, A., Langston, J., Jennum, P., Sorensen, H. B., Mignot, E., During, E. 2022

  Abstract

  BACKGROUND: Isolated rapid-eye-movement sleep behavior disorder (iRBD) is in most cases a prodrome of neurodegenerative synucleinopathies, affecting 1% to 2% of middle-aged and older adults; however, accurate ambulatory diagnostic methods are not available. Questionnaires lack specificity in nonclinical populations. Wrist actigraphy can detect characteristic features in individuals with RBD; however, high-frequency actigraphy has been rarely used.OBJECTIVE: The aim was to develop a machine learning classifier using high-frequency (1-second resolution) actigraphy and a short patient survey for detecting iRBD with high accuracy and precision.METHODS: The method involved analysis of home actigraphy data (for seven nights and more) and a nine-item questionnaire (RBD Innsbruck inventory and three synucleinopathy prodromes of subjective hyposmia, constipation, and orthostatic dizziness) in a data set comprising 42 patients with iRBD, 21 sleep clinic patients with other sleep disorders, and 21 community controls.RESULTS: The actigraphy classifier achieved 95.2% (95% confidence interval [CI]: 88.3-98.7) sensitivity and 90.9% (95% CI: 82.1-95.8) precision. The questionnaire classifier achieved 90.6% accuracy and 92.7% precision, exceeding the performance of the Innsbruck RBD Inventory and prodromal questionnaire alone. Concordant predictions between actigraphy and questionnaire reached a specificity and precision of 100% (95% CI: 95.7-100.0) with 88.1% sensitivity (95% CI: 79.2-94.1) and outperformed any combination of actigraphy and a single question on RBD or prodromal symptoms.CONCLUSIONS: Actigraphy detected iRBD with high accuracy in a mixed clinical and community cohort. This cost-effective fully remote procedure can be used to diagnose iRBD in specialty outpatient settings and has potential for large-scale screening of iRBD in the general population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.29249

  View details for PubMedID 36258659

• Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls. Sleep medicine Torstensen, E. W., Haubjerg Osterby, N. C., Pizza, F., Plazzi, G., Antelmi, E., Moresco, M., Mignot, E., Jorgensen, N. R., Christensen, G. L., Wanscher, B., Kornum, B. R., Jennum, P. J. 2022; 101: 213-220

  Abstract

  STUDY OBJECTIVES: The assay currently used worldwide to measure cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) for diagnosing narcolepsy uses a competitive radioimmunoassay with polyclonal anti-hcrt-1 antibodies. This assay detects multiple hypocretin-1 immunoreactive species in the CSF that are all derived from full-length hcrt-1. We aimed to revalidate CSF-hcrt-1 cut-offs for narcolepsy type 1 (NT1) diagnosis and to evaluate temporal changes in CSF-hcrt-1 levels in patients suspected of having central hypersomnia.METHOD: We carried out a repeat lumbar puncture with a mean follow-up of 4.0 years, to measure CSF-hcrt-1 in patients suspected of having central hypersomnia in a follow-up study. Data from CSF samples of patients with NT1 and of controls without known hypersomnia, from the Italian-Stanford and Danish populations, were examined using a receiver-operating characteristic analysis.RESULTS: The optimal CSF-hcrt-1 cut-offs for identifying NT1 were 129pg/ml and 179pg/ml for the Italian-Stanford and Danish populations, respectively. The sensitivity was 0.93-0.99 and the specificity was 1. Follow-up lumbar puncture measurements of CSF-hcrt-1 were obtained from 73 patients. 30 of 32 patients with low CSF-hcrt-1 levels continued to be categorized as low, with an unaltered diagnosis; two patients showed a marked increase in CSF-hcrt-1, attaining normal values at follow-up. One of these patients relapsed to low CSF-hcrt-1 after follow-up. All 41 patients with normal CSF-hcrt-1 at baseline had normal CSF-hcrt-1 at follow-up.CONCLUSION: CSF-hcrt-1 measurement can provide an accurate test for diagnosing NT1, although it is important to validate the CSF-hcrt-1 cut-off for specific testing locations. Stable CSF-hcrt-1 levels support the already established prognosis of narcolepsy as permanent once the disorder has fully developed.

  View details for DOI 10.1016/j.sleep.2022.10.004

  View details for PubMedID 36427467

• Protective Association of HLA-DRB1*04 Subtypes in Neurodegenerative Diseases Implicates Acetylated Tau PHF6 Sequences Mignot, E. M., Luo, G., Guen, Y., Ambati, A., Yogeshwar, S. M., Peris-Sempere, V., Lambert, J., Greicius, M., ADPD Collaborators, Study Group WILEY. 2022: S58

  View details for Web of Science ID 000867884200047

• Characterization of t cell receptors reactive to HCRTNH2, PHA(273)-(287) and NP17-(31) in control and narcolepsy patients Luo, G., Zhang, J., Lin, L., Mignot, E. WILEY. 2022

  View details for Web of Science ID 000870433500244

• Genetics of Anti-NMDAR Encephalitis Muniz-Castrillo, S., Peris-Sempere, V., Fagundes-Bueno, F., Lomba, S., Honnorat, J., Mignot, E., Anti-Nmdare Collaborators Grp WILEY. 2022: S139

  View details for Web of Science ID 000867884200230

• Rank Wise Effect of HLA-DQ5 Explains Risk for the Development of Anti-IgLON5 Disease Yogeshwar, S. M., Peris-Sempere, V., Muniz-Castrillo, S., Luo, G., Finke, C., Honnorat, J., Mignot, E. WILEY. 2022: S143

  View details for Web of Science ID 000867884200239

• Understanding and approaching excessive daytime sleepiness. Lancet (London, England) Perez-Carbonell, L., Mignot, E., Leschziner, G., Dauvilliers, Y. 2022

  Abstract

  Excessive daytime sleepiness (EDS) is a public health issue. However, it remains largely undervalued, scarcely diagnosed, and poorly supported. Variations in the definition of EDS and limitations in clinical assessment lead to difficulties in its epidemiological study, but the relevance of this symptom from a socioeconomic perspective is inarguable. EDS might be a consequence of several behavioural issues leading to insufficient or disrupted sleep, as well as a consequence of sleep disorders including sleep apnoea syndrome, circadian disorders, central hypersomnolence disorders (narcolepsy and idiopathic hypersomnia), other medical or psychiatric conditions, or medications. Furthermore, EDS can have implications for health as it is thought to act as a risk factor for other conditions, such as cardiovascular and neurodegenerative disorders. Because of the heterogeneous causes of EDS and the complexity of its pathophysiology, management will largely depend on the cause, with the final aim of making treatment specific to the individual using precision medicine and personalised medicine.

  View details for DOI 10.1016/S0140-6736(22)01018-2

  View details for PubMedID 36115367

• Cerebellar Ataxia With Anti-DNER Antibodies: Outcomes and Immunologic Features. Neurology(R) neuroimmunology & neuroinflammation Peter, E., Do, L. D., Hannoun, S., Muniz-Castrillo, S., Vogrig, A., Wucher, V., Pinto, A., Chounlamountri, N., Zakaria, W., Rogemond, V., Picard, G., Hedou, J., Ambati, A., Alentorn, A., Traverse-Glehen, A., Manto, M., Psimaras, D., Mignot, E., Cotton, F., Desestret, V., Honnorat, J., Joubert, B. 2022; 9 (5)

  Abstract

  BACKGROUND AND OBJECTIVES: There is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor-related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies.METHODS: Patients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface.RESULTS: Twenty-eight patients were included (median age, 52 years, range 19-81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3-238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro.DISCUSSION: DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell-targeting treatments.

  View details for DOI 10.1212/NXI.0000000000200018

  View details for PubMedID 35940913

• Proteomic Biomarkers of Kleine-Levin Syndrome. Sleep Hedou, J., Cederberg, K. L., Ambati, A., Lin, L., Farber, N., Dauvilliers, Y., Quadri, M., Bourgin, P., Plazzi, G., Andlauer, O., Hong, S. C., Huang, Y., Leu-Semenescu, S., Arnulf, I., Taheri, S., Mignot, E. 2022

  Abstract

  STUDY OBJECTIVES: Kleine-Levin Syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls.METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in 7 cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEA) were performed on DEPs.RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (False Discovery Rate, FDR<0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1 and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility and activation. TEA analysis of up- and down-regulated proteins revealed changes in brain proteins (p<6x10 -5), notably from the pons, medulla and midbrain. A multi-variate machine learning classifier performed robustly, achieving a receiver operating curve (ROC) Area Under the Curve of 0.90 (95% CI=0.78-1.0,p=0.0006) in CSF and 1.0 (95% CI=1.0-1.0,p=0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases.CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.

  View details for DOI 10.1093/sleep/zsac097

  View details for PubMedID 35859339

• End-to-end Deep Learning of Polysomnograms for Classification of REM Sleep Behavior Disorder. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Brink-Kjaer, A., Gunter, K. M., Mignot, E., During, E., Jennum, P., Sorensen, H. B. 2022; 2022: 2941-2944

  Abstract

  Rapid eye movement (REM) sleep behavior disorder (RBD) is parasomnia and a prodromal manifestation of Parkinson's disease. The current diagnostic method relies on manual scoring of polysomnograms (PSGs), a procedure that is time and effort intensive, subject to interscorer variability, and requires high level of expertise. Here, we present an automatic and interpretable diagnostic tool for RBD that analyzes PSGs using end-to-end deep neural networks. We optimized hierarchical attention networks in a 5-fold cross validation directly to classify RBD from PSG data recorded in 143 participants with RBD and 147 age-and sex-matched controls. An ensemble model using logistic regression was implemented to fuse decisions from networks trained in various signal combinations. We interpreted the networks using gradient SHAP that attribute relevance of input signals to model decisions. The ensemble model achieved a sensitivity of 91.4 % and a specificity of 86.3 %. Interpretation showed that electroencephalography (EEG) and leg electromyography (EMG) exhibited most patterns with high relevance. This study validates a robust diagnostic tool for RBD and proposes an interpretable and fully automatic framework for end-to-end modeling of other sleep disorders from PSG data. Clinical relevance- This study presents a novel diagnostic tool for RBD that considers neurophysiologic biomarkers in multiple modalities.

  View details for DOI 10.1109/EMBC48229.2022.9871576

  View details for PubMedID 36086216

• Detection of Cheyne-Stokes Breathing using a transformer-based neural network. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Helge, A. W., Hanif, U., Joergensen, V. H., Jennum, P., Mignot, E., Sorensen, H. B. 2022; 2022: 4580-4583

  Abstract

  Annotation of sleep disordered breathing, including Cheyne-Stokes Breathing (CSB), is an expensive and time-consuming process for the clinician. To solve the problem, this paper presents a deep learning-based algorithm for automatic sample-wise detection of CSB in nocturnal polysomnographic (PSG) recordings. 523 PSG recordings were retrieved from four different sleep cohorts and subsequently scored for CSB by three certified sleep technicians. The data was pre-processed and 16 time domain features were extracted and passed into a neural network inspired by the transformer unit. Finally, the network output was post-processed to achieve physiologically meaningful predictions. The algorithm reached a F1-score of 0.76, close to the certified sleep technicians showing that it is possible to automatically detect CSB with the proposed model. The algorithm had difficulties distinguishing between severe obstructive sleep apnea and CSB but this was not dissimilar to technician performance. In conclusion, the proposed algorithm showed promising results and a confirmation of the performance could make it relevant as a screening tool in a clinical setting.

  View details for DOI 10.1109/EMBC48229.2022.9871537

  View details for PubMedID 36086293

• Increased Incidence of Pediatric Narcolepsy Following the 2009 H1N1 Pandemic: A Report from the Pediatric Working Group of the Sleep Research Network. Sleep Simakajornboon, N., Mignot, E., Maski, K., Owens, J., Rosen, C., Ibrahim, S., Hassan, F., Chervin, R. D., Perry, G., Brooks, L., Kheirandish-Gozal, L., Gozal, D., Mason, T., Robinson, A., Malow, B., Naqvi, K., Chen, M. L., Jambhekar, S., Halbower, A., Graw-Panzer, K., Dayyat, E., Lew, J., Melendres, C., Kotagal, S., Jain, S., Super, E., Dye, T., Hossain, M. M., Tadesse, D. 2022

  Abstract

  This study was aimed to evaluate yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multi-center retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and relationship to historical H1N1 influenza data. 950 subjects were included in the analysis; 487 subjects were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6±3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (P<0.0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (P<0.05). Cross correlation analysis demonstrated significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (rho=0.397, P<0.0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics.

  View details for DOI 10.1093/sleep/zsac137

  View details for PubMedID 35695235

• Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Lecendreux, M., Plazzi, G., Dauvilliers, Y., Rosen, C. L., Ruoff, C., Black, J., Parvataneni, R., Guinta, D., Wang, Y. G., Mignot, E. 2022

  Abstract

  STUDY OBJECTIVES: Evaluate long-term efficacy and safety of sodium oxybate (SXB) in children and adolescents (aged 7-16 years) with narcolepsy with cataplexy.METHODS: A double-blind randomized withdrawal study was conducted. Prior to randomization, SXB-naive participants were titrated to an efficacious and tolerable dose of SXB; participants taking SXB entered on their established dose. Following a 2-week stable-dose period (SDP) and 2-week, double-blind, randomized withdrawal period (DBRWP), participants entered an open-label period (OLP; ≤47 weeks). Efficacy measures during the OLP included number of weekly cataplexy attacks, cataplexy-free days, and Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Safety outcomes included treatment-emergent adverse events (TEAEs); assessments of depression, anxiety, and suicidality; and polysomnography.RESULTS: Of 106 enrolled participants, 95 entered and 85 completed the OLP. In SXB-naive participants and participants previously taking SXB, efficacy of SXB established prior to the DBRWP was maintained throughout the OLP for number of weekly cataplexy attacks (median [Q1, Q3] change from the SDP to end of the OLP: 0.0 [-2.5, 4.9] and 0.0 [-3.4, 2.6], respectively) and ESS-CHAD scores (0.0 [-3.0, 2.5] and 1.0 [-3.0, 3.0], respectively). Median (Q1, Q3) number of cataplexy-free days per week was 2.3 (0.0, 6.0) in OLP week 1 and 3.8 (0.5, 5.5) in week 48. TEAEs (≥5%) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis, upper respiratory tract infection, and dizziness.CONCLUSIONS: SXB demonstrated long-term maintenance of efficacy in pediatric narcolepsy with cataplexy, with a safety profile consistent with that observed in adults.CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: A Multicenter Study of the Efficacy and Safety of Xyrem With an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy; Identifier: NCT02221869; URL: https://clinicaltrials.gov/ct2/show/NCT02221869.

  View details for DOI 10.5664/jcsm.10090

  View details for PubMedID 35689598

• AGE ESTIMATION FROM SLEEP USING DEEP LEARNING PREDICTS LIFE EXPECTANCY Brink-Kjaer, A., Leary, E., Sun, H., Westover, M., Stone, K., Peppard, P., Lane, N., Cawthon, P., Redline, S., Jennum, P., Mignot, E., Sorensen, H. OXFORD UNIV PRESS INC. 2022: A143

  View details for Web of Science ID 000838094800316

• AT-HOME DETECTION OF REM SLEEP BEHAVIOR DISORDER USING A MACHINE LEARNING APPROACH AND WRIST ACTIGRAPHY Brink-Kjaer, A., Gupta, N., Marin, E., Zitser, J., Sum-Ping, O., Hekmat, A., Bueno, F., Cahuas, A., Jennum, P., Sorensen, H., Mignot, E., During, E. OXFORD UNIV PRESS INC. 2022: A243-A244

  View details for Web of Science ID 000838094800549

• PROTEOMIC BIOMARKERS OF OBSTRUCTIVE SLEEP APNEA Cederberg, K., Hanif, U., Leary, E., Schneider, L., Morse, A., Blackman, A., Schweitzer, P., Kotagal, S., Bogan, R., Kushida, C., Mignot, E. OXFORD UNIV PRESS INC. 2022: A326

  View details for Web of Science ID 000838094800743

• PROTEOMIC APPROACH FOR UNDERSTANDING THE MECHANISMS OF PERIODIC LIMB MOVEMENTS AND RESTLESS LEGS SYNDROME Cederberg, K., Hanif, U., Leary, E., Schneider, L., Morse, A., Blackman, A., Schweitzer, P., Kotagal, S., Bogan, R., Kushida, C., Mignot, E. OXFORD UNIV PRESS INC. 2022: A244

  View details for Web of Science ID 000838094800550

• ESTIMATED PREVALENCE OF IDIOPATHIC HYPERSOMNIA IN THE WISCONSIN SLEEP COHORT Peppard, P., Plante, D., Hagen, E., Barnet, J., Mignot, E. OXFORD UNIV PRESS INC. 2022: A185

  View details for Web of Science ID 000838094800410

• Digital markers of sleep architecture to characterize the impact of different lockdown regimens on sleep health during the COVID-19 pandemic. Sleep Pepin, J., Bailly, S., Mignot, E., Gaucher, J., Chouraki, A., Cals-Maurette, M., Ben Messaoud, R., Tamisier, R., Arnal, P. J. 2022

  View details for DOI 10.1093/sleep/zsac074

  View details for PubMedID 35429392

• Risks of Withdrawal Symptoms and Rebound Insomnia after Discontinuation of Daridorexant in Patients with Insomnia Kinter, D., Leger, D., Fietze, I., Pain, S., Flamion, B., Mignot, E. SPRINGER HEIDELBERG. 2022: 320-321

  View details for Web of Science ID 000790756600037

• Dissecting the HLA locus in Parkinson's disease in Europeans Yu, E., Ambati, A., Andersen, M. S., Krohn, L., Estiar, M. A., Saini, P., Senkevich, K., Sosero, Y. L., Sreelatha, A. K., Ruskey, J. A., Asayesh, F., Spiegelman, D., Toft, M., Viken, M. K., Sharma, M., Blauwendraat, C., Pihlstrom, L., Mignot, E., Gan-Or, Z. SPRINGERNATURE. 2022: 293

  View details for Web of Science ID 000779367701231

• Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis. Neurology(R) neuroimmunology & neuroinflammation Peris Sempere, V., Muniz-Castrillo, S., Ambati, A., Binks, S., Pinto, A., Rogemond, V., Pittock, S. J., Dubey, D., Geschwind, M. D., Gelfand, J. M., Dilwali, S., Lee, S., Knight, J., Elliott, K. S., Irani, S., Honnorat, J., Mignot, E. 1800; 9 (2)

  Abstract

  BACKGROUND AND OBJECTIVES: To study human leukocyte antigen (HLA) allele associations in anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.METHODS: A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using chi2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.RESULTS: DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e-50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 * 10-6 and OR = 8.93, p = 2.50 * 10-3, respectively). DRB1*04:02 was also independently associated with younger age at onset (beta = -6.68, p = 9.78 * 10-3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms.DISCUSSION: In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

  View details for DOI 10.1212/NXI.0000000000001140

  View details for PubMedID 35115410

• Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. The Lancet. Neurology Mignot, E., Mayleben, D., Fietze, I., Leger, D., Zammit, G., Bassetti, C. L., Pain, S., Kinter, D. S., Roth, T., investigators 1800; 21 (2): 125-139

  Abstract

  BACKGROUND: Daytime functioning is impaired in people with insomnia disorder. Currently available dual orexin receptor antagonists have shown efficacy in insomnia disorder, but do not address all aspects of this disease. We aimed to assess safety and efficacy of daridorexant, a novel orexin receptor antagonist, on night-time and daytime symptoms of insomnia.METHODS: We did two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials at 156 sites in 17 countries. Adults (aged ≥18 years) with insomnia disorder were randomly assigned using interactive response technology (1:1:1) to receive daridorexant 50 mg, 25 mg, or placebo (study 1) or daridorexant 25 mg, 10 mg, or placebo (study 2) every evening for 3 months. Participants, investigators, and site personnel were masked to treatment allocation. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. The secondary endpoints were change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3. Study-wise type I error rate (5%) was controlled for all pairwise comparisons. Efficacy was analysed in all randomly assigned participants, and safety in all participants who received at least one dose of treatment. The studies are registered at ClinicalTrials.gov, NCT03545191 (study 1) and NCT03575104 (study 2).FINDINGS: Between June 4, 2018 and Feb 25, 2020, 930 participants were randomly assigned to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310) in study 1. Between May 29, 2018, and May 14, 2020, 924 participants were randomly assigned to receive daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) in study 2. In study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group compared with participants in the placebo group at month 1 (least squares mean [LSM] difference -22·8 min [95% CI -28·0 to -17·6], p<0·0001 for WASO; -11·4 min [-16·0 to -6·7], p<0·0001 for LPS) and month 3 (-18·3 min [-23·9 to -12·7], p<0·0001 for WASO; -11·7 min [-16·3 to -7·0], p<0·0001 for LPS). WASO and LPS were significantly reduced among participants in the daridorexant 25 mg group compared with the placebo group at month 1 (LSM difference -12·2 min [-17·4 to -7·0], p<0·0001 for WASO; -8·3 min [-13·0 to -3·6], p=0·0005 for LPS) and month 3 (-11·9 min [-17·5 to -6·2], p<0·0001 for WASO; -7·6 min [-12·3 to -2·9], p=0·0015 for LPS). Compared with placebo, participants in the daridorexant 50 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 22·1 min [14·4 to 29·7], p<0·0001) and month 3 (19·8 min [10·6 to 28·9], p<0·0001), and IDSIQ sleepiness domain scores at month 1 (-1·8 [-2·5 to -1·0], p<0·0001) and month 3 (-1·9 [-2·9 to -0·9], p=0·0002). Compared with the placebo group, participants in the daridorexant 25 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 12·6 min [5·0 to 20·3], p=0·0013) and month 3 (9·9 min [0·8 to 19·1], p=0·033), but not IDSIQ sleepiness domain scores (-0·8 [-1·5 to 0·01], p=0·055 at month 1; -1·0 [-2·0 to 0·01], p=0·053 at month 3). In study 2, WASO was significantly reduced among participants in the daridorexant 25 mg group compared with participants in the placebo group at month 1 (LSM difference -11·6 min [-17·6 to -5·6], p=0·0001) and month 3 (-10·3 min [-17·0 to -3·5], p=0·0028), whereas no significant differences in LPS were observed at month 1 (-6·5 min [-12·3 to -0·6], p=0·030) or month 3 (-9·0 [-15·3 to -2·7], p=0·0053). Compared with the placebo group, participants in the daridorexant 25 mg group had significant improvement in self-reported total sleep time at month 1 (LSM difference 16·1 min [8·2 to 24·0], p<0·0001) and month 3 (19·1 [10·1 to 28·0], p<0·0001), but not in IDSIQ sleepiness domain scores (-0·8 [-1·6 to 0·1], p=0·073 at month 1; -1·3 [-2·2 to -0·3], p=0·012 at month 3). Compared with the placebo group, no significant differences were observed among participants in the daridorexant 10 mg group for WASO (LSM difference -2·7 min [-8·7 to 3·2], p=0·37 at month 1; -2·0 [-8·7 to 4·8], p=0·57 at month 3), LPS (-2·6 min [-8·4 to 3·2], p=0·38 at month 1; -3·2 min [-9·5 to 3·1], p=0·32 at month 3), self-reported total sleep time (13·4 min [5·5 to 21·2], p=0·0009 at month 1; 13·6 min [4·7 to 22·5], p=0·0028 at month 3), nor IDSIQ sleepiness domain scores (-0·4 [-1·3 to 0·4], p=0·30 at month 1; -0·7 [-1·7 to 0·2], p=0·14 at month 3). Overall incidence of adverse events was comparable between treatment groups (116 [38%] of 308 participants in the daridorexant 50 mg group, 117 [38%] of 310 in the daridorexant 25 mg group, and 105 [34%] of 309 in the placebo group in study 1; 121 [39%] of 308 participants in the daridorexant 25 mg group, 117 [38%] of 306 in the daridorexant 10 mg group, and 100 [33%] of 306 in the placebo group). Nasopharyngitis and headache were the most common adverse events in all groups. One death (cardiac arrest) occurred in the daridorexant 25 mg group in study 1, which was not deemed to be treatment-related.INTERPRETATION: Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favourable safety profile.FUNDING: Idorsia Pharmaceuticals.

  View details for DOI 10.1016/S1474-4422(21)00436-1

  View details for PubMedID 35065036

• Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials LANCET NEUROLOGY Mignot, E., Mayleben, D., Fietze, I., Leger, D., Zammit, G., Bassetti, C. A., Pain, S., Kinter, D., Roth, T. 2022; 21 (2): 125-139

  View details for Web of Science ID 000769111800014

• Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study. The Lancet. Neurology Dauvilliers, Y., Arnulf, I., Foldvary-Schaefer, N., Morse, A. M., Sonka, K., Thorpy, M. J., Mignot, E., Chandler, P., Parvataneni, R., Black, J., Sterkel, A., Chen, D., Skobieranda, F., Bogan, R. K. 1800; 21 (1): 53-65

  Abstract

  BACKGROUND: Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia.METHODS: This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18-75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10-14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants' baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5-9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete.FINDINGS: Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study.INTERPRETATION: Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults.FUNDING: Jazz Pharmaceuticals.

  View details for DOI 10.1016/S1474-4422(21)00368-9

  View details for PubMedID 34942138

• Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study LANCET NEUROLOGY Dauvilliers, Y., Arnulf, I., Foldvary-Schaefer, N., Morse, A., Sonka, K., Thorpy, M. J., Mignot, E., Chandler, P., Parvataneni, R., Black, J., Sterkel, A., Chen, D., Skobieranda, F., Bogan, R. K. 2022; 21 (1): 53-65

  View details for Web of Science ID 000734663200022

• Narcolepsy with intermediate cerebrospinal level of hypocretin-1. Sleep Postiglione, E., Barateau, L., Pizza, F., Lopez, R., Antelmi, E., Rassu, A., Vandi, S., Chenini, S., Mignot, E., Dauvilliers, Y., Plazzi, G. 1800

  Abstract

  STUDY OBJECTIVES: To describe the phenotype of narcolepsy with intermediate cerebrospinal hypocretin-1 levels (CSF hcrt-1).METHODS: From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/ml). Clinical, neurophysiological and biological data were contrasted for the presence of cataplexy, HLA-DQB1*06:02, and median CSF hcrt-1 levels (149.34 pg/mL).RESULTS: Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1*06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset REM periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA DQB1*06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations.CONCLUSION: Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA DQB1*06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

  View details for DOI 10.1093/sleep/zsab285

  View details for PubMedID 34902030

• Fine mapping of the HLA locus in Parkinson's disease in Europeans. NPJ Parkinson's disease Yu, E., Ambati, A., Andersen, M. S., Krohn, L., Estiar, M. A., Saini, P., Senkevich, K., Sosero, Y. L., Sreelatha, A. A., Ruskey, J. A., Asayesh, F., Spiegelman, D., Toft, M., Viken, M. K., Sharma, M., Blauwendraat, C., Pihlstrom, L., Mignot, E., Gan-Or, Z. 2021; 7 (1): 84

  Abstract

  We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson's disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes-11V, 13H, and 33H (OR=0.87, 95% CI: 0.83-0.90, p<8.23*10-9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

  View details for DOI 10.1038/s41531-021-00231-5

  View details for PubMedID 34548497

• Disrupted nighttime sleep and sleep instability in narcolepsy. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Maski, K., Mignot, E., Plazzi, G., Dauvilliers, Y. 2021

  Abstract

  STUDY OBJECTIVES: This review aimed to summarize current knowledge about disrupted nighttime sleep (DNS) and sleep instability in narcolepsy, including self-reported and objective assessments, potential causes of sleep instability, health consequences and functional burden, and management.METHODS: One hundred and two peer-reviewed publications from a PubMed search were included.RESULTS: DNS is a key symptom of narcolepsy but has received less attention than excessive daytime sleepiness (EDS) and cataplexy. There has been a lack of clarity regarding the definition of DNS, as many sleep-related symptoms and conditions disrupt sleep quality in narcolepsy (eg, hallucinations, sleep paralysis, rapid eye movement sleep behavior disorder, nightmares, restless legs syndrome/periodic leg movements, nocturnal eating, sleep apnea, depression, anxiety). In addition, the intrinsic sleep instability of narcolepsy results in frequent spontaneous wakings and sleep stage transitions, contributing to DNS. Sleep instability likely emerges in the setting of orexin insufficiency/deficiency, but its exact pathophysiology remains unknown. DNS impairs quality of life among people with narcolepsy, and more research is needed to determine its contributions to cardiovascular risk. Multimodal treatment is appropriate for DNS management, including behavioral therapies, counseling on sleep hygiene, and/or medication. There is strong evidence showing improvement of self-reported sleep quality and objective sleep stability measures with sodium oxybate, but rigorous clinical trials with other pharmacotherapies are needed. Treatment may be complicated by comorbidities, concomitant medications, and mood disorders.CONCLUSIONS: DNS is a common symptom of narcolepsy deserving consideration in clinical care and future research.

  View details for DOI 10.5664/jcsm.9638

  View details for PubMedID 34463249

• Arousal Characteristics in Patients with Parkinson's Disease and Isolated Rapid Eye Movement Sleep Behavior Disorder. Sleep Brink-Kjar, A., Cesari, M., Sixel-Doring, F., Mollenhauer, B., Trenkwalder, C., Mignot, E., Sorensen, H. B., Jennum, P. 2021

  Abstract

  STUDY OBJECTIVES: Patients diagnosed with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and Parkinson's disease (PD) have altered sleep stability reflecting neurodegeneration in brainstem structures. We hypothesize that neurodegeneration alters the expression of cortical arousals in sleep.METHODS: We analyzed polysomnography data recorded from 88 healthy controls (HC), 22 iRBD patients, 82 de novo PD patients without RBD and 32 with RBD (PD+RBD). These patients were also investigated at a 2-year follow-up. Arousals were analyzed using a previously validated automatic system, which used a central EEG lead, electrooculography, and chin electromyography. Multiple linear regression models were fitted to compare group differences at baseline and change to follow-up for arousal index (ArI), shifts in electroencephalographic signals associated with arousals, and arousal chin muscle tone. The regression models were adjusted for known covariates affecting the nature of arousal.RESULTS: In comparison to HC, patients with iRBD and PD+RBD showed increased ArI during REM sleep and their arousals showed a significantly lower shift in alpha-band power at arousals and a higher muscle tone during arousals. In comparison to HC, the PD patients were characterized by a decreased ArI in NREM sleep at baseline. ArI during NREM sleep decreased further at the 2-year follow-up, although not significantly.CONCLUSIONS: Patients with PD and iRBD present with abnormal arousal characteristics as scored by an automated method. These abnormalities are likely to be caused by neurodegeneration of the reticular activation system due to alpha-synuclein aggregation.

  View details for DOI 10.1093/sleep/zsab167

  View details for PubMedID 34214165

• Genetic risk for subjective reports of insomnia associate only weakly with polygraphic measures of insomnia in 2,770 adults. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Foldager, J., Peppard, P. E., Hagen, E. W., Stone, K. L., Evans, D. S., Tranah, G. J., Sorensen, H., Jennum, P., Mignot, E., Schneider, L. 2021

  Abstract

  STUDY OBJECTIVES: Subjective insomnia complaints and objective sleep changes are mostly studied outside of clinical trial studies. In this study, we tested whether 240 genetic variants associated with subjectively reported insomnia were also associated with objective insomnia parameters extracted from polysomnographic recordings (PSG) in three studies.METHODS: The study sample (total N = 2,770) was composed of the Wisconsin Sleep Cohort (N = 1,091) and the Osteoporotic Fractures in Men (N = 1,026) study, two population-based studies, and the Stanford Sleep Cohort, a sleep center patient-based sample (N = 653). Seven objective PSG features related to insomnia defined outcome variables, with each variant allele serving as predictor. Meta-regression was performed, accounting for common confounders as well as variance differences between studies. Additionally, a normalized genetic risk score (nGRS) was generated for each subject to serve as a predictor variable in separate linear mixed models assessing objective insomnia features.RESULTS: After correction for multiple testing, single nucleotide polymorphisms (SNPs) associated with subjective insomnia were not significantly associated with 6 of 7 objective sleep measures. Only periodic limb movement index (PLMI) was significantly associated with rs113851554 (MEIS1), as found in previous studies. The nGRS was only weakly associated with arousal index and duration of wake after sleep onset.CONCLUSIONS: Our findings suggest that subjective insomnia does not have a strong genetic signature mapping onto objective (PSG) sleep variables.

  View details for DOI 10.5664/jcsm.9468

  View details for PubMedID 34170227

• Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis. Neurology(R) neuroimmunology & neuroinflammation Muniz-Castrillo, S., Haesebaert, J., Thomas, L., Vogrig, A., Pinto, A., Picard, G., Blanc, C., Do, L., Joubert, B., Berzero, G., Psimaras, D., Alentorn, A., Rogemond, V., Dubois, V., Ambati, A., Tamouza, R., Mignot, E., Honnorat, J. 2021; 8 (3)

  Abstract

  OBJECTIVE: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear.METHODS: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients.RESULTS: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI (p < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms (p < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found (p > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered.CONCLUSIONS: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.

  View details for DOI 10.1212/NXI.0000000000000974

  View details for PubMedID 33848259

• AN UNUSUAL CASE OF POST-TRAUMATIC BRAIN INJURY KLEINE-LEVIN SYNDROME WITH ANTI-GAD-65 AUTOANTIBODIES Tse, C., Mignot, E., Lim, M. OXFORD UNIV PRESS INC. 2021: A320

  View details for Web of Science ID 000698984300818

• ABSENCE OF WITHDRAWAL SYMPTOMS AND REBOUND INSOMNIA UPON DISCONTINUATION OF DARIDOREXANT IN PATIENTS WITH INSOMNIA Leger, D., Fietze, I., Pain, S., Kinter, D., Flamion, B., Mignot, E. OXFORD UNIV PRESS INC. 2021: A139

  View details for Web of Science ID 000698984300347

• Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain : a journal of neurology Muniz-Castrillo, S., Hedou, J. J., Ambati, A., Jones, D., Vogrig, A., Pinto, A., Benaiteau, M., de Broucker, T., Fechtenbaum, L., Labauge, P., Murnane, M., Nocon, C., Taifas, I., Vialatte de Pemille, C., Psimaras, D., Joubert, B., Dubois, V., Wucher, V., Desestret, V., Mignot, E., Honnorat, J. 2021

  Abstract

  Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leukocyte antigen (HLA), and CSF proteomic profiles. Patients with anti-AK5 LE were mostly men (20/26, 76.9%) of median age 66 years old (range 48-94). Predominant symptom was severe episodic amnesia in all patients, frequently associated with depression (17/25, 68.0%). Weight loss, asthenia, and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%), and increased Tau (11/14, 78.6%). Temporal lobe hyper-intensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably toward a severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with highest titres in nine CSF-serum paired samples. Temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T-cells, intense granzyme B expression, and abundant macrophages/microglia. HLA analysis in 11 patients showed a striking association with HLA-B*08:01 (7/11, 63.6%; OR=13.4, 95% CI [3.8-47.4]), C*07:01 (8/11, 72.7%; OR=11.0, 95% CI [2.9-42.5]), DRB1*03:01 (8/11, 72.7%; OR=14.4, 95% CI [3.7-55.7]), DQB1*02:01 (8/11, 72.7%; OR=13.5, 95% CI [3.5-52.0]), and DQA1*05:01 (8/11, 72.7%; OR=14.4, 95% CI [3.7-55.7]) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR=16.5, 95% CI [4.8-57.1]). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 controls and 10 cases with other more common non-paraneoplastic LE (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed, respectively, 31 and seven significantly up-regulated proteins in anti-AK5 LE, mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 LE result from a distinct T-cell mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

  View details for DOI 10.1093/brain/awab153

  View details for PubMedID 33843981

• T cell reactivity to regulatory factor X4 in type 1 narcolepsy. Scientific reports Luo, G., Yogeshwar, S., Lin, L., Mignot, E. J. 2021; 11 (1): 7841

  Abstract

  Type 1 narcolepsy is strongly (98%) associated with human leukocyte antigen (HLA) class II DQA1*01:02/DQB1*06:02 (DQ0602) and highly associated with T cell receptor (TCR) alpha locus polymorphism as well as other immune regulatory loci. Increased incidence of narcolepsy was detected following the 2009 H1N1 pandemic and linked to Pandemrix vaccination, strongly supporting that narcolepsy is an autoimmune disorder. Although recent results suggest CD4+T cell reactivity to neuropeptide hypocretin/orexin and cross-reactive flu peptide is involved, identification of other autoantigens has remained elusive. Here we study whether autoimmunity directed against Regulatory Factor X4 (RFX4), a protein co-localized with hypocretin, is involved in some cases of narcolepsy. Studying human serum, we found that autoantibodies against RFX4 were rare. Using RFX4 peptides bound to DQ0602 tetramers, antigen RFX4-86, -95, and -60 specific human CD4+T cells were detected in 4/10 patients and 2 unaffected siblings, but not in others. Following culture with each cognate peptide, enriched autoreactive TCRalphabeta clones were isolated by single-cell sorting and TCR sequenced. Homologous clones bearing TRBV4-2 and recognizing RFX4-86 in patients and one twin control of patient were identified. These results suggest the involvement of RFX4 CD4+T cell autoreactivity in some cases of narcolepsy, but also in healthy donors.

  View details for DOI 10.1038/s41598-021-87481-8

  View details for PubMedID 33837283

• Greatest changes in objective sleep architecture during COVID-19 lockdown in night-owls with increased REM sleep. Sleep Pepin, J., Bailly, S., Mordret, E., Gaucher, J., Tamisier, R., Ben Messaoud, R., Arnal, P. J., Mignot, E. 2021

  Abstract

  STUDY OBJECTIVES: The Covid-19 pandemic has had dramatic effects on society and people's daily habits. In this observational study we recorded objective data on sleep macro- and microarchitecture repeatedly over several nights before and during the Covid-19 government-imposed lockdown. The main objective was to evaluate changes in patterns of sleep duration and architecture during home confinement using the pre-confinement period as a control.METHODS: Participants were regular users of a sleep-monitoring headband that records, stores, and automatically analyses physiological data in real time, equivalent to polysomnography. We measured: sleep onset duration (SOD), total sleep time (TST), duration of sleep stages (N2, N3 and REM), and sleep continuity. Via the user's smartphone application participants filled-in questionnaires on how lockdown changed working hours, eating behaviour, and daily-life at home. They also filled-in the Insomnia Severity Index, reduced Morningness-Eveningness Questionnaire and Hospital Anxiety and Depression Scale questionnaires allowing us to create selected sub-groups.RESULTS: The 599 participants were mainly men (71%) of median age 47 [IQR: 36;59]. Compared to before lockdown, during lockdown individuals slept more overall (mean +3·83min; SD: ±1.3), had less deep sleep (N3), more light sleep (N2) and longer REM sleep (mean +3·74min; SD: ±0.8). They exhibited less week-end specific changes, suggesting less sleep restriction during the week. Changes were most pronounced in individuals reporting eveningness preferences, suggesting relative sleep deprivation in this population and exacerbated sensitivity to societal changes.CONCLUSIONS: This unique dataset should help us understand the effects of lockdown on sleep architecture and on our health.

  View details for DOI 10.1093/sleep/zsab075

  View details for PubMedID 33769511

• Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci. Proceedings of the National Academy of Sciences of the United States of America Ambati, A., Hillary, R., Leu-Semenescu, S., Ollila, H. M., Lin, L., During, E. H., Farber, N., Rico, T. J., Faraco, J., Leary, E., Goldstein-Piekarski, A. N., Huang, Y., Han, F., Sivan, Y., Lecendreux, M., Dodet, P., Honda, M., Gadoth, N., Nevsimalova, S., Pizza, F., Kanbayashi, T., Peraita-Adrados, R., Leschziner, G. D., Hasan, R., Canellas, F., Kume, K., Daniilidou, M., Bourgin, P., Rye, D., Vicario, J. L., Hogl, B., Hong, S. C., Plazzi, G., Mayer, G., Landtblom, A. M., Dauvilliers, Y., Arnulf, I., Mignot, E. J. 2021; 118 (12)

  Abstract

  Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 * 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R 2 = 0.15; P < 2.0 * 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

  View details for DOI 10.1073/pnas.2005753118

  View details for PubMedID 33737391

• Living to Dream-Reply. JAMA neurology Leary, E. B., Stone, K. L., Mignot, E. 2021

  View details for DOI 10.1001/jamaneurol.2021.0056

  View details for PubMedID 33646274

• Sleep Problems in Narcolepsy and the Role of Hypocretin/Orexin Deficiency. Frontiers of neurology and neuroscience Mignot, E., Zeitzer, J., Pizza, F., Plazzi, G. 2021; 45: 103-116

  Abstract

  Since its description in the 19th century, narcolepsy type 1 (NT1) has been considered as a model sleep disorder, and after the discovery of rapid eye movement (REM) sleep onset in the disorder, a gateway to understanding REM sleep. The discovery that NT1 is caused by hypocretin/orexin deficiency, together with neurochemical studies of this system, has helped to establish how this neuropeptide regulates the organization of sleep and wake in humans. Current analyses suggest that the main functions of the hypocretin/orexin system are (1) maintenance of wakefulness in the face of moderate sleep deprivation; (2) passive wake promotion, especially in the evening, driven by the circadian clock; (3) inhibition of REM sleep, with possible differential modulating effects on various subcomponents of the sleep-stage, explaining REM sleep dissociation events in NT1. Narcolepsy is also associated with an inability to consolidate sleep, a more complex phenotype that may result from secondary changes or be central to the role of hypocretin in coordinating the activity of other sleep- and wake-promoting systems. Novel technologies, such as the use of deep learning analysis of electroencephalographic signals, is revealing a complex pattern of sleep abnormalities in human narcolepsy that can be used diagnostically. The availability of novel devices measuring sleep 24 h per day also holds promise to provide new insights into how brain electrical activity and muscle tone are regulated by hypocretin.

  View details for DOI 10.1159/000514959

  View details for PubMedID 34052809

• Upper Airway Classification in Sleep Endoscopy Examinations using Convolutional Recurrent Neural Networks. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Hanif, U., Kezirian, E., Kiar, E. K., Mignot, E., Sorensen, H. B., Jennum, P. 2021; 2021: 3957-3960

  Abstract

  Assessing the upper airway (UA) of obstructive sleep apnea patients using drug-induced sleep endoscopy (DISE) before potential surgery is standard practice in clinics to determine the location of UA collapse. According to the VOTE classification system, UA collapse can occur at the velum (V), oropharynx (O), tongue (T), and/or epiglottis (E). Analyzing DISE videos is not trivial due to anatomical variation, simultaneous UA collapse in several locations, and video distortion caused by mucus or saliva. The first step towards automated analysis of DISE videos is to determine which UA region the endoscope is in at any time throughout the video: V (velum) or OTE (oropharynx, tongue, or epiglottis). An additional class denoted X is introduced for times when the video is distorted to an extent where it is impossible to determine the region. This paper is a proof of concept for classifying UA regions using 24 annotated DISE videos. We propose a convolutional recurrent neural network using a ResNet18 architecture combined with a two-layer bidirectional long short-term memory network. The classifications were performed on a sequence of 5 seconds of video at a time. The network achieved an overall accuracy of 82% and F1-score of 79% for the three-class problem, showing potential for recognition of regions across patients despite anatomical variation. Results indicate that large-scale training on videos can be used to further predict the location(s), type(s), and degree(s) of UA collapse, showing potential for derivation of automatic diagnoses from DISE videos eventually.

  View details for DOI 10.1109/EMBC46164.2021.9630098

  View details for PubMedID 34892097

• Polysomnographic Plethysmography Excursions are Reduced in Obese Elderly Men. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kjar, M. R., Brink-Kjar, A., Hanif, U., Mignot, E., Jennum, P., Sorensen, H. B. 2021; 2021: 2396-2399

  Abstract

  Sleep apnea is a widespread disorder and is defined by the complete or partial cessation of breathing. Obstructive sleep apnea (OSA) is caused by an obstruction in the upper airway while central sleep apnea (CSA) is characterized by a diminished or absent respiratory effort. It is crucial to differentiate between these respiratory subtypes as they require radically different treatments. Currently, diagnostic polysomnography (PSG) is used to determine respiratory thoracic and abdominal movement patterns using plethysmography belt signals, to distinguish between OSA and CSA. There is significant manual technician interrater variability between these classifications, especially in the evaluation of CSA. We hypothesize that an increased body mass index (BMI) will cause decreased belt signal excursions that increase false scorings of CSA. The hypothesis was investigated by calculating the envelope as a continuous signal of belt signals in 2833 subjects from the MrOS Sleep Study and extracting a mean value of each of the envelopes for each subject. Using linear regression, we found that an increased BMI was associated with lower excursions during REM sleep (-0.013 [mV] thoracic and -0.018 [mV] abdominal, per BMI) and non-REM (-0.014 [mV] thoracic and -0.012 [mV] abdominal, per BMI). We conclude that increased BMI leads to lower excursions in the belt signals during event-free sleep, and that OSA and CSA events are harder to distinguish in subjects with high BMI. This has a major implication for the correct identification of CSA/OSA and its treatment.

  View details for DOI 10.1109/EMBC46164.2021.9630145

  View details for PubMedID 34891764

• Automatic Segmentation to Cluster Patterns of Breathing in Sleep Apnea. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Joergensen, V. H., Hanif, U., Jennum, P., Mignot, E., Helge, A. W., Sorensen, H. B. 2021; 2021: 164-168

  Abstract

  Annotation of polysomnography (PSG) recordings for diagnosis of obstructive sleep apnea (OSA) is a standard procedure but an expensive and time-consuming process for clinicians. To aid clinicians in this process we present a data driven unsupervised hierarchical clustering approach for detection and visual presentation of breathing patterns in PSG recordings. The aim was to develop a model independent of manual annotations to detect and visualize respiratory events related to OSA. 10 recordings from the Sleep Heart Health Study database were used, and the proposed algorithm was evaluated based on the manually annotated events for each recording. The algorithm reached an F1-score of 0.58 across the 10 recordings when detecting the presence of an event vs. no event and a 100% correct diagnosis prediction of OSA when predicting if apnea-hypopnea index (AHI) ≥ 15, which is a clinically meaningful cut-off. The F1-score may be due to imprecise placement of events, difficulty distinguishing between hypopneas and stable breathing, and variations in scoring. In conclusion the performance can be improved despite the strong agreement in diagnostics. The method is a proof of concept that a clustering method can detect and visualize breathing patterns related to OSA while maintaining a correct diagnosis.

  View details for DOI 10.1109/EMBC46164.2021.9629624

  View details for PubMedID 34891263

• Estimation of Apnea-Hypopnea Index using Deep Learning on 3D Craniofacial Scans. IEEE journal of biomedical and health informatics Hanif, U. R., Leary, E. B., Schneider, L. D., Paulsen, R. R., Morse, A. M., Blackman, A., Schweitzer, P. K., Kushida, C. A., Liu, S. Y., Jennum, P., Sorensen, H. B., Mignot, E. 2021; PP

  Abstract

  Obstructive sleep apnea (OSA) is characterized by decreased breathing events that occur through the night, with severity reported as the apnea-hypopnea index (AHI), which is associated with certain craniofacial features. In this study, we used data from 1366 patients collected as part of Stanford Technology Analytics and Genomics in Sleep (STAGES) across 11 US and Canadian sleep clinics and analyzed 3D craniofacial scans with the goal of predicting AHI, as measured using gold standard nocturnal polysomnography (PSG). First, the algorithm detects pre-specified landmarks on mesh objects and aligns scans in 3D space. Subsequently, 2D images and depth maps are generated by rendering and rotating scans by 45-degree increments. Resulting images were stacked as channels and used as input to multi-view convolutional neural networks, which were trained and validated in a supervised manner to predict AHI values derived from PSGs. The proposed model achieved a mean absolute error of 11.38 events/hour, a Pearson correlation coefficient of 0.4, and accuracy for predicting OSA of 67% using 10-fold cross-validation. The model improved further by adding patient demographics and variables from questionnaires. We also show that the model performed at the level of three sleep medicine specialists, who used clinical experience to predict AHI based on 3D scan displays. Finally, we created topographic displays of the most important facial features used by the model to predict AHI, showing importance of the neck and chin area. The proposed algorithm has potential to serve as an inexpensive and efficient screening tool for individuals with suspected OSA.

  View details for DOI 10.1109/JBHI.2021.3078127

  View details for PubMedID 33961569

• Acoustic stimulation time-locked to the beginning of sleep apnea events reduces oxygen desaturations: a pilot-study. Sleep medicine Waeber, A., Arnal, P. J., Lecciso, G., Albir, D., Mignot, E., Heinzer, R. 2020; 78: 38–42

  Abstract

  STUDY OBJECTIVES: We aimed to determine whether bone-conducted acoustic stimulation could prematurely terminate sleep apnea events, thereby decreasing amplitude and duration of subsequent oxygen desaturation. As oxygen desaturation has been linked to cardiovascular consequences, we postulate this could be a viable therapy in some cases.METHODS: Eight patients with severe Obstructive Sleep Apnea (2 women, 45 [20-68] y.o. Apnea-Hypopnea Index: 77.7±22.3/h) underwent polysomnography at the Lausanne University Sleep Center. Short acoustic stimulations were administered by bone conduction every second event of sleep apnea. Sounds were remotely administered using a Dreem headband worn by patients while undergoing nocturnal polysomnography. Amplitude (%) and duration(s) of oxygen desaturations following terminated apneas were compared to that of non-stimulated previous and subsequent events.RESULTS: 549 stimulations (68.6±38 sounds per patient) in N1 (16.2%), N2 (69.9%), N3 (4.2%), and REM(9.6%) were conducted. Compared to the previous and subsequent non-stimulated apnea, stimulations reduced event duration by 21.4% (-3.4±7.2s, p<0.0001) while oxygen desaturation amplitude and duration were reduced by 30.4% (mean absolute difference±SD:-1.9±2.8%, p<0.0001), and 39.6% (-5.7±9.2s, p<0.0001) respectively. For these variables, each patient showed a significant improvement following acoustic stimulation. Sound-associated discomfort was rated 1.14±1.53 on an 8 points scale (8=worst) and only 6.8% of emitted sounds were perceived by the patients, suggesting a well-tolerated intervention.CONCLUSIONS: Bone-conducted sound stimuli decreased apnea events duration as well as duration and amplitude of associated oxygen desaturations. Stimulations were well tolerated and rarely perceived by patients. This therapeutic approach deserves further investigation, with monitoring of effects on sleep quality, daytime function/sleepiness and cardiovascular parameters.

  View details for DOI 10.1016/j.sleep.2020.12.006

  View details for PubMedID 33383395

• Cataplexy-Free Days during Sodium Oxybate Treatment in Children and Adolescents with Narcolepsy with Cataplexy Mignot, E., Rosen, C. L., Menno, D., Wang, Y., Profant, J., Dauvilliers, Y. WILEY. 2020: S249

  View details for Web of Science ID 000572509100469

• Autoimmunity to Hypocretin/Orexin and Molecular Mimicry to Flu in Type 1 Narcolepsy Luo, G., Ambati, A., Lin, L., Partinen, M., Ji, X., Maecker, H., Mignot, E. WILEY. 2020: S53

  View details for Web of Science ID 000572509100022

• Sodium Oxybate Treatment Effects on Sleep Architecture in Pediatric Patients with Narcolepsy with Cataplexy Mignot, E., Bogan, R. K., Parvataneni, R., Wang, Y., Dauvilliers, Y. WILEY. 2020: S249–S250

  View details for Web of Science ID 000572509100470

• Kleine-Levin Syndrome is Associated with Trank1 Gene Variants in Conjunction with Birth Difficulties Ambati, A., Hillary, R., Leu-Semenescu, S., Ollila, H. M., Lin, L., Arnulf, I., Mignot, E. WILEY. 2020: S256

  View details for Web of Science ID 000572509100484

• Genetics of Anti-NMDAR Encephalitis Implicates Natural Killer Cells Ambati, A., Lin, L., Muniz-Castrillo, S., Pinto, A. M., Ollila, H., Rogemond, V., Finke, C., Leypoldt, F., Titulaer, M., Honnorat, J., Mignot, E., NMDAR-Ab Working Grp WILEY. 2020: S52

  View details for Web of Science ID 000572509100019

• Automatic sleep stage classification with deep residual networks in a mixed-cohort setting. Sleep Olesen, A. N., Jennum, P. J., Mignot, E., Sorensen, H. B. 2020

  Abstract

  STUDY OBJECTIVES: Sleep stage scoring is performed manually by sleep experts and is prone to subjective interpretation of scoring rules with low intra- and interscorer reliability. Many automatic systems rely on few small-scale databases for developing models, and generalizability to new datasets is thus unknown. We investigated a novel deep neural network to assess the generalizability of several large-scale cohorts.METHODS: A deep neural network model was developed using 15684 polysomnography studies from five different cohorts. We applied four different scenarios: 1) impact of varying time-scales in the model; 2) performance of a single cohort on other cohorts of smaller, greater or equal size relative to the performance of other cohorts on a single cohort; 3) varying the fraction of mixed-cohort training data compared to using single-origin data; and 4) comparing models trained on combinations of data from 2, 3, and 4 cohorts.RESULTS: Overall classification accuracy improved with increasing fractions of training data (0.25%: 0.782 ± 0.097, 95% CI [0.777 - 0.787]; 100%: 0.869 ± 0.064, 95% CI [0.864 - 0.872]), and with increasing number of data sources (2: 0.788 ± 0.102, 95% CI [0.787 - 0.790]; 3: 0.808 ± 0.092, 95% CI [0.807 - 0.810]; 4: 0.821 ± 0.085, 95% CI [0.819 - 0.823]). Different cohorts show varying levels of generalization to other cohorts.CONCLUSION: Automatic sleep stage scoring systems based on deep learning algorithms should consider as much data as possible from as many sources available to ensure proper generalization. Public datasets for benchmarking should be made available for future research.

  View details for DOI 10.1093/sleep/zsaa161

  View details for PubMedID 32844179

• Association of Rapid Eye Movement Sleep With Mortality in Middle-aged and Older Adults. JAMA neurology Leary, E. B., Watson, K. T., Ancoli-Israel, S., Redline, S., Yaffe, K., Ravelo, L. A., Peppard, P. E., Zou, J., Goodman, S. N., Mignot, E., Stone, K. L. 2020

  Abstract

  Importance: Rapid eye movement (REM) sleep has been linked with health outcomes, but little is known about the relationship between REM sleep and mortality.Objective: To investigate whether REM sleep is associated with greater risk of mortality in 2 independent cohorts and to explore whether another sleep stage could be driving the findings.Design, Setting, and Participants: This multicenter population-based cross-sectional study used data from the Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study and Wisconsin Sleep Cohort (WSC). MrOS participants were recruited from December 2003 to March 2005, and WSC began in 1988. MrOS and WSC participants who had REM sleep and mortality data were included. Analysis began May 2018 and ended December 2019.Main Outcomes and Measures: All-cause and cause-specific mortality confirmed with death certificates.Results: The MrOS cohort included 2675 individuals (2675 men [100%]; mean [SD] age, 76.3[5.5] years) and was followed up for a median (interquartile range) of 12.1 (7.8-13.2) years. The WSC cohort included 1386 individuals (753 men [54.3%]; mean [SD] age, 51.5[8.5] years) and was followed up for a median (interquartile range) of 20.8 (17.9-22.4) years. MrOS participants had a 13% higher mortality rate for every 5% reduction in REM sleep (percentage REM sleep SD=6.6%) after adjusting for multiple demographic, sleep, and health covariates (age-adjusted hazard ratio,1.12; fully adjusted hazard ratio,1.13; 95% CI, 1.08-1.19). Results were similar for cardiovascular and other causes of death. Possible threshold effects were seen on the Kaplan-Meier curves, particularly for cancer; individuals with less than 15% REM sleep had a higher mortality rate compared with individuals with 15% or more for each mortality outcome with odds ratios ranging from 1.20 to 1.35. Findings were replicated in the WSC cohort despite younger age, inclusion of women, and longer follow-up (hazard ratio,1.13; 95% CI, 1.08-1.19). A random forest model identified REM sleep as the most important sleep stage associated with survival.Conclusions and Relevance: Decreased percentage REM sleep was associated with greater risk of all-cause, cardiovascular, and other noncancer-related mortality in 2 independent cohorts.

  View details for DOI 10.1001/jamaneurol.2020.2108

  View details for PubMedID 32628261

• Narcolepsy risk and COVID-19. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Mignot, E., Black, S. 2020

  View details for DOI 10.5664/jcsm.8668

  View details for PubMedID 32621581

• Prediction of Patient Demographics using 3D Craniofacial Scans and Multi-view CNNs. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Hanif, U., Paulsen, R. R., Leary, E. B., Mignot, E., Jennum, P., Sorensen, H. B. 2020; 2020: 1950–53

  Abstract

  3D data is becoming increasingly popular and accessible for computer vision tasks. A popular format for 3D data is the mesh format, which can depict a 3D surface accurately and cost-effectively by connecting points in the (x, y, z) plane, known as vertices, into triangles that can be combined to approximate geometrical surfaces. However, mesh objects are not suitable for standard deep learning techniques due to their non-euclidean structure. We present an algorithm which predicts the sex, age, and body mass index of a subject based on a 3D scan of their face and neck. This algorithm relies on an automatic pre-processing technique, which renders and captures the 3D scan from eight different angles around the x-axis in the form of 2D images and depth maps. Subsequently, the generated data is used to train three convolutional neural networks, each with a ResNet18 architecture, to learn a mapping between the set of 16 images per subject (eight 2D images and eight depth maps from different angles) and their demographics. For age and body mass index, we achieved a mean absolute error of 7.77 years and 4.04 kg/m2 on the respective test sets, while Pearson correlation coefficients of 0.76 and 0.80 were obtained, respectively. The prediction of sex yielded an accuracy of 93%. The developed framework serves as a proof of concept for prediction of more clinically relevant variables based on 3D craniofacial scans stored in mesh objects.

  View details for DOI 10.1109/EMBC44109.2020.9176333

  View details for PubMedID 33018384

• Proteomic biomarkers of sleep apnea. Sleep Ambati, A., Ju, Y., Lin, L., Olesen, A. N., Koch, H., Hedou, J. J., Leary, E. B., Sempere, V. P., Mignot, E., Taheri, S. 2020

  Abstract

  Obstructive sleep apnea (OSA) is characterized by recurrent partial to complete upper airway obstructions during sleep, leading to repetitive arousals and oxygen desaturations. Although many OSA biomarkers have been reported individually, only a small subset have been validated through both cross-sectional and intervention studies. Here, we used a highly multiplexed aptamer array (SomaScan) for proteomic analysis of serum samples from 713 individuals in the Stanford Sleep Cohort, a patient-based registry. Outcome measures derived from overnight polysomnography included Obstructive Apnea Hypopnea Index (OAHI), Central Apnea Index (CAI), 2% Oxygen Desaturation index, mean and minimum oxygen saturation indices during sleep. Additionally, a separate intervention-based cohort of 16 individuals was used to assess proteomic profiles pre- and post-intervention with positive airway pressure. After statistical adjustment for age, age of sample, gender and body mass index, OAHI was associated with 65 proteins, predominantly pathways of complement, coagulation, cytokine signaling, and hemostasis which were upregulated. CAI was associated with two proteins including Roundabout homolog 3 (ROBO3), a protein involved in bilateral synchronization of the pre-Botzinger complex and cystatin F. Analysis of pre- and post- intervention samples were less revealing as only 2 proteins that were differentially associated with active treatment: Insulin-like growth factor-binding protein3 (IGFBP-3) increased while LEAP1 (Hepicidin) decreased with intervention. An OAHI machine learning classifier (OAHI >=15 vs OAHI<15) trained on SomaScan protein measures alone performed robustly, achieving 76% accuracy in a validation dataset. Multiplex protein assays offer diagnostic potential and provide new insights into the biological basis of sleep disordered breathing.

  View details for DOI 10.1093/sleep/zsaa086

  View details for PubMedID 32369590

• Low C4 Copy Number of Total C4 Gene, C4B Gene and C4BL Gene in Children with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Kalinowski, A., Lee, J., Hedlin, H., Pattini, R., Ollila, H., Mignot, E., Levinson, D., Swedo, S., Murphy, T., Chan, A., Thienemann, M., Urban, A., Frankovich, J. WILEY. 2020: 254–55

  View details for Web of Science ID 000542687800145

• Cataplexy-Free Days With Sodium Oxybate Treatment in Children/Adolescents With Narcolepsy With Cataplexy Mignot, E., Rosen, C. L., Menno, D., Wang, Y., Profant, J., Dauvilliers, Y. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002088

• Sodium Oxybate Treatment Effects on Sleep Architecture in Pediatric Patients With Narcolepsy With Cataplexy Mignot, E., Bogan, R. K., Black, J., Parvataneni, R., Menno, D., Wang, Y., Dauvilliers, Y. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002057

• Autoimmunity to Hypocretin/Orexin and Molecular Mimicry to Flu in Type 1 Narcolepsy Luo, G., Ambati, A., Lin, L., Partinen, M., Ji, X., Maecker, H., Mignot, E. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058008221

• Treatment of narcolepsy with natalizumab. Sleep Scammell, T. E., Luo, G., Borker, P., Sullivan, L., Biddle, K., Mignot, E. 2020

  View details for DOI 10.1093/sleep/zsaa050

  View details for PubMedID 32249922

• Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies. Journal of neurology Muniz-Castrillo, S., Ambati, A., Dubois, V., Vogrig, A., Joubert, B., Rogemond, V., Picard, G., Lin, L., Fabien, N., Mignot, E., Honnorat, J. 2020

  Abstract

  The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01-DQB1*02:01-DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p=0.03, OR 3.96, 95% CI [1.54-10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p=0.05, OR 3.54, 95% CI [1.40-8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p=0.05, OR 0.15, 95% CI [0.02-0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p>0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

  View details for DOI 10.1007/s00415-020-09782-8

  View details for PubMedID 32152690

• Design of a deep learning model for automatic scoring of periodic and non-periodic leg movements during sleep validated against multiple human experts. Sleep medicine Carvelli, L., Olesen, A. N., Brink-Kjar, A., Leary, E. B., Peppard, P. E., Mignot, E., Sorensen, H. B., Jennum, P. 2020; 69: 109–19

  Abstract

  OBJECTIVE: Currently, manual scoring is the gold standard of leg movement scoring (LMs) and periodic LMs (PLMS) in overnight polysomnography (PSG) studies, which is subject to inter-scorer variability. The objective of this study is to design and validate an end-to-end deep learning system for the automatic scoring of LMs and PLMS in sleep.METHODS: The deep learning system was developed, validated and tested, with respect to manual annotations by expert technicians on 800 overnight PSGs using a leg electromyography channel. The study includes data from three cohorts, namely, the Wisconsin Sleep Cohort (WSC), Stanford Sleep Cohort (SSC) and MrOS Sleep Study. The performance of the system was further compared against individual expert technicians and existing PLM detectors.RESULTS: The system achieved an F1 score of 0.83, 0.71, and 0.77 for the WSC, SSC, and an ancillary study (Osteoporotic Fractures in Men Study, MrOS) cohorts, respectively. In a total of 60 PSGs from the WSC and the SSC scored by nine expert technicians, the system performed better than two and comparable to seven of the individual scorers with respect to a majority-voting consensus of the remaining scorers. In 60 PSGs from the WSC scored accurately for PLMS, the system outperformed four previous PLM detectors, which were all evaluated on the same data, with an F1 score of 0.85.CONCLUSIONS: The proposed system performs better or comparable to individual expert technicians while outperforming previous automatic detectors. Thereby, the study validates fully automatic methods for scoring LMs in sleep.

  View details for DOI 10.1016/j.sleep.2019.12.032

  View details for PubMedID 32062037

• DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism. Human molecular genetics Maresca, A. n., Del Dotto, V. n., Capristo, M. n., Scimonelli, E. n., Tagliavini, F. n., Morandi, L. n., Tropeano, C. V., Caporali, L. n., Mohamed, S. n., Roberti, M. n., Scandiffio, L. n., Zaffagnini, M. n., Rossi, J. n., Cappelletti, M. n., Musiani, F. n., Contin, M. n., Riva, R. n., Liguori, R. n., Pizza, F. n., La Morgia, C. n., Antelmi, E. n., Polosa, P. L., Mignot, E. n., Zanna, C. n., Plazzi, G. n., Carelli, V. n. 2020

  Abstract

  ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of the DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders and mitochondrial dysfunction was first observed in ADCA-DN. To explore mitochondrial involvement we studied the effects of DNMT1 mutations in fibroblasts from four ADCA-DN and two HSN-IE patients. We documented impaired activity of purified DNMT1 mutant proteins, which in fibroblasts results in increased DNMT1 amount. We demonstrated that DNMT1 is not localized within mitochondria but it is associated to the mitochondrial outer membrane. Concordantly, mitochondrial DNA failed to show meaningful CpG methylation. Strikingly, we found activated mitobiogenesis and OXPHOS with significant increase of H2O2, sharply contrasting with a reduced ATP content. Metabolomics profiling of mutant cells highlighted purine, arginine/urea cycle and glutamate metabolisms as the most consistently altered pathways, similar to primary mitochondrial diseases. The most severe mutations showed activation of energy shortage AMPK-dependent sensing, leading to mTORC1 inhibition. We propose that DNMT1 RFTS mutations deregulate metabolism lowering ATP levels, as the result of increased purine catabolism and urea cycle pathways. This is associated with a paradoxical mitochondrial hyper-function and increased oxidative stress, possibly resulting in neurodegeneration in non-dividing cells.

  View details for DOI 10.1093/hmg/ddaa014

  View details for PubMedID 31984424

• Predicting Age with Deep Neural Networks from Polysomnograms Brink-Kjaer, A., Mignot, E., Sorensen, H. D., Fennum, P., IEEE IEEE. 2020: 146–49

  View details for Web of Science ID 000621592200036

• Deep transfer learning for improving single-EEG arousal detection Olesen, A., Jennum, P., Mignot, E., Sorensen, H. D., IEEE IEEE. 2020: 99–103

  View details for Web of Science ID 000621592200025

• Prediction of Patient Demographics using 3D Craniofacial Scans and Multi-view CNNs Hanif, U., Paulsen, R. R., Leary, E. B., Mignot, E., Jennum, P., Sorensen, H. D., IEEE IEEE. 2020: 1950–53

  View details for Web of Science ID 000621592202071

• Mass Spectrometric Characterization of Narcolepsy-Associated Pandemic 2009 Influenza Vaccines. Vaccines Ambati, A. n., Luo, G. n., Pradhan, E. n., Louis, J. n., Lin, L. n., Leib, R. D., Ollila, H. M., Poiret, T. n., Adams, C. n., Mignot, E. n. 2020; 8 (4)

  Abstract

  The onset of narcolepsy, an irreversible sleep disorder, has been associated with 2009 influenza pandemic (pH1N1) infections in China, and with ASO3-adjuvanted pH1N1 vaccinations using Pandemrix in Europe. Intriguingly, however, the increased incidence was only observed following vaccination with Pandemrix but not Arepanrix in Canada. In this study, the mutational burden of actual vaccine lots of Pandemrix (n = 6) and Arepanrix (n = 5) sourced from Canada, and Northern Europe were characterized by mass spectrometry. The four most abundant influenza proteins across both vaccines were nucleoprotein NP, hemagglutinin HA, matrix protein M1, with the exception that Pandemrix harbored a significantly increased proportion of neuraminidase NA (7.5%) as compared to Arepanrix (2.6%). Most significantly, 17 motifs in HA, NP, and M1 harbored mutations, which significantly differed in Pandemrix versus Arepanrix. Among these, a 6-fold higher deamidation of HA146 (p.Asn146Asp) in Arepanrix was found relative to Pandemrix, while NP257 (p.Thr257Ala) and NP424 (p.Thr424Ile) were increased in Pandemrix. DQ0602 binding and tetramer analysis with mutated epitopes were conducted in Pandemrix-vaccinated cases versus controls but were unremarkable. Pandemrix harbored lower mutational burden than Arepanrix, indicating higher similarity to wild-type 2009 pH1N1, which could explain differences in narcolepsy susceptibility amongst the vaccines.

  View details for DOI 10.3390/vaccines8040630

  View details for PubMedID 33142956

• Deep transfer learning for improving single-EEG arousal detection. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Olesen, A. N., Jennum, P., Mignot, E., Sorensen, H. B. 2020; 2020: 99–103

  Abstract

  Datasets in sleep science present challenges for machine learning algorithms due to differences in recording setups across clinics. We investigate two deep transfer learning strategies for overcoming the channel mismatch problem for cases where two datasets do not contain exactly the same setup leading to degraded performance in single-EEG models. Specifically, we train a baseline model on multivariate polysomnography data and subsequently replace the first two layers to prepare the architecture for single-channel electroencephalography data. Using a fine-tuning strategy, our model yields similar performance to the baseline model (F1=0.682 and F1=0.694, respectively), and was significantly better than a comparable single-channel model. Our results are promising for researchers working with small databases who wish to use deep learning models pre-trained on larger databases.

  View details for DOI 10.1109/EMBC44109.2020.9176723

  View details for PubMedID 33017940

• Predicting Age with Deep Neural Networks from Polysomnograms. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Brink-Kjaer, A., Mignot, E., Sorensen, H. B., Jennum, P. 2020; 2020: 146–49

  Abstract

  The aim of this study was to design a new deep learning framework for end-to-end processing of polysomnograms. This framework can be trained to analyze whole-night polysomnograms without the limitations of and bias towards clinical scoring guidelines. We validated the framework by predicting the age of subjects. We designed a hierarchical attention network architecture, which can be pre-trained to predict labels based on 5-minute epochs of data and fine-tuned to predict based on whole-night polysomnography recordings. The model was trained on 511 recordings from the Cleveland Family study and tested on 146 test subjects aged between 6 to 88 years. The proposed network achieved a mean absolute error of 7.36 years and a correlation to true age of 0.857. Sleep can be analyzed using our end-to-end deep learning framework, which we expect can generalize to learning other subject-specific labels such as sleep disorders. The difference in the predicted and chronological age is further proposed as an estimate of biological age.

  View details for DOI 10.1109/EMBC44109.2020.9176254

  View details for PubMedID 33017951

• PSG Validation of minute-to-minute scoring for sleep and wake periods in a consumer wearable device. PloS one Cheung, J. n., Leary, E. B., Lu, H. n., Zeitzer, J. M., Mignot, E. n. 2020; 15 (9): e0238464

  Abstract

  Actigraphs are wrist-worn devices that record tri-axial accelerometry data used clinically and in research studies. The expense of research-grade actigraphs, however, limit their widespread adoption, especially in clinical settings. Tri-axial accelerometer-based consumer wearable devices have gained worldwide popularity and hold potential for a cost-effective alternative. The lack of independent validation of minute-to-minute accelerometer data with polysomnographic data or even research-grade actigraphs, as well as access to raw data has hindered the utility and acceptance of consumer-grade actigraphs.Sleep clinic patients wore a consumer-grade wearable (Huami Arc) on their non-dominant wrist while undergoing an overnight polysomnography (PSG) study. The sample was split into two, 20 in a training group and 21 in a testing group. In addition to the Arc, the testing group also wore a research-grade actigraph (Philips Actiwatch Spectrum). Sleep was scored for each 60-s epoch on both devices using the Cole-Kripke algorithm.Based on analysis of our training group, Arc and PSG data were aligned best when a threshold of 10 units was used to examine the Arc data. Using this threshold value in our testing group, the Arc has an accuracy of 90.3%±4.3%, sleep sensitivity (or wake specificity) of 95.5%±3.5%, and sleep specificity (wake sensitivity) of 55.6%±22.7%. Compared to PSG, Actiwatch has an accuracy of 88.7%±4.5%, sleep sensitivity of 92.6%±5.2%, and sleep specificity of 60.5%±20.2%, comparable to that observed in the Arc.An optimized sleep/wake threshold value was identified for a consumer-grade wearable Arc trained by PSG data. By applying this sleep/wake threshold value for Arc generated accelerometer data, when compared to PSG, sleep and wake estimates were adequate and comparable to those generated by a clinical-grade actigraph. As with other actigraphs, sleep specificity plateaus due to limitations in distinguishing wake without movement from sleep. Further studies are needed to evaluate the Arc's ability to differentiate between sleep and wake using other sources of data available from the Arc, such as high resolution accelerometry and photoplethysmography.

  View details for DOI 10.1371/journal.pone.0238464

  View details for PubMedID 32941498

• COMMENTARY on Lammers et al, Diagnosis of central disorders of hypersomnolence: Challenges in defining central disorders of hypersomnolence. Sleep medicine reviews Maski, K. n., Mignot, E. n., Scammell, T. E. 2020; 52: 101327

  View details for DOI 10.1016/j.smrv.2020.101327

  View details for PubMedID 32554241

• Robust, ECG-based algorithm for Sleep Disordered Breathing detection in large population-based cohorts using an automatic, data-driven approach. Sleep Olsen, M., Mignot, E., Jennum, P. J., Sorensen, H. B. 2019

  Abstract

  STUDY OBJECTIVES: Up to 5% of adults in Western countries have undiagnosed sleep disordered breathing (SDB). Studies have shown that electrocardiogram (ECG)-based algorithms can identify SDB and may provide alternative screening. Most studies however have limited generalizability as they have been conducted using the Apnea-ECG database, a small sample database that lacks complex SDB cases.METHODS: Here, we developed a fully automatic, data-driven algorithm that classifies apnea and hypopnea events based on the ECG using almost 10.000 polysomnographic sleep recordings from two large population-based samples, the Sleep Heart Health Study (SHHS) and the Multi-Ethnic Study of Atherosclerosis (MESA), which contain subjects with a broad range of sleep and cardiovascular diseases (CVD) to ensure heterogeneity.RESULTS: Performances on average were Se=68.7%, Pr=69.1%, F1=66.6% per subject, and accuracy of correctly classifying AHI severity score was Acc=84.9%. Target apnea-hypopnea index (AHI) and predicted AHI were highly correlated (R2=0.828) across subjects, indicating validatity in predicting SDB severity. Our algorithm proved to be statistically robust between databases, between different Periodic Leg Movement Index (PLMI) severity groups, and for subjects with previous CVD incidents. Further, our algorithm achieved state-of-the-art performance of Se=87.8%, Sp=91.1%, Acc=89.9% using independent comparisons and Se=90.7%, Sp=95.7%, Acc=93.8% using a transfer learning comparison on the Apnea-ECG database.CONCLUSION: Our robust and automatic algorithm constitutes a minimally intrusive and inexpensive screening system for the detection of SDB event using the ECG to alleviate the current problems and costs associated with diagnosing SDB cases and to provide a system capable of identifying undiagnosed SDB cases.

  View details for DOI 10.1093/sleep/zsz276

  View details for PubMedID 31738833

• Validation of Multiple Sleep Latency Test for the diagnosis of pediatric narcolepsy type 1. Neurology Pizza, F., Barateau, L., Jaussent, I., Vandi, S., Antelmi, E., Mignot, E., Dauvilliers, Y., Plazzi, G., MonBo Study Group 2019

  Abstract

  OBJECTIVE: To validate polysomnographic markers (sleep latency and sleep-onset REM periods [SOREMPs] at the Multiple Sleep Latency Test [MSLT] and nocturnal polysomnography [PSG]) for pediatric narcolepsy type 1 (NT1) against CSF hypocretin-1 (hcrt-1) deficiency and presence of cataplexy, as no criteria are currently validated in children.METHODS: Clinical, neurophysiologic, and, when available, biological data (HLA-DQB1*06:02 positivity, CSF hcrt-1 levels) of 357 consecutive children below 18 years of age evaluated for suspected narcolepsy were collected. Best MSLT cutoffs were obtained by receiver operating characteristic (ROC) curve analysis by contrasting among patients with available CSF hcrt-1 assay (n = 228) with vs without CSF hcrt-1 deficiency, and further validated in patients without available CSF hcrt-1 against cataplexy (n = 129).RESULTS: Patients with CSF hcrt-1 deficiency were best recognized using a mean MSLT sleep latency ≤8.2 minutes (area under the ROC curve of 0.985), or by at least 2 SOREMPs at the MSLT (area under the ROC curve of 0.975), or the combined PSG + MSLT (area under the ROC curve of 0.977). Although specificity and sensitivity of reference MSLT sleep latency ≤8 minutes and ≥2 SOREMPs (nocturnal SOREMP included) was 100% and 94.87%, the combination of MSLT sleep latency and SOREMP counts did not improve diagnostic accuracy. Age or sex also did not significantly influence these results in our pediatric population.CONCLUSIONS: At least 2 SOREMPs or a mean sleep latency ≤8.2 minutes at the MSLT are valid and reliable markers for pediatric NT1 diagnosis, a result contrasting with adult NT1 criteria.CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for children with suspected narcolepsy, polysomnographic and MSLT markers accurately identify those with narcolepsy type 1.

  View details for DOI 10.1212/WNL.0000000000008094

  View details for PubMedID 31405906

• Cardiovascular autonomic dysfunction, altered sleep architecture, and muscle overactivity during nocturnal sleep in pediatric patients with narcolepsy type 1. Sleep Vandi, S., Rodolfi, S., Pizza, F., Moresco, M., Antelmi, E., Ferri, R., Mignot, E., Plazzi, G., Silvani, A. 2019

  Abstract

  STUDY OBJECTIVES: arterial blood pressure (ABP) decreases during sleep compared to wakefulness and this change is blunted in mouse models of and adult patients with narcolepsy type 1 (NT1). We tested whether: 1) pediatric patients with NT1 have similar cardiovascular autonomic abnormalities during nocturnal sleep; and 2) these abnormalities can be linked to hypocretin-1 cerebrospinal fluid concentration (CSF HCRT-1), sleep architecture or muscle activity.METHODS: laboratory polysomnographic studies were performed in 27 consecutive drug-naive NT1 children or adolescents and in 19 matched controls. Nocturnal sleep architecture and submentalis (SM), tibialis anterior (TA), and hand extensor (HE) electromyographic (EMG) activity were analyzed. Cardiovascular autonomic function was assessed through the analysis of pulse transit time (PTT) and heart period (HP).RESULTS: PTT showed reduced lengthening during total sleep and REM sleep compared to nocturnal wakefulness in NT1 patients than in controls, whereas HP did not. NT1 patients had altered sleep architecture, higher SM EMG during REM sleep, and higher TA and HE EMG during N1-N3 and REM sleep when compared to controls. PTT alterations found in NT1 patients were more severe in subjects with lower CSF HRCT-1, but did not cluster or correlate with sleep architecture alterations or muscle overactivity during sleep.CONCLUSION: our results suggest that pediatric NT1 patients close to disease onset have impaired capability to modulate ABP as a function of nocturnal wake-sleep transitions, possibly as a direct consequence of hypocretin neuron loss. The relevance of this finding for cardiovascular risk later in life remains to be determined.

  View details for DOI 10.1093/sleep/zsz169

  View details for PubMedID 31353416

• Towards a Flexible Deep Learning Method for Automatic Detection of Clinically Relevant Multi-Modal Events in the Polysomnogram. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Olesen, A. N., Chambon, S., Thorey, V., Jennum, P., Mignot, E., Sorensen, H. B. 2019; 2019: 556–61

  Abstract

  Much attention has been given to automatic sleep staging algorithms in past years, but the detection of discrete events in sleep studies is also crucial for precise characterization of sleep patterns and possible diagnosis of sleep disorders. We propose here a deep learning model for automatic detection and annotation of arousals and leg movements. Both of these are commonly seen during normal sleep, while an excessive amount of either is linked to disrupted sleep patterns, excessive daytime sleepiness impacting quality of life, and various sleep disorders. Our model was trained on 1,485 subjects and tested on 1,000 separate recordings of sleep. We tested two different experimental setups and found optimal arousal detection was attained by including a recurrent neural network module in our default model with a dynamic default event window (F1 = 0.75), while optimal leg movement detection was attained using a static event window (F1 = 0.65). Our work show promise while still allowing for improvements. Specifically, future research will explore the proposed model as a general-purpose sleep analysis model.

  View details for DOI 10.1109/EMBC.2019.8856570

  View details for PubMedID 31945960

• Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk. Human molecular genetics Pouget, J. G., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Han, B., Wu, Y., Mignot, E., Ollila, H. M., Barker, J., Spain, S., Dand, N., Trembath, R., Martin, J., Mayes, M. D., Bossini-Castillo, L., Lopez-Isac, E., Jin, Y., Santorico, S. A., Spritz, R. A., Hakonarson, H., Polychronakos, C., Raychaudhuri, S., Knight, J. 2019

  Abstract

  Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn's disease via altered methylation and expression of EPHB4 - a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD Score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg=0.12±0.03, p=2.49x10-4), Crohn's disease (rg=0.097±0.06, p=3.27x10-3), ulcerative colitis (rg=0.11±0.04, p=4.05x10-3), primary biliary cirrhosis (rg=0.13±0.05, p=3.98x10-3), psoriasis (rg=0.18±0.07, p=7.78x10-3), and systemic lupus erythematosus (rg=0.13±0.05, p=3.76x10-3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

  View details for DOI 10.1093/hmg/ddz145

  View details for PubMedID 31211845

• Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3) A Randomized Controlled Trial AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Schweitzer, P. K., Rosenberg, R., Zammit, G. K., Gotfried, M., Chen, D., Carter, L. P., Wang, H., Lu, Y., Black, J., Malhotra, A., Strohl, K. P. 2019; 199 (11): 1421–31

  View details for DOI 10.1164/rccm.201806-1100OC

  View details for Web of Science ID 000469959100018

• Meeting report narcolepsy and pandemic influenza vaccination: What we know and what we need to know before the next pandemic? A report from the 2nd IABS meeting. Biologicals : journal of the International Association of Biological Standardization Edwards, K., Hanquet, G., Black, S., Mignot, E., Jankosky, C., Shimabukuro, T., Miller, E., Nohynek, H., Neels, P. 2019

  Abstract

  A group of scientific and public health experts and key stakeholders convened to discuss the state of knowledge on the relationship between adjuvanted monovalent inactivated 2009 influenza A H1N1 vaccines used during the 2009 influenza pandemic and narcolepsy. There was consensus that an increased risk of narcolepsy was consistently observed after Pandemrix (AS03-adjuvanted) vaccine, but similar associations following Arepanrix (AS03-adjuvanted) or Focetria (MF59-adjuvanted) vaccines were not observed. Whether the differences are due to vaccine composition or other factors such as the timing of large-scale vaccination programs relative to H1N1pdm09 wild-type virus circulation in different geographic regions is not clear. The limitations of retrospective observational methodologies could also be contributing to some of the differences across studies. More basic and epidemiologic research is needed to further elucidate the association between adjuvanted influenza vaccine and narcolepsy and its mechanism and to inform planning and preparation for vaccination programs in advance of the next influenza pandemic.

  View details for DOI 10.1016/j.biologicals.2019.05.005

  View details for PubMedID 31130313

• The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight SCIENCE Garrett-Bakelman, F. E., Darshi, M., Green, S. J., Gur, R. C., Lin, L., Macias, B. R., McKenna, M. J., Meydan, C., Mishra, T., Nasrini, J., Piening, B. D., Rizzardi, L. F., Sharma, K., Siamwala, J. H., Taylor, L., Vitaterna, M., Afkarian, M., Afshinnekoo, E., Ahadi, S., Ambati, A., Arya, M., Bezdan, D., Callahan, C. M., Chen, S., Choi, A. K., Chlipala, G. E., Contrepois, K., Covington, M., Crucian, B. E., De Vivo, I., Dinges, D. F., Ebert, D. J., Feinberg, J. I., Gandara, J. A., George, K. A., Goutsias, J., Grills, G. S., Hargens, A. R., Heer, M., Hillary, R. P., Hoofnagle, A. N., Hook, V. H., Jenkinson, G., Jiang, P., Keshavarzian, A., Laurie, S. S., Lee-McMullen, B., Lumpkins, S. B., MacKay, M., Maienschein-Cline, M. G., Melnick, A. M., Moore, T. M., Nakahira, K., Patel, H. H., Pietrzyk, R., Rao, V., Saito, R., Salins, D. N., Schilling, J. M., Sears, D. D., Sheridan, C. K., Stenger, M. B., Tryggvadottir, R., Urban, A. E., Vaisar, T., Van Espen, B., Zhang, J., Ziegler, M. G., Zwart, S. R., Charles, J. B., Kundrot, C. E., Scott, G. I., Bailey, S. M., Basner, M., Feinberg, A. P., Lee, S. C., Mason, C. E., Mignot, E., Rana, B. K., Smith, S. M., Snyder, M. P., Turek, F. W. 2019; 364 (6436): 144-+

  View details for DOI 10.1126/science.aau8650

  View details for Web of Science ID 000464620000031

• Physical activity, sleep and cardiovascular health data for 50,000 individuals from the MyHeart Counts Study. Scientific data Hershman, S. G., Bot, B. M., Shcherbina, A., Doerr, M., Moayedi, Y., Pavlovic, A., Waggott, D., Cho, M. K., Rosenberger, M. E., Haskell, W. L., Myers, J., Champagne, M. A., Mignot, E., Salvi, D., Landray, M., Tarassenko, L., Harrington, R. A., Yeung, A. C., McConnell, M. V., Ashley, E. A. 2019; 6 (1): 24

  Abstract

  Studies have established the importance of physical activity and fitness for long-term cardiovascular health, yet limited data exist on the association between objective, real-world large-scale physical activity patterns, fitness, sleep, and cardiovascular health primarily due to difficulties in collecting such datasets. We present data from the MyHeart Counts Cardiovascular Health Study, wherein participants contributed data via an iPhone application built using Apple's ResearchKit framework and consented to make this data available freely for further research applications. In this smartphone-based study of cardiovascular health, participants recorded daily physical activity, completed health questionnaires, and performed a 6-minute walk fitness test. Data from English-speaking participants aged 18 years or older with a US-registered iPhone who agreed to share their data broadly and who enrolled between the study's launch and the time of the data freeze for this data release (March 10 2015-October 28 2015) are now available for further research. It is anticipated that releasing this large-scale collection of real-world physical activity, fitness, sleep, and cardiovascular health data will enable the research community to work collaboratively towards improving our understanding of the relationship between cardiovascular indicators, lifestyle, and overall health, as well as inform mobile health research best practices.

  View details for PubMedID 30975992

• Physical activity, sleep and cardiovascular health data for 50,000 individuals from the MyHeart Counts Study SCIENTIFIC DATA Hershman, S. G., Bot, B. M., Shcherbina, A., Doerr, M., Moayedi, Y., Pavlovic, A., Waggott, D., Cho, M. K., Rosenberger, M. E., Haskell, W. L., Myers, J., Champagne, M., Mignot, E., Salvi, D., Landray, M., Tarassenko, L., Harrington, R. A., Yeung, A. C., McConnell, M. V., Ashley, E. A. 2019; 6

  View details for DOI 10.1038/s41597-019-0016-7

  View details for Web of Science ID 000464198800001

• PROTEOMIC BIOMARKERS OF CIRCADIAN TIME Ambati, A., Lin, L., Zitting, K., Duffy, J. F., Zeitzer, J., Spiegel, D., Czeisler, C. A., Mignot, E. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071000044

• TOWARDS A DEEP LEARNING-BASED JOINT DETECTION MODEL FOR NOCTURNAL POLYSOMNOGRAM EVENTS Olesen, A. N., Thybo, J., Chambon, S., Thorey, V., Jennum, P. J., Sorensen, H. B., Mignot, E. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071001098

• DEVELOPMENT OF COMPLEX DATA PLATFORM FOR THE STANFORD TECHNOLOGY ANALYTICS AND GENOMICS IN SLEEP (STAGES) STUDY Leary, E. B., Seeger-Zybok, R. K., Mazurek, M., Voronoy, A., Lawlor, B., Stephenson, C., Kushida, C., Mignot, E. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071001102

• EVALUATION OF CATAPLEXY-FREE DAYS IN CHILDREN/ ADOLESCENTS WITH NARCOLEPSY WITH CATAPLEXY TREATED WITH SODIUM OXYBATE Mignot, E., Rosen, C. L., Menno, D., Wang, G., Profant, J., Dauvilliers, Y. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071003053

• LONG-TERM SAFETY OF SODIUM OXYBATE IN PEDIATRIC NARCOLEPSY WITH CATAPLEXY: OPEN-LABEL CONTINUATION POST 1-YEAR OF TREATMENT Strunc, M. J., Mignot, E., Wang, G., Black, J., Chakravarthy, D., Parvataneni, R., Plazzi, G. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071003054

• AUTOIMMUNITY TO HYPOCRETIN AND MOLECULAR MIMICRY TO FLU IN TYPE 1 NARCOLEPSY Luo, G., Ambati, A., Lin, L., Bonvalet, M., Partinen, M., Ji, X., Maecker, H., Mignot, E. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071000018

• Knowledge Gaps in the Perioperative Management of Adults With Narcolepsy: A Call for Further Research. Anesthesia and analgesia Hershner, S., Dauvilliers, Y., Chung, F., Singh, M., Wong, J., Gali, B., Kakkar, R., Mignot, E., Thorpy, M., Auckley, D. 2019

  Abstract

  There is increasing awareness that sleep disorders may be associated with increased perioperative risk. The Society of Anesthesia and Sleep Medicine created the Narcolepsy Perioperative Task Force: (1) to investigate the current state of knowledge of the perioperative risk for patients with narcolepsy, (2) to determine the viability of developing perioperative guidelines for the management of patients with narcolepsy, and (3) to delineate future research goals and clinically relevant outcomes. The Narcolepsy Perioperative Task Force established that there is evidence for increased perioperative risk in patients with narcolepsy; however, this evidence is sparse and based on case reviews, case series, and retrospective reviews. Mechanistically, there are a number of potential mechanisms by which patients with narcolepsy could be at increased risk for perioperative complications. These include aggravation of the disease itself, dysautonomia, narcolepsy-related medications, anesthesia interactions, and withdrawal of narcolepsy-related medications. At this time, there is inadequate research to develop an expert consensus or guidelines for the perioperative management of patients with narcolepsy. The paucity of available literature highlights the critical need to determine if patients with narcolepsy are at an increased perioperative risk and to establish appropriate research protocols and clearly delineated patient-centered outcomes. There is a real need for collaborative research among sleep medicine specialists, surgeons, anesthesiologists, and perioperative providers. This future research will become the foundation for the development of guidelines, or at a minimum, a better understanding how to optimize the perioperative care of patients with narcolepsy.

  View details for DOI 10.1213/ANE.0000000000004088

  View details for PubMedID 30882519

• Non-invasive machine learning estimation of effort differentiates sleep-disordered breathing pathology. Physiological measurement Hanif, U., Schneider, L. D., Trap, L., Leary, E. B., Moore Iv, H., Guilleminault, C., Jennum, P. J., Bjarup Dissing Sorensen, H., Mignot, E. J. 2019

  Abstract

  OBJECTIVE: Obstructive sleep-disordered breathing (SDB) events, unlike central events, are associated with increased respiratory effort. Esophageal pressure (Pes) monitoring is the gold standard for measuring respiratory effort, but it is typically poorly tolerated because of its invasive nature. The objective was to investigate whether machine learning can be applied to routinely collected non-invasive, polysomnography (PSG) measures to accurately model peak negative Pes. Approach: 1119 patients from the Stanford Sleep Clinic with PSGs containing Pes served as the sample. The selected non-invasive PSG signals included nasal pressure, oral airflow, thoracoabdominal effort, and snoring. A long short-term memory (LSTM) neural network was implemented to achieve a context-based mapping between the non-invasive features and the Pes values. A hold-out dataset served as a prospective validation of the algorithm without needing to undertake a costly new study with the impractically invasive Pes. Main results: The median difference between the measured and predicted Pes was 0.61 cmH2O with an interquartile range (IQR) of 2.99 cmH2O and 5th and 95th percentiles of -5.85 cmH2O and 5.47 cmH2O, respectively. The model performed well when compared to actual esophageal pressure signal (rhomedian=0.581, p=0.01; IQR = 0.298; rho5% = 0.106; rho95% = 0.843). Significance: A significant difference in predicted Pes was shown between normal breathing and all obstructive SDB events; whereas, central apneas did not significantly differ from normal breathing. The developed system may be used as a tool for quantifying respiratory effort from the existing clinical practice of PSG without the need for Pes, improving characterization of SDB events as obstructive or not. .

  View details for PubMedID 30736016

• Non-invasive machine learning estimation of effort differentiates sleep-disordered breathing pathology PHYSIOLOGICAL MEASUREMENT Hanif, U., Schneider, L. D., Trap, L., Leary, E. B., Moore, H., Guilleminault, C., Jennum, P., Sorensen, H. D., Mignot, E. M. 2019; 40 (2)

  View details for DOI 10.1088/1361-6579/ab0559

  View details for Web of Science ID 000459885000004

• HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy. Scientific reports Sakai, N., Matsumura, M., Lin, L., Mignot, E., Nishino, S. 2019; 9 (1): 477

  Abstract

  Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin (hcrt) neurons in the hypothalamus. Cerebrospinal fluid (CSF) hcrt-1 measurement has been well established as a gold standard of narcolepsy diagnosis, although some portions of narcoleptic patients show normal hcrt-1 levels. We aimed to examine peptide degradation of hcrt-1 and its abnormality in the CSF of patients by using high performance liquid chromatography (HPLC) followed by radioimmunoassay (RIA). CSF was collected from healthy controls, narcoleptic patients of type 1 with hcrt-1 deficiency, type 1 with normal hcrt-1 level, and type 2 with normal hcrt-1 level. We found that the majority of hcrt-1 immunoreactivity in extracted CSF was derived from unauthentic hcrt-1 peaks, which are predicted to be inactive metabolites, and the intact hcrt-1 peptide was less than 10% of the gross amount, suggesting that the regular RIA for CSF hcrt-1 measures largely reflect the unauthentic hcrt-1-related metabolites rather than the intact one. As expected, all hcrt-1-related peaks were abolished in type 1 with hcrt-1 deficiency. Importantly, we also found that the sum of the authentic hcrt-1 peptide (peaks 3 and 4) significantly decreased in non-deficient type 1 and tended to decrease in type 2 narcoleptic patients although the levels with the regular RIA in non-extracted CSF was equivalent to healthy controls. Immunoreactivity with unauthentic hcrt-1 metabolites may masks the possible decline in authentic hcrt-1 level caused by the partial loss of hcrt neurons. Our findings may provide new insights into the degradation of the hcrt-1 peptide and the pathophysiology of narcolepsy.

  View details for PubMedID 30679597

• HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy SCIENTIFIC REPORTS Sakai, N., Matsumura, M., Lin, L., Mignot, E., Nishino, S. 2019; 9

  View details for DOI 10.1038/s41598-018-36942-8

  View details for Web of Science ID 000456553400043

• TRANSETHNIC ANALYSIS OF HIGH-RESOLUTION HLA ALLELES AND COMPLEMENT 4 STRUCTURAL POLYMORPHISMS IN SCHIZOPHRENIA Ollila, H., Li, M., Mindrinos, M., Wang, C., Fernandez-Vina, M., Kuehn, R., Krishnakumar, S., Wilhelmy, J., Tsuang, M. T., Glatt, S. J., Mignot, E., Levinson, D. F. ELSEVIER SCIENCE BV. 2019: S937

  View details for DOI 10.1016/j.euroneuro.2017.08.278

  View details for Web of Science ID 000462156400407

• Towards a Flexible Deep Learning Method for Automatic Detection of Clinically Relevant Multi-Modal Events in the Polysomnogram Olesen, A., Chambon, S., Thorey, V., Jennum, P., Mignot, E., Sorensen, H. D., IEEE IEEE. 2019: 556–61

  View details for Web of Science ID 000557295300129

• [Narcolepsy: From the discovery of a wake promoting peptide to autoimmune T cell biology and molecular mimicry with flu epitopes]. Biologie aujourd'hui Ravel, J. M., Mignot, E. J. 2019; 213 (3-4): 87–108

  Abstract

  Narcolepsy-cataplexy was first described in the late 19th century in Germany and France. Prevalence was established to be 0.05 % and a canine model was discovered in the 1970s. In 1983, a Japanese study found that all patients carried HLA-DR2, suggesting autoimmunity as the cause of the disease. Studies in the canine model established that dopaminergic stimulation underlies anti-narcoleptic action of psychostimulants, while antidepressants were found to suppress cataplexy through adrenergic reuptake inhibition. No HLA association was found in canines. A linkage study initiated in 1988 revealed in hypocretin (orexin) receptor two mutations as the cause of canine narcolepsy in 1999. In 1992, studies on African Americans showed that DQ0602 was a better marker than DR2 across all ethnic groups. In 2000, hypocretin-1/orexin A levels were measured in the cerebrospinal fluid (CSF) and found to be undetectable in most patients, establishing hypocretin deficiency as the cause of narcolepsy. Decreased CSF hypocretin-1 was then found to be secondary to the loss of the 70,000 neurons producing hypocretin in the hypothalamus, suggesting immune destruction of these cells as the cause of the disease. Additional genetic studies, notably genome wide associations (GWAS), found multiple genetic predisposing factors for narcolepsy. These were almost all involved in other autoimmune diseases, although a strong and unique association with T cell receptor (TCR) alpha and beta loci were observed. Nonetheless, all attempts to demonstrate presence of autoantibodies against hypocretin cells in narcolepsy failed, and the presumed autoimmune cause remained unproven. In 2009, association with strep throat infections were found, and narcolepsy onsets were found to occur more frequently in spring and summer, suggesting upper away infections as triggers. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, molecular mimicry with influenza A virus was suggested in 2010. This hypothesis was later confirmed by peptide screening showing higher activity of CD4+ T cell reactivity to a specific post-translationally amidated segment of hypocretin (HCRT-NH2) and cross-reactivity of specific TCRs with a pH1N1-specific segment of hemagglutinin that shares homology with HCRT-NH2. Strikingly, the most frequent TCR recognizing these antigens was found to carry sequences containing TRAJ24 or TRVB4-2, segments modulated by narcolepsy-associated genetic polymorphisms. Cross-reactive CD4+ T cells with these cross-reactive TCRs likely subsequently recruit CD8+ T cells that are then involved in hypocretin cell destruction. Additional flu mimics are also likely to be discovered since narcolepsy existed prior to 2009. The work that has been conducted over the years on narcolepsy offers a unique perspective on the conduct of research on the etiopathogeny of a specific disease.

  View details for DOI 10.1051/jbio/2019026

  View details for PubMedID 31829930

• Factors associated with fatigue in patients with insomnia. Journal of psychiatric research Kim, S. J., Kim, S. n., Jeon, S. n., Leary, E. B., Barwick, F. n., Mignot, E. n. 2019; 117: 24–30

  Abstract

  Although fatigue is common in insomnia, the clinical associates of fatigue in patients with insomnia are largely unknown. We aimed to investigate the clinical associates of fatigue in patients with insomnia. Patients visiting the Stanford Sleep Medicine Center completed the Insomnia Severity Index (ISI), Insomnia Symptom Questionnaire (ISQ), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), and the Patient Health Questionnaire (PHQ-9). Among 6367 patients, 2024 were diagnosed with insomnia (age 43.06 ± 15.19 years; 1110 women and 914 men) according to the ISI and the ISQ. Insomnia patients with severe fatigue (n = 1306) showed higher insomnia symptoms, daytime sleepiness, depression and longer habitual sleep duration than those without severe fatigue (n = 718). Higher insomnia symptoms, daytime sleepiness and depressive symptoms, and longer habitual sleep duration, independently predicted higher fatigue scores. Among insomnia patients with daytime sleepiness (ESS≥10), only habitual sleep duration and depression predicted fatigue scores. The interaction between insomnia severity and daytime sleepiness significantly predicted the severity of fatigue. Depression was a significant mediator between insomnia and fatigue. For 598 insomnia patients undergoing overnight polysomnography (PSG), no significant correlations were found between fatigue and any PSG parameters. The current study suggests that managing insomnia or depression may reduce the fatigue of insomnia patients, whereas arbitrary efforts to prolong sleep duration may worsen their fatigue.

  View details for DOI 10.1016/j.jpsychires.2019.06.021

  View details for PubMedID 31272015

• Response to "H1N1 hemagglutinin-specific HLA-DQ6-restricted CD4+ T cells can be readily detected in narcolepsy type 1 patients and healthy controls". Journal of neuroimmunology Mignot, E. n., Ambati, A. n., Luo, G. n. 2019; 333: 476959

  View details for DOI 10.1016/j.jneuroim.2019.04.019

  View details for PubMedID 31108400

• GENETICS OF VACCINATION RELATED NARCOLEPSY Ollila, H., Wennerstrom, A., Partinen, M., Mignot, E., Saarela, J., Saavalainen, P., Vaarala, O., Tienari, P., Perola, M. ELSEVIER SCIENCE BV. 2019: S994

  View details for DOI 10.1016/j.euroneuro.2017.08.379

  View details for Web of Science ID 000462156400508

• The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science (New York, N.Y.) Garrett-Bakelman, F. E., Darshi, M. n., Green, S. J., Gur, R. C., Lin, L. n., Macias, B. R., McKenna, M. J., Meydan, C. n., Mishra, T. n., Nasrini, J. n., Piening, B. D., Rizzardi, L. F., Sharma, K. n., Siamwala, J. H., Taylor, L. n., Vitaterna, M. H., Afkarian, M. n., Afshinnekoo, E. n., Ahadi, S. n., Ambati, A. n., Arya, M. n., Bezdan, D. n., Callahan, C. M., Chen, S. n., Choi, A. M., Chlipala, G. E., Contrepois, K. n., Covington, M. n., Crucian, B. E., De Vivo, I. n., Dinges, D. F., Ebert, D. J., Feinberg, J. I., Gandara, J. A., George, K. A., Goutsias, J. n., Grills, G. S., Hargens, A. R., Heer, M. n., Hillary, R. P., Hoofnagle, A. N., Hook, V. Y., Jenkinson, G. n., Jiang, P. n., Keshavarzian, A. n., Laurie, S. S., Lee-McMullen, B. n., Lumpkins, S. B., MacKay, M. n., Maienschein-Cline, M. G., Melnick, A. M., Moore, T. M., Nakahira, K. n., Patel, H. H., Pietrzyk, R. n., Rao, V. n., Saito, R. n., Salins, D. N., Schilling, J. M., Sears, D. D., Sheridan, C. K., Stenger, M. B., Tryggvadottir, R. n., Urban, A. E., Vaisar, T. n., Van Espen, B. n., Zhang, J. n., Ziegler, M. G., Zwart, S. R., Charles, J. B., Kundrot, C. E., Scott, G. B., Bailey, S. M., Basner, M. n., Feinberg, A. P., Lee, S. M., Mason, C. E., Mignot, E. n., Rana, B. K., Smith, S. M., Snyder, M. P., Turek, F. W. 2019; 364 (6436)

  Abstract

  To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.

  View details for PubMedID 30975860

• Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Luo, G., Ambati, A., Lin, L., Bonvalet, M., Partinen, M., Ji, X., Maecker, H., Mignot, E. 2018; 115 (52): E12323-E12332

  View details for DOI 10.1073/pnas.1818150116

  View details for Web of Science ID 000454302600026

• Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proceedings of the National Academy of Sciences of the United States of America Luo, G., Ambati, A., Lin, L., Bonvalet, M., Partinen, M., Ji, X., Maecker, H. T., Mignot, E. J. 2018

  Abstract

  Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273-287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3beta TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273-287-tetramers, suggesting molecular mimicry. This public CDR3beta uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-alpha/beta CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3alpha, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-alpha/beta CDR3 sequences found in pHA273-287, NP17-31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-gamma-secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.

  View details for PubMedID 30541895

• Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy NATURE COMMUNICATIONS Stephansen, J. B., Olesen, A. N., Olsen, M., Ambati, A., Leary, E. B., Moore, H. E., Carrillo, O., Lin, L., Han, F., Yan, H., Sun, Y. L., Dauvilliers, Y., Scholz, S., Barateau, L., Hogl, B., Stefani, A., Hong, S., Kim, T., Pizza, F., Plazzi, G., Vandi, S., Antelmi, E., Perrin, D., Kuna, S. T., Schweitzer, P. K., Kushida, C., Peppard, P. E., Sorensen, H. D., Jennum, P., Mignot, E. 2018; 9

  View details for DOI 10.1038/s41467-018-07229-3

  View details for Web of Science ID 000452283400001

• Periodic limb movements in sleep: Prevalence and associated sleepiness in the Wisconsin Sleep Cohort CLINICAL NEUROPHYSIOLOGY Leary, E. B., Moore, H. E., Schneider, L. D., Finn, L. A., Peppard, P. E., Mignot, E. 2018; 129 (11): 2306-2314

  View details for DOI 10.1016/j.clinph.2018.08.022

  View details for Web of Science ID 000447765400012

• Periodic limb movements in sleep: Prevalence and associated sleepiness in the Wisconsin Sleep Cohort. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Leary, E. B., Moore, H. E., Schneider, L. D., Finn, L. A., Peppard, P. E., Mignot, E. 2018; 129 (11): 2306–14

  Abstract

  OBJECTIVES: Periodic limb movements in sleep (PLMS) are thought to be prevalent in elderly populations, but their impact on quality of life remains unclear. We examined the prevalence of PLMS, impact of age on prevalence, and association between PLMS and sleepiness.METHODS: We identified limb movements in 2335 Wisconsin Sleep Cohort polysomnograms collected over 12 years. Prevalence of periodic limb movement index (PLMI) ≥15 was calculated at baseline (n = 1084). McNemar's test assessed changes in prevalence over time. Association of sleepiness and PLMS evaluated using linear mixed modeling and generalized estimating equations. Models adjusted for confounders.RESULTS: Prevalence of PLMI ≥15 at baseline was 25.3%. Longitudinal prevalence increased significantly with age (p = 2.97 * 10-14). Sleepiness did not differ significantly between PLMI groups unless stratified by restless legs syndrome (RLS) symptoms. The RLS+/PLM+ group was sleepier than the RLS+/PLM- group. Multiple Sleep Latency Test trended towards increased alertness in the RLS-/PLM+ group compared to RLS-/PLM-.CONCLUSIONS: A significant number of adults have PLMS and prevalence increased with age. No noteworthy association between PLMI category and sleepiness unless stratified by RLS symptoms.SIGNIFICANCE: Our results indicate that RLS and PLMS may have distinct clinical consequences and interactions that can help guide treatment approach.

  View details for PubMedID 30243181

• Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation LANCET CHILD & ADOLESCENT HEALTH Plazzi, G., Ruoff, C., Lecendreux, M., Dauvilliers, Y., Rosen, C. L., Black, J., Parvataneni, R., Guinta, D., Wang, Y., Mignot, E. 2018; 2 (7): 483–94

  View details for DOI 10.1016/S2352-4642(18)30133-0

  View details for Web of Science ID 000437267600015

• Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma CANCER IMMUNOLOGY IMMUNOTHERAPY Wang, W., Ollila, H. M., Whittemore, A. S., Demehri, S., Ioannidis, N. M., Jorgenson, E., Mignot, E., Asgari, M. M. 2018; 67 (7): 1123-1133

  View details for DOI 10.1007/s00262-018-2168-2

  View details for Web of Science ID 000435591800009

• Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma. Cancer immunology, immunotherapy : CII Wang, W., Ollila, H. M., Whittemore, A. S., Demehri, S., Ioannidis, N. M., Jorgenson, E., Mignot, E., Asgari, M. M. 2018

  Abstract

  BACKGROUND: The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated.METHODS: Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes.RESULTS: Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR=1.20, p=9.88*10-11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR=1.17, p=2.48*10-10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR=1.14, p=2.34*10-9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR=1.18, p=5.86*10-10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions.CONCLUSIONS: Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

  View details for PubMedID 29754218

• BUILDING A HIGH RESOLUTION HAPLOTYPE DATABASE FOR 11 HUMAN LEUKOCYTE ANTIGEN LOCI FROM FAMILY TRIOS Kountouris, E., Levinson, D., Fernandez-Vina, M. A., Ollila, H., Mignot, E., Tsuang, M., Glatt, S., Li, M., Mindrinos, M. WILEY. 2018: 435–36

  View details for Web of Science ID 000430290800240

• A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of Sodium Oxybate (SXB) in Pediatric Participants with Narcolepsy Type 1 (NT1) Ruoff, C., Plazzi, G., Lecendreux, M., Dauvilliers, Y., Rosen, C., Black, J., Parvataneni, R., Guinta, D., Wang, Y., Mignot, E. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090805240

• Improved primary CNS hypersomnia diagnosis with statistical machine learning Jiang, L., Cheung, J., Mignot, E., Schneider, L. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090800116

• Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease SLEEP MEDICINE Moresco, M., Lecciso, M., Ocadlikova, D., Filardi, M., Melzi, S., Kornum, B., Antelmi, E., Pizza, F., Mignot, E., Curti, A., Plazzi, G. 2018; 44: 53–60

  Abstract

  Type 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course.Immune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses.The NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4+ terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4+ terminally differentiated effector memory T cells and an increased frequency of NK CD56bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4+ terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls.Significant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology.

  View details for PubMedID 29530370

• A comparative study of methods for automatic detection of rapid eye movement abnormal muscular activity in narcolepsy SLEEP MEDICINE Olesen, A., Cesari, M., Christensen, J., Sorensen, H., Mignot, E., Jennum, P. 2018; 44: 97–105

  Abstract

  To evaluate rapid eye movement (REM) muscular activity in narcolepsy by applying five algorithms to electromyogram (EMG) recordings, and to investigate its value for narcolepsy diagnosis.A modified version of phasic EMG metric (mPEM), muscle activity index (MAI), REM atonia index (RAI), supra-threshold REM EMG activity metric (STREAM), and Frandsen method (FR) were calculated from polysomnography recordings of 20 healthy controls, 18 clinic controls (subjects suspected with narcolepsy but finally diagnosed without any sleep abnormality), 16 narcolepsy type one without REM sleep behavior disorder (RBD), nine narcolepsy type one with RBD, and 18 narcolepsy type two. Diagnostic value of metrics in differentiating between groups was quantified by area under the receiver operating characteristic curve (AUC). Correlations among the metrics and cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) values were calculated using linear models.All metrics excluding STREAM found significantly higher muscular activity in narcolepsy one cases versus controls (p < 0.05). Moreover, RAI showed high sensitivity in the detection of RBD. The mPEM achieved the highest AUC in differentiating healthy controls from narcoleptic subjects. The RAI best differentiated between narcolepsy 1 and 2. Lower CSF-hcrt-1 values correlated with high muscular activity quantified by mPEM, sMAI, lMAI, PEM and FR (p < 0.05).This automatic analysis showed higher number of muscle activations in narcolepsy 1 compared to controls. This finding might play a supportive role in diagnosing narcolepsy and in discriminating narcolepsy subtypes. Moreover, the negative correlation between CSF-hcrt-1 level and REM muscular activity supported a role for hypocretin in the control of motor tone during REM sleep.

  View details for PubMedID 29530376

• Sleepyhead: Narcolepsy, Neuroscience and the Search for a Good Night (Book Review) NATURE Book Review Authored by: Mignot, E. 2018; 555 (7694): 22–23

  View details for Web of Science ID 000426247600015

• Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies JOURNAL OF NEUROIMMUNOLOGY Hillary, R. P., Ollila, H. M., Lin, L., Desestret, V., Rogemond, V., Picard, G., Small, M., Arnulf, I., Dauvillers, Y., Honnorat, J., Mignot, E. 2018; 315: 28–32

  Abstract

  Anti-Yo paraneoplastic cerebellar degeneration (PCD) is a devastating autoimmune complication of gynecological cancers. We hypothesized that as for other autoimmune diseases, specific HLA haplotypes are associated. We conducted high resolution HLA typing of Class I/Class II in 40 cases versus ethnically matched controls. Three cases with anti-Yo antibodies and peripheral neuropathy were also included. We detected protective effects of DPA1*01:03~DPB1*04:01 (OR=0, p=0.0008), DRB1*04:01~DQA1*03:03(OR=0, p=0.0016) and DPA1*01:03~DPB1*04:01 (OR=0.35, p=0.0047) overall. Increased DRB1*13:01~DQA1*01:03~DQB1*06:03 was also found in PCD ovarian cases (OR=5.4, p=0.0016). These results suggest differential genetic susceptibility to anti-Yo per cancer and with a primary HLA Class II involvement.

  View details for PubMedID 29306402

• Automatic, ECG-based detection of autonomic arousals and their association with cortical arousals, leg movements, and respiratory events in sleep. Sleep Olsen, M. n., Schneider, L. D., Cheung, J. n., Peppard, P. E., Jennum, P. J., Mignot, E. n., Sorensen, H. B. 2018

  Abstract

  The current definition of sleep arousals neglects to address the diversity of arousals and their systemic cohesion. Autonomic arousals (AA) are autonomic activations often associated with cortical arousals (CA), but they may also occur in isolation in relation to a respiratory event, a leg movement event or spontaneously, without any other physiological associations. AA should be acknowledged as essential events to understand and explore the systemic implications of arousals.We developed an automatic AA detection algorithm based on intelligent feature selection and advanced machine learning using the electrocardiogram. The model was trained and tested with respect to CA systematically scored in 258 (181 training size/77 test size) polysomnographic recordings from the Wisconsin Sleep Cohort.A precision value of 0.72 and a sensitivity of 0.63 were achieved when evaluated with respect to CA. Further analysis indicated that 81% of the non-CA-associated AAs were associated with leg movement (38%) or respiratory (43%) events.The presented algorithm shows good performance when considering that more than 80% of the false positives (FP) found by the detection algorithm appeared in relation to either leg movement or respiratory events. This indicates that most FP constitute autonomic activations that are indistinguishable from those with cortical cohesion. The proposed algorithm provides an automatic system trained in a clinical environment, which can be utilized to analyse the systemic and clinical impacts of arousals.

  View details for PubMedID 29329416

• A DEEP LEARNING ARCHITECTURE TO DETECT EVENTS IN EEG SIGNALS DURING SLEEP Chambon, S., Thorey, V., Arnal, P. J., Mignot, E., Gramfort, A., Pustelnik, N., Ma, Z., Tan, Z. H., Larsen, J. IEEE. 2018

  View details for Web of Science ID 000450651000061

• Multiplex family with GAD65-Abs neurologic syndromes NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Belbezier, A., Joubert, B., Montero-Martin, G., Fernandez-Vina, M., Fabien, N., Rogemond, V., Mignot, E., Honnorat, J. 2018; 5 (1): e416

  Abstract

  Neurologic autoimmune syndromes associated with anti-glutamate acid decarboxylase 65 antibodies (GAD65-Abs) are rare and mostly sporadic.We describe a niece and her aunt with GAD65-Abs neurologic syndromes. High-resolution HLA typing of Class I and Class II alleles was performed using next-generation sequencing.The proband had cerebellar ataxia and probable limbic encephalitis features, whereas her niece had stiff-person syndrome. Both had a high titer of GAD65-Abs in serum and CSF and showed signs of inflammation in CSF. Both affected members carried the same rare recombinant DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype, which may or may not be involved in disease susceptibility. Of interest, other unaffected members of the family either had the same HLA haplotype but normal serum GAD65-Abs or had different HLA types but a high titer of serum GAD65-Abs without neurologic symptoms, suggesting cumulative effects.This unique association strengthens the concept that hereditary factors, possibly including specific HLA haplotypes, play a role in neurologic syndromes associated with GAD65-Abs.

  View details for PubMedID 29379821

• Increased EEG Theta Spectral Power in Sleep in Myotonic Dystrophy Type 1. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Cheung, J. n., Ruoff, C. n., Moore, H. n., Hagerman, K. A., Perez, J. n., Sakamuri, S. n., Warby, S. C., Mignot, E. n., Day, J. n., Sampson, J. n. 2018; 14 (2): 229–35

  Abstract

  Myotonic dystrophy type 1 (DM1) is a multisystemic disorder that involves the central nervous system (CNS). Individuals with DM1 commonly present with sleep dysregulation, including excessive daytime sleepiness and sleep-disordered breathing. We aim to characterize electroencephalogram (EEG) power spectra from nocturnal polysomnography (PSG) in patients with DM1 compared to matched controls to better understand the potential CNS sleep dysfunction in DM1.A retrospective, case-control (1:2) chart review of patients with DM1 (n = 18) and matched controls (n = 36) referred for clinical PSG at the Stanford Sleep Center was performed. Controls were matched based on age, sex, apnea-hypopnea index (AHI), body mass index (BMI), and Epworth Sleepiness Scale (ESS). Sleep stage and respiratory metrics for the two groups were compared. Power spectral analysis of the EEG C3-M2 signal was performed using the fast Fourier transformation.Patients with DM1 had significantly increased theta percent power in stage N2 sleep compared to matched controls. Theta/beta and theta/alpha percent power spectral ratios were found to be significantly increased in stage N2, N3, all sleep stages combined, and all wake periods combined in patients with DM1 compared to controls. A significantly lower nadir O2saturation was also found in patients with DM1 versus controls.Compared to matched controls, patients with DM1 had increased EEG theta spectral power. Increased theta/beta and theta/alpha power spectral ratios in nocturnal PSG may reflect DM1 pathology in the CNS.

  View details for PubMedID 29394960

• The MSLT is Repeatable in Narcolepsy Type 1 But Not Narcolepsy Type 2: A Retrospective Patient Study. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Ruoff, C. n., Pizza, F. n., Trotti, L. M., Sonka, K. n., Vandi, S. n., Cheung, J. n., Pinto, S. n., Einen, M. n., Simakajornboon, N. n., Han, F. n., Peppard, P. n., Nevsimalova, S. n., Plazzi, G. n., Rye, D. n., Mignot, E. n. 2018; 14 (1): 65–74

  Abstract

  To examine repeatability of Multiple Sleep Latency Test (MSLT) results in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) according to the criteria of the International Classification of Sleep Disorders, Third Edition (ICSD-3).Repeatability of the MSLT was retrospectively evaluated in NT1 (n = 60) and NT2 (n = 54) cases, and controls (n = 15). All subjects had documented HLA-DQB1*06:02 status and/or hypocretin-1 levels from cerebrospinal fluid. All subjects had undergone 2 MSLTs (≥ 1 meeting ICSD-3 criteria for narcolepsy). Repeatability was explored in children versus adults and in those on versus not on medication(s). Subsample and multivariate analysis were performed.Both MSLTs in unmedicated patients were positive for narcolepsy in 78%, 18%, and 7% of NT1, NT2, and controls, respectively. NT2 cases changed to idiopathic hypersomnia or to a negative MSLT 26% and 57% of the time, respectively. Although NT1 cases were 10 to 14 times more likely to demonstrate a second positive MSLT compared to NT2 cases (P < 10-5) and controls (P < 10-4), respectively, NT2 cases were not significantly different from controls (P = .64). Medication use (P = .009) but not adult versus children status (P = .85) significantly decreased the likelihood of a repeat positive MSLT.In a clinical setting, a positive MSLT for narcolepsy is a more reproducible and stable feature in NT1 than NT2. The retrospective design of this study hinders interpretation of these data, as there are many different, and possibly opposing, reasons to repeat a MSLT in NT1 versus NT2 (ie, ascertainment bias). Additional systematic MSLT repeatability studies independent of confounds are ideally needed to confirm these findings.

  View details for PubMedID 29198301

  View details for PubMedCentralID PMC5734895

• Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels BRAIN Ju, Y. S., Ooms, S. J., Sutphen, C., Macauley, S. L., Zangrilli, M. A., Jerome, G., Fagan, A. M., Mignot, E., Zempel, J. M., Claassen, J. R., Holtzman, D. M. 2017; 140: 2104–11

  Abstract

  See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-β, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-β or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-β, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-β40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-β, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-β levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep.

  View details for PubMedID 28899014

  View details for PubMedCentralID PMC5790144

• Shallow Mixing Layer Downstream from a Sudden Expansion JOURNAL OF HYDRAULIC ENGINEERING Han, L., Mignot, E., Riviere, N. 2017; 143 (5)

  View details for DOI 10.1061/(ASCE)HY.1943-7900.0001274

  View details for Web of Science ID 000398565200006

• Increased EEG theta spectral power in polysomnography of myotonic dystrophy type 1 compared to matched controls. Ruoff, C., Cheung, J., Perez, J., Sakamuri, S., Mignot, E., Day, J., Sampson, J. LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000577381503279

• Diagnostic value of sleep stage dissociation as visualized on a 2-Dimensional sleep state space in human narcolepsy. Journal of neuroscience methods Olsen, A. V., Stephansen, J., Leary, E., Peppard, P. E., Sheungshul, H., Jenum, P., Sorensen, H., Mignot, E. 2017

  Abstract

  Type 1 narcolepsy (NT1) is characterized by symptoms believed to represent Rapid Eye Movement (REM) sleep stage dissociations, occurrences where features of wake and REM sleep are intermingled, resulting in a mixed state. We hypothesized that sleep stage dissociations can be objectively detected through the analysis of nocturnal Polysomnography (PSG) data, and that those affecting REM sleep can be used as a diagnostic feature for narcolepsy.A Linear Discriminant Analysis (LDA) model using 38 features extracted from EOG, EMG and EEG was used in control subjects to select features differentiating wake, stage N1, N2, N3 and REM sleep. Sleep stage differentiation was next represented in a 2D projection. Features characteristic of sleep stage differences were estimated from the residual sleep stage probability in the 2D space. Using this model we evaluated PSG data from NT1 and non-narcoleptic subjects. An LDA classifier was used to determine the best separation plane.This method replicates the specificity/sensitivity from the training set to the validation set better than many other methods.Eight prominent features could differentiate narcolepsy and controls in the validation dataset. Using a composite measure and a specificity cut off 95% in the training dataset, sensitivity was 43%. Specificity/sensitivity was 94%/38% in the validation set. Using hypersomnia subjects, specificity/sensitivity was 84%/15%. Analyzing treated narcoleptics the specificity/sensitivity was 94%/10%.Sleep stage dissociation can be used for the diagnosis of narcolepsy. However the use of some medications and presence of undiagnosed hypersomnolence patients impacts the result.

  View details for DOI 10.1016/j.jneumeth.2017.02.004

  View details for PubMedID 28219726

• Analysis of Hypoxic and Hypercapnic Ventilatory Response in Healthy Volunteers PLOS ONE Goldberg, S., Ollila, H. M., Lin, L., Sharifi, H., Rico, T., Andlauer, O., Aran, A., Bloomrosen, E., Faraco, J., Fang, H., Mignot, E. 2017; 12 (1)

  Abstract

  A previous study has suggested that the Human Leukocyte Antigen (HLA) allele DQB1*06:02 affects hypoxic ventilatory response (HVR) but not hypercapnic ventilatory response (HCVR) in an Asian population. The current study evaluated the relationship in Caucasians and Asians. In addition we assessed whether gender or polymorphisms in genes participating in the control of breathing affect HVR and HCVR.A re-breathing system was used to measure HVR and HCVR in 551 young adults (56.8% Caucasians, 30% Asians). HLA-DQB1*06:02 and tagged polymorphisms and coding variants in genes participating in breathing (PHOX2B, GPR4 and TASK2/KCNK5) were analyzed. The associations between HVR/HCVR and HLA-DQB1*06:02, genetic polymorphisms, and gender were evaluated using ANOVA or frequentist association testing with SNPTEST.HVR and gender are strongly correlated. HCVR and gender are not. Mean HVR in women was 0.276±0.168 (liter/minute/%SpO2) compared to 0.429±0.266 (liter/minute/%SpO2) in men, p<0.001 (55.4% higher HVR in men). Women had lower baseline minute ventilation (8.08±2.36 l/m vs. 10.00±3.43l/m, p<0.001), higher SpO2 (98.0±1.3% vs. 96.6±1.7%, p<0.001), and lower EtCO2 (4.65±0.68% vs. 4.82±1.02%, p = 0.025). One hundred and two (18.5%) of the participants had HLA-DQB1*06:02. No association was seen between HLA-DQB1*06:02 and HVR or HCVR. Genetic analysis revealed point wise, uncorrected significant associations between two TASK2/KCNK5 variants (rs2815118 and rs150380866) and HCVR.This is the largest study to date reporting the relationship between gender and HVR/ HCVR and the first study assessing the association between genetic polymorphisms in humans and HVR/HCVR. The data suggest that gender has a large effect on hypoxic breathing response.

  View details for DOI 10.1371/journal.pone.0168930

  View details for Web of Science ID 000391612300073

  View details for PubMedID 28045995

  View details for PubMedCentralID PMC5207520

• Computing flooding of crossroads with obstacles using a 2D numerical model JOURNAL OF HYDRAULIC RESEARCH Bazin, P., Mignot, E., Paquier, A. 2017; 55 (1): 72-84

  View details for DOI 10.1080/00221686.2016.1217947

  View details for Web of Science ID 000393177900007

• Sedative-Hypnotics AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHOPHARMACOLOGY, 5TH EDITION Nishino, S., Sakai, N., Mishima, K., Mignot, E., Dement, W. C., Schatzberg, A. F., Nemeroff, C. B. 2017: 1051-1082

  View details for Web of Science ID 000550981300061

• Longitudinal associations of hypersomnolence and depression in the Wisconsin Sleep Cohort Study. Journal of affective disorders Plante, D. T., Finn, L. A., Hagen, E. W., Mignot, E., Peppard, P. E. 2017; 207: 197-202

  Abstract

  Hypersomnolence is common in depression, however longitudinal associations of excessive daytime sleepiness (EDS), long habitual sleep duration, and objective sleep propensity with depressive symptomatology are not well established.Data from adults participating in the Wisconsin Sleep Cohort Study who had multiple assessments at 4-year intervals were utilized in analyses. Conditional (intrasubject) logistic regression estimated the likelihood of development of depression and three primary hypersomnolence measures: subjective EDS [Epworth Sleepiness Scale (ESS) >10], habitual sleep duration ≥9h/day, and increased physiological sleep propensity [multiple sleep latency test (MSLT) mean sleep latency <8min].After adjusting for all covariates, the odds for development of depression were significantly increased 1.67-fold (95% CI 1.02-2.73, p=0.04) in participants who also developed subjective EDS. However, development of increased physiological sleep propensity on the MSLT was associated with a trend towards reduced odds for development of depression (odds ratio 0.50, 95% CI 0.24-1.06, p=0.07). No significant longitudinal association between excessive sleep duration and depression was observed.Depression was not verified by psychiatric interview and an objective measure of sleep duration was not utilized.Our results demonstrate a significant longitudinal association between increased subjective EDS and depression. However, increased physiological sleep propensity on the MSLT was paradoxically marginally protective against the development of depression. Further research is indicated to determine the mechanism underling divergent effects of various aspects of hypersomnolence on the course of mood disorders.

  View details for DOI 10.1016/j.jad.2016.08.039

  View details for PubMedID 27723544

  View details for PubMedCentralID PMC5107142

• Autoimmunity in narcolepsy. Current opinion in pulmonary medicine Bonvalet, M. n., Ollila, H. M., Ambati, A. n., Mignot, E. n. 2017; 23 (6): 522–29

  Abstract

  Summarize the recent findings in narcolepsy focusing on the environmental and genetic risk factors in disease development.Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Recent studies suggest both humoral and cellular immune responses in the disease development.Narcolepsy is a severe sleep disorder, in which neurons producing orexin/hypocretin in the hypothalamus are destroyed. The core symptoms of narcolepsy are debilitating, extreme sleepiness, cataplexy, and abnormalities in the structure of sleep. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Importantly, the highest environmental risk is seen with influenza-A infection and immunization. However, how the cells are destroyed is currently unknown. In this review we summarize the disease symptoms, and focus on the immunological findings in narcolepsy. We also discuss the environmental and genetic risk factors as well as propose a model for disease development.

  View details for PubMedID 28991006

  View details for PubMedCentralID PMC5773260

• Diagnosis and Management of Narcolepsy. Seminars in neurology Schneider, L. n., Mignot, E. n. 2017; 37 (4): 446–60

  View details for PubMedID 28837992

• Breathing Disturbances Without Hypoxia Are Associated With Objective Sleepiness in Sleep Apnea. Sleep Koch, H. n., Schneider, L. D., Finn, L. A., Leary, E. B., Peppard, P. E., Hagen, E. n., Sorensen, H. B., Jennum, P. n., Mignot, E. n. 2017; 40 (11)

  Abstract

  To determine whether defining two subtypes of sleep-disordered breathing (SDB) events-with or without hypoxia-results in measures that are more strongly associated with hypertension and sleepiness.A total of 1022 participants with 2112 nocturnal polysomnograms from the Wisconsin Sleep Cohort were analyzed with our automated algorithm, developed to detect breathing disturbances and desaturations. Breathing events were time-locked to desaturations, resulting in two indices-desaturating (hypoxia-breathing disturbance index [H-BDI]) and nondesaturating (nonhypoxia-breathing disturbance index [NH-BDI]) events-regardless of arousals. Measures of subjective (Epworth Sleepiness Scale) and objective (2981 multiple sleep latency tests from a subset of 865 participants) sleepiness were analyzed, in addition to clinically relevant clinicodemographic variables. Hypertension was defined as BP ≥ 140/90 or antihypertensive use.H-BDI, but not NH-BDI, correlated strongly with SDB severity indices that included hypoxia (r ≥ 0.89, p ≤ .001 with 3% oxygen-desaturation index [ODI] and apnea hypopnea index with 4% desaturations). A doubling of desaturation-associated events was associated with hypertension prevalence, which was significant for ODI but not H-BDI (3% ODI OR = 1.06, 95% CI = 1.00-1.12, p < .05; H-BDI OR 1.04, 95% CI = 0.98-1.10) and daytime sleepiness (β = 0.20 Epworth Sleepiness Scale [ESS] score, p < .0001; β = -0.20 minutes in MSL on multiple sleep latency test [MSLT], p < .01). Independently, nondesaturating event doubling was associated with more objective sleepiness (β = -0.52 minutes in MSL on MSLT, p < .001), but had less association with subjective sleepiness (β = 0.12 ESS score, p = .10). In longitudinal analyses, baseline nondesaturating events were associated with worsening of H-BDI over a 4-year follow-up, suggesting evolution in severity.In SDB, nondesaturating events are independently associated with objective daytime sleepiness, beyond the effect of desaturating events.

  View details for PubMedID 29029253

• Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases. PloS one Luo, G. n., Lin, L. n., Jacob, L. n., Bonvalet, M. n., Ambati, A. n., Plazzi, G. n., Pizza, F. n., Leib, R. n., Adams, C. M., Partinen, M. n., Mignot, E. J. 2017; 12 (12): e0187305

  Abstract

  A recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies.MS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (≤6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA).NP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA), a mimic to HCRTR234-45 (YDDEEFLRYLWR), was not found to bind to DQ0602. Three or four subjects were found positive for anti-HCRTR2 autoantibodies using two strategies or the third one, respectively. None of the post Pandemrix® narcolepsy cases (0 of 40 sera) was found positive with all three strategies.Anti-HCRTR2 autoantibody is not a significant biological feature of narcolepsy or of post Pandemrix® autoimmune responses.

  View details for PubMedID 29220370

  View details for PubMedCentralID PMC5722318

• Feasibility of Obtaining Measures of Lifestyle From a Smartphone App: The MyHeart Counts Cardiovascular Health Study. JAMA cardiology McConnell, M. V., Shcherbina, A., Pavlovic, A., Homburger, J. R., Goldfeder, R. L., Waggot, D., Cho, M. K., Rosenberger, M. E., Haskell, W. L., Myers, J., Champagne, M. A., Mignot, E., Landray, M., Tarassenko, L., Harrington, R. A., Yeung, A. C., Ashley, E. A. 2017; 2 (1): 67-76

  Abstract

  Studies have established the importance of physical activity and fitness, yet limited data exist on the associations between objective, real-world physical activity patterns, fitness, sleep, and cardiovascular health.To assess the feasibility of obtaining measures of physical activity, fitness, and sleep from smartphones and to gain insights into activity patterns associated with life satisfaction and self-reported disease.The MyHeart Counts smartphone app was made available in March 2015, and prospective participants downloaded the free app between March and October 2015. In this smartphone-based study of cardiovascular health, participants recorded physical activity, filled out health questionnaires, and completed a 6-minute walk test. The app was available to download within the United States.The feasibility of consent and data collection entirely on a smartphone, the use of machine learning to cluster participants, and the associations between activity patterns, life satisfaction, and self-reported disease.From the launch to the time of the data freeze for this study (March to October 2015), the number of individuals (self-selected) who consented to participate was 48 968, representing all 50 states and the District of Columbia. Their median age was 36 years (interquartile range, 27-50 years), and 82.2% (30 338 male, 6556 female, 10 other, and 3115 unknown) were male. In total, 40 017 (81.7% of those who consented) uploaded data. Among those who consented, 20 345 individuals (41.5%) completed 4 of the 7 days of motion data collection, and 4552 individuals (9.3%) completed all 7 days. Among those who consented, 40 017 (81.7%) filled out some portion of the questionnaires, and 4990 (10.2%) completed the 6-minute walk test, made available only at the end of 7 days. The Heart Age Questionnaire, also available after 7 days, required entering lipid values and age 40 to 79 years (among 17 245 individuals, 43.1% of participants). Consequently, 1334 (2.7%) of those who consented completed all fields needed to compute heart age and a 10-year risk score. Physical activity was detected for a mean (SD) of 14.5% (8.0%) of individuals' total recorded time. Physical activity patterns were identified by cluster analysis. A pattern of lower overall activity but more frequent transitions between active and inactive states was associated with equivalent self-reported cardiovascular disease as a pattern of higher overall activity with fewer transitions. Individuals' perception of their activity and risk bore little relation to sensor-estimated activity or calculated cardiovascular risk.A smartphone-based study of cardiovascular health is feasible, and improvements in participant diversity and engagement will maximize yield from consented participants. Large-scale, real-world assessment of physical activity, fitness, and sleep using mobile devices may be a useful addition to future population health studies.

  View details for DOI 10.1001/jamacardio.2016.4395

  View details for PubMedID 27973671

• Longitudinal associations of hypersomnolence and depression in the Wisconsin Sleep Cohort Study JOURNAL OF AFFECTIVE DISORDERS Plante, D. T., Finn, L. A., Hagen, E. W., Mignot, E., Peppard, P. E. 2017; 207: 197-202

  Abstract

  Hypersomnolence is common in depression, however longitudinal associations of excessive daytime sleepiness (EDS), long habitual sleep duration, and objective sleep propensity with depressive symptomatology are not well established.Data from adults participating in the Wisconsin Sleep Cohort Study who had multiple assessments at 4-year intervals were utilized in analyses. Conditional (intrasubject) logistic regression estimated the likelihood of development of depression and three primary hypersomnolence measures: subjective EDS [Epworth Sleepiness Scale (ESS) >10], habitual sleep duration ≥9h/day, and increased physiological sleep propensity [multiple sleep latency test (MSLT) mean sleep latency <8min].After adjusting for all covariates, the odds for development of depression were significantly increased 1.67-fold (95% CI 1.02-2.73, p=0.04) in participants who also developed subjective EDS. However, development of increased physiological sleep propensity on the MSLT was associated with a trend towards reduced odds for development of depression (odds ratio 0.50, 95% CI 0.24-1.06, p=0.07). No significant longitudinal association between excessive sleep duration and depression was observed.Depression was not verified by psychiatric interview and an objective measure of sleep duration was not utilized.Our results demonstrate a significant longitudinal association between increased subjective EDS and depression. However, increased physiological sleep propensity on the MSLT was paradoxically marginally protective against the development of depression. Further research is indicated to determine the mechanism underling divergent effects of various aspects of hypersomnolence on the course of mood disorders.

  View details for DOI 10.1016/j.jad.2016.08.039

  View details for Web of Science ID 000389088600029

  View details for PubMedCentralID PMC5107142

• Typology of the flow structures in dividing open channel flows JOURNAL OF HYDRAULIC RESEARCH Momplot, A., Kouyi, G. L., Mignot, E., Riviere, N., Bertrand-Krajewski, J. 2017; 55 (1): 63-71

  View details for DOI 10.1080/00221686.2016.1212409

  View details for Web of Science ID 000393177900006

• Turbulent Viscosity Concept Downstream an Open-Channel Sudden Expansion JOURNAL OF APPLIED FLUID MECHANICS Han, L., Mignot, E., Riviere, N. 2016; 9 (5): 2311-2319

  View details for Web of Science ID 000383413800022

• Effect of liraglutide 3.0?mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. International journal of obesity Blackman, A., Foster, G. D., Zammit, G., Rosenberg, R., Aronne, L., Wadden, T., Claudius, B., Jensen, C. B., Mignot, E. 2016; 40 (8): 1310-1319

  Abstract

  Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity.To investigate whether liraglutide 3.0 mg reduces OSA severity compared with placebo using the primary end point of change in apnea-hypopnea index (AHI) after 32 weeks. Liraglutide's weight loss efficacy was also examined.In this randomized, double-blind trial, non-diabetic participants with obesity who had moderate (AHI 15-29.9 events h(-1)) or severe (AHI ⩾30 events h(-1)) OSA and were unwilling/unable to use continuous positive airway pressure therapy were randomized for 32 weeks to liraglutide 3.0 mg (n=180) or placebo (n=179), both as adjunct to diet (500 kcal day(-1) deficit) and exercise. Baseline characteristics were similar between groups (mean age 48.5 years, males 71.9%, AHI 49.2 events h(-1), severe OSA 67.1%, body weight 117.6 kg, body mass index 39.1 kg m(-2), prediabetes 63.2%, HbA1c 5.7%).After 32 weeks, the mean reduction in AHI was greater with liraglutide than with placebo (-12.2 vs -6.1 events h(-1), estimated treatment difference: -6.1 events h(-1) (95% confidence interval (CI), -11.0 to -1.2), P=0.0150). Liraglutide produced greater mean percentage weight loss compared with placebo (-5.7% vs -1.6%, estimated treatment difference: -4.2% (95% CI, -5.2 to -3.1%), P<0.0001). A statistically significant association between the degree of weight loss and improvement in OSA end points (P<0.01, all) was demonstrated post hoc. Greater reductions in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) were seen with liraglutide versus placebo (both P<0.001). The safety profile of liraglutide 3.0 mg was similar to that seen with doses ⩽1.8 mg.As an adjunct to diet and exercise, liraglutide 3.0 mg was generally well tolerated and produced significantly greater reductions than placebo in AHI, body weight, SBP and HbA1c in participants with obesity and moderate/severe OSA. The results confirm that weight loss improves OSA-related parameters.

  View details for DOI 10.1038/ijo.2016.52

  View details for PubMedID 27005405

  View details for PubMedCentralID PMC4973216

• Familial Kleine-Levin Syndrome: A Specific Entity? SLEEP Quang Tuan Remy Nguyen, Q. T., Groos, E., Leclair-Visonneau, L., Monaca-Charley, C., Rico, T., Farber, N., Mignot, E., Arnulf, I. 2016; 39 (8): 1535-1542

  Abstract

  Kleine-Levin syndrome (KLS) is a rare, mostly sporadic disorder, characterized by intermittent episodes of hypersomnia plus cognitive and behavior disorders. Although its cause is unknown, multiplex families have been described. We contrasted the clinical and biological features of familial versus sporadic KLS.Two samples of patients with KLS from the United States and France (n = 260) were studied using clinical interviews and human leukocyte antigen (HLA) genotyping. A multiplex family contained two or more first- or second-degree affected relatives (familial cases).Twenty-one patients from 10 multiplex families (siblings: n = 12, including two pairs of monozygotic twins; parent-child: n = 4; cousins: n = 2; uncle-nephews: n = 3) and 239 patients with sporadic KLS were identified, yielding to 4% multiplex families and 8% familial cases. The simplex and multiplex families did not differ for autoimmune, neurological, and psychiatric disorders. Age, sex ratio, ethnicity, HLA typing, karyotyping, disease course, frequency, and duration of KLS episodes did not differ between groups. Episodes were less frequent in familial versus sporadic KLS (2.3 ± 1.8/y versus 3.8 ± 3.7/y, P = 0.004). Menses triggered more frequently KLS onset in the nine girls with familial KLS (relative risk, RR = 4.12, P = 0.03), but not subsequent episodes. Familial cases had less disinhibited speech (RR = 3.44, P = 0.049), less combined hypophagia/hyperphagia (RR = 4.38, P = 0.006), more abrupt termination of episodes (RR = 1.45, P = 0.04) and less postepisode insomnia (RR = 2.16, P = 0.008). There was similar HLA DQB1 distribution in familial versus sporadic cases and no abnormal karyotypes.Familial KLS is mostly present in the same generation, and is clinically similar to but slightly less severe than sporadic KLS.

  View details for DOI 10.5665/sleep.6014

  View details for Web of Science ID 000381746800008

  View details for PubMedID 27253765

  View details for PubMedCentralID PMC4945312

• Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area SLEEP Gavrilov, Y. V., Ellison, B. A., Yamamoto, M., Reddy, H., Haybaeck, J., Mignot, E., Baumann, C. R., Scammell, T. E., Valko, P. O. 2016; 39 (5): 1059-1062

  Abstract

  To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients.Postmortem examination of five narcolepsy and eight control brains.VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544).A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease.

  View details for DOI 10.5665/sleep.5754

  View details for Web of Science ID 000375188400013

  View details for PubMedID 26951397

  View details for PubMedCentralID PMC4835304

• Clear-Water Scouring Process in a Flow in Supercritical Regime JOURNAL OF HYDRAULIC ENGINEERING Mignot, E., Moyne, T., Doppler, D., Riviere, N. 2016; 142 (4)

  View details for DOI 10.1061/(ASCE)HY.1943-7900.0001100

  View details for Web of Science ID 000372803100002

• AN ACCURATE GENOTYPING METHOD FOR HUMAN LEUKOCYTE ANTIGEN BASED ON NEXT GENERATION SEQUENCING TECHNOLOGY Li, M., Mindrinos, M., Wang, C., Sargsyan, O., Thorstenson, Y., Babrzaeh, F., Mignot, E., Ollila, H., Vina, M., Levinson, D. WILEY-BLACKWELL. 2016: 280–81

  View details for Web of Science ID 000383951500196

• FEASIBILITY OF GENETIC ASSOCIATION STUDIES WITH THE HIGH THROUGHPUT MIA FORA NGS ASSAY Wang, C., Li, M., Krishnakumar, S., Sargsyan, O., Gaule, A., Thorstenson, Y., Simonovich, J., Munoz, A., Draina, E., Fukushima, M., Babrzadeh, F., Kuehn, R., Abraham, E., Bugtong, K., Fernandez-Vina, M., Mignot, E., Ollila, H., Levinson, D., Mindrinos, M. WILEY-BLACKWELL. 2016: 284–85

  View details for Web of Science ID 000383951500206

• Coherent turbulent structures at the mixing-interface of a square open-channel lateral cavity PHYSICS OF FLUIDS Mignot, E., Cai, W., Launay, G., Riviere, N., Escauriaza, C. 2016; 28 (4)

  View details for DOI 10.1063/1.4945264

  View details for Web of Science ID 000377709000032

• Subjective and Objective Measures of Hypersomnolence Demonstrate Divergent Associations with Depression among Participants in the Wisconsin Sleep Cohort Study JOURNAL OF CLINICAL SLEEP MEDICINE Plante, D. T., Finn, L. A., Hagen, E. W., Mignot, E., Peppard, P. E. 2016; 12 (4): 571-578

  Abstract

  To examine associations of depression with habitual sleep duration, daytime sleepiness, and objective sleep propensity in a nonclinical population.Data from adults participating in the Wisconsin Sleep Cohort Study were utilized in analyses. There were 1,287 adults (3,324 observations) who were used in the analysis of subjective hypersomnolence measures; 1,155 adults (2,981 observations) were used in the analysis of objective sleep propensity assessed by the multiple sleep latency test (MSLT). Repeated-measures logistic regression estimated associations between presence of depression (defined as modified Zung Self-Rating Depression Scale ≥ 50 or use of antidepressant medications) and three primary hypersomnolence measures: subjective excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] ≥ 11), self-reported sleep duration ≥ 9 h/d, and objective sleep propensity (MSLT mean sleep latency < 8 min).After adjusting for age, sex, body mass index, chronic medical conditions, sedative hypnotic medication use, caffeine, tobacco, and alcohol use, sleep disordered breathing, as well as insomnia and sleep duration when appropriate, estimated odd ratios (95% confidence interval) for depression were: 1.56 (1.31,1.86) for ESS ≥ 11; 2.01 (1.49, 2.72) for habitual sleep time ≥ 9 h; and 0.76 (0.63-0.92) for MSLT mean sleep latency < 8 min.Our results demonstrate divergent associations between subjective and objective symptoms of hypersomnolence and depression, with subjective sleepiness and excessive sleep duration associated with increased odds of depression, but objective sleep propensity as measured by the MSLT associated with decreased odds of depression. Further research is indicated to explain this paradox and the impact of different hypersomnolence measures on the course of mood disorders.A commentary on this article appears in this issue on page 467.

  View details for DOI 10.5664/jcsm.5694

  View details for Web of Science ID 000374140000016

  View details for PubMedID 26888592

  View details for PubMedCentralID PMC4795285

• VALIDATION OF GENOTYPING METHOD FOR HUMAN LEUKOCYTE ANTIGEN BASED ON NEXT GENERATION SEQUENCING TECHNOLOGY Li, M., Mindrinos, M., Wang, C., Drainas, E., Babrzadeh, F., Vina, M., Mignot, E., Ollila, H., Levinson, D. ELSEVIER SCIENCE INC. 2016: 118

  View details for DOI 10.1016/j.humimm.2016.07.174

  View details for Web of Science ID 000383313500163

• Immunologic and Genetic Aspects of Type 1 Narcolepsy GENOMICS, CIRCUITS, AND PATHWAYS IN CLINICAL NEUROPSYCHIATRY Jacob, L., Ollila, H. M., Mahlios, J., Mignot, E., Lehner, T., Miller, B. L., State, M. W. 2016: 635–52

  View details for DOI 10.1016/B978-0-12-800105-9.00039-1

  View details for Web of Science ID 000416943300040

• Urban domestic wastewater: how to reduce individual injection? WATER SCIENCE AND TECHNOLOGY Polome, P., Mignot, E., Nasri, A., Kouyi, G. L., Campan, L., Hooge, C., Riviere, N. 2016; 73 (1): 144-152

  Abstract

  The present paper aims to identify ways to reduce pollution injected by residents in the urban wastewater network system. Two approaches are considered. The first one uses flow and pollutant calculation to test whether a polluter can easily be identified in a neighborhood. The second approach uses a survey to examine what incentive would be most effective to influence residents' behavior. Hydrodynamic simulation results show that concentration profiles at the network outlet corresponding to all possible polluters are similar and thus do not point out specific resident source of pollution. Household-level survey results show that most socio-economic and public-good-related characteristics do not play a significant role in explaining choices to discard in the home wastewater network. Apart from the nature of the waste itself, by far the belief that the respondent has about neighbors' and relatives' discarding behavior is the main driver of the choice.

  View details for DOI 10.2166/wst.2015.473

  View details for Web of Science ID 000374395100016

  View details for PubMedID 26744945

• Sleep-stage transitions during polysomnographic recordings as diagnostic features of type 1 narcolepsy. Sleep medicine Christensen, J. A., Carrillo, O., Leary, E. B., Peppard, P. E., Young, T., Sorensen, H. B., Jennum, P., Mignot, E. 2015; 16 (12): 1558-1566

  Abstract

  Type 1 narcolepsy/hypocretin deficiency is characterized by excessive daytime sleepiness, sleep fragmentation, and cataplexy. Short rapid eye movement (REM) latency (≤15 min) during nocturnal polysomnography (PSG) or during naps of the multiple sleep latency test (MSLT) defines a sleep-onset REM sleep period (SOREMP), a diagnostic hallmark. We hypothesized that abnormal sleep transitions other than SOREMPs can be identified in type 1 narcolepsy.Sleep-stage transitions (one to 10 epochs to one to five epochs of any other stage) and bout length features (one to 10 epochs) were extracted from PSGs. The first 15 min of sleep were excluded when a nocturnal SOREMP was recorded. F(0.1) measures and receiver operating characteristic curves were used to identify specific (≥98%) features. A data set of 136 patients and 510 sex- and age-matched controls was used for the training. A data set of 19 cases and 708 sleep-clinic patients was used for the validation.(1) ≥5 transitions from ≥5 epochs of stage N1 or W to ≥2 epochs of REM sleep, (2) ≥22 transitions from ≥3 epochs of stage N2 or N3 to ≥2 epochs of N1 or W, and (3) ≥16 bouts of ≥6 epochs of N1 or W were found to be highly specific (≥98%). Sensitivity ranged from 16% to 30%, and it did not vary substantially with and without medication or a nocturnal SOREMP. In patients taking antidepressants, nocturnal SOREMPs occurred much less frequently (16% vs. 36%, p < 0.001).Increased sleep-stage transitions notably from ≥2.5 min of W/N1 into REM are specifically diagnostic for narcolepsy independent of a nocturnal SOREMP.

  View details for DOI 10.1016/j.sleep.2015.06.007

  View details for PubMedID 26299470

• The diagnostic value of power spectra analysis of the sleep electroencephalography in narcoleptic patients SLEEP MEDICINE Christensen, J. A., Munk, E. G., Peppard, P. E., Young, T., Mignot, E., Sorensen, H. B., Jennum, P. 2015; 16 (12): 1516-1527

  Abstract

  Manifestations of narcolepsy with cataplexy (NC) include disturbed nocturnal sleep - hereunder sleep-wake instability, decreased latency to rapid eye movement (REM) sleep, and dissociated REM sleep events. In this study, we characterized the electroencephalography (EEG) of various sleep stages in NC versus controls.EEG power spectral density (PSD) was computed in 136 NC patients and 510 sex- and age-matched controls. Features reflecting differences in PSD curves were computed. A Lasso-regularized regression model was used to find an optimal feature subset, which was validated on 19 NC patients and 708 non-NC patients from a sleep clinic. Reproducible features were analyzed using receiver operating characteristic (ROC) curves.Thirteen features were selected based on the training dataset. Three were applicable in the validation dataset, indicating that NC patients show (1) increased alpha power in REM sleep, (2) decreased sigma power in wakefulness, and (3) decreased delta power in stage N1 versus wakefulness. Sensitivity of these features ranged from 4% to 10% with specificity around 98%, and it did not vary substantially with and without treatment.EEG spectral analysis of REM sleep, wake, and differences between N1 and wakefulness contain diagnostic features of NC. These traits may represent sleepiness and dissociated REM sleep in patients with NC. However, the features are not sufficient for differentiating NC from controls, and further analysis is needed to completely evaluate the diagnostic potential of these features.

  View details for DOI 10.1016/j.sleep.2015.09.005

  View details for Web of Science ID 000365348900010

  View details for PubMedID 26611950

• Narcolepsy in African Americans SLEEP Kawai, M., O'Hara, R., Einen, M., Lin, L., Mignot, E. 2015; 38 (11): 1673-1681

  Abstract

  Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States.Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level.182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy.Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%).Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy.

  View details for DOI 10.5665/sleep.5140

  View details for Web of Science ID 000363740100006

  View details for PubMedCentralID PMC4813366

• Narcolepsy in African Americans. Sleep Kawai, M., O'Hara, R., Einen, M., Lin, L., Mignot, E. 2015; 38 (11): 1673-81

  Abstract

  Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States.Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level.182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy.Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%).Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy.

  View details for DOI 10.5665/sleep.5140

  View details for PubMedID 26158891

  View details for PubMedCentralID PMC4813366

• Association of low ferritin with PLM in the Wisconsin Sleep Cohort. Sleep medicine Li, J., Moore, H., Lin, L., Young, T., Finn, L., Peppard, P. E., Mignot, E. 2015; 16 (11): 1413-1418

  Abstract

  The origins of periodic leg movements (PLMs), a strong correlate of restless legs syndrome (RLS), are uncertain. This study was performed to assess the relationship between PLMs and peripheral iron deficiency, as measured with ferritin levels corrected for inflammation.We included a cross-sectional sample of a cohort study of 801 randomly selected people (n = 1008 assays, mean age 58.6 ± 0.3 years) from Wisconsin state employee agencies. A previously validated automatic detector was used to measure PLMs during sleep. The patients were categorized into RLS symptoms-positive and RLS symptoms-negative based on a mailed survey response and prior analysis. Analyses were performed using a linear model with PLM category above and below 15 PLM/h (periodic leg movement index, PLMI) as the dependent variable, and adjusting for known covariates, including previously associated single-nucleotide polymorphisms (SNPs) within BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Ferritin and C-reactive protein (CRP) levels were measured in serum, and ferritin levels corrected for inflammation using CRP levels.After controlling for cofactors, PLMI ≥ 15 was associated with low (≤50 ng/mL) ferritin levels (OR = 1.55, p = 0.020). The best model was found using quasi-least squares regression of ferritin as a function of PLMI, with an increase of 0.0034 PLM/h predicted by a decrease of 1 ng/mL ferritin (p = 0.00447).An association was found between low ferritin and greater PLMs in a general population of older adults, independent of genetic polymorphisms, suggesting a role of low iron stores in the expression of these phenotypes. Patients with high PLMI may require to be checked for iron deficiency.

  View details for DOI 10.1016/j.sleep.2015.05.015

  View details for PubMedID 26498245

• Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Molecular psychiatry Gottlieb, D. J., Hek, K., Chen, T., Watson, N. F., Eiriksdottir, G., Byrne, E. M., Cornelis, M., Warby, S. C., Bandinelli, S., Cherkas, L., Evans, D. S., Grabe, H. J., Lahti, J., Li, M., Lehtimäki, T., Lumley, T., Marciante, K. D., Pérusse, L., Psaty, B. M., Robbins, J., Tranah, G. J., Vink, J. M., Wilk, J. B., Stafford, J. M., Bellis, C., Biffar, R., Bouchard, C., Cade, B., Curhan, G. C., Eriksson, J. G., Ewert, R., Ferrucci, L., Fülöp, T., Gehrman, P. R., Goodloe, R., Harris, T. B., Heath, A. C., Hernandez, D., Hofman, A., Hottenga, J., Hunter, D. J., Jensen, M. K., Johnson, A. D., Kähönen, M., Kao, L., Kraft, P., Larkin, E. K., Lauderdale, D. S., Luik, A. I., Medici, M., Montgomery, G. W., PALOTIE, A., Patel, S. R., Pistis, G., Porcu, E., Quaye, L., Raitakari, O., Redline, S., Rimm, E. B., Rotter, J. I., Smith, A. V., Spector, T. D., Teumer, A., Uitterlinden, A. G., Vohl, M., Widen, E., Willemsen, G., Young, T., Zhang, X., Liu, Y., Blangero, J., Boomsma, D. I., Gudnason, V., Hu, F., Mangino, M., Martin, N. G., O'Connor, G. T., Stone, K. L., Tanaka, T., Viikari, J., Gharib, S. A., Punjabi, N. M., Räikkönen, K., Völzke, H., Mignot, E., Tiemeier, H. 2015; 20 (10): 1232-1239

  Abstract

  Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

  View details for DOI 10.1038/mp.2014.133

  View details for PubMedID 25469926

  View details for PubMedCentralID PMC4430294

• A new flow structure in a dividing open channel HOUILLE BLANCHE-REVUE INTERNATIONALE DE L EAU Momplot, A., Lipeme Kouyi, G., Mignot, E., Riviere, N., Bertrand-Krajewski, J. 2015: 78-83

  View details for DOI 10.1051/lhb/20150058

  View details for Web of Science ID 000364452300010

• Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset BRAIN BEHAVIOR AND IMMUNITY Kornum, B. R., Pizza, F., Knudsen, S., Plazzi, G., Jennum, P., Mignot, E. 2015; 49: 54-58

  Abstract

  Type 1 narcolepsy is caused by a loss of hypocretin (orexin) signaling in the brain. Genetic data suggests the disorder is caused by an autoimmune attack on hypocretin producing neurons in hypothalamus. This hypothesis has however not yet been confirmed by consistent findings of autoreactive antibodies or T-cells in patient samples. One explanation for these negative results may be that the autoimmune process is no longer active when patients present to the clinic. With increasing awareness in recent years, more and more patients have been diagnosed closer and closer to disease onset. In this study, we tested whether an active immune process in the brain could be detected in these patients, as reflected by increased cytokine levels in the cerebrospinal fluid (CSF). Using multiplex analysis, we measured the levels of 51 cytokines and chemokines in the CSF of 40 type 1 narcolepsy patients having varying disease duration. For comparison, we used samples from 9 healthy controls and 9 patients with other central hypersomnia. Cytokine levels did not differ significantly between controls and patients, even in 5 patients with disease onset less than a month prior to CSF sampling.

  View details for DOI 10.1016/j.bbi.2015.03.004

  View details for Web of Science ID 000361257900008

  View details for PubMedID 25771509

  View details for PubMedCentralID PMC4567452

• EIF3G is associated with narcolepsy across ethnicities EUROPEAN JOURNAL OF HUMAN GENETICS Holm, A., Lin, L., Faraco, J., Mostafavi, S., Battle, A., Zhu, X., Levinson, D. F., Han, F., Gammeltoft, S., Jennum, P., Mignot, E., Kornum, B. R. 2015; 23 (11): 1573-1580

  Abstract

  Type 1 narcolepsy, an autoimmune disease affecting hypocretin (orexin) neurons, is strongly associated with HLA-DQB1*06:02. Among polymorphisms associated with the disease is single-nucleotide polymorphism rs2305795 (c.*638G>A) located within the P2RY11 gene. P2RY11 is in a region of synteny conserved in mammals and zebrafish containing PPAN, EIF3G and DNMT1 (DNA methyltransferase 1). As mutations in DNMT1 cause a rare dominant form of narcolepsy in association with deafness, cerebellar ataxia and dementia, we questioned whether the association with P2RY11 in sporadic narcolepsy could be secondary to linkage disequilibrium with DNMT1. Based on genome-wide association data from two cohorts of European and Chinese ancestry, we found that the narcolepsy association signal drops sharply between P2RY11/EIF3G and DNMT1, suggesting that the association with narcolepsy does not extend into the DNMT1 gene region. Interestingly, using transethnic mapping, we identified a novel single-nucleotide polymorphism rs3826784 (c.596-260A>G) in the EIF3G gene also associated with narcolepsy. The disease-associated allele increases EIF3G mRNA expression. EIF3G is located in the narcolepsy risk locus and EIF3G expression correlates with PPAN and P2RY11 expression. This suggests shared regulatory mechanisms that might be affected by the polymorphism and are of relevance to narcolepsy.

  View details for DOI 10.1038/ejhg.2015.4

  View details for PubMedID 25669430

• Applying the Test-Negative Design to Vaccine Safety Studies: Risk of Narcolepsy Associated with A/H1N1 (2009) Pandemic Influenza Vaccination in Quebec Cohet, C., Montplaisir, J., Petit, D., Quinn, M., Ouakki, M., Deceuninck, G., Desautels, A., Mignot, E., Bauchau, V., Shinde, V., De Wals, P. WILEY-BLACKWELL. 2015: 406–7

  View details for Web of Science ID 000369980201005

• Inter-expert and intra-expert reliability in sleep spindle scoring. Clinical neurophysiology Wendt, S. L., Welinder, P., Sorensen, H. B., Peppard, P. E., Jennum, P., Perona, P., Mignot, E., Warby, S. C. 2015; 126 (8): 1548-1556

  Abstract

  To measure the inter-expert and intra-expert agreement in sleep spindle scoring, and to quantify how many experts are needed to build a reliable dataset of sleep spindle scorings.The EEG dataset was comprised of 400 randomly selected 115s segments of stage 2 sleep from 110 sleeping subjects in the general population (57±8, range: 42-72years). To assess expert agreement, a total of 24 Registered Polysomnographic Technologists (RPSGTs) scored spindles in a subset of the EEG dataset at a single electrode location (C3-M2). Intra-expert and inter-expert agreements were calculated as F1-scores, Cohen's kappa (κ), and intra-class correlation coefficient (ICC).We found an average intra-expert F1-score agreement of 72±7% (κ: 0.66±0.07). The average inter-expert agreement was 61±6% (κ: 0.52±0.07). Amplitude and frequency of discrete spindles were calculated with higher reliability than the estimation of spindle duration. Reliability of sleep spindle scoring can be improved by using qualitative confidence scores, rather than a dichotomous yes/no scoring system.We estimate that 2-3 experts are needed to build a spindle scoring dataset with 'substantial' reliability (κ: 0.61-0.8), and 4 or more experts are needed to build a dataset with 'almost perfect' reliability (κ: 0.81-1).Spindle scoring is a critical part of sleep staging, and spindles are believed to play an important role in development, aging, and diseases of the nervous system.

  View details for DOI 10.1016/j.clinph.2014.10.158

  View details for PubMedID 25434753

  View details for PubMedCentralID PMC4426257

• Nocturnal Sleep Dynamics Identify Narcolepsy Type 1. Sleep Pizza, F., Vandi, S., Iloti, M., Franceschini, C., Liguori, R., Mignot, E., Plazzi, G. 2015; 38 (8): 1277-84

  Abstract

  To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence.Cross-sectional.Sleep laboratory.One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52).None.Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1.Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P < 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P < 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P < 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P < 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P < 0.0001) and at MSLT (0.956 ± 0.015, P < 0.0001).Sleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies hypocretin-deficient narcolepsy type 1 among central disorders of hypersomnolence.

  View details for DOI 10.5665/sleep.4908

  View details for PubMedID 25845690

  View details for PubMedCentralID PMC4507733

• Nocturnal Sleep Dynamics Identify Narcolepsy Type 1 SLEEP Pizza, F., Vandi, S., Iloti, M., Franceschini, C., Liguori, R., Mignot, E., Plazzi, G. 2015; 38 (8): 1277-U132

  Abstract

  To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence.Cross-sectional.Sleep laboratory.One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52).None.Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1.Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P < 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P < 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P < 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P < 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P < 0.0001) and at MSLT (0.956 ± 0.015, P < 0.0001).Sleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies hypocretin-deficient narcolepsy type 1 among central disorders of hypersomnolence.

  View details for DOI 10.5665/sleep.4908

  View details for Web of Science ID 000358838100017

  View details for PubMedCentralID PMC4507733

• Serum cytokine levels in Kleine-Levin syndrome SLEEP MEDICINE Kornum, B. R., Rico, T., Lin, L., Huang, Y., Arnulf, I., Jennum, P., Mignot, E. 2015; 16 (8): 961-965

  Abstract

  Kleine-Levin Syndrome (KLS) is a rare sleep disorder causing recurrent symptomatic episodes of severe hypersomnia, cognitive impairment, apathy, and derealization. These episodes are interspersed with long periods of normal sleep, cognition, and behavior. The pathogenesis of KLS is still unknown. The objective of this study was to determine serum cytokine levels in patients with KLS during and between episodes.Fifty-two typical KLS patients were included in the study of whom 17 patients donated blood samples both during and between episodes. Blood samples were collected in USA, France, and Taiwan in a clinical setting. Processing of the samples was performed at the Stanford Center for Sleep Sciences and Medicine.We did not observe any changes in serum cytokine levels during KLS episodes compared to between episodes. In a small cohort of asymptomatic KLS patients and age- and gender matched healthy controls (n = 8/group) whose blood samples were all collected and processed at the same day; asymptomatic KLS patients had significantly higher levels of serum sVCAM1 cytokine compared to healthy controls.These data suggest that KLS episodes are not accompanied by an abnormal systemic immune reaction.

  View details for DOI 10.1016/j.sleep.2015.02.540

  View details for Web of Science ID 000358087000011

• Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain, behavior, and immunity Jacob, L., Leib, R., Ollila, H. M., Bonvalet, M., Adams, C. M., Mignot, E. 2015; 47: 44-57

  Abstract

  Narcolepsy onset in children has been associated with the 2009 influenza A H1N1 pandemic and vaccination with Pandemrix. However it was not clearly observed with other adjuvanted pH1N1 vaccines such as Arepanrix or Focetria. Our aim was to characterize the differences between Pandemrix and Arepanrix that might explain the risk for narcolepsy after Pandemrix vaccination using 2D-DIGE and mass spectrometry (MS). We found that Pandemrix (2009 batch) and Arepanrix (2010 batch) showed 5 main viral proteins: hemagglutinin HA1 and HA2 subunits, neuraminidase NA, nucleoprotein NP, and matrix protein MA1 and non-viral proteins from the Gallus gallus growth matrix used in the manufacturing of the vaccines. Latticed patterns of HA1, HA2 and NA indicated charge and molecular weight heterogeneity, a phenomenon likely caused by glycosylation and sulfation. Overall, Pandemrix contained more NP and NA, while Arepanrix displayed a larger diversity of viral and chicken proteins, with the exception of five chicken proteins (PDCD6IP, TSPAN8, H-FABP, HSP and TUB proteins) that were relatively more abundant in Pandemrix. Glycosylation patterns were similar in both vaccines. A higher degree of deamidation and dioxidation was found in Pandemrix, probably reflecting differential degradation across batches. Interestingly, HA1 146N (residue 129N in the mature protein) displayed a 10-fold higher deamidation in Arepanrix versus Pandemrix. In recent vaccine strains and Focetria, 146N is mutated to D which is associated with increased production yields suggesting that 146N deamidation may have also occurred during the manufacturing of Arepanrix. The presence of 146N in large relative amounts in Pandemrix and the wild type virus and in lower relative quantities in Arepanrix or other H1N1 vaccines may have affected predisposition to narcolepsy.

  View details for DOI 10.1016/j.bbi.2014.11.004

  View details for PubMedID 25452148

• History of narcolepsy at Stanford University (vol 58, pg 315, 2014) IMMUNOLOGIC RESEARCH Mignot, E. M. 2015; 62 (2): 253

  View details for PubMedID 25948476

  View details for PubMedCentralID PMC4643605

• Sleep spindle alterations in patients with Parkinson's disease FRONTIERS IN HUMAN NEUROSCIENCE Christensen, J. A., Nikolic, M., Warby, S. C., Koch, H., Zoetmulder, M., Frandsen, R., Moghadam, K. K., Sorensen, H. B., Mignot, E., Jennum, P. J. 2015; 9

  Abstract

  The aim of this study was to identify changes of sleep spindles (SS) in the EEG of patients with Parkinson's disease (PD). Five sleep experts manually identified SS at a central scalp location (C3-A2) in 15 PD and 15 age- and sex-matched control subjects. Each SS was given a confidence score, and by using a group consensus rule, 901 SS were identified and characterized by their (1) duration, (2) oscillation frequency, (3) maximum peak-to-peak amplitude, (4) percent-to-peak amplitude, and (5) density. Between-group comparisons were made for all SS characteristics computed, and significant changes for PD patients vs. control subjects were found for duration, oscillation frequency, maximum peak-to-peak amplitude and density. Specifically, SS density was lower, duration was longer, oscillation frequency slower and maximum peak-to-peak amplitude higher in patients vs.We also computed inter-expert reliability in SS scoring and found a significantly lower reliability in scoring definite SS in patients when compared to controls. How neurodegeneration in PD could influence SS characteristics is discussed. We also note that the SS morphological changes observed here may affect automatic detection of SS in patients with PD or other neurodegenerative disorders (NDDs).

  View details for DOI 10.3389/fnhum.2015.00233

  View details for Web of Science ID 000356009000001

  View details for PubMedID 25983685

  View details for PubMedCentralID PMC4416460

• HLA-DQ Allele Competition in Narcolepsy: A Comment on Tafti et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe SLEEP Ollila, H. M., Fernandez-Vina, M., Mignot, E. 2015; 38 (1): 147-151

  Abstract

  Although HLA-DQB1*06:02 is the strongest predisposing genetic factor for narcolepsy, the effect of this gene must be considered alongside that of its polymorphic partner, DQA1. In this paper, we extend an analysis of the effect of HLA-DQB1 on narcolepsy risk published recently by Tafti et al.Imputing allelic variation at the level of HLA-DQA1, we show that this locus also has a considerable effect on disease susceptibility. Our data are also compatible with previous findings in multi-ethnic group data sets showing that allele competition effects within the DQ1 group determine the amount of DQ0602 (the DQA1*01:02/DQB1*06:02 heterodimer), and consequently, the risk of developing narcolepsy. We also found an independent predisposing effect of DQB1*03:01 via a currently unknown mechanism.Both DQA1 and DQB1 influence narcolepsy risk.

  View details for DOI 10.5665/sleep.4342

  View details for Web of Science ID 000347169300017

  View details for PubMedID 25325462

  View details for PubMedCentralID PMC4262948

• Sleep Disorders NEUROBIOLOGY OF BRAIN DISORDERS: BIOLOGICAL BASIS OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS Kornum, B., Mignot, E., Zigmond, M. J., Rowland, L. P., Coyle, J. T. 2015: 585–611

  View details for DOI 10.1016/B978-0-12-398270-4.00036-7

  View details for Web of Science ID 000348393900037

• MULTIETHNIC RNA SEQUENCING ANALYSIS OF HLA REVEALS HLA-ALLELE SPECIFIC EQTLS. Ollila, H. M., Jolanki, O., Hollenbach, J. A., Norman, P., Mignot, E. ELSEVIER SCIENCE INC. 2015: 20

  View details for DOI 10.1016/j.humimm.2015.07.029

  View details for Web of Science ID 000363001300024

• SEV – a software toolbox for large scale analysis and visualization of polysomnography data Computer Methods in Biomechanics and Biomedical Engineering: Imaging & Visualization Moore, H. E., Mignot, E. 2015; 3 (3): 123-135

  View details for DOI 10.1080/21681163.2014.891076

• PRIMARY PROGRESSIVE NARCOLEPSY TYPE 1: THE OTHER SIDE OF THE COIN NEUROLOGY Pizza, F., Vandi, S., Liguori, R., Parchi, P., Avoni, P., Mignot, E., Plazzi, G. 2014; 83 (23): 2189–90

  View details for PubMedID 25355832

  View details for PubMedCentralID PMC4276406

• HLA DQB1*06:02 Negative Narcolepsy with Hypocretin/Orexin Deficiency SLEEP Han, F., Lin, L., Schormair, B., Pizza, F., Plazzi, G., Ollila, H. M., Nevsimalova, S., Jennum, P., Knudsen, S., Winkelmann, J., Coquillard, C., Babrzadeh, F., Strom, T. M., Wang, C., Mindrinos, M., Vina, M. F., Mignot, E. 2014; 37 (10): 1601-1608

  Abstract

  To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

  View details for DOI 10.5665/sleep.4066

  View details for Web of Science ID 000343147400006

  View details for PubMedCentralID PMC4173917

• Mixing layer in open-channel junction flows ENVIRONMENTAL FLUID MECHANICS Mignot, E., Vinkovic, I., Doppler, D., Riviere, N. 2014; 14 (5): 1027-1041

  View details for DOI 10.1007/s10652-013-9310-7

  View details for Web of Science ID 000345519700006

• Modeling Flow Exchanges between a Street and an Underground Drainage Pipe during Urban Floods JOURNAL OF HYDRAULIC ENGINEERING Bazin, P., Nakagawa, H., Kawaike, K., Paquier, A., Mignot, E. 2014; 140 (10)

  View details for DOI 10.1061/(ASCE)HY.1943-7900.0000917

  View details for Web of Science ID 000342227400004

• HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep Han, F., Lin, L., Schormair, B., Pizza, F., Plazzi, G., Ollila, H. M., Nevsimalova, S., Jennum, P., Knudsen, S., Winkelmann, J., Coquillard, C., Babrzadeh, F., Strom, T. M., Wang, C., Mindrinos, M., Fernandez Vina, M., Mignot, E. 2014; 37 (10): 1601-1608

  Abstract

  To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

  View details for DOI 10.5665/sleep.4066

  View details for PubMedID 25197808

• Risk of Narcolepsy Associated with Inactivated Adjuvanted (AS03) A/H1N1 (2009) Pandemic Influenza Vaccine in Quebec PLOS ONE Montplaisir, J., Petit, D., Quinn, M., Ouakki, M., Deceuninck, G., Desautels, A., Mignot, E., De Wals, P. 2014; 9 (9)

  Abstract

  An association between an adjuvanted (AS03) A/H1N1 pandemic vaccine and narcolepsy has been reported in Europe.To assess narcolepsy risk following administration of a similar vaccine in Quebec.Retrospective population-based study.Neurologists and lung specialists in the province were invited to report narcolepsy cases to a single reference centre.Patients were interviewed by two sleep experts and standard diagnostic tests were performed. Immunization status was verified in the provincial pandemic influenza vaccination registry.Confirmed narcolepsy with or without cataplexy with onset of excessive daytime sleepiness between January 1st, 2009, and December 31st, 2010. Relative risks (RRs) were calculated using a Poisson model in a cohort analysis, by a self-controlled case series (SCCS) and a case-control method.A total of 24 cases were included and overall incidence rate was 1.5 per million person-years. A cluster of 7 cases was observed among vaccinated persons in the winter 2009-2010. In the primary cohort analysis, 16-week post-vaccination RR was 4.32 (95% CI: 1.50-11.12). RR was 2.07 (0.70-6.17) in the SCCS, and 1.48 (0.37-7.03) using the case-control method. Estimates were lower when observation was restricted to the period of pandemic influenza circulation, and tended to be higher in persons <20 years old and for cataplexy cases.Results are compatible with an excess risk of approximately one case per million vaccine doses, mainly in persons less than 20 years of age. However, a confounding effect of the influenza infection cannot be ruled out.

  View details for DOI 10.1371/journal.pone.0108489

  View details for Web of Science ID 000345745400081

  View details for PubMedID 25264897

  View details for PubMedCentralID PMC4180737

• MICA, a gene contributing strong susceptibility to ankylosing spondylitis ANNALS OF THE RHEUMATIC DISEASES Zhou, X., Wang, J., Zou, H., Ward, M. M., Weisman, M. H., Espitia, M. G., Xiao, X., Petersdorf, E., Mignot, E., Martin, J., Gensler, L. S., Scheet, P., Reveille, J. D. 2014; 73 (8): 1552-1557

  Abstract

  The human major histocompatibility complex class I chain-related gene A (MICA) controls the immune process by balancing activities of  natural killer cells, γδ T cells and αβ CD8 T cells, and immunosuppressive CD4 T cells. MICA is located near HLA-B on chromosome 6. Recent genomewide association studies indicate that genes most strongly linked to ankylosing spondylitis (AS) susceptibility come from the region containing HLA-B and MICA. While HLA-B27 is a well-known risk genetic marker for AS, the potential effect of linkage disequilibrium (LD) shields any associations of genes around HLA-B with AS. The aim of this study was to investigate a novel independent genetic association of MICA to AS.We examined 1543 AS patients and 1539 controls from two ethnic populations by sequencing MICA and genotyping HLA-B alleles. Initially, 1070 AS patients and 1003 controls of European ancestry were used as a discovery cohort, followed by a confirmation cohort of 473 Han Chinese AS patients and 536 controls. We performed a stratified analysis based on HLA-B27 carrier status. We also conducted logistic regression with a formal interaction term.Sequencing of MICA identified that MICA*007:01 is a significant risk allele for AS in both Caucasian and Han Chinese populations, and that MICA*019 is a major risk allele in Chinese AS patients. Conditional analysis of MICA alleles on HLA-B27 that unshielded LD effect confirmed associations of the MICA alleles with AS.Parallel with HLA-B27, MICA confers strong susceptibility to AS in US white and Han Chinese populations.

  View details for DOI 10.1136/annrheumdis-2013-203352

  View details for Web of Science ID 000338696800025

  View details for PubMedID 23727634

  View details for PubMedCentralID PMC3874076

• Retraction of the Research Article: "CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy". Science translational medicine De la Herrán-Arita, A. K., Kornum, B. R., Mahlios, J., Jiang, W., Lin, L., Hou, T., Macaubas, C., Einen, M., Plazzi, G., Crowe, C., Newell, E. W., Davis, M. M., Mellins, E. D., Mignot, E. 2014; 6 (247): 247rt1-?

  View details for DOI 10.1126/scitranslmed.3009995

  View details for PubMedID 25080479

• History of narcolepsy at Stanford University IMMUNOLOGIC RESEARCH Mignot, E. J. 2014; 58 (2-3): 315-339

  Abstract

  Although narcolepsy was first described in the late nineteenth century in Germany and France, much of the research on this disorder has been conducted at Stanford University, starting with Drs. William C. Dement and Christian Guilleminault in the 1970s. The prevalence of narcolepsy was established, and a canine model discovered. Following the finding in Japan that almost all patients with narcolepsy carry a specific HLA subtype, HLA-DR2, Hugh Mac Devitt, F. Carl Grumet, and Larry Steinman initiated immunological studies, but results were generally negative. Using the narcoleptic canines, Dr. Nishino and I established that stimulants increased wakefulness by stimulating dopaminergic transmission while antidepressants suppress cataplexy via adrenergic reuptake inhibition. A linkage study was initiated with Dr. Grumet in 1988, and after 10 years of work, the canine narcolepsy gene was cloned by in 1999 and identified as the hypocretin (orexin) receptor 2. In 1992, studying African Americans, we also found that DQ0602 rather than DR2 was a better marker for narcolepsy across all ethnic groups. In 2000, Dr. Nishino and I, in collaboration with Dr. Lammers in the Netherlands, found that hypocretin 1 levels in the cerebrospinal fluid (CSF) were undetectable in most cases, establishing hypocretin deficiency as the cause of narcolepsy. Pursuing this research, our and Dr. Siegel's group, examining postmortem brains, found that the decreased CSF hypocretin 1 was secondary to the loss the 70,000 neurons producing hypocretin in the hypothalamus. This finding revived the autoimmune hypothesis but attempts at demonstrating immune targeting of hypocretin cells failed until 2013. At this date, Dr. Elisabeth Mellins and I discovered that narcolepsy is characterized by the presence of autoreactive CD4(+) T cells to hypocretin fragments when presented by DQ0602. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, our groups also established that a small epitope of pH1N1 resembles hypocretin and is likely involved in molecular mimicry. Although much remains to be done, these achievements, establishing hypocretin deficiency as the cause of narcolepsy, demonstrating its autoimmune basis, and showing molecular mimicry between hypocretin and sequences derived from a pandemic strain of influenza, are likely to remain classics in human immunology.

  View details for DOI 10.1007/s12026-014-8513-4

  View details for Web of Science ID 000336333700019

  View details for PubMedID 24825774

  View details for PubMedCentralID PMC4028550

• Circulating CD4+T cells in narcolepsy patients react to hypocretin and cross-react with hemagglutinin from an influenza strain linked to increased narcolepsy incidence Mellins, E., Macaubas, C., Jiang, W., De la Herran-Arita, A., Kornum, B., Mahlios, J., Hou, T., Mignot, E. AMER ASSOC IMMUNOLOGISTS. 2014

  View details for Web of Science ID 000209765001065

• The structured Diagnostic Interview for Sleep Patterns and Disorders: rationale and initial evaluation SLEEP MEDICINE Merikangas, K. R., Zhang, J., Emsellem, H., Swanson, S. A., Vgontzas, A., BELOUAD, F., BLANK, M. M., Chen, W., Einen, M., He, J. P., Heaton, L., Nakamura, E., Rooholamini, S., Mignot, E. 2014; 15 (5): 530-535

  Abstract

  We aimed to describe and report the initial validity of a newly developed structured interview for sleep disorders (Diagnostic Interview for Sleep Patterns and Disorders [DISP]) administered by trained lay interviewers.A total of 225 patients with various sleep disorders were recruited from two nationally recognized sleep centers in the United States. The International Classification of Sleep Disorders, second edition (ICSD-2) criteria, were used to classify sleep disorders (e.g., delayed sleep phase disorder, hypersomnia, narcolepsy with cataplexy [NC], restless legs syndrome [RLS], periodic limb movement disorder [PLMD], insomnia, rapid eye movement sleep behavior disorder [RBD], and obstructive sleep apnea [OSA]). Interview diagnoses were compared with final diagnoses by sleep specialists (reference diagnosis based on clinical history, examination, and polysomnography [PSG] when indicated).DISP diagnoses had fair to substantial concordance with clinician diagnoses for various sleep disorders, with area under the receiver operator characteristic curves (AUC) ranging from 0.65 to 0.84. Participants classified by the clinician as having a sleep disorder were moderately well-detected (sensitivity ranging from 0.50 for RBD disorder to 0.87 for insomnia). Substantial specificity (>0.8) also was seen for five of the eight sleep disorders (i.e., delayed sleep phase, hypersomnia, NC, PLMD, and RBD). Interviews were more likely than clinicians to detect disorders secondary to the primary sleep problem.The DISP provides an important tool for the detection of a wide range of sleep disorders in clinical settings and is particularly valuable in the detection of secondary disorders that were not the primary referral diagnosis.

  View details for DOI 10.1016/j.sleep.2013.10.011

  View details for Web of Science ID 000335917400009

  View details for PubMedID 24780136

• Analysis of Flow Separation Using a Local Frame Axis: Application to the Open-Channel Bifurcation JOURNAL OF HYDRAULIC ENGINEERING Mignot, E., Doppler, D., Riviere, N., Vinkovic, I., Gence, J., Simoens, S. 2014; 140 (3): 280-290

  View details for DOI 10.1061/(ASCE)HY.1943-7900.0000828

  View details for Web of Science ID 000332657600005

• Exploring medical diagnostic performance using interactive, multi-parameter sourced receiver operating characteristic scatter plots Computers in Biology and Medicine Moore, H., Andlauer, O., Simon, N., Mignot, E. 2014

  View details for DOI 10.1016/j.compbiomed.2014.01.012

• Dual Cases of Type 1 Narcolepsy with Schizophrenia and Other Psychotic Disorders JOURNAL OF CLINICAL SLEEP MEDICINE Canellas, F., Lin, L., Rosa Julia, M., Clemente, A., Vives-Bauza, C., Ollila, H. M., Hong, S. C., Arboleya, S. M., Einen, M. A., Faraco, J., Fernandez-Vina, M., Mignot, E. 2014; 10 (9): 1011-1018

  Abstract

  Cases of narcolepsy in association with psychotic features have been reported but never fully characterized. These patients present diagnostic and treatment challenges and may shed new light on immune associations in schizophrenia.Our case series was gathered at two narcolepsy specialty centers over a 9-year period. A questionnaire was created to improve diagnosis of schizophrenia or another psychotic disorder in patients with narcolepsy. Pathophysiological investigations included full HLA Class I and II typing, testing for known systemic and intracellular/synaptic neuronal antibodies, recently described neuronal surface antibodies, and immunocytochemistry on brain sections to detect new antigens.Ten cases were identified, one with schizoaffective disorder, one with delusional disorder, two with schizophreniform disorder, and 6 with schizophrenia. In all cases, narcolepsy manifested first in childhood or adolescence, followed by psychotic symptoms after a variable interval. These patients had auditory hallucinations, which was the most differentiating clinical feature in comparison to narcolepsy patients without psychosis. Narcolepsy therapy may have played a role in triggering psychotic symptoms but these did not reverse with changes in narcolepsy medications. Response to antipsychotic treatment was variable. Pathophysiological studies did not reveal any known autoantibodies or unusual brain immunostaining pattern. No strong HLA association outside of HLA DQB1*06:02 was found, although increased DRB3*03 and DPA1*02:01 was notable.Narcolepsy can occur in association with schizophrenia, with significant diagnostic and therapeutic challenges. Dual cases maybe under diagnosed, as onset is unusually early, often in childhood. Narcolepsy and psychosis may share an autoimmune pathology; thus, further investigations in larger samples are warranted.

  View details for DOI 10.5664/jcsm.4040

  View details for Web of Science ID 000341999700012

  View details for PubMedID 25142772

  View details for PubMedCentralID PMC4153110

• Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Sleep Moore, H., Winkelmann, J., Lin, L., Finn, L., Peppard, P., Mignot, E. 2014; 37 (9)

  Abstract

  To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response.Prevalence of PLMI ≥ 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.

  View details for PubMedID 25142570

• CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Science translational medicine De la Herrán-Arita, A. K., Kornum, B. R., Mahlios, J., Jiang, W., Lin, L., Hou, T., Macaubas, C., Einen, M., Plazzi, G., Crowe, C., Newell, E. W., Davis, M. M., Mellins, E. D., Mignot, E. 2013; 5 (216): 216ra176-?

  Abstract

  Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities. It is caused by the loss of ~70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99, that activated a subpopulation of CD4(+) T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT56-68- and HCRT87-99-reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1275-287, with homology to HCRT56-68 and HCRT87-99. In vitro stimulation of narcolepsy CD4(+) T cells with pH1N1 proteins or pHA1275-287 increased the frequency of HCRT56-68- and HCRT87-99-reactive T cells. Our data indicate the presence of CD4(+) T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1275-287.

  View details for DOI 10.1126/scitranslmed.3007762

  View details for PubMedID 24353159

• Increase of Histaminergic Tuberomammillary Neurons in Narcolepsy ANNALS OF NEUROLOGY Valko, P. O., Gavrilov, Y. V., Yamamoto, M., Reddy, H., Haybaeck, J., Mignot, E., Baumann, C. R., Scammell, T. E. 2013; 74 (6): 794-804

  Abstract

  Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy.We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice.Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 vs 120,455 ± 10,665, p < 0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with ≤75% orexin neuron loss (252,279 ± 46,264 vs 186,804 ± 1,256, p = 0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase.This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development.

  View details for DOI 10.1002/ana.24019

  View details for Web of Science ID 000329891100010

  View details for PubMedID 24006291

• The autoimmune basis of narcolepsy. Current opinion in neurobiology Mahlios, J., De la Herrán-Arita, A. K., Mignot, E. 2013; 23 (5): 767-773

  Abstract

  Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections.

  View details for DOI 10.1016/j.conb.2013.04.013

  View details for PubMedID 23725858

• A Novel de novo Exon 21 DNMT1 Mutation Causes Cerebellar Ataxia, Deafness, and Narcolepsy in a Brazilian Patient SLEEP Pedroso, J. L., Povoas Barsottini, O. G., Lin, L., Melberg, A., Oliveira, A. S., Mignot, E. 2013; 36 (8): 1257-1259

  Abstract

  Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges.Clinical and genetic investigation in a patient and family members.Ataxia clinic, São Paulo, Brazil.One patient and her family members.N/A.Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient.The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.

  View details for DOI 10.5665/sleep.2898

  View details for Web of Science ID 000322578500020

  View details for PubMedID 23904686

  View details for PubMedCentralID PMC3700723

• CFD modeling of multiphase transient flows through complex structures in sewers: performances and sensitivities of models HOUILLE BLANCHE-REVUE INTERNATIONALE DE L EAU Momplot, A., Kouyi, G. L., Bertrand-Krajewski, J., Mignot, E., Riviere, N. 2013: 16-24

  View details for DOI 10.1051/lhb/2013028

  View details for Web of Science ID 000325669100002

• Impact of topographic obstacles on the discharge distribution in open-channel bifurcations JOURNAL OF HYDROLOGY Mignot, E., Zeng, C., Dominguez, G., Li, C., Riviere, N., Bazin, P. 2013; 494: 10-19

  View details for DOI 10.1016/j.jhydrol.2013.04.023

  View details for Web of Science ID 000321466200002

• Genetic association, seasonal infections and autoimmune basis of narcolepsy. Journal of autoimmunity Singh, A. K., Mahlios, J., Mignot, E. 2013; 43: 26-31

  Abstract

  In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.

  View details for DOI 10.1016/j.jaut.2013.02.003

  View details for PubMedID 23497937

• Hypocretin (orexin) neuropeptide precursor gene, HCRT, polymorphisms in early-onset narcolepsy with cataplexy SLEEP MEDICINE Dong, X. S., Ma, S. F., Cao, C. W., Li, J., An, P., Zhao, L., Liu, N. Y., Yan, H., Hu, Q. T., Mignot, E., Strohl, K. P., Gao, Z. C., Zeng, C., Han, F. 2013; 14 (6): 482-487

  Abstract

  To test if the hypocretin (orexin) neuropeptide precursor (HCRT) gene, HCRT, mutations are implicated in the development of narcolepsy with cataplexy deficiency in young children.The entire HCRT gene and ~2000 bp promoter region was first sequenced in 181 patients and 153 controls, and rare polymorphisms including three nonsynonymous amino acid changes were identified. Next the 557 bp region of exon 2 harboring the three nonsynonymous changes was sequenced in an additional 298 early-onset subjects and in 148 control samples.A previously known common polymorphism (rs760282) and nine rare novel polymorphisms were identified in subjects and controls without significant differences. Two nonsynonymous exon 2 substitutions (+977 H54A, +979 G55R) were detected in two subjects with early onset at 7 and 6 years, respectively, but were not found in any controls. These substitutions are not likely to vastly change peptide binding to hypocretin receptors. One additional exon 2 substitution (+1019, K68R) was found in two patients and one control. Additional sequencing that focused on exon 2 showed additional subjects and controls with the +1019 K68R polymorphism and without significant differences between the subjects and the control. Segregation of two of these three nonsynonymous single nucleotide polymorphisms (SNPs) were observed from unaffected parents to offspring.Sequencing of a large number of early-onset narcolepsy subjects revealed three novel nonsynonymous substitutions within the preprohypocretin protein, two of which were only found in patients with early-onset narcolepsy but are not likely to be functionally significant, especially in heterozygote subjects.

  View details for DOI 10.1016/j.sleep.2013.01.016

  View details for Web of Science ID 000319502300003

  View details for PubMedID 23643651

• Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia PEERJ Khor, S., Miyagawa, T., Toyoda, H., Yamasaki, M., Kawamura, Y., Tanii, H., Okazaki, Y., Sasaki, T., Lin, L., Faraco, J., Rico, T., Honda, Y., Honda, M., Mignot, E., Tokunaga, K. 2013; 1

  Abstract

  Essential hypersomnia (EHS), a sleep disorder characterized by excessive daytime sleepiness, can be divided into two broad classes based on the presence or absence of the HLA-DQB1*06:02 allele. HLA-DQB1*06:02-positive EHS and narcolepsy with cataplexy are associated with the same susceptibility genes. In contrast, there are fewer studies of HLA-DQB1*06:02 negative EHS which, we hypothesized, involves a different pathophysiological pathway than does narcolepsy with cataplexy. In order to identify susceptibility genes associated with HLA-DQB1*06:02 negative EHS, we conducted a genome-wide association study (GWAS) of 125 unrelated Japanese EHS patients lacking the HLA-DQB1*06:02 allele and 562 Japanese healthy controls. A comparative study was also performed on 268 HLA-DQB1*06:02 negative Caucasian hypersomnia patients and 1761 HLA-DQB1*06:02 negative Caucasian healthy controls. We identified three SNPs that each represented a unique locus- rs16826005 (P = 1.02E-07; NCKAP5), rs11854769 (P = 6.69E-07; SPRED1), and rs10988217 (P = 3.43E-06; CRAT) that were associated with an increased risk of EHS in this Japanese population. Interestingly, rs10988217 showed a similar tendency in its association with both HLA-DQB1*06:02 negative EHS and narcolepsy with cataplexy in both Japanese and Caucasian populations. This is the first GWAS of HLA-DQB1*06:02 negative EHS, and the identification of these three new susceptibility loci should provide additional insights to the pathophysiological pathway of this condition.

  View details for DOI 10.7717/peerj.66

  View details for Web of Science ID 000209186400001

  View details for PubMedCentralID PMC3642778

• Physiology. The perfect hypnotic? Science Mignot, E. 2013; 340 (6128): 36-38

  View details for DOI 10.1126/science.1237998

  View details for PubMedID 23559238

• Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin JOURNAL OF SLEEP RESEARCH Pizza, F., Moghadam, K. K., Vandi, S., Detto, S., Poli, F., Mignot, E., Ferri, R., Plazzi, G. 2013; 22 (1): 32-40

  Abstract

  In the diagnostic work-up of hypersomnias of central origin, the complaint of excessive daytime sleepiness should be objectively confirmed by MSLT findings. Indeed, the features and diagnostic utility of spontaneous daytime sleep at 24 h continuous polysomnography (PSG) have never been investigated. We compared daytime PSG features to MSLT data in 98 consecutive patients presenting with excessive daytime sleepiness and with a final diagnosis of narcolepsy with cataplexy/hypocretin deficiency (n = 39), narcolepsy without cataplexy (n = 7), idiopathic hypersomnia without long sleep time (n = 19), and 'hypersomnia' with normal sleep latency at MSLT (n = 33). Daytime sleep time was significantly higher in narcolepsy-cataplexy but similar in the other groups. Receiver operating characteristics (ROC) curves showed that the number of naps during daytime PSG predicted a mean sleep latency ≤8 min at MSLT with an area under the curve of 0.67 ± 0.05 (P = 0.005). The number of daytime sleep-onset REM periods (SOREMPs) in spontaneous naps strikingly predicted the scheduled occurrence of two or more SOREMPs at MSLT, with an area under the ROC curve of 0.93 ± 0.03 (P < 10(-12) ). One spontaneous SOREMP during daytime had a sensitivity of 96% with specificity of 74%, whereas two SOREMPs had a sensitivity of 75%, with a specificity of 95% for a pathological REM sleep propensity at MSLT. The features of spontaneous daytime sleep well correlated with MSLT findings. Notably, the occurrence of multiple spontaneous SOREMPs during daytime clearly identified patients with narcolepsy, as well as during the MSLT.

  View details for DOI 10.1111/j.1365-2869.2012.01032.x

  View details for Web of Science ID 000313732000005

  View details for PubMedID 22716477

• Obituary for Charlotte McCutchen, MD SLEEP Malow, B., Rye, D., Mignot, E., Sato, S. 2013; 36 (2): 291

  View details for DOI 10.5665/sleep.2394

  View details for Web of Science ID 000314393700020

• ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy PLOS GENETICS Faraco, J., Lin, L., Kornum, B. R., Kenny, E. E., Trynka, G., Einen, M., Rico, T. J., Lichtner, P., Dauvilliers, Y., Arnulf, I., Lecendreux, M., Javidi, S., Geisler, P., Mayer, G., Pizza, F., Poli, F., Plazzi, G., Overeem, S., Lammers, G. J., Kemlink, D., Sonka, K., Nevsimalova, S., Rouleau, G., Desautels, A., Montplaisir, J., Frauscher, B., Ehrmann, L., Hoegl, B., Jennum, P., Bourgin, P., Peraita-Adrados, R., Iranzo, A., Bassetti, C., Chen, W., Concannon, P., Thompson, S. D., Damotte, V., Fontaine, B., Breban, M., Gieger, C., Klopp, N., Deloukas, P., Wijmenga, C., Hallmayer, J., Onengut-Gumuscu, S., Rich, S. S., Winkelmann, J., Mignot, E. 2013; 9 (2)

  Abstract

  Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

  View details for DOI 10.1371/journal.pgen.1003270

  View details for Web of Science ID 000315638300028

  View details for PubMedID 23459209

  View details for PubMedCentralID PMC3573113

• High Prevalence of Precocious Puberty and Obesity in Childhood Narcolepsy with Cataplexy SLEEP Poli, F., Pizza, F., Mignot, E., Ferri, R., Pagotto, U., Taheri, S., Finotti, E., Bernardi, F., Pirazzoli, P., Cicognani, A., Balsamo, A., Nobili, L., Bruni, O., Plazzi, G. 2013; 36 (2): 175-181

  Abstract

  We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses.Cross-sectional on consecutive recruitment.Hospital sleep center and pediatric unit.Forty-three children and adolescents with NC versus 52 age-matched obese children as controls.N/A.Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74%) and a higher occurrence of precocious puberty (17%) than obese controls (1.9%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence.NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities and the potential related risks require a multidiagnostic approach and a tailored therapeutic management.

  View details for DOI 10.5665/sleep.2366

  View details for Web of Science ID 000314393700006

  View details for PubMedID 23372264

  View details for PubMedCentralID PMC3543059

• Association of Sleep Disordered Breathing and Cognitive Deficit in APOE e4 Carriers. Sleep Nikodemova, M., Finn, L., Mignot, E., Salzieder, N., Peppard, P. E. 2013; 36 (6): 873-880

  Abstract

  The aim of the study was to determine whether apolipoprotein E epsilon 4 genotype (APOE4) modifies the association of sleep disordered breathing (SDB) with cognitive function in a middle-aged population.Cross-sectional analysis of a community-dwelling cohort.Sleep laboratory at the Clinical Research Unit of the University of Wisconsin Hospitals and Clinics.There were 755 adults from the Wisconsin Sleep Cohort who provided a total of 1,843 polysomnography and cognitive evaluations (most participants were assessed multiple times at approximately 4-y intervals); 56% males, average age 53.9 years (range 30-81 years).None.In-laboratory overnight polysomnography was used to assess SDB. Cognition was evaluated by a battery of six neurocognitive tests assessing memory and learning, attention, executive function, and psychomotor efficiency. The APOE4 genotype (ε3/ε4 or ε4/ ε4) was identified in 200 participants. Data were analyzed using linear mixed-effects models, accounting for multiple observations per participant. Cognitive test scores were regressed on SDB categories (AHI < 5, 5 ≤ AHI < 15, AHI ≥ 15); APOE4 and their interaction; and age, education, sex, and body mass index. There was no statistically significant association between SDB and cognitive performance among APOE4-negative individuals. However, in APOE4-positive individuals, those with AHI ≥ 15 had significantly worse performance on the Auditory Verbal Learning Test and the Controlled Oral Word Association Test.In APOE4-positive individuals, moderate to severe sleep disordered breathing (AHI ≥ 15) was associated with poorer performance on cognitive tests that require both memory and executive function engagement.

  View details for DOI 10.5665/sleep.2714

  View details for PubMedID 23729930

  View details for PubMedCentralID PMC3649829

• Narcolepsy with cataplexy mimicry: the strange case of two sisters. Journal of clinical sleep medicine Pizza, F., Vandi, S., Poli, F., Moghadam, K. K., Franceschini, C., Bellucci, C., Cipolli, C., Ingravallo, F., Natalini, G., Mignot, E., Plazzi, G. 2013; 9 (6): 611-612

  Abstract

  We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyo-graphic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases.Pizza F; Vandi S; Poli F; Moghadam KK; Fran-ceschini C; Bellucci C; Cipolli C; Ingravallo F; Natalini G; Mignot E; Plazzi G. Narcolepsy with cataplexy mimicry: the strange case of two sisters. J Clin Sleep Med 2013;9(6):611-612.

  View details for DOI 10.5664/jcsm.2764

  View details for PubMedID 23772196

  View details for PubMedCentralID PMC3659383

• Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia. PeerJ Khor, S., Miyagawa, T., Toyoda, H., Yamasaki, M., Kawamura, Y., Tanii, H., Okazaki, Y., Sasaki, T., Lin, L., Faraco, J., Rico, T., Honda, Y., Honda, M., Mignot, E., Tokunaga, K. 2013; 1

  Abstract

  Essential hypersomnia (EHS), a sleep disorder characterized by excessive daytime sleepiness, can be divided into two broad classes based on the presence or absence of the HLA-DQB1*06:02 allele. HLA-DQB1*06:02-positive EHS and narcolepsy with cataplexy are associated with the same susceptibility genes. In contrast, there are fewer studies of HLA-DQB1*06:02 negative EHS which, we hypothesized, involves a different pathophysiological pathway than does narcolepsy with cataplexy. In order to identify susceptibility genes associated with HLA-DQB1*06:02 negative EHS, we conducted a genome-wide association study (GWAS) of 125 unrelated Japanese EHS patients lacking the HLA-DQB1*06:02 allele and 562 Japanese healthy controls. A comparative study was also performed on 268 HLA-DQB1*06:02 negative Caucasian hypersomnia patients and 1761 HLA-DQB1*06:02 negative Caucasian healthy controls. We identified three SNPs that each represented a unique locus- rs16826005 (P = 1.02E-07; NCKAP5), rs11854769 (P = 6.69E-07; SPRED1), and rs10988217 (P = 3.43E-06; CRAT) that were associated with an increased risk of EHS in this Japanese population. Interestingly, rs10988217 showed a similar tendency in its association with both HLA-DQB1*06:02 negative EHS and narcolepsy with cataplexy in both Japanese and Caucasian populations. This is the first GWAS of HLA-DQB1*06:02 negative EHS, and the identification of these three new susceptibility loci should provide additional insights to the pathophysiological pathway of this condition.

  View details for DOI 10.7717/peerj.66

  View details for PubMedID 23646285

• Cerebrospinal fluid cytokine levels in narcolepsy with cataplexy patients close to onset Kornum, B. R., Goldenberger, O., Jennum, P., Mignot, E. ELSEVIER SCIENCE BV. 2012: 143–44

  View details for Web of Science ID 000312764800385

• Treatment of Sleep Disorders NEUROTHERAPEUTICS Pelayo, R., Mignot, E. 2012; 9 (4): 685-686

  View details for DOI 10.1007/s13311-012-0153-6

  View details for Web of Science ID 000310325000001

  View details for PubMedID 23070732

  View details for PubMedCentralID PMC3480573

• Diagnosis, disease course, and management of patients with Kleine-Levin syndrome LANCET NEUROLOGY Arnulf, I., Rico, T. J., Mignot, E. 2012; 11 (10): 918-928

  Abstract

  Kleine-Levin syndrome is a rare sleep disorder that mainly affects adolescents and is characterised by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealisation, and psychiatric and behavioural disturbances. Boys are more frequently affected than girls. Just over half of patients have hyperphagia, are hypersexual (mainly boys), or have depressed mood (mainly girls), and 30% become anxious, delusional, and have hallucinations. Although some symptoms are similar to those in patients with encephalopathy, imaging and laboratory findings are unremarkable. The first episode of hypersomnia is often triggered by an infection, with relapses occurring every 1-12 months for a median of 14 years; disease duration can be much longer with childhood or adult onset than in patients with adolescent onset. Between episodes, patients generally have normal sleep patterns, cognition, mood, and eating habits. During episodes, electroencephalography might show diffuse or local slow activity. Functional imaging studies have revealed hypoactivity in thalamic and hypothalamic regions, and in the frontal and temporal lobes. Stimulants and mood stabilisers can be beneficial in the treatment of severe cases.

  View details for Web of Science ID 000309634300016

  View details for PubMedID 22995695

• A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes NEUROTHERAPEUTICS Mignot, E. J. 2012; 9 (4): 739-752

  Abstract

  Narcolepsy and other syndromes associated with excessive daytime sleepiness can be challenging to treat. New classifications now distinguish narcolepsy/hypocretin deficiency (also called type 1 narcolepsy), a lifelong disorder with well-established diagnostic procedures and etiology, from other syndromes with hypersomnolence of unknown causes. Klein-Levin Syndrome, a periodic hypersomnia associated with cognitive and behavioral abnormalities, is also considered a separate entity with separate therapeutic protocols. Non hypocretin-related hypersomnia syndromes are diagnoses of exclusion. These diagnoses are only made after eliminating sleep deprivation, sleep apnea, disturbed nocturnal sleep, and psychiatric comorbidities as the primary cause of daytime sleepiness. The treatment of narcolepsy/hypocretin deficiency is well-codified, and involves pharmacotherapies using sodium oxybate, stimulants, and/or antidepressants, plus behavioral modifications. These therapies are almost always needed, and the risk-to-benefit ratio is clear, notably in children. Detailed knowledge of the pharmacological profile of each compound is needed to optimize use. Treatment for other syndromes with hypersomnolence is more challenging and less codified. Preferably, therapy should be conservative (such as modafinil, atomoxetine, behavioral modifications), but it may have to be more aggressive (high-dose stimulants, sodium oxybate, etc.) on a case-by-case, empirical trial basis. As cause and evolution are unknown in these conditions, it is important to challenge diagnosis and therapy over time, keeping in mind the possibility of tolerance and the development of stimulant addiction. Kleine-Levin Syndrome is usually best left untreated, although lithium can be considered in severe cases with frequent episodes. Guidelines are provided based on the literature and personal experience of the author.

  View details for DOI 10.1007/s13311-012-0150-9

  View details for PubMedID 23065655

• Clinical phenotype of patients with narcolepsy with cataplexy, cerebellar ataxia, deafness and neuropathy associated to DNMT1 gene mutation 21st Congress of the European-Sleep-Research-Society Moghadam, K. K., Pizza, F., Poli, F., Franceschini, C., Tonon, C., Carelli, V., Lodi, R., Seri, M., Winkelmann, J., Mignot, E., Plazzi, G. WILEY-BLACKWELL. 2012: 311–311

  View details for Web of Science ID 000307963201317

• EARLY IVIg TREATMENT HAS NO EFFECT ON POST-H1N1 NARCOLEPSY PHENOTYPE OR HYPOCRETIN DEFICIENCY NEUROLOGY Knudsen, S., Biering-Sorensen, B., Kornum, B. R., Petersen, E. R., Ibsen, J. D., Gammeltoft, S., Mignot, E., Jennum, P. J. 2012; 79 (1): 102-103

  View details for DOI 10.1212/WNL.0b013e31825dce03

  View details for Web of Science ID 000306176000021

  View details for PubMedID 22722630

• Time-course of cerebrospinal fluid histamine in the wake-consolidated squirrel monkey JOURNAL OF SLEEP RESEARCH Zeitzer, J. M., Kodama, T., Buckmaster, C. L., Honda, Y., Lyons, D. M., Nishino, S., Mignot, E. 2012; 21 (2): 189-194

  Abstract

  Central nervous system (CNS) histamine is low in individuals with narcolepsy, a disease characterized by severe fragmentation of both sleep and wake. We have developed a primate model, the squirrel monkey, with which we can examine the role of the CNS in the wake-consolidation process, as these primates are day-active, have consolidated wake and sleep and have cerebrospinal fluid (CSF) that is readily accessible. Using this model and three distinct protocols, we report herein on the role of CNS histamine in the wake consolidation process. CSF histamine has a robust daily rhythm, with a mean of 24.9 ± 3.29 pg mL(-1) , amplitude of 31.7 ± 6.46 pg mL(-1) and a peak at 17:49 ± 70.3 min (lights on 07:00-19:00 hours). These levels are not significantly affected by increases (up to 161 ± 40.4% of baseline) or decreases (up to 17.2 ± 2.50% of baseline) in locomotion. In direct contrast to the effects of sleep deprivation in non-wake-consolidating mammals, in whom CSF histamine increases, pharmacologically induced sleep (γ-hydroxybutyrate) and wake (modafinil) have no direct effects on CSF histamine concentrations. These data indicate that the time-course of histamine in CSF in the wake-consolidated squirrel monkey is robust against variation in activity and sleep and wake-promoting pharmacological compounds, and may indicate that histamine physiology plays a role in wake-consolidation such as is present in the squirrel monkey and humans.

  View details for DOI 10.1111/j.1365-2869.2011.00957.x

  View details for Web of Science ID 000301931500010

  View details for PubMedID 21910776

  View details for PubMedCentralID PMC3237761

• DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status HUMAN IMMUNOLOGY Lachmi, K. W., Lin, L., Kornum, B. R., Rico, T., Lo, B., Aran, A., Mignot, E. 2012; 73 (4): 405-410

  Abstract

  The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single-allele human leukocyte antigen (HLA) associations. In this study, we explored genome-wide expression in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and observed the largest differences between the groups in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did not reveal any difference, a result we explain by the lack of proper control of allelic diversity in Affymetrix HLA probes. Rather, a clear effect of DQB1*06:02 allelic dosage on DQB1*06:02 mRNA levels (1.65-fold) and protein (1.59-fold) could be demonstrated independent of disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain the increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes.

  View details for DOI 10.1016/j.humimm.2012.01.004

  View details for Web of Science ID 000302986200014

  View details for PubMedID 22326585

  View details for PubMedCentralID PMC3501142

• TCRA, P2RY11, and CPT1B/CHKB associations in Chinese narcolepsy SLEEP MEDICINE Han, F., Lin, L., Li, J., Aran, A., Dong, S. X., An, P., Zhao, L., Li, Q. Y., Yan, H., Wang, J. S., Gao, H. Y., Li, M., Gao, Z. C., Strohl, K. P., Mignot, E. 2012; 13 (3): 269-272

  Abstract

  Polymorphisms in the TCRA and P2RY11, two immune related genes, are associated with narcolepsy in Caucasians and Asians. In contrast, CPT1B/CHKB polymorphisms have only been shown to be associated with narcolepsy in Japanese, with replication in a small group of Koreans. Our aim was to study whether these polymorphisms are associated with narcolepsy and its clinical characteristics in Chinese patients with narcolepsy.We collected clinical data on 510 Chinese patients presenting with narcolepsy/hypocretin deficiency. Patients were included either when hypocretin deficiency was documented (CSF hypocretin-1≤110 pg/ml, n=91) or on the basis of the presence of clear cataplexy and HLA-DQB1∗0602 positivity (n=419). Genetic data was compared to typing obtained in 452 controls matched for geographic origin within China. Clinical evaluations included demographics, the Stanford Sleep Inventory (presence and age of onset of each symptom), and Multiple Sleep Latency Test (MSLT) data.Chinese narcolepsy was strongly and dose dependently associated with TCRA (rs1154155C) and P2RY11 (rs2305795A) but not CPT1B/CHKB (rs5770917C) polymorphisms. CPT1B/CHKB polymorphisms were not associated with any specific clinical characteristics. TCRA rs1154155A homozygotes (58 subjects) had a later disease onset, but this was not significant when corrected for multiple comparisons, thus replication is needed. CPT1B/CHKB or P2RY11 polymorphisms were not associated with any specific clinical characteristics.The study extends on the observation of a strong multiethnic association of polymorphisms in the TCRA and P2RY11 with narcolepsy, but does not confirm the association of CPT1B/CHKB (rs5770917) in the Chinese population.

  View details for DOI 10.1016/j.sleep.2011.06.020

  View details for Web of Science ID 000301695600008

  View details for PubMedID 22177342

  View details for PubMedCentralID PMC3288279

• CSF Levels of Hypocretin-1 (Orexin-A) Peak during Early Infancy in Humans SLEEP Aran, A., Shors, I., Lin, L., Mignot, E., Schimmel, M. S. 2012; 35 (2): 187-191

  Abstract

  Hypocretin (orexin) is a unique neuropeptide involved in the consolidation of wakefulness and sleep. Although hypocretin-1 levels in the cerebrospinal fluid (CSF) are stable after infancy, how levels change in preterm and term human infants is unknown.Hypocretin-1 levels were measured in CSF samples, obtained from 284 preterm (25-37 gestational weeks) and full-term infants in the first 4 months of life and 35 older children (ages 0.5-13 years), in a tertiary hospital.Detailed clinical and laboratory data were collected for each of the 319 participants. Based on that data, 108 neurologically intact children were selected (95 infants [43 preterm and 52 term] and 13 older children). CSF hypocretin-1 was measured by direct radioimmunoassay. Hypocretin-1 levels at the first weeks of the 3rd embryonic trimester (gestational age [GA] 28-34 weeks) were 314 ± 65 pg/mL (n = 17). The levels linearly increased during the third trimester and early infancy (r = 0.6), peaking in infants of 2-4 months ages (476 ± 72 pg/mL; n = 16) and decreasing thereafter; hypocretin levels in 2- to 4-month-old infants were significantly higher than those in children 0.5-13 years old (353 ± 78 pg/mL, n = 13; P = 0.0001).The present findings indicate that in human infants, CSF hypocretin-1 increases during the third embryonic trimester and is highest at 4 months of life. Thereafter, and consistent with previously published results, hypocretin levels are lower and stable until the geriatric age. This pattern may reflect the role of hypocretin in the dramatic process of sleep and wakefulness consolidation that occurs during early infancy.

  View details for DOI 10.5665/sleep.1618

  View details for Web of Science ID 000299779800005

  View details for PubMedID 22294808

  View details for PubMedCentralID PMC3250357

• ALLIANCE SLEEP QUESTIONNAIRE (ASQ) FEASIBILITY PILOT STUDY 26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS) Leary, E. B., GRIFFIN, K. S., Malunjkar, S., Qadri, S., Ruoff, C. M., Sullivan, S. S., Walsh, J. K., Mignot, E. AMER ACAD SLEEP MEDICINE. 2012: A432–A433

  View details for Web of Science ID 000312996502520

• LEG MOVEMENT DETECTION SOFTWARE AND PERIODIC LEG MOVEMENT INDEX CALCULATOR 26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS) MOORE, H. E., Warby, S., Woodward, S. H., Peppard, P. E., Young, T., Mignot, E. AMER ACAD SLEEP MEDICINE. 2012: A264–A264

  View details for Web of Science ID 000312996502022

• MUTATIONS IN DNMT1 CAUSE AUTOSOMAL DOMINANT CEREBELLAR ATAXIA, DEAFNESS AND NARCOLEPSY 26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS) Winkelmann, J., Lin, L., Schormair, B., Kornum, B. R., Faraco, J., Plazzi, G., Melberg, A., Cornellio, F., Pizza, F., Mignot, E. AMER ACAD SLEEP MEDICINE. 2012: A11–A11

  View details for Web of Science ID 000312996500024

• ALLIANCE SLEEP QUESTIONNAIRE (ASQ): A COLLABORATIVE ONLINE SLEEP ASSESSMENT QUESTIONNAIRE 26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS) Leary, E. B., Barger, L., Hall-Porter, J. M., Maislin, G., Peppard, P. E., Rajaratnam, S. M., Rumble, M., Sullivan, S. S., Walsh, J. K., Mignot, E. AMER ACAD SLEEP MEDICINE. 2012: A432–A432

  View details for Web of Science ID 000312996502519

• Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain Plazzi, G., Pizza, F., Palaia, V., Franceschini, C., Poli, F., Moghadam, K. K., Cortelli, P., Nobili, L., Bruni, O., Dauvilliers, Y., Lin, L., Edwards, M. J., Mignot, E., Bhatia, K. P. 2011; 134: 3480-3492

  Abstract

  Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of 'negative' (hypotonia) and 'active' (ranging from perioral movements to dyskinetic-dystonic movements or stereotypies) motor disturbances. 'Active' and 'negative' motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas 'negative' motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities.

  View details for DOI 10.1093/brain/awr244

  View details for PubMedID 21930661

• Complex movement disorders at disease onset in childhood narcolepsy with cataplexy BRAIN Plazzi, G., Pizza, F., Palaia, V., Franceschini, C., Poli, F., Moghadam, K. K., Cortelli, P., Nobili, L., Bruni, O., Dauvilliers, Y., Lin, L., Edwards, M. J., Mignot, E., Bhatia, K. P. 2011; 134: 3477-3489

  Abstract

  Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of 'negative' (hypotonia) and 'active' (ranging from perioral movements to dyskinetic-dystonic movements or stereotypies) motor disturbances. 'Active' and 'negative' motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas 'negative' motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities.

  View details for DOI 10.1093/brain/awr244

  View details for Web of Science ID 000298189800007

  View details for PubMedCentralID PMC3235554

• Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain CURRENT OPINION IN NEUROBIOLOGY Kornum, B. R., Faraco, J., Mignot, E. 2011; 21 (6): 897-903

  Abstract

  The loss of hypothalamic hypocretin/orexin (hcrt) producing neurons causes narcolepsy with cataplexy. An autoimmune basis for the disease has long been suspected and recent results have greatly strengthened this hypothesis. Narcolepsy with hcrt deficiency is now known to be associated with a Human Leukocyte Antigen (HLA) and T-cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a single peptide unique to hcrt-cells via specific HLA-peptide-TCR interactions. Recent data have shown a robust seasonality of disease onset in children and associations with Streptococcus Pyogenes, and influenza A H1N1-infection and H1N1-vaccination, pointing towards processes such as molecular mimicry or bystander activation as crucial for disease development. We speculate that upper airway infections may be common precipitants of a whole host of CNS autoimmune complications including narcolepsy.

  View details for DOI 10.1016/j.conb.2011.09.003

  View details for Web of Science ID 000299972600011

  View details for PubMedID 21963829

• Narcolepsy with Cataplexy Associated with Nocturnal Compulsive Behaviors: A Case-Control Study SLEEP Palaia, V., Poli, F., Pizza, F., Antelmi, E., Franceschini, C., Moghadam, K. K., Provini, F., Pagotto, U., Montagna, P., Schenck, C. H., Mignot, E., Plazzi, G. 2011; 34 (10): 1365-U100

  Abstract

  To assess the prevalence of sleep related-eating disorder (SRED) and nocturnal smoking (NS) in patients with narcolepsy with cataplexy (NC).Case-control study.University hospital.65 consecutive adult NC patients (33 men; mean age 43.9 ± 19.2 years) and 65 age-, sex-, and geographical origin-matched controls.Validated questionnaires were used to investigate SRED, NS, restless legs syndrome (RLS), and psychopathological traits (using Eating Disorder Inventory-2 [EDI-2]; Maudsley Obsessive-Compulsive Inventory [MOCI]; and Beck Depression Inventory [BDI]).NC patients showed a higher prevalence of SRED (32% vs 3%, P=0.00001), NS (21% vs 0%, P=0.00006), and RLS (18% vs 5%, P=0.013) than controls. Moreover, NC patients presented more frequently with an eating-related pathological profile on the EDI-2 (80% vs 46%, P=0.00006) and had a higher prevalence of depressed mood on the BDI (41% vs 18%, P=0.004). In comparison to patients without SRED, NC patients with SRED were more frequently women (71% vs 39%, P=0.013), had higher "bulimic" (29% vs 2%, P=0.004) and "social insecurity" (48% vs 18%, P=0.013) traits on the EDI-2, had higher obsessive-compulsiveness on the MOCI (29% vs 4%, P = 0.009), and were more depressed on the BDI (67% vs 29%, P=0.005). NC patients with NS showed more frequent pathological profiles on the EDI-2 (100% vs 75%, P=0.035), including the "bulimic" (29% vs 6%, P=0.015), "perfectionism" (43% vs 14%, P=0.016), and "social insecurity" (50% vs 22, P=0.035) profiles.Our study shows a strong association of the compulsive nocturnal behaviors SRED and NS with adult NC.

  View details for DOI 10.5665/SLEEP.1280

  View details for Web of Science ID 000295624800013

  View details for PubMedID 21966068

  View details for PubMedCentralID PMC3174838

• Post-Streptococcal Antibodies Are Associated with Metabolic Syndrome in a Population-Based Cohort PLOS ONE Aran, A., Lin, L., Finn, L. A., Weiner, K., Peppard, P., Young, T., Mignot, E. 2011; 6 (9)

  Abstract

  Streptococcal infections are known to trigger autoimmune disorders, affecting millions worldwide. Recently, we found an association between post-streptococcal autoantibodies against Protein Disulphide Isomerase (PDI), an enzyme involved in insulin degradation and insulin resistance. This led us to evaluate associations between post-streptococcal antibodies and metabolic syndrome, as defined by the updated National Cholesterol Education Program definition, 2005.Metabolic data (HDL, triglycerides, fasting glucose, blood pressure, waist circumference, BMI, smoking), post-streptococcal antibodies (anti-Streptolysin O (ASO) and anti-PDI), and C-reactive protein (CRP, as a general inflammatory marker), were assessed in 1156 participants of the Wisconsin Sleep Cohort Study. Anti-PDI antibodies were found in 308 participants (26.6%), ASO≥100 in 258 (22.3%), and 482 (41.7%) met diagnostic criteria for metabolic syndrome. Anti-PDI antibodies but not ASO were significantly associated with metabolic syndrome [n = 1156, OR 1.463 (95% CI 1.114, 1.920), p = 0.0062; adjusted for age, gender, education, smoking]. Importantly, the anti-PDI-metabolic syndrome association remained significant after adjusting for CRP and fasting insulin.Post-streptococcal anti-PDI antibodies are associated with metabolic syndrome regardless of fasting insulin and CRP levels. Whereas these data are in line with a growing body of evidence linking infections, immunity and metabolism, additional studies are necessary to establish the post-streptococcal-metabolic syndrome association.

  View details for DOI 10.1371/journal.pone.0025017

  View details for Web of Science ID 000295260400036

  View details for PubMedID 21949836

  View details for PubMedCentralID PMC3176794

• Genetics of Sleep and Sleep Disorders CELL Sehgal, A., Mignot, E. 2011; 146 (2): 194-207

  Abstract

  Sleep remains one of the least understood phenomena in biology--even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ∼14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep.

  View details for DOI 10.1016/j.cell.2011.07.004

  View details for Web of Science ID 000293013000004

  View details for PubMedID 21784243

  View details for PubMedCentralID PMC3153991

• Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1 PLOS GENETICS Winkelmann, J., Czamara, D., Schormair, B., Knauf, F., Schulte, E. C., Trenkwalder, C., Dauvilliers, Y., Polo, O., Hoegl, B., Berger, K., Fuhs, A., Gross, N., Stiasny-Kolster, K., Oertel, W., Bachmann, C. G., Paulus, W., Xiong, L., Montplaisir, J., Rouleau, G. A., Fietze, I., Vavrova, J., Kemlink, D., Sonka, K., Nevsimalova, S., Lin, S., Wszolek, Z., Vilarino-Gueell, C., Farrer, M. J., Gschliesser, V., Frauscher, B., Falkenstetter, T., Poewe, W., Allen, R. P., Earley, C. J., Ondo, W. G., Le, W., Spieler, D., Kaffe, M., Zimprich, A., Kettunen, J., Perola, M., Silander, K., Cournu-Rebeix, I., Francavilla, M., Fontenille, C., Fontaine, B., Vodicka, P., Prokisch, H., Lichtner, P., Peppard, P., Faraco, J., Mignot, E., Gieger, C., Illig, T., Wichmann, H., Mueller-Myhsok, B., Meitinger, T. 2011; 7 (7)

  Abstract

  Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

  View details for DOI 10.1371/journal.pgen.1002171

  View details for Web of Science ID 000293338600020

  View details for PubMedID 21779176

  View details for PubMedCentralID PMC3136436

• Presentations of Primary Hypersomnia in Chinese Children SLEEP Han, F., Lin, L., Li, J., Aran, A., Dong, S. X., Zhao, L., Li, M., Li, Q. Y., Yan, H., Wang, J. S., Gao, H. Y., Li, M., Gao, Z. C., Strohl, K. P., Mignot, E. 2011; 34 (5): 627-632A

  Abstract

  To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population.A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) DQB1*0602 typing, and MSLT recordings. CSF hypocretin-1 was measured in 47 cases to document hypocretin deficiency. A subgroup ("narcolepsy/hypocretin deficiency") with likely hypocretin deficiency (low hypocretin-1 or HLA positive with clear-cut cataplexy) was further examined for presentations prior to, around, or after puberty.Narcolepsy with (n = 361) or without (n = 17) cataplexy presented at an earlier age and with increased male predominance when compared to idiopathic hypersomnia (n = 39, P < 0.01). Nearly 70% of those with narcolepsy/hypocretin deficiency (n = 271) had disease onset before age 10 y, and 15% had onset before age 6, an unusually young age distribution. Onset was prior to puberty in 78% of cases. Clinical features were similar in presentations across puberty groups except for sleep paralysis, which increased in frequency with age/puberty. Mean sleep latency (MSL) decreased and the number of sleep onset REM periods (SOREMPs) increased with age/puberty, but MSLT diagnosis criteria (MSL ≤ 8 min, ≥ 2 SOREMPs) were similarly positive across groups. Familial clustering was present in only 1.7% of probands.In children presenting with a complaint of primary hypersomnia to a sleep clinic in China, 86% (361/417) meet criteria for narcolepsy with cataplexy. Puberty did not affect positivity on the MSLT as a diagnostic feature. Sleep paralysis was the only symptom that increased with increasing age. In addition, narcolepsy with cataplexy in our clinic population appeared to begin at a younger age than usually reported in other studies.

  View details for Web of Science ID 000291145800013

  View details for PubMedID 21532956

  View details for PubMedCentralID PMC3079942

• Genetics of Narcolepsy SLEEP MEDICINE CLINICS Faraco, J., Mignot, E. 2011; 6 (2): 217–28

  View details for DOI 10.1016/j.jsmc.2011.03.001

  View details for Web of Science ID 000218386600010

• beta 2 ADRENERGIC RECEPTOR POLYMORPHISMS AND NOCTURNAL BLOOD PRESSURE DIPPING STATUS IN THE WISCONSIN SLEEP COHORT STUDY Vardeny, O., Finn, L. A., Faraco, J., Mignot, E., Hla, K., Young, T., Peppard, P. E. ELSEVIER SCIENCE INC. 2011: E1296

  View details for DOI 10.1016/S0735-1097(11)61296-5

  View details for Web of Science ID 000291695101299

• beta 2 adrenergic receptor polymorphisms and nocturnal blood pressure dipping status in the Wisconsin Sleep Cohort Study JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Vardeny, O., Peppard, P. E., Finn, L. A., Faraco, J. H., Mignot, E., Hla, K. M. 2011; 5 (2): 114-122

  Abstract

  Nondipping nocturnal blood pressure (BP) is associated with target organ damage and cardiovascular disease. We hypothesized that β1- and β2-AR-associated single nucleotide polymorphisms (SNPs) would associate with nondipping BP patterns. Participants (n = 497, age range 30-74 years, 40% female) of the Wisconsin Sleep Cohort Study with at least one ambulatory BP monitoring test were included. Nondipping was defined as less than a 10% dip in sleep BP compared with wake BP. Dipping ratios were calculated as sleep/wake BP. Single nucleotide polymorphisms in the β1-AR (rs7076938, tagging for Gly389Arg) and β2-AR (rs17778257 and rs2400707, tagging for Arg16Gly and Gln27Glu) were selected. β2-AR SNP rs2400707 A-positive subjects (tagging for Glu27) had higher systolic and diastolic dipping ratios in a dose-response fashion. Systolic dipping ratios were: GG = 0.846; AG = 0.854; AA = 0.861 (P = .015). Diastolic dip ratios were: GG = 0.807; AG = 0.815; AA = 0.824 (P = .026). The β2-AR rs17778257/rs2400707 A/A haplotype was associated with dipping ratios and systolic nondipping status (nondipping odds radio 2.0 [1.0-3.8] for A/A versus A/G). Results were similar when models included participants on antihypertensive medications. Higher dipping ratios indicating a lack of nocturnal BP dipping are associated with β2-AR polymorphisms. Nocturnal dipping patterns may be modulated by β2-AR polymorphisms.

  View details for DOI 10.1016/j.jash.2011.01.005

  View details for Web of Science ID 000289136500007

  View details for PubMedID 21414566

  View details for PubMedCentralID PMC3071556

• Hydraulic Models of the Flow Distribution in a Four Branch Open Channel Junction with Supercritical Flow JOURNAL OF HYDRAULIC ENGINEERING Mignot, E., Riviere, N., Paquier, A., Perkins, R. J. 2011; 137 (3): 289-299

  View details for DOI 10.1061/(ASCE)HY.1943-7900.0000302

  View details for Web of Science ID 000287882800003

• POST-STREPTOCOCCAL ANTIBODIES ARE ASSOCIATED WITH METABOLIC SYNDROME IN A POPULATION-BASED SAMPLE OF HEALTHY ADULTS 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) Aran, A., Lin, L., Finn, L., Weiner, K., Peppard, P. E., Young, T., Mignot, E. AMER ACAD SLEEP MEDICINE. 2011: A222–A222

  View details for Web of Science ID 000299834400642

• Etiology and Genetics of Human Narcolepsy Mignot, E., Baumann, C. R., Bassetti, C. L., Scammell, T. E. SPRINGER. 2011: 3–17

  View details for DOI 10.1007/978-1-4419-8390-9_1

  View details for Web of Science ID 000395493100001

• Narcolepsy CONTEMPORARY SLEEP MEDICINE FOR PHYSICIANS Mignot, E., Ioachimescu, O. C. 2011: 182–92

  View details for Web of Science ID 000387377900013

• Transcriptional regulation of the hypocretin/orexin gene by NR6A1 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Tanaka, S., Kodama, T., Nonaka, T., Toyoda, H., Arai, M., Fukazawa, M., Honda, Y., Honda, M., Mignot, E. 2010; 403 (2): 178-183

  Abstract

  The hypocretin (also known as orexin) neuropeptide system coordinates the regulation of various physiological processes. A reduction in Nr6a1 expression was observed in hypocretin neuron-ablated transgenic mice. To show that prepro-hypocretin transcription is functionally modulated by NR6A1, we performed chromatin immunoprecipitation (ChIP) analysis, double-immunostaining, a luciferase reporter assay, and an in utero electroporation study. ChIP analysis showed that endogenous NR6A1 binds to a putative NR6A1-binding site. Double-immunostaining indicated almost all hypocretin neurons were positive for NR6A1 immunoreactivity. NR6A1 overexpression in SH-SY5Y cells modulated hypocretin promoter activity, an effect that was countered by lacking a putative NR6A1-binding site. Electroporation with Nr6a1 in the foetal hypothalamus promoted hypocretin transcription as compared to GFP-electroporation. These experiments confirmed that NR6A1 works as a regulator for hypocretin transcription.

  View details for DOI 10.1016/j.bbrc.2010.11.001

  View details for Web of Science ID 000285534500004

  View details for PubMedID 21056546

  View details for PubMedCentralID PMC3012206

• Clinical and Therapeutic Aspects of Childhood Narcolepsy-Cataplexy: A Retrospective Study of 51 Children SLEEP Aran, A., Einen, M., Lin, L., Plazzi, G., Nishino, S., Mignot, E. 2010; 33 (11): 1457-1464

  Abstract

  to report on symptoms and therapies used in childhood narcolepsy-cataplexy.retrospective series of 51 children who completed the Stanford Sleep Inventory. HLA-DQB1*0602 typing (all tested, and 100% positive), polysomnography or Multiple Sleep Latency Test (76%), and cerebrospinal fluid hypocretin-1 measurements (26%, all with low levels) were also conducted. Prospective data on medication response was collected in 78% using a specially designed questionnaire.patients were separated into children with onset of narcolepsy prior to (53%), around (29%), and after (18%) puberty. None of the children had secondary narcolepsy. Clinical features were similar across puberty groups, except for sleep paralysis, which increased in frequency with age. Common features included excessive weight gain (84% ≥ 4 kg within 6 months of onset of narcolepsy) and earlier puberty (when compared with family members), notably in subjects who gained the most weight. Streptococcus-positive throat infections were reported in 20% of cases within 6 months of onset of narcolepsy. Polysomnographic features were similar across groups, but 3 prepubertal children did not meet Multiple Sleep Latency Test diagnostic criteria. Regarding treatment, the most used and continued medications were modafinil (84% continued), sodium oxybate (79%), and venlafaxine (68%). Drugs such as methylphenidate, tricyclic antidepressants, or selective serotonin reuptake inhibitors were often tried but rarely continued. Modafinil was reported to be effective for treating sleepiness, venlafaxine for cataplexy, and sodium oxybate for all symptoms, across all puberty groups. At the conclusion of the study, half of children with prepubertal onset of narcolepsy were treated "off label" with sodium oxybate alone or with the addition of one other compound. In older children, however, most patients needed more than 2 drugs.this study reports on the clinical features of childhood narcolepsy and documents the safe use of treatments commonly used in adults in young children.

  View details for Web of Science ID 000285212600009

  View details for PubMedID 21102987

  View details for PubMedCentralID PMC2954695

• Post-H1N1 Narcolepsy-Cataplexy SLEEP Dauvilliers, Y., Montplaisir, J., Cochen, V., Desautels, A., Einen, M., Lin, L., Kawashima, M., Bayard, S., Monaca, C., Tiberge, M., Filipini, D., Tripathy, A., Nguyen, B. H., Kotagal, S., Mignot, E. 2010; 33 (11): 1428-1430

  View details for Web of Science ID 000285212600003

  View details for PubMedID 21102981

  View details for PubMedCentralID PMC2954689

• DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue NEUROLOGY Goel, N., Banks, S., Mignot, E., Dinges, D. F. 2010; 75 (17): 1509-1519

  Abstract

  The human leukocyte antigen (HLA) DQB1*0602 allele is closely associated with narcolepsy, a neurologic disorder characterized by excessive daytime sleepiness, fragmented sleep, and shortened REM sleep latency. We evaluated whether DQB1*0602 was a novel marker of interindividual differences by determining its relationship to sleep homeostatic, sleepiness, and cognitive responses to baseline and chronic partial sleep deprivation (PSD) conditions.Ninety-two DQB1*0602-negative and 37 DQB1*0602-positive healthy adults participated in a protocol of 2 baseline 10 hours time in bed (TIB) nights followed by 5 consecutive 4 hours TIB nights. DQB1*0602 allelic frequencies did not differ significantly between Caucasians and African Americans.During baseline, although DQB1*0602-positive subjects were subjectively sleepier and more fatigued, they showed greater sleep fragmentation, and decreased sleep homeostatic pressure and differentially sharper declines during the night (measured by non-REM EEG slow-wave energy [SWE]). During PSD, DQB1*0602-positive subjects were sleepier and showed more fragmented sleep, despite SWE elevation comparable to negative subjects. Moreover, they showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Both groups demonstrated comparable cumulative decreases in cognitive performance.DQB1*0602 positivity in a healthy population may represent a continuum of some sleep-wake features of narcolepsy. DQB1*0602 was associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue-but not in cognitive measures-during baseline and chronic PSD. Thus, DQB1*0602 may represent a genetic biomarker for predicting such individual differences in basal and sleep loss conditions.

  View details for Web of Science ID 000283819600006

  View details for PubMedID 20975052

  View details for PubMedCentralID PMC2974463

• Circadian and Homeostatic Regulation of Structural Synaptic Plasticity in Hypocretin Neurons NEURON Appelbaum, L., Wang, G., Yokogawa, T., Skariah, G. M., Smith, S. J., Mourrain, P., Mignot, E. 2010; 68 (1): 87-98

  Abstract

  Neurons exhibit rhythmic activity that ultimately affects behavior such as sleep. In living zebrafish larvae, we used time-lapse two-photon imaging of the presynaptic marker synaptophysin in hypocretin/orexin (HCRT) neurons to determine the dynamics of synaptic modifications during the day and night. We observed circadian rhythmicity in synapse number in HCRT axons. This rhythm is regulated primarily by the circadian clock but is also affected by sleep deprivation. Furthermore, NPTX2, a protein implicated in AMPA receptor clustering, modulates circadian synaptic changes. In zebrafish, nptx2b is a rhythmic gene that is mostly expressed in hypothalamic and pineal gland cells. Arrhythmic transgenic nptx2b overexpression (hcrt:NPTX2b) increases synapse number and abolishes rhythmicity in HCRT axons. Finally, hcrt:NPTX2b fish are resistant to the sleep-promoting effects of melatonin. This behavioral effect is consistent with NPTX2b-mediated increased activity of HCRT circuitry. These data provide real-time in vivo evidence of circadian and homeostatic regulation of structural synaptic plasticity.

  View details for DOI 10.1016/j.neuron.2010.09.006

  View details for Web of Science ID 000283704200010

  View details for PubMedID 20920793

  View details for PubMedCentralID PMC2969179

• Sleep Well and Stay Slim: Dream or Reality? ANNALS OF INTERNAL MEDICINE Taheri, S., Mignot, E. 2010; 153 (7): 475-?

  View details for Web of Science ID 000282517000008

  View details for PubMedID 20921547

• Effects of sleep on the cardiovascular and thermoregulatory systems: a possible role for hypocretins JOURNAL OF APPLIED PHYSIOLOGY Schwimmer, H., Stauss, H. M., Abboud, F., Nishino, S., Mignot, E., Zeitzer, J. M. 2010; 109 (4): 1053-1063

  Abstract

  Sleep influences the cardiovascular, endocrine, and thermoregulatory systems. Each of these systems may be affected by the activity of hypocretin (orexin)-producing neurons, which are involved in the etiology of narcolepsy. We examined sleep in male rats, either hypocretin neuron-ablated orexin/ataxin-3 transgenic (narcoleptic) rats or their wild-type littermates. We simultaneously monitored electroencephalographic and electromyographic activity, core body temperature, tail temperature, blood pressure, electrocardiographic activity, and locomotion. We analyzed the daily patterns of these variables, parsing sleep and circadian components and changes between states of sleep. We also analyzed the baroreceptor reflex. Our results show that while core temperature and heart rate are affected by both sleep and time of day, blood pressure is mostly affected by sleep. As expected, we found that both blood pressure and heart rate were acutely affected by sleep state transitions in both genotypes. Interestingly, hypocretin neuron-ablated rats have significantly lower systolic and diastolic blood pressure during all sleep stages (non-rapid eye movement, rapid eye movement) and while awake (quiet, active). Thus, while hypocretins are critical for the normal temporal structure of sleep and wakefulness, they also appear to be important in regulating baseline blood pressure and possibly in modulating the effects of sleep on blood pressure.

  View details for DOI 10.1152/japplphysiol.00516.2010

  View details for Web of Science ID 000285344900016

  View details for PubMedID 20705949

• Post-Streptococcal Auto-Antibodies Inhibit Protein Disulfide Isomerase and Are Associated with Insulin Resistance PLOS ONE Aran, A., Weiner, K., Lin, L., Finn, L. A., Greco, M. A., Peppard, P., Young, T., Ofran, Y., Mignot, E. 2010; 5 (9)

  Abstract

  Post-streptococcal autoimmunity affects millions worldwide, targeting multiple organs including the heart, brain, and kidneys. To explore the post-streptococcal autoimmunity spectrum, we used western blot analyses, to screen 310 sera from healthy subjects with (33%) and without (67%) markers of recent streptococcal infections [anti-Streptolysin O (ASLO) or anti-DNAse B (ADB)]. A 58 KDa protein, reacting strongly with post-streptococcal sera, was identified as Protein Disulfide Isomerase (PDI), an abundant protein with pleiotropic metabolic, immunologic, and thrombotic effects. Anti-PDI autoantibodies, purified from human sera, targeted similar epitopes in Streptolysin O (SLO, P51-61) and PDI (P328-338). The correlation between post-streptococcal status and anti-human PDI auto-immunity was further confirmed in a total of 2987 samples (13.6% in 530 ASLO positive versus 5.6% in 2457 ASLO negative samples, p<0.0001). Finally, anti-PDI auto-antibodies inhibited PDI-mediated insulin degradation in vitro (n = 90, p<0.001), and correlated with higher serum insulin (14.1 iu/ml vs. 12.2 iu/ml, n = 1215, p = 0.039) and insulin resistance (Homeostatic Model Assessment (HOMA) 4.1 vs. 3.1, n = 1215, p = 0.004), in a population-based cohort. These results identify PDI as a major target of post-streptococcal autoimmunity, and establish a new link between infection, autoimmunity, and metabolic disturbances.

  View details for DOI 10.1371/journal.pone.0012875

  View details for Web of Science ID 000282091100004

  View details for PubMedID 20886095

  View details for PubMedCentralID PMC2944800

• Anti-Tribbles Homo log 2 (TRIB2) Autoantibodies in Narcolepsy are Associated with Recent Onset of Cataplexy SLEEP Kawashima, M., Lin, L., Tanaka, S., Jennum, P., Knudsen, S., Nevsimalova, S., Plazzi, G., Mignot, E. 2010; 33 (7): 869-874

  Abstract

  Recent studies have found increased autoantibodies against Tribbles homolog 2 (anti-TRIB2) and anti-streptolysin O (ASO) in narcolepsy. In this study, we replicated this finding with a primary focus on recent onset cases.Participants included (1) 90 cases with cataplexy, (2) 57 cases without cataplexy, and (3) 156 age-sex matched controls, including 73 human leukocyte antigen (HLA)-DQB1*0602 allele carriers. A radioligand binding assay was used to detect anti-TRIB2 antibodies.Anti-TRIB2 antibodies were prevalent in HLA-DQB1*0602 positive cases with cataplexy (25.0% of 76) and rare in cases without cataplexy (3.5% of 57, OR = 9.2, 95% CI = 2.5 - 33.5, P = 6.0 x 10(-4)) or controls (4.5% of 156, OR = 7.1, 95% CI = 3.1 - 16.2, P = 9.3 x 10(-6)). Anti-TRIB2 positivity in controls was not associated with DQB1*0602. In DQB1*0602 narcolepsy-cataplexy cases, the presence of anti-TRIB2 was associated with short disease duration (2.3 years from cataplexy onset), with 41.0% positive in this group (OR = 7.4 versus cases with onset > 2.3 years, 95% CI = 1.9- 28.5, P = 9.0 x 10(-4)). Anti-TRIB2 positivity in 39 DQB1*0602 positive recent onset cases was associated with increased ASO antibody (> 200 IU) (OR = 6.2, 95% CI = 1.6 - 24.6, P = 0.01), but did not correlate with age, gender, or body mass index.Anti-TRIB2 autoantibodies are strongly associated with narcolepsy close to cataplexy onset (< or = 2.3 years). Anti-TRIB2 was rarely found in cases without cataplexy or with distant onset.

  View details for Web of Science ID 000279365600006

  View details for PubMedID 20614846

• Narcolepsy with Cataplexy Associated with Holoprosencephaly Misdiagnosed as Epileptic Drop Attacks MOVEMENT DISORDERS Plazzi, G., Tonon, C., Rubboli, G., Franceschini, C., Pizza, F., Bisulli, A., Rizzo, G., Mignot, E., Montagna, P., Lodi, R. 2010; 25 (6): 788-790

  View details for DOI 10.1002/mds.23008

  View details for Web of Science ID 000277311500023

  View details for PubMedID 20131387

• Behavioural and neurophysiological correlates of human cataplexy: A video-polygraphic study CLINICAL NEUROPHYSIOLOGY Vetrugno, R., D'Angelo, R., Moghadam, K. K., Vandi, S., Franceschini, C., Mignot, E., Montagna, P., Plazzi, G. 2010; 121 (2): 153-162

  Abstract

  To investigate the behavioural and neurophysiological pattern of cataplexy.Seven narcolepsy with cataplexy patients underwent daytime videopolygraphy using humorous movies or/and jokes to trigger cataplectic attacks.During segmental cataplectic attacks, EMG showed brief and irregular periods of silencing focally involving facial, neck, axial or limb muscles, sometimes coinciding with bursts of rapid eye movements. All patients enacted intentional movements in response to these segmental postural lapses. During global cataplectic attacks, EMG showed suppression of activity alternated with patterned enhancement, enhanced EMG activity in neck muscles preceding that of other cranial, axial and lower limb muscles. This waxing and waning EMG pattern ended with a complete body collapse and persistent muscle atonia. Breathing irregularities, heart rate (HR) instability and EEG desynchronization were observed during global cataplectic attacks without any appreciable blood pressure changes, but with HR deceleration and silencing of sympathetic skin response while in complete atonia. Patients subjectively perceived the involuntary postural lapses as startling and alarming.Cataplexy in our patients showed many of the features of tonic REM sleep.Cataplexy can be construed as a "freezing-like" perturbation of the orienting response with transient impairment of posture and movements resulting in a "patchwork-compromise-behaviour".

  View details for DOI 10.1016/j.clinph.2009.10.012

  View details for Web of Science ID 000274557700007

  View details for PubMedID 19955018

• Sodium oxybate is an effective and safe treatment for narcolepsy SLEEP MEDICINE Lammers, G. J., Bassetti, C., Billiard, M., Black, J., Broughton, R., Dauvilliers, Y., Strambi, L. F., Garcia-Borreguero, D., Goswami, M., Hoegl, B., Iranzo, A., Jennum, P., Khatami, R., Lecendreux, M., Mayer, G., Mignot, E., Montplaisir, J., Nevsimalova, S., Peraita-Adrados, R., Plazzi, G., Scammell, T., Silber, M., Sonka, K., Tafti, M., Thorpy, M. 2010; 11 (1): 105-106

  View details for DOI 10.1016/j.sleep.2009.08.003

  View details for Web of Science ID 000274321000022

  View details for PubMedID 19846338

• Narcolepsy: Genetic Predisposition and Pathophysiology NARCOLEPSY: A CLINICAL GUIDE Mignot, E., Goswami, M., PandiPerumal, Thorpy, M. J. 2010: 3–21

  View details for DOI 10.1007/978-1-4419-0854-4_1

  View details for Web of Science ID 000272515300003

• Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Appelbaum, L., Wang, G. X., Maro, G. S., Mori, R., Tovin, A., Marin, W., Yokogawa, T., Kawakami, K., Smith, S. J., Gothilf, Y., Mignot, E., Mourrain, P. 2009; 106 (51): 21942-21947

  Abstract

  In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr-/-). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in hcrtr-/- pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore, hcrtr-/- fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr-/- fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.

  View details for DOI 10.1073/pnas.906637106

  View details for Web of Science ID 000272994200086

  View details for PubMedID 19966231

  View details for PubMedCentralID PMC2799794

• Characterization of Two Melanin-Concentrating Hormone Genes in Zebrafish Reveals Evolutionary and Physiological Links with the Mammalian MCH System JOURNAL OF COMPARATIVE NEUROLOGY Berman, J. R., Skariah, G., Maro, G. S., Mignot, E., Mourrain, P. 2009; 517 (5): 695-710

  Abstract

  Melanin-concentrating hormone (MCH) regulates feeding and complex behaviors in mammals and pigmentation in fish. The relationship between fish and mammalian MCH systems is not well understood. Here, we identify and characterize two MCH genes in zebrafish, Pmch1 and Pmch2. Whereas Pmch1 and its corresponding MCH1 peptide resemble MCH found in other fish, the zebrafish Pmch2 gene and MCH2 peptide share genomic structure, synteny, and high peptide sequence homology with mammalian MCH. Zebrafish Pmch genes are expressed in closely associated but non-overlapping neurons within the hypothalamus, and MCH2 neurons send numerous projections to multiple MCH receptor-rich targets with presumed roles in sensory perception, learning and memory, arousal, and homeostatic regulation. Preliminary functional analysis showed that whereas changes in zebrafish Pmch1 expression correlate with pigmentation changes, the number of MCH2-expressing neurons increases in response to chronic food deprivation. These findings demonstrate that zebrafish MCH2 is the putative structural and functional ortholog of mammalian MCH and help elucidate the nature of MCH evolution among vertebrates.

  View details for DOI 10.1002/cne.22171

  View details for Web of Science ID 000271112000011

  View details for PubMedID 19827161

  View details for PubMedCentralID PMC3427774

• T-box 3 is expressed in the adult mouse hypothalamus and medulla BRAIN RESEARCH Eriksson, K. S., Mignot, E. 2009; 1302: 233-239

  Abstract

  Using microarray analysis, in situ hybridization and immunocytochemistry, we found that the transcription factor TBX3 is produced in three discrete neuronal populations of the adult mouse brain, the arcuate nucleus (including in NPY but not dopaminergic neurons), the histaminergic tuberomammillary nucleus and in cholinergic neurons of the solitary tract nucleus. The immunoreactive protein had a nuclear location in these neurons, consistent with its function as a transcription factor. Although the function of tbx3 in these neurons is unknown, a review of the literature strongly suggests that these neuronal populations may be abnormal in Ulnar-Mammary syndrome patients with tbx3 mutations, explaining previously overlooked phenotypes in this syndrome, such as obesity, sexual dysfunction and possibly sleep abnormalities.

  View details for DOI 10.1016/j.brainres.2009.08.101

  View details for Web of Science ID 000272071600024

  View details for PubMedID 19765559

  View details for PubMedCentralID PMC2805014

• Body Mass Index-Independent Metabolic Alterations in Narcolepsy with Cataplexy SLEEP Poli, F., Plazzi, G., Di Dalmazi, G., Ribichini, D., Vicennati, V., Pizza, F., Mignot, E., Montagna, P., Pasquali, R., Pagotto, U. 2009; 32 (11): 1491-1497

  Abstract

  To contribute to the anthropometric and metabolic phenotyping of orexin-A-deficient narcoleptic patients, and to explore a possible risk of their developing a metabolic syndrome.We performed a cross-sectional study comparing metabolic alterations in patients with narcolepsy with cataplexy (NC) and patients with idiopathic hypersomnia without long sleep time.University hospital.Fourteen patients with narcolepsy with cataplexy and 14 sex and age-matched patients with idiopathic hypersomnia without long sleep time. Interventions: N/A.Metabolic parameters were evaluated by measuring body mass index (BMI), waist circumference (also with abdominal computed tomography), blood pressure, and daily calorie intake (3-day diary). Chronotypes were assessed through the morningness-eveningness questionnaire. Lumbar puncture for cerebrospinal fluid orexin-A determination and HLA typing were performed. Patients with narcolepsy with cataplexy (all HLA DQB1*0602 positive and with cerebrospinal fluid orexin-A levels < 110 pg/mL) had a higher BMI and BMI-independent metabolic alterations, namely waist circumference, high-density lipoprotein cholesterol, and glucose/insulin ratio (an insulin resistance index), with respect to patients with idiopathic hypersomnia without long sleep time (cerebrospinal fluid orexin-A levels > 300 pg/mL). Despite lower daily food intake, patients with narcolepsy with cataplexy displayed significant alterations in metabolic parameters resulting in a diagnosis of metabolic syndrome in more than half the cases.BMI-independent metabolic alterations and the relative hypophagia of patients with narcolepsy with cataplexy, as compared with patients with idiopathic hypersomnia without long sleep time, suggest that orexin-A influences the etiology of this phenotype. Moreover, considering that these dysmetabolic alterations are present from a young age, a careful metabolic follow-up of patients diagnosed with narcolepsy with cataplexy is mandatory.

  View details for Web of Science ID 000271693700012

  View details for PubMedID 19928388

  View details for PubMedCentralID PMC2768955

• In memoriam of Dr. Yutaka Honda (1929-2009), A Pioneer in Sleep Medicine and Narcolepsy Research OBITUARY SLEEP Mignot, E. 2009; 32 (11): 1528–29

  View details for DOI 10.1093/sleep/32.11.1528

  View details for Web of Science ID 000271693700017

• Modafinil and gamma-hydroxybutyrate have sleep state-specific pharmacological actions on hypocretin-1 physiology in a primate model of human sleep BEHAVIOURAL PHARMACOLOGY Zeitzer, J. M., Buckmaster, C. L., Landoltd, H., Lyons, D. M., Mignot, E. 2009; 20 (7): 643-652

  Abstract

  Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing γ-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.

  View details for DOI 10.1097/FBP.0b013e328331b9db

  View details for Web of Science ID 000270483300010

  View details for PubMedID 19752724

  View details for PubMedCentralID PMC2939929

• Distribution of neurochemical abnormalities in patients with narcolepsy with cataplexy: An in vivo brain proton MR spectroscopy study BRAIN RESEARCH BULLETIN Tonon, C., Franceschini, C., Testa, C., Manners, D. N., Poli, F., Mostacci, B., Mignot, E., Montagna, P., Barbiroli, B., Lodi, R., Plazzi, G. 2009; 80 (3): 147-150

  Abstract

  Narcolepsy with cataplexy is characterised by excessive daytime sleepiness, sudden drops of muscle tone triggered by emotions, termed cataplexy, disrupted nocturnal sleep and other dissociated rapid eye movement (REM) sleep phenomena. Narcolepsy has been linked to a loss of hypothalamic neurons producing hypocretins, neuropeptides implicated in the regulation of the arousal system. Neuroimaging and neurometabolic studies have shown the pathophysiological involvement of other brain structures such as cerebral cortex and thalamus, but, overall with inconsistent results. We investigated, by using an advanced quantitative MR technique, proton MR spectroscopy ((1)H-MRS), the distribution of brain neurochemical abnormalities in narcolepsy with cataplexy patients. Single voxel (1)H-MRS study was performed in the thalamus, hypothalamus, and parietal-occipital cortex of hypocretin deficient, narcolepsy with cataplexy patients, HLA-DQB1*0602-positive, drug free. No significant changes were detected in the thalamus and parietal-occipital cortex of the patients. On the other hand, the neuronal marker N-acetyl-aspartate was reduced in the hypothalamus of narcolepsy with cataplexy patients compared to controls. These (1)H-MRS findings further support that in narcolepsy with cataplexy patients, the hypothalamus is the primary site of neural lesions. The absence of (1)H-MRS neurodegenerative changes in the thalamus and cerebral cortex suggests that the abnormalities detected in these brain regions by other neuroimaging techniques are likely of functional nature.

  View details for DOI 10.1016/j.brainresbull.2009.05.010

  View details for Web of Science ID 000270259300009

  View details for PubMedID 19463917

• Resting Our Cortices by Going DOWN to Sleep NEURON Mignot, E., Huguenard, J. R. 2009; 63 (6): 719-721

  Abstract

  In this issue of Neuron, Vyazovskiy et al. reports on progressive changes in cortical unit activity within extended wakefulness and within extended sleep paralleling changes in EEG slow-wave sleep activity. Sleep debt may be integrated at the level of individual cortical neurons, providing support for the synaptic homeostasis theory.

  View details for DOI 10.1016/j.neuron.2009.09.008

  View details for Web of Science ID 000270569700004

  View details for PubMedID 19778500

• Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy NEUROLOGY Honda, M., Arai, T., Fukazawa, M., Honda, Y., Tsuchiya, K., Salehi, A., Akiyama, H., Mignot, E. 2009; 73 (7): 511-517

  Abstract

  The cause of hypocretin cell loss in human narcolepsy-cataplexy is unknown but has been suggested to be neurodegenerative in nature. To test this hypothesis, we evaluated the remaining hypocretin cells in human narcolepsy brains for the presence of aggregated protein inclusions, gliosis, and inflammation.Brains were examined by routine histologic methods for potential comorbid neurodegenerative diseases and through immunohistochemical screening for protein inclusions in the hypothalamus. Hypothalamic sections of 4 subjects with narcolepsy and 5 nonneurologic controls were examined immunohistochemically with antibodies against ubiquitin (a marker of aggregated protein), allograft inflammatory factor 1 (AIF1, a microglial activation marker), glial fibrillary acidic protein (GFAP, a reactive astrocytic marker), and hypocretin. Hypothalami of subjects with narcolepsy were additionally examined for the presence of known components of protein aggregates (tau, alpha-synuclein, amyloid beta, and TDP-43).Hypocretin cells were markedly decreased in all 4 subjects with narcolepsy. Ubiquitinated inclusions were not observed in the total of 96 remaining hypocretin cells in these subjects. Further, we noted that even in patients with dementia neuropathology, the lateral hypothalamic hypocretin area was spared from ubiquitinated inclusions. AIF1 and GFAP staining in the perifornical area was unremarkable.Our findings suggest that hypocretin cell loss does not involve ubiquitinated inclusions, the hallmark of most neurodegenerative diseases. The lack of increased markers of inflammation also argues against a progressive and continuous neurodegenerative process.

  View details for DOI 10.1212/WNL.0b013e3181b2a6af

  View details for Web of Science ID 000269038300005

  View details for PubMedID 19687452

  View details for PubMedCentralID PMC2730798

• Elevated Anti-Streptococcal Antibodies in Patients with Recent Narcolepsy Onset SLEEP Aran, A., Lin, L., Nevsimalova, S., Plazzi, G., Hong, S. C., Weiner, K., Zeitzer, J., Mignot, E. 2009; 32 (8): 979-983

  Abstract

  Narcolepsy-cataplexy has long been thought to have an autoimmune origin. Although susceptibility to narcolepsy, like many autoimmune conditions, is largely genetically determined, environmental factors are involved based on the high discordance rate (approximately 75%) of monozygotic twins. This study evaluated whether Streptococcus pyogenes and Helicobacter pylori infections are triggers for narcolepsy.Retrospective, case-control.Sleep centers of general hospitals.200 patients with narcolepsy/hypocretin deficiency, with a primary focus on recent onset cases and 200 age-matched healthy controls. All patients were DQB1*0602 positive with low CSF hypocretin-1 or had clear-cut cataplexy.Participants were tested for markers of immune response to beta hemolytic streptococcus (anti-streptolysin O [ASO]; anti DNAse B [ADB]) and Helicobacter pylori [Anti Hp IgG], two bacterial infections known to trigger autoimmunity. A general inflammatory marker, C-reactive protein (CRP), was also studied. When compared to controls, ASO and ADB titers were highest close to narcolepsy onset, and decreased with disease duration. For example, ASO > or = 200 IU (ADB > or = 480 IU) were found in 51% (45%) of 67 patients within 3 years of onset, compared to 19% (17%) of 67 age matched controls (OR = 4.3 [OR = 4.1], P < 0.0005) or 20% (15%) of 69 patients with long-standing disease (OR = 4.0 [OR = 4.8], P < 0.0005]. CRP (mean values) and Anti Hp IgG (% positive) did not differ from controls.Streptococcal infections are probably a significant environmental trigger for narcolepsy.

  View details for Web of Science ID 000268557600004

  View details for PubMedID 19725248

• The effects of sleep on the cardiovascular and the thermoregulatory systems - possible role for hypocretin Schwimmer, H., Zeitzer, J. M., Yanagisawa, M., Nishino, S., Stauss, H. M., Abboud, F. M., Mignot, E. FEDERATION AMER SOC EXP BIOL. 2009

  View details for Web of Science ID 000208621505350

• Decreased CSF Histamine in Narcolepsy With and Without Low CSF Hypocretin-1 in Comparison to Healthy Controls SLEEP Nishino, S., Sakurai, E., Nevsimalova, S., Yoshida, Y., Watanabe, T., Yanai, K., Mignot, E. 2009; 32 (2): 175-180

  Abstract

  To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1.Patients meeting the ICSD-2 criteria for narcolepsy with and without cataplexy and who had CSF hypocretin-1 results available were selected from the Stanford Narcolepsy Database on the basis of CSF availability and adequate age and sex matching across 3 groups: narcolepsy with low CSF hypocretin-1 (n=34, 100% with cataplexy), narcolepsy without low CSF hypocretin-1 (n=24, 75% with cataplexy), and normal controls (n=23). Low CSF hypocretin-1 was defined as CSF < or =110 pg/mL (1/3 of mean control values). Six of 34 patients with low CSF hypocretin-1, six of 24 subjects with normal CSF hypocretin-1, and all controls were unmedicated at the time of CSF collection. CSF histamine was measured in all samples using a fluorometric HPLC system.Mean CSF histamine levels were: 133.2 +/- 20.1 pg/mL in narcoleptic subjects with low CSF hypocretin-1, 233.3 +/- 46.5 pg/mL in patients with normal CSF hypocretin-1 (204.9 +/- 89.7 pg/mL if only patients without cataplexy are included), and 300.5 +/- 49.7 pg/mL in controls, reaching statistically significant differences between the 3 groups.CSF histamine levels are reduced in human narcolepsy. The reduction of CSF histamine levels was more evident in the cases with low CSF hypocretin-1, and levels were intermediate in other narcolepsy cases. As histamine is a wake-promoting amine known to decrease during sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.

  View details for Web of Science ID 000262890300008

  View details for PubMedID 19238804

• HLA DQB1*0602 IS ASSOCIATED WITH SLEEP PERCEPTION IN OLDER INDIVIDUALS WITH INSOMNIA 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Zeitzer, J., Grove, M. E., Mignot, E., Yesavage, J. A., Friedman, L. AMER ACAD SLEEP MEDICINE. 2009: A262–A262

  View details for Web of Science ID 000265542001152

• Sedative-Hypnotics AMERICAN PSYCHIATRIC PUBLISHING TEXTBOOK OF PSYCHOPHARMACOLOGY, 4TH EDITION Nishino, S., Mishima, K., Mignot, E., Dement, W. C., Schatzberg, A. F., Nemeroff, C. B. 2009: 821–41

  View details for Web of Science ID 000310050700043

• A Consensus Definition of Cataplexy in Mouse Models of Narcolepsy SLEEP Scammell, T. E., Willie, J. T., Guilleminault, C., Siegel, J. M., Int Working Grp Rodent Models Nar 2009; 32 (1): 111–16

  Abstract

  People with narcolepsy often have episodes of cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of murine cataplexy. The group concluded that murine cataplexy is an abrupt episode of nuchal atonia lasting at least 10 seconds. In addition, theta activity dominates the EEG during the episode, and video recordings document immobility. To distinguish a cataplexy episode from REM sleep after a brief awakening, at least 40 seconds of wakefulness must precede the episode. Bouts of cataplexy fitting this definition are common in mice with disrupted orexin/hypocretin signaling, but these events almost never occur in wild type mice. It remains unclear whether murine cataplexy is triggered by strong emotions or whether mice remain conscious during the episodes as in people with narcolepsy. This working definition provides helpful insights into murine cataplexy and should allow objective and accurate comparisons of cataplexy in future studies using mouse models of narcolepsy.

  View details for Web of Science ID 000262075600018

  View details for PubMedID 19189786

  View details for PubMedCentralID PMC2625315

• Sympathetic and cardiovascular activity during cataplexy in narcolepsy. Journal of sleep research Donadio, V., Plazzi, G., Vandi, S., Franceschini, C., Karlsson, T., Montagna, P., Vetrugno, R., Bugiardini, E., Mignot, E., Liguori, R. 2008; 17 (4): 458-463

  Abstract

  Autonomic nervous system activity changes have been described during cataplexy as playing a role in triggering it. To confirm these previous findings, we investigated the time course of sympathetic and cardiovascular activities during cataplexy. We made for the first time microneurographic recordings of 10 cataplectic episodes in three patients with hypocretin-deficient narcolepsy. During microneurography, muscle sympathetic nerve activity (MSNA) was recorded simultaneously with heart rate (HR), respiratory movements, arterial finger blood pressure (BP), electroencephalography, electro-oculogram and superficial electromyogram. Results showed no significant autonomic changes before the onset of the cataplectic episodes. Cataplexy was associated with a significant increase in MSNA and BP compared with baseline, whereas HR was markedly decreased. An irregular breathing pattern mainly characterized by apnea typically occurred during the attacks. In conclusion, our findings did not show significant changes in autonomic activity prior to cataplexy onset, ruling out a triggering role of the autonomic system. However, cataplexy was associated with co-activation of sympathetic and parasympathetic autonomic systems, a pattern reminiscent of that reported during the vigilance reaction in animals.

  View details for DOI 10.1111/j.1365-2869.2008.00682.x

  View details for PubMedID 19021855

• 'The devil lay upon her and held her down' Hypnagogic hallucinations and sleep paralysis described by the Dutch physician Isbrand van Diemerbroeck (1609-1674) in 1664 JOURNAL OF SLEEP RESEARCH Donadio, V., Plazzi, G., Vandi, S., Franceschini, C., Karlsson, T., Montagna, P., Vetrugno, R., Bugiardini, E., Mignot, E., Liguori, R. 2008; 17 (4): 458-463

  Abstract

  An impaired ability to arouse from sleep may play an important role in the pathogenesis of sudden infant death syndrome (SIDS). This study aimed to investigate the effects of prone sleeping on the nature of both induced and spontaneous arousal responses in infants. Thirteen healthy term infants were studied longitudinally at 2-4 weeks, 2-3 months and 5-6 months postnatal age. A pulsatile jet of air to the nostrils was used to induce arousal from both active sleep and quiet sleep in both prone and supine positions. For each stimulus, arousals were classified as sub-cortical activations and cortical arousals, scored using physiological and electroencephalogram changes and expressed as a percentage of the total number of arousals. Spontaneous arousals were similarly analysed. Increased proportions of cortical arousals, hence decreased proportions of sub-cortical activations, were observed in the prone position at 2-3 months. This distinct peak in the proportion of cortical arousals occurred regardless of sleep state and regardless of whether the arousal occurred spontaneously or was induced by air-jet stimulation. The nature of arousal responses in healthy term infants is altered in the prone sleeping position at 2-3 months after birth, the age where SIDS incidence is highest. We postulate that a greater propensity for cortical arousal may be a protective mechanism to promote complete arousal in a vulnerable sleeping position and/or a vulnerable period of maturation. Inadequate or incomplete cortical arousals may explain the increased risk of SIDS associated with the prone position at this age.

  View details for DOI 10.1111/j.1365-2869.2008.00672.x

  View details for Web of Science ID 000261263300014

• Variant between CPT1B and CHKB associated with susceptibility to narcolepsy NATURE GENETICS Miyagawa, T., Kawashima, M., Nishida, N., Ohashi, J., Kimura, R., Fujimoto, A., Shimada, M., Morishita, S., Shigeta, T., Lin, L., Hong, S., Faraco, J., Shin, Y., Jeong, J., Okazaki, Y., Tsuji, S., Honda, M., Honda, Y., Mignot, E., Tokunaga, K. 2008; 40 (11): 1324-1328

  Abstract

  Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 x 10(-7)) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates beta-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.

  View details for DOI 10.1038/ng.231

  View details for Web of Science ID 000260501500025

  View details for PubMedID 18820697

• Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy JOURNAL OF NEUROLOGY Plazzi, G., Poli, F., Franceschini, C., Parmeggiani, A., Pirazzoli, P., Bernardi, F., Mignot, E., Cicognani, A., Montagna, P. 2008; 255 (10): 1549-1554

  Abstract

  We report on the outcome of intravenous high-dose immunoglobulin (IVIg) treatment in four children with narcolepsy and cataplexy, in whom the early diagnosis and the extreme disease severity were indications for this potentially efficacious therapy. One of four patients showed an objective and persistent improvement in clinical features during and after IVIg treatment. Our data partially support the recent report of the efficacy of IVIg treatment in early diagnosed narcolepsy with cataplexy and support the need for a controlled multicenter clinical trial on IVIg in narcolepsy.

  View details for DOI 10.1007/s00415-008-0983-7

  View details for Web of Science ID 000260877600016

  View details for PubMedID 18769859

• Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy SLEEP Mishima, K., Fujiki, N., Yoshida, Y., Sakurai, T., Honda, M., Mignot, E., Nishino, S. 2008; 31 (8): 1119-1126

  Abstract

  To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy.Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years).27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression.Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy.

  View details for Web of Science ID 000258111000009

  View details for PubMedID 18714784

• CSF hypocretin-1 assessment in sleep and neurological disorders LANCET NEUROLOGY Bourgin, P., Zeitzer, J. M., Mignot, E. 2008; 7 (7): 649-662

  Abstract

  Concentrations of CSF hypocretin-1 (formerly orexin A) have been measured in many patients with sleep or neurological conditions. Low CSF hypocretin-1 is most predictive of narcolepsy in patients positive for HLA allele DQB1*0602, most of whom have cataplexy. By contrast, the diagnostic significance of low CSF hypocretin-1 is unclear in the presence of acute CNS inflammation or trauma. The clinical usefulness of CSF testing in hypersomnia that is symptomatic of a neurological disorder remains to be evaluated. Determination of CSF hypocretin-1 concentration to diagnose narcolepsy might be most useful in ambulatory patients with cataplexy but with a normal multiple sleep latency test (MSLT) result, or if MSLT is not interpretable, conclusive, or feasible. Because 98% of patients with hypocretin-1 deficiency are positive for HLA DQB1*0602, we suggest that HLA typing is a useful screen before lumbar puncture. Although hypocretin-1 deficiency in narcolepsy might have therapeutic relevance, additional research is needed in this area.

  View details for Web of Science ID 000257213600021

  View details for PubMedID 18565458

• Flow patterns in a four-branch junction with supercritical flow JOURNAL OF HYDRAULIC ENGINEERING Mignot, E., Riviere, N., Perkins, R., Paquier, A. 2008; 134 (6): 701-713

  View details for DOI 10.1061/(ASCE)0733-9429(2008)134:6(701)

  View details for Web of Science ID 000255970400003

• Anomalous Hypothalamic Responses to Humor in Cataplexy PLOS ONE Reiss, A. L., Hoeft, F., Tenforde, A. S., Chen, W., Mobbs, D., Mignot, E. J. 2008; 3 (5)

  Abstract

  Cataplexy is observed in a subset of patients with narcolepsy and affects approximately 1 in 2,000 persons. Cataplexy is most often triggered by strong emotions such as laughter, which can result in transient, yet debilitating, muscle atonia. The objective of this study was to examine the neural systems underlying humor processing in individuals with cataplexy.While undergoing functional Magnetic Resonance Imaging (fMRI), we showed ten narcolepsy-cataplexy patients and ten healthy controls humorous cartoons. In addition, we examined the brain activity of one subject while in a full-blown cataplectic attack. Behavioral results showed that participants with cataplexy rated significantly fewer humorous cartoons as funny compared to controls. Concurrent fMRI showed that patients, when compared to controls and in the absence of overt cataplexy symptoms, showed pronounced activity in the emotional network including the ventral striatum and hypothalamus while viewing humorous versus non-humorous cartoons. Increased activity was also observed in the right inferior frontal gyri--a core component of the inhibitory circuitry. In comparison, the one subject who experienced a cataplectic attack showed dramatic reductions in hypothalamic activity.These findings suggest an overdrive of the emotional circuitry and possible compensatory suppression by cortical inhibitory regions in cataplexy. Moreover, during cataplectic attacks, the hypothalamus is characterized by a marked decrease in activity similar to that observed during sleep. One possible explanation for these findings is an initial overdrive and compensatory shutdown of the hypothalamus resulting in full cataplectic symptoms.

  View details for DOI 10.1371/journal.pone.0002225

  View details for Web of Science ID 000262258700033

  View details for PubMedID 18493621

  View details for PubMedCentralID PMC2377337

• Sleep and EEG features in genetic models of Down syndrome NEUROBIOLOGY OF DISEASE Colas, D., Valletta, J. S., Takimoto-Kimura, R., Nishino, S., Fujiki, N., Mobley, W. C., Mignot, E. 2008; 30 (1): 1-7

  Abstract

  Down syndrome is characterized by a host of behavioral abnormalities including sleep disturbances. Sleep and EEG was studied at the age of 3 months in two mouse models of the condition, Ts65Dn and Ts1Cje, carrying one extra copy of partially overlapping segments of the mmu chromosome 16 (equivalent to the human chromosome 21). We found that the Ts65Dn mice showed increased waking amounts at the expense of non-REM sleep, increased theta power during sleep and a delayed sleep rebound after sleep deprivation. In contrast, Ts1Cje had limited sleep and EEG abnormalities, showing only a delayed sleep rebound after sleep deprivation and no difference in theta power. We previously found that mice over-expressing the human APPwt transgene, a gene triplicated in Ts65Dn but not Ts1Cje, also show increased wake and theta power during sleep. These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations.

  View details for DOI 10.1016/j.nbd.2007.07.014

  View details for Web of Science ID 000254665100001

  View details for PubMedID 18282758

• Excessive daytime sleepiness: Population and etiology versus nosology SLEEP MEDICINE REVIEWS Mignot, E. 2008; 12 (2): 87-94

  View details for DOI 10.1016/j.smrv.2007.12.006

  View details for Web of Science ID 000254992900001

  View details for PubMedID 18342260

• The type III neurofilament peripherin is expressed in the tuberomammillary neurons of the mouse BMC NEUROSCIENCE Eriksson, K. S., Zhang, S., Lin, L., Lariviere, R. C., Julien, J., Mignot, E. 2008; 9

  Abstract

  Peripherin, a type III neuronal intermediate filament, is widely expressed in neurons of the peripheral nervous system and in selected central nervous system hindbrain areas with projections towards peripheral structures, such as cranial nerves and spinal cord neurons. Peripherin appears to play a role in neurite elongation during development and axonal regeneration, but its exact function is not known. We noticed high peripherin expression in the posterior hypothalamus of mice, and decided to investigate further the exact location of expression and function of peripherin in the mouse posterior hypothalamus.In situ hybridization indicated expression of peripherin in neurons with a distribution reminiscent of the histaminergic neurons, with little signal in any other part of the forebrain. Immunocytochemical staining for histidine decarboxylase and peripherin revealed extensive colocalization, showing that peripherin is produced by histaminergic neurons in all parts of the tuberomammillary nucleus. We next used histamine immunostaining in peripherin knockout, overexpressing and wild type mice to study if altered peripherin expression affects these neurons, but could not detect any visible difference in the appearance of these neurons or their axons. Peripherin knockout mice and heterozygotic littermates were used for measurement of locomotor activity, feeding, drinking, and energy expenditure. Both genotypes displayed diurnal rhythms with all the parameters higher during the dark period. The respiratory quotient, an indicator of the type of substrate being utilized, also exhibited a significant diurnal rhythm in both genotypes. The diurnal patterns and the average values of all the recorded parameters for 24 h, daytime and night time were not significantly different between the genotypes, however.In conclusion, we have shown that peripherin is expressed in the tuberomammillary neurons of the mouse hypothalamus. Monitoring of locomotor activity, feeding, drinking, and energy expenditure in mice either lacking or overexpressing peripherin did not reveal any difference, so the significance of peripherin in these neurons remains to be determined. The complete overlap between histidine decarboxylase and peripherin, both the protein and its mRNA, renders peripherin a useful new marker for histaminergic neurons in the hypothalamus.

  View details for DOI 10.1186/1471-2202-9-26

  View details for Web of Science ID 000253966200001

  View details for PubMedID 18294400

  View details for PubMedCentralID PMC2266937

• The hypocretin neurotransmission system in myotonic dystrophy type 1 NEUROLOGY Ciafaloni, E., Mignot, E., Sansone, V., Hilbert, J. E., Lin, L., Lin, X., Liu, L. C., Pigeon, W. R., Perlis, M. L., Thornton, C. A. 2008; 70 (3): 226-230

  Abstract

  Patients with myotonic dystrophy type 1 (DM1) frequently have symptoms of excessive daytime sleepiness (EDS). Some patients with DM1 show sleep-onset REM, similar to that observed in narcolepsy. Narcolepsy is characterized by impaired hypocretin (Hcrt) neurotransmission.To test for dysregulation of Hcrt neurotransmission in a prospective cohort of patients with DM1.Hcrt levels in CSF were measured by radioimmunoassay. Sleep physiology was assessed by overnight polysomnography (PSG) and a multiple sleep latency test (MSLT). Splicing of Hcrt receptor 1 and 2 (HcrtR1 and HcrtR2) mRNA was examined in postmortem samples of temporal cortex.Seventeen of 38 patients with DM1 reported symptoms of EDS. Among patients with DM1 with EDS who underwent PSG/MSLT, 7 of 13 showed reduced sleep latency, sleep-onset REM, or both. However, CSF Hcrt levels in DM1 (mean 277 pg/mL, n = 38) were not different from controls (mean 277 pg/mL, n = 33). Also, splicing of HcrtR1 and HcrtR2 mRNA in patients with DM1 was similar to controls.Excessive daytime sleepiness and dysregulation of REM sleep occur frequently in patients with myotonic dystrophy type 1 (DM1). However, the pathophysiologic basis is distinct from narcolepsy, as patients with DM1 do not have a consistent defect of Hcrt release or receptor splicing.

  View details for Web of Science ID 000252505000012

  View details for PubMedID 18195268

• Hypocretin neuron morphology and neurotransmitter identity in zebrafish 22nd Annual Meeting of the Associated-Professional-Sleep-Societies Appelbaum, L., Wang, G., Marin, W., Mignot, E., Mourrain, P. AMER ACAD SLEEP MEDICINE. 2008: A5–A5

  View details for Web of Science ID 000255419000014

• Experimental and numerical modeling of symmetrical four-branch supercritical cross junction flow JOURNAL OF HYDRAULIC RESEARCH Mignot, E., Paquier, A., Riviere, N. 2008; 46 (6): 723-738

  View details for DOI 10.3826/jhr.2008.2961

  View details for Web of Science ID 000263908200001

• Insulin-like growth factor binding protein-3 reduces hypocretin/orexin transmission 22nd Annual Meeting of the Associated-Professional-Sleep-Societies Zhang, S., Lin, L., Zhang, J., Tanaka, S., Honda, M., Mignot, E. AMER ACAD SLEEP MEDICINE. 2008: A16–A17

  View details for Web of Science ID 000255419000052

• REM behavior disorder (RBD) can be one of the first symptoms of childhood narcolepsy SLEEP MEDICINE Nevsimalova, S., Prihodova, I., Kemlink, D., Lin, L., Mignot, E. 2007; 8 (7-8): 784-786

  Abstract

  More than one in three adult patients suffering from narcolepsy-cataplexy experience rapid eye movement (REM) behavior disorder (RBD), while RBD in childhood is extremely rare. We present the cases of two girls (aged 9 and 7 years old) with narcolepsy-cataplexy, in whom RBD was one of the first symptoms of the disease. The coincidence of RBD was seen by nocturnal video-polysomnography (v-PSG), and narcolepsy was diagnosed from short sleep latency and multiple sleep onset REMs (SOREMs) during a multiple sleep latency test (MSLT). Both girls were human leukocyte antigen (HLA)-DQB1 *0602 positive, and their cerebrospinal fluid (CSF) hypocretin level (Hcrt-1) was extremely low.

  View details for DOI 10.1016/j.sleep.2006.11.018

  View details for Web of Science ID 000250794300015

  View details for PubMedID 17569582

• Comparative expression of p2x receptors and ecto-nucleoside triphosphate diphosphohydrolase 3 in hypocretin and sensory neurons in zebrafish BRAIN RESEARCH Appelbaum, L., Skariah, G., Mourrain, P., Mignot, E. 2007; 1174: 66-75

  Abstract

  The hypocretin/orexin (HCRT/ORX) excitatory neuropeptides are expressed in a small population of lateral hypothalamic cells in mammals and fish. In humans, loss of these cells causes the sleep disorder narcolepsy. Identification of genes expressed in HCRT-producing cells may be revealing as to the regulation of sleep and the pathophysiology of narcolepsy. In this study, in situ hybridization analyses were performed to characterize the expression pattern of receptors and enzyme, which regulate ATP-mediated transmission in hypocretin cells of zebrafish larvae. The zebrafish cDNA encoding the ecto-nucleoside triphosphate diphosphohydrolase 3 (ENTPD3/NTPDase3) was isolated. This transcript was found to be expressed in zebrafish HCRT cells as previously reported in mammals. It was also expressed in the cranial nerves (gV, gVII, gIV and gX) and in primary sensory neurons (i.e., Rohon-Beard neurons) in the spinal cord. The expression of known zebrafish p2rx purinergic receptor family members was next studied and found to overlap with the entpd3 expression pattern. Specifically, p2rx2, p2rx3.1, p2rx3.2 and p2rx8 were expressed in the trigeminal ganglia and subsets of Rohon-Beard neurons. In contrast to mammals, p2rx2 was not expressed in HCRT cells; rather, p2rx8 was expressed with entpd3 in this hypothalamic region. The conservation of expression of these genes in HCRT cells and sensory neurons across vertebrates suggests an important role for ATP mediated transmission in the regulation of sleep and the processing of sensory inputs.

  View details for DOI 10.1016/j.brainres.2007.06.103

  View details for Web of Science ID 000250612200008

  View details for PubMedID 17868657

• Increasing length of wakefulness and modulation of hypocretin-1 in the wake-consolidated squirrel monkey AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., Mignot, E. 2007; 293 (4): R1736-R1742

  Abstract

  The neuropeptides hypocretins (orexins), the loss of which results in the sleep disorder narcolepsy, are hypothesized to be involved in the consolidation of wakefulness and have been proposed to be part of the circadian-driven alertness signal. To elucidate the role of hypocretins in the consolidation of human wakefulness we examined the effect of wake extension on hypocretin-1 in squirrel monkeys, primates that consolidate wakefulness during the daytime as do humans. Wake was extended up to 7 h with hypocretin-1, cortisol, ghrelin, leptin, locomotion, and feeding, all being assayed. Hypocretin-1 (P < 0.01), cortisol (P < 0.001), and locomotion (P < 0.005) all increased with sleep deprivation, while ghrelin (P = 0.79) and leptin (P = 1.00) did not change with sleep deprivation. Using cross-correlation and multivariate modeling of these potential covariates along with homeostatic pressure (a measure of time awake/asleep), we found that time of day and homeostatic pressure together explained 44% of the variance in the hypocretin-1 data (P < 0.001), while cortisol did not significantly contribute to the overall hypocretin-1 variance. Locomotion during the daytime, but not during the nighttime, helped explain < 5% of the hypocretin-1 variance (P < 0.05). These data are consistent with earlier evidence indicating that in the squirrel monkey hypocretin-1 is mainly regulated by circadian inputs and homeostatic sleep pressure. Concomitants of wakefulness that affect hypocretin-1 in polyphasic species, such as locomotion, food intake, and food deprivation, likely have a more minor role in monophasic species, such as humans.

  View details for DOI 10.1152/ajpregu.00460.2007

  View details for Web of Science ID 000250088000033

  View details for PubMedID 17686881

• Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants PLOS BIOLOGY Yokogawa, T., Marin, W., Faraco, J., Pezeron, G., Appelbaum, L., Zhang, J., Rosa, F., Mourrain, P., Mignot, E. 2007; 5 (10): 2379-2397

  Abstract

  Sleep is a fundamental biological process conserved across the animal kingdom. The study of how sleep regulatory networks are conserved is needed to better understand sleep across evolution. We present a detailed description of a sleep state in adult zebrafish characterized by reversible periods of immobility, increased arousal threshold, and place preference. Rest deprivation using gentle electrical stimulation is followed by a sleep rebound, indicating homeostatic regulation. In contrast to mammals and similarly to birds, light suppresses sleep in zebrafish, with no evidence for a sleep rebound. We also identify a null mutation in the sole receptor for the wake-promoting neuropeptide hypocretin (orexin) in zebrafish. Fish lacking this receptor demonstrate short and fragmented sleep in the dark, in striking contrast to the excessive sleepiness and cataplexy of narcolepsy in mammals. Consistent with this observation, we find that the hypocretin receptor does not colocalize with known major wake-promoting monoaminergic and cholinergic cell groups in the zebrafish. Instead, it colocalizes with large populations of GABAergic neurons, including a subpopulation of Adra2a-positive GABAergic cells in the anterior hypothalamic area, neurons that could assume a sleep modulatory role. Our study validates the use of zebrafish for the study of sleep and indicates molecular diversity in sleep regulatory networks across vertebrates.

  View details for DOI 10.1371/journal.pbio.0050277

  View details for Web of Science ID 000251072700025

  View details for PubMedID 17941721

  View details for PubMedCentralID PMC2020497

• Depression: relationships to sleep paralysis and other sleep disturbances in a community sample JOURNAL OF SLEEP RESEARCH Szklo-Coxe, M., Young, T., Finn, L., Mignot, E. 2007; 16 (3): 297-312

  Abstract

  Sleep disturbances are important correlates of depression, with epidemiologic research heretofore focused on insomnia and sleepiness. This epidemiologic study's aim was to investigate, in a community sample, depression's relationships to other sleep disturbances: sleep paralysis (SP), hypnagogic/hypnopompic hallucinations (HH), cataplexy - considered rapid eye movement-related disturbances - and automatic behavior (AB). Although typical of narcolepsy, these disturbances are prevalent, albeit under-studied, in the population. Cross-sectional analyses (1998-2002), based on Wisconsin Sleep Cohort Study population-based data from 866 participants (mean age 54, 53% male), examined: depression (Zung Self-Rating Depression Scale), trait anxiety (Spielberger State-Trait Anxiety Inventory, STAI-T >or= 75th percentile), and self-reported sleep disturbances. Descriptive sleep data were obtained by overnight polysomnography. Adjusted logistic regression models estimated depression's associations with each (>few times ever) outcome - SP, HH, AB, and cataplexy. Depression's associations with self-reported SP and cataplexy were not explained by anxiety. After anxiety adjustment, severe depression (Zung >or=55), vis-à-vis Zung <50, increased SP odds approximately 500% (P = 0.0008). Depression (Zung >or=50), after stratification by anxiety given an interaction (P = 0.02), increased self-reported cataplexy odds in non-anxious (OR 8.9, P = 0.0008) but not anxious (OR 1.1, P = 0.82) participants. Insomnia and sleepiness seemed only partial mediators or confounders for depression's associations with self-reported cataplexy and SP. Anxiety (OR 1.9, P = 0.04) partially explained depression's (Zung >or=55) association with HH (OR 2.2, P = 0.08). Anxiety (OR 1.6, P = 0.02) was also more related than depression to AB. Recognizing depression's relationships to oft-neglected sleep disturbances, most notably SP, might assist in better characterizing depression and the full range of its associated sleep problems in the population. Longitudinal studies are warranted to elucidate mediators and causality.

  View details for Web of Science ID 000249329000009

  View details for PubMedID 17716279

  View details for PubMedCentralID PMC2800990

• The development of hypocretin (orexin) deficiency in hypocretin/ataxin-3 transgenic rats NEUROSCIENCE Zhang, S., Lin, L., Kaur, S., Thankachan, S., Blanco-Centurion, C., Yanagisawa, M., Mignot, E., Shiromani, P. J. 2007; 148 (1): 34-43

  Abstract

  Narcolepsy is linked to a widespread loss of neurons containing the neuropeptide hypocretin (HCRT), also named orexin. A transgenic (TG) rat model has been developed to mimic the neuronal loss found in narcoleptic humans. In these rats, HCRT neurons gradually die as a result of the expression of a poly-glutamine repeat under the control of the HCRT promoter. To better characterize the changes in HCRT-1 levels in response to the gradual HCRT neuronal loss cerebrospinal fluid (CSF) HCRT-1 levels were measured in various age groups (2-82 weeks) of wild-type (WT) and TG Sprague-Dawley rats. TG rats showed a sharp decline in CSF HCRT-1 level at week 4 with levels remaining consistently low (26%+/-9%, mean+/-S.D.) thereafter compared with WT rats. In TG rats, HCRT-1 levels were dramatically lower in target regions such as the cortex and brainstem (100-fold), indicating decreased HCRT-1 levels at terminals. In TG rats, CSF HCRT-1 levels significantly increased in response to 6 h of prolonged waking, indicating that the remaining HCRT neurons can be stimulated to release more neuropeptide. Rapid eye movement (REM) sleep in TG rats (n=5) was consistent with a HCRT deficiency. In TG rats HCRT immunoreactive (HCRT-ir) neurons were present in the lateral hypothalamus (LH), even in old rats (24 months) but some HCRT-ir somata were in various stages of disintegration. The low output of these neurons is consistent with a widespread dysfunction of these neurons, and establishes this model as a tool to investigate the consequences of partial hypocretin deficiency.

  View details for DOI 10.1016/j.neuroscience.2007.05.029

  View details for Web of Science ID 000249157900004

  View details for PubMedID 17618058

• A step forward for restless legs syndrome NATURE GENETICS Mignot, E. 2007; 39 (8): 938-939

  View details for Web of Science ID 000248446900005

  View details for PubMedID 17660808

• Correlates of serum C-reactive protein (CRP) - No association with sleep duration or sleep disordered breathing SLEEP Taheri, S., Austin, D., Lin, L., Nieto, F. J., Young, T., Mignot, E. 2007; 30 (8): 991-996

  Abstract

  Increasing evidence suggests that alterations in sleep duration are associated with cardiovascular disease (CVD) and mortality. Additionally, sleep disordered breathing (SDB), which is associated with disturbed nighttime sleep and hypoxemia, may be an independent risk factor for CVD. The inflammatory marker, C-reactive protein (CRP), is an important predictor of CVD. We investigated potential associations between circulating CRP, sleep duration, and SDB.Cross-sectional Study.Participants were 907 adults from the Wisconsin Sleep Cohort Study (WSCS).CRP was measured after overnight polysomnography. The relationships between CRP and sleep parameters were evaluated using multiple linear regression with and without controlling for age, sex, and body mass index (BMI) and other potential confounders. CRP was found to be higher for women and had a strong positive correlation with age and BMI. CRP showed a significant positive association with current smoking, waist-hip ratio (WHR), LDL-cholesterol, triglycerides, leptin, and insulin, independent of age, sex, and BMI. Significant independent negative associations for CRP were observed with HDL-cholesterol (HDL), insulin sensitivity (quantitative insulin sensitivity check index [QUICKI]), and hours of exercise. There was a significant positive association between CRP levels and the apnea-hypopnea index (AHI, the measure of SDB), but these relationships were not significant after adjustment for age, sex, and BMI. No significant association between CRP levels and measures of sleep duration (polysomnographic and self-reported) were found.There was no significant association between CRP levels and sleep duration. The lack of an independent association between CRP levels and SDB suggests that the reported relationship between these 2 variables may be primarily driven by their association with obesity.

  View details for Web of Science ID 000248515800007

  View details for PubMedID 17702268

  View details for PubMedCentralID PMC1978379

• Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy JOURNAL OF PHYSIOLOGY-LONDON Zhang, S., Zeitzer, J. M., Sakurai, T., Nishino, S., Mignot, E. 2007; 581 (2): 649-663

  Abstract

  Recent population studies have identified important interrelationships between sleep duration and body weight regulation. The hypothalamic hypocretin/orexin neuropeptide system is able to influence each of these. Disruption of the hypocretin system, such as occurs in narcolepsy, leads to a disruption of sleep and is often associated with increased body mass index. We examined the potential interrelationship between the hypocretin system, metabolism and sleep by measuring locomotion, feeding, drinking, body temperature, sleep/wake and energy metabolism in a mouse model of narcolepsy (ataxin-ablation of hypocretin-expressing neurons). We found that locomotion, feeding, drinking and energy expenditure were significantly reduced in the narcoleptic mice. These mice also exhibited severe sleep/wake fragmentation. Upon awakening, transgenic and control mice displayed a similar rate of increase in locomotion and food/water intake with time. A lack of long wake episodes partially or entirely explains observed differences in overall locomotion, feeding and drinking in these transgenic mice. Like other parameters, energy expenditure also rose and fell depending on the sleep/wake status. Unlike other parameters, however, energy expenditure in control mice increased upon awakening at a greater rate than in the narcoleptic mice. We conclude that the profound sleep/wake fragmentation is a leading cause of the reduced locomotion, feeding, drinking and energy expenditure in the narcoleptic mice under unperturbed conditions. We also identify an intrinsic role of the hypocretin system in energy expenditure that may not be dependent on sleep/wake regulation, locomotion, or food intake. This investigation illustrates the need for coordinated study of multiple phenotypes in mouse models with altered sleep/wake patterns.

  View details for DOI 10.1113/jphysiol.2007.129510

  View details for Web of Science ID 000246756000022

  View details for PubMedID 17379635

  View details for PubMedCentralID PMC2075199

• Reduced expression of TACI, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain BMC NEUROSCIENCE Lindberg, J., Saetre, P., Nishino, S., Mignot, E., Jazin, E. 2007; 8

  Abstract

  Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals.By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice.These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans.

  View details for DOI 10.1186/1471-2202-8-34

  View details for Web of Science ID 000247020700001

  View details for PubMedID 17521418

  View details for PubMedCentralID PMC1885801

• Normal cerebrospinal fluid levels of hypocretin-1 (orexin A) in patients with fibromyalgia syndrome SLEEP MEDICINE Taiwo, O. B., Russell, I. J., Mignot, E., Lin, L., Michalek, J. E., Haynes, W., Xiao, Y., Zeiter, J. M., Larson, A. A. 2007; 8 (3): 260-265

  Abstract

  The hypothalamic neuropeptide hypocretin (orexin) modulates sleep-wake, feeding and endocrine functions. Cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) concentrations are low in patients with narcolepsy-cataplexy, a sleep disorder characterized by hypersomnolence and rapid eye movement (REM) sleep abnormalities.We determined CSF Hcrt-1 concentrations of patients with the fibromyalgia syndrome (FMS), a condition characterized by fatigue, insomnia and in some cases daytime hypersomnolence.Basal CSF levels of Hcrt-1 in FMS did not differ from those in healthy normal controls.These findings suggest that abnormally low Hcrt-1 is not a likely cause of fatigue in FMS.

  View details for DOI 10.1016/j.sleep.2006.08.015

  View details for Web of Science ID 000246343100010

  View details for PubMedID 17369087

• Genomic and functional conservation of sedative-hypnotic targets in the zebrafish PHARMACOGENETICS AND GENOMICS Renier, C., Faraco, J. H., Bourgin, P., Motley, T., Bonaventure, P., Rosa, F., Mignot, E. 2007; 17 (4): 237-253

  Abstract

  The zebrafish is an ideally suited vertebrate animal model for large-scale genetic screens and is emerging as a model organism in pharmacological and behavioral research. We investigated the effects of sedative hypnotics commonly used in humans on zebrafish locomotor activity and identified the corresponding genomic and receptor binding targets.We studied radioreceptor binding and behavioral responses to compounds with known sedative hypnotic properties representing multiple pharmacological classes. These included GABAergic hypnotics such as benzodiazepines, barbiturates, and baclofen; alpha-2 adrenergic agonists; and histaminergic H1 antagonists. An automated system was used to quantify behavioral effects. Zebrafish homologs of histamine receptor H1, gamma-amino-n-butyric acid type A (alpha-subunit), and gamma-amino-n-butyric acid type B (1 and 2) receptor genes were identified through translating queries of the zebrafish Zv4 database with human receptor protein sequences. A pilot screen of 154 N-ethyl-N-nitroso-urea-mutagenized F2 families was conducted with pentobarbital, flurazepam and mepyramine.Radioreceptor binding studies revealed high affinity binding sites for known gamma-amino-n-butyric acid type A, gamma-amino-n-butyric acid type B, and histaminergic ligands. Drug immersion of 5-7-day-old larvae reduced mobility and, in some cases, produced a complete state of unresponsive immobility similar to anesthesia. These effects were dose-dependent and rapidly reversible in water. As established in mammals, (R)-baclofen was more active behaviorally and had higher affinity in binding studies when compared with (S)-baclofen. In this model, (S)-baclofen only partially reduced activity at high dose and blocked (R)-baclofen behavioral hypnotic effects. Genomic sequences with high similarity to the corresponding pharmacological targets were identified, but no mutants were found in the pilot screen.These results demonstrate conservation of gene, protein and function for many established sedative hypnotic pathways. The results indicate feasibility of conducting large-scale pharmacogenomic screens to isolate novel proteins modulating susceptibility to hypnotic compounds in a vertebrate system.

  View details for Web of Science ID 000245374200002

  View details for PubMedID 17496723

• Analysis of extended HLA haplotypes in multiple sclerosis and narcolepsy families confirms a predisposing effect for the class I region in Tasmanian MS patients IMMUNOGENETICS Rubio, J. P., Bahlo, M., Stankovich, J., Burfoot, R. K., Johnson, L. J., Huxtable, S., Butzkueven, H., Lin, L., Taylor, B. V., Speed, T. P., Kilpatrick, T. J., Mignot, E., Foote, S. J. 2007; 59 (3): 177-186

  Abstract

  Human leucocyte antigen (HLA)-DRB1*15 is associated with predisposition to multiple sclerosis (MS), although conjecture surrounds the possible involvement of an alternate risk locus in the class I region of the HLA complex. We have shown previously that an alternate MS risk allele(s) may be encompassed by the telomerically extended DRB1*15 haplotype, and here, we have attempted to map the putative variant. Thirteen microsatellite markers encompassing a 6.79-megabase (D6S2236-G51152) region, and the DRB1 and DQB1 genes, were genotyped in 166 MS simplex families and 104 control families from the Australian State of Tasmania and 153 narcolepsy simplex families (trios) from the USA. Complementary approaches were used to investigate residual predisposing effects of microsatellite alleles comprising the extended DRB1*15 haplotype taking into account the strong predisposing effect of DRB1*15: (1) Disease association of the extended DRB1*15 haplotype was compared for MS and narcolepsy families--predisposing effects were observed for extended class I microsatellite marker alleles in MS families, but not narcolepsy families; (2) disease association of the extended DRB1*15 haplotype was investigated after conditioning MS and control haplotypes on the absence of DRB1*15--a significant predisposing effect was observed for a 627-kb haplotype (D6S258 allele 8-MOGCA allele 4; MOG, myelin oligodendrocyte glycoprotein) spanning the extended class I region. MOGCA allele 4 displayed the strongest predisposing effect in DRB1*15-conditioned haplotypes (p = 0.0006; OR 2.83 [1.54-5.19]). Together, these data confirm that an alternate MS risk locus exists in the extended class I region in Tasmanian MS patients independent of DRB1*15.

  View details for DOI 10.1007/s00251-006-0183-5

  View details for Web of Science ID 000244066300001

  View details for PubMedID 17256150

• Narcolepsy with cataplexy LANCET Dauvilliers, Y., Amulf, I., Mignot, E. 2007; 369 (9560): 499-511

  Abstract

  Narcolepsy with cataplexy is a disabling sleep disorder affecting 0.02% of adults worldwide. It is characterised by severe, irresistible daytime sleepiness and sudden loss of muscle tone (cataplexy), and can be associated with sleep-onset or sleep-offset paralysis and hallucinations, frequent movement and awakening during sleep, and weight gain. Sleep monitoring during night and day shows rapid sleep onset and abnormal, shortened rapid-eye-movement sleep latencies. The onset of narcolepsy with cataplexy is usually during teenage and young adulthood and persists throughout the lifetime. Pathophysiological studies have shown that the disease is caused by the early loss of neurons in the hypothalamus that produce hypocretin, a wakefulness-associated neurotransmitter present in cerebrospinal fluid. The cause of neural loss could be autoimmune since most patients have the HLA DQB1*0602 allele that predisposes individuals to the disorder. Treatment is with stimulant drugs to suppress daytime sleepiness, antidepressants for cataplexy, and gamma hydroxybutyrate for both symptoms. Because narcolepsy is an under-recognised disease, it is important that general practitioners and other primary health-care workers identify abnormal daytime sleepiness early.

  View details for Web of Science ID 000244188300033

  View details for PubMedID 17292770

• A circadian sleep disorder reveals a complex clock CELL Mignot, E., Takahashi, J. S. 2007; 128 (1): 22-23

  Abstract

  Circadian rhythms are established by transcription of clock genes and autoregulatory transcriptional feedback loops. In this issue, Xu et al. (2007) characterize mice expressing a human Per2 mutation identified in patients with familial advanced sleep phase syndrome. Their results reveal that PER2 phosphorylation, by CK1delta and other kinases, is surprisingly complex and has opposite effects on PER2 levels and period length.

  View details for DOI 10.1016/j.cell.2006.12.024

  View details for Web of Science ID 000244420400009

  View details for PubMedID 17218251

• DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans HUMAN IMMUNOLOGY Hong, S., Lin, L., Lo, B., Jeong, J., Shin, Y., Kim, S., Kweon, Y., Zhang, J., Einen, M., Smith, A., Hansen, J., Grumet, F. C., Mignot, E. 2007; 68 (1): 59-68

  Abstract

  The association of narcolepsy with HLA-DQB1*0602 is established in Japanese, African-Americans, European, and North American Caucasians. We examined DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 in 163 patients with centrally mediated daytime sleepiness (100 with narcolepsy) and 211 Korean controls. In this population, the DQB1*0602 association was always evident in the context of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. The DQB1*0602 association was highest in cases with hypocretin deficiency (100% vs 13% in controls), most of which had narcolepsy-cataplexy (81%). A weaker DQB1*0602 (45%) association was present in cases without cataplexy. No human leukocyte antigen (HLA) association was present in idiopathic hypersomnia or in cases with normal cerebrospinal fluid (CSF) hypocretin-1. As in other populations, DQB1*0602 homozygosity increased risk in cases with cataplexy and/or hypocretin deficiency (odds ratio = 2.0 vs heterozygotes). Non-DQB1*0602 allelic effects were also observed but could not be interpreted in the context of DQB1*0602 overabundance and linkage disequilibrium. We therefore next analyzed compound heterozygote effects in 77 subjects with either hypocretin deficiency or cataplexy and one copy of DRB1*1501-DQA1*0102-DQB1*0602, a sample constructed to maximize etiologic homogeneity. In this analysis, we found additional predisposing effects of DQB1*0301 and protective effects for DQA1*0103-DQB1*0601. Unexpectedly, the predisposing effects of DQB1*0301 were present in the context of various DQA1-bearing haplotypes. A predisposing effect of DQA1*0303 was also suggested. These results indicate a remarkable consistency in the complex HLA association present in narcolepsy across multiple ethnic groups.

  View details for DOI 10.1016/j.humimm.2006.10.006

  View details for Web of Science ID 000243570200007

  View details for PubMedID 17207713

• Neurobiology of Narcolepsy and Hypersomnia NEUROBIOLOGY OF DISEASE Mignot, E., Zeitzer, J. M., Gilman, S. 2007: 715–22

  View details for DOI 10.1016/B978-012088592-3/50068-2

  View details for Web of Science ID 000310853000067

• Hypocretin-1 is inversely associated with wake fragmentation in Alzheimer's disease 21st Annual Meeting of the American-Professional-Sleep-Societies Zeitzer, J., Friedman, L., Lin, L., Mignot, E., Peskind, E., Yesavage, J. AMER ACAD SLEEP MEDICINE. 2007: A302–A302

  View details for Web of Science ID 000246224900882

• Identification of novel transcripts expressed in hypocretin-containing neurons 21st Annual Meeting of the American-Professional-Sleep-Societies Bourgin, P., Lin, L., Priest, M., Renier, C., Sakurai, T., De Lecea, L., Mignot, E. AMER ACAD SLEEP MEDICINE. 2007: A223–A223

  View details for Web of Science ID 000246224900659

• A novel candidate gene for narcolepsy colocalized in human and mouse hypocretin/orexin neurons 21st Annual Meeting of the American-Professional-Sleep-Societies Honda, M., Eriksson, K., Lin, L., Salehi, A., Tanaka, S., Gans, S., Honda, Y., Mignot, E. AMER ACAD SLEEP MEDICINE. 2007: A218–A218

  View details for Web of Science ID 000246224900645

• A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness 21st Annual Meeting of the American-Professional-Sleep-Societies Hong, S., Lin, L., Jeong, J., Shin, Y., Han, J., Lee, J., Lee, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2007: A214–A214

  View details for Web of Science ID 000246224900634

• English Translations Of The First Clinical Reports On Narcolepsy And Cataplexy By Westphal And Gelineau In The Late 19th Century, With Commentary JOURNAL OF CLINICAL SLEEP MEDICINE Schenck, C. H., Bassetti, C. L., Arnulf, I., Mignot, E. 2007; 3 (3): 301-311

  Abstract

  To publish the first English translations, with commentary, of the original reports describing narcolepsy and cataplexy by Westphal in German (1877) and by Gélineau in French (1880).A professional translation service translated the 2 reports from either German or French to English, with each translation then being slightly edited by one of the authors. All authors then provided commentary.Both Westphal and Gélineau correctly identified and described the new clinical entities of cataplexy and narcolepsy, with recurrent, self-limited sleep attacks and/or cataplectic attacks affecting 2 otherwise healthy people. Narcolepsy was named by Gélineau (and cataplexy was named by Henneberg in 1916). The evidence in both cases is sufficiently convincing to conclude that they were likely each HLA-DQB1*0602 positive and hypocretin deficient.The original descriptions of narcolepsy and cataplexy are now available in English, allowing for extensive clinical and historical commentary.

  View details for Web of Science ID 000209776200013

  View details for PubMedCentralID PMC2564780

• Different periodicity and time structure of leg movements during sleep in narcolepsy/cataplexy and restless legs syndrome SLEEP Ferri, R., Zucconi, M., Manconi, M., Bruni, O., Ferini-Strambi, L., Vandi, S., Montagna, P., Mignot, E., Plazzi, G. 2006; 29 (12): 1587-1594

  Abstract

  To analyze periodic leg movements (PLM) during sleep in patients with narcolepsy and compare the results with those obtained in normal controls and subjects with restless legs syndrome (RLS).We recruited 40 HLA DQB1*0602-positive patients with narcolepsy/cataplexy, 22 with RLS, and 22 controls. The time structure of their polysomnographically recorded LMs was analyzed by means of an approach particularly able to consider their periodicity.Nineteen patients with narcolepsy had a PLM index greater than 15. The distribution of inter-LM intervals was clearly bimodal in RLS and narcoleptics, with 1 peak at 2 to 4 seconds and another at around 22 to 26 seconds; in the range 22 to 40 seconds, patients with RLS had values significantly higher than patients with narcolepsy. All periodicity parameters were significantly lower in the narcolepsy group. Finally, the distribution of the number of PLM per hour of sleep was bell shaped in normal controls and patients with narcolepsy, whereas patients with RLS showed a progressive decrease throughout the night.Most narcoleptic patients show a high number of LMs that are significantly less periodic than those of patients with RLS. PLM are in functional interrelationship with the cyclic alternating pattern, which is reduced in patients with narcolepsy; decreased arousal fluctuations during sleep may be one of the factors influencing the reduction in periodicity of LMs during sleep in narcolepsy.

  View details for Web of Science ID 000243067900008

  View details for PubMedID 17252889

• Narcolepsy: From animal models to the human disorder Mignot, E. NATURE PUBLISHING GROUP. 2006: S10

  View details for Web of Science ID 000242215900032

• A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness SLEEP Hong, S., Lin, L., Jeong, J., Shin, Y., Han, J., Lee, J., Lee, S., Zhang, J., Einen, M., Mignot, E. 2006; 29 (11): 1429-1438

  Abstract

  To study DQB1*0602 status and hypocretin-1 levels in the cerebrospinal fluid (CSF) in a cohort of patients with hypersomnolence and to test International Classification of Sleep Disorders-2 (ICSD-2) criteria for hypersomnia of central origin.Retrospective case series.One hundred sixty-three consecutive patients with unexplained sleepiness and 282 controls recruited at St. Vincent's Hospital, Korea. The gold standard for diagnosis was ICSD-2 criteria. Patients and controls completed the Stanford Sleep Inventory, and agreed to HLA typing. Polysomnography (87%), Multiple Sleep Latency Test (MSLT) (96%), and CSF hypocretin-1 measurements (53%) were conducted in patients.Most patients (80%) could be classified using the ICSD-2. The 33 patients who could not be classified were without cataplexy (4 with low CSF hypocretin-1). These could not be included because of sleep apnea (apnea-hypopnea index > or = 5/h, 84%) and/or because sleep prior to MSLT was less than 6 hours (27%). Narcolepsy with cataplexy cases were 92% HLA positive with low hypocretin-1. Cataplexy at interview was predicted by validated Stanford Sleep Inventory questions regarding cataplexy triggers. In contrast, cataplexy-like events were frequently reported in all groups, including controls. Cases with narcolepsy without cataplexy were frequently men (73%) and heterogeneous biologically (36% HLA positive, 40% with low CSF hypocretin-1). None of the controls had low CSF hypocretin-1, whereas 13% were HLA positive.The ICSD-2 was easily applicable in cases with typical cataplexy. In these cases, the MSLT and further evaluations were almost always positive and may thus not always be needed. Many patients without cataplexy were difficult to classify because of difficulties in interpreting the MSLT in the presence of sleep apnea or reduced sleep.

  View details for Web of Science ID 000242181700015

  View details for PubMedID 17162989

• Regulation of hypocretin (orexin) expression in embryonic zebrafish JOURNAL OF BIOLOGICAL CHEMISTRY Faraco, J. H., Appelbaum, L., Marin, W., Gaus, S. E., Mourrain, P., Mignot, E. 2006; 281 (40): 29753-29761

  Abstract

  Hypocretins/orexins are neuropeptides involved in the regulation of sleep and energy balance in mammals. Conservation of gene sequence, hypothalamic localization of cell bodies, and projection patterns in adult zebrafish suggest that the architecture and function of the hypocretin system are conserved in fish. We report on the complete genomic structure of the zebrafish and Tetraodon hypocretin genes and the complete predicted hypocretin protein sequences from five teleosts. Using whole mount in situ hybridization, we have traced the development of hypocretin cells in zebrafish from onset of expression at 22 h post-fertilization through the first week of development. Promoter elements of similar size from zebrafish and Tetraodon were capable of driving efficient and specific expression of enhanced green fluorescent protein in developing zebrafish embryos, thus defining a minimal promoter region able to accurately mimic the native hypocretin pattern. This enhanced green fluorescent protein expression also revealed a complex pattern of projections within the hypothalamus, to the midbrain, and to the spinal cord. To further analyze the promoter, a series of deletion and substitution constructs were injected into embryos, and resulting promoter activity was monitored in the first week of development. A critical region of 250 base pairs was identified containing a core 13-base pair element essential for hypocretin expression.

  View details for DOI 10.1074/jbc.M605811200

  View details for Web of Science ID 000240896300037

  View details for PubMedID 16867991

• CSF versus serum leptin in narcolepsy: Is there an effect of hypocretin deficiency? SLEEP Arnulf, I., Lin, L., Zhang, J., Russell, I. J., Ripley, B., Einen, M., Nevsimalova, S., Bassetti, C., Bourgin, P., Nishino, S., Mignot, E. 2006; 29 (8): 1017-1024

  Abstract

  To determine if hypocretin deficiency is associated with abnormally low serum leptin levels, a putative cause of increased body mass index in narcoleptics.Cross-sectional controlled study.Three hundred seventy subjects, including 111 healthy controls, 93 narcoleptic subjects with hypocretin deficiency (cerebrospinal fluid [CSF] hypocretin-1 levels < 110 pg/mL), 72 narcoleptic subjects with normal hypocretin levels, and 89 subjects with other sleep disordersAfter completing the Stanford Sleepiness Inventory, participants underwent spinal taps and blood sampling for measurement of CSF leptin and hypocretin-1 levels, HLA DQB1*0602 phenotyping, and serum leptin and C-reactive protein levels.Serum leptin levels were similar in narcoleptic subjects, whether hypocretin-deficient (13.2 +/- 1.7 ng/mL, mean +/- SEM) or not (13.0 +/- 1.8 ng/mL), controls (10.1 +/- 1.1 ng/mL) and subjects with other sleep disorders (11.5 +/- 1.6 ng/mL). Similarly, the CSF leptin levels and the CSF: serum leptin ratios (an indicator of brain leptin uptake) were not different between groups. Serum and CSF leptin levels were higher in women and in subjects with higher body mass indexes. Leptin brain uptake decreased in women, in the aged, and in more-obese subjects. In contrast with a presumed inhibitory effect of leptin on hypocretin-containing cells, CSF leptin levels tended to correlate positively with CSF hypocretin-1 levels. C-reactive protein was higher (4.2 +/- 0.9 mg/L) in narcoleptic subjects with hypocretin deficiency than in controls (1.4 +/- 0.3 mg/L, p = .0055), a difference still significant after adjustment on confounding factors.Our data do not support a role for leptin in mediating increased body mass index in narcolepsy. A moderate but selective increase in C-reactive protein in hypocretin-1 deficient subjects should prompt research on inflammation in narcolepsy.

  View details for Web of Science ID 000240046400004

  View details for PubMedID 16944669

• The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions TRENDS IN PHARMACOLOGICAL SCIENCES Zeitzer, J. M., Nishin, S., Mignot, E. 2006; 27 (7): 368-374

  Abstract

  Narcolepsy is characterized by excessive daytime sleepiness, cataplexy and other manifestations of dissociated rapid eye movement sleep. Narcolepsy is typically treated with amphetamine-like stimulants (sleepiness) and antidepressants (cataplexy). Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used. Recent discoveries indicate that the major pathophysiology of human narcolepsy is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient. This has led to the development of new diagnostic tests (cerebrospinal fluid hypocretin-1 measurements). Hypocretin receptor agonists are likely to be ideal therapeutic options for hypocretin-deficient narcolepsy but such compounds are still not available in humans.

  View details for DOI 10.1016/j.tips.2006.05.006

  View details for Web of Science ID 000239368900005

  View details for PubMedID 16766052

• Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults BRAIN Mignot, E., Lin, g. L., Finn, L., Lopes, C., Pluff, K., Sundstrom, M. L., Young, T. 2006; 129: 1609-1623

  Abstract

  The diagnosis of narcolepsy without documented cataplexy is based on the observation of two or more sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT). We report on the prevalence and correlates of SOREMPs in the community-based Wisconsin Sleep Cohort Study. MSLTs were conducted following nocturnal polysomnography (NPSG) and daily sleep diaries in 289 males and 267 females (age 35-70, 97% Caucasians). Multiple SOREMPs were observed in 13.1% of males and 5.6% of females. An MSLT mean sleep latency < or =8 min and > or =2 SOREMPs (diagnostic of narcolepsy) was observed in 5.9% (males) and 1.1% (females), all without cataplexy. Because of significant sex interactions, analyses were stratified by sex. Increased prevalence of HLA-DQB1*0602, a marker of narcolepsy, was observed in males but not in females with > or =2 SOREMPs. Males with multiple SOREMPs compared with those with no SOREMPs had shorter rapid eye movement (REM) latency during NPSG, were sleepier on the MSLT and reported increased sleepiness, hypnagogic hallucinations and cataplexy-like symptoms, suggesting a narcolepsy-like phenotype. In males only, the occurrence of SOREMPs increased with shift work and some indirect markers of sleep restriction, such as shorter sleep a day before NPSG. SOREMPs were unrelated to age, body mass index, depression (Zung Scale), anxiety (State-Trait Anxiety Scale) and the number of apnea and hypopnea events per hour of sleep (AHI), but were associated with decreased mean lowest oxygen saturation in males. Finally, we found that both males and females with SOREMPs reported taking more antidepressants, but those were of the types known not to suppress REM sleep. These results suggest a high prevalence of narcolepsy without cataplexy, as defined by the International Classification of Sleep Disorders, and/or a large number of false-positives for the MSLT.

  View details for DOI 10.1093/brain/wal079

  View details for Web of Science ID 000238224900025

  View details for PubMedID 16597649

• Narcolepsy-cataplexy associated with precocious puberty NEUROLOGY Plazzi, G., Parmeggiani, A., Mignot, E., Lin, L., Scano, M. C., Posar, A., Bernardi, F., Lodi, R., Tonon, C., Barbiroli, B., Montagna, P., Cicognani, A. 2006; 66 (10): 1577-1579

  Abstract

  In children, narcolepsy may be the symptom of a brain lesion or genetic disease. The authors report two cases with severe narcolepsy-cataplexy emerging in childhood in close temporal association with obesity and precocious puberty.

  View details for Web of Science ID 000237706900027

  View details for PubMedID 16717224

• The neurobiology of narcolepsy and hypocretins Mignot, E. ELSEVIER SCIENCE INC. 2006: 108S

  View details for Web of Science ID 000236767300347

• HLA-DQB1*0602 and hypocretin in Korean narcoleptics with cataplexy 20th Annual Meeting of the Associated-Professional-Sleep-Societies Hong, S., Jeong, J., Han, J., Lee, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2006: A221–A221

  View details for Web of Science ID 000237916701029

• Gene expression profiling in postmortem posterior hypothalamic tissue reveals narcolepsy specific genes 20th Annual Meeting of the Associated-Professional-Sleep-Societies Honda, M., Eriksson, K., Salehi, A., Hesla, P., Maehlen, J., Gaus, S., Einen, M., Tanaka, S., Honda, Y., Mignot, E. AMER ACAD SLEEP MEDICINE. 2006: A219–A219

  View details for Web of Science ID 000237916701023

• Kleine-Levin syndrome: a systematic review of 186 cases in the literature BRAIN Arnulf, I., Zeitzer, J. M., File, J., Farber, N., Mignot, E. 2005; 128: 2763-2776

  Abstract

  Kleine-Levin syndrome (KLS) is a rare disorder with symptoms that include periodic hypersomnia, cognitive and behavioural disturbances. Large series of patients are lacking. In order to report on various KLS symptoms, identify risk factors and analyse treatment response, we performed a systematic review of 195 articles, written in English and non-English languages, which are available on Medline dating from 1962 to 2004. Doubtful or duplicate cases, case series without individual details and reviews (n = 56 articles) were excluded. In addition, the details of 186 patients from 139 articles were compiled. Primary KLS cases (n = 168) were found mostly in men (68%) and occurred sporadically worldwide. The median age of onset was 15 years (range 4-82 years, 81% during the second decade) and the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values) with the disease lasting longer in women and in patients with less frequent episodes during the first year. It was precipitated most frequently by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Common symptoms were hypersomnia (100%), cognitive changes (96%, including a specific feeling of derealization), eating disturbances (80%), hypersexuality (43%), compulsions (29%), and depressed mood (48%). In 75 treated patients (213 trials), somnolence decreased using stimulants (mainly amphetamines) in 40% of cases, while neuroleptics and antidepressants were of poor benefit. Only lithium (but not carbamazepine or other antiepileptics) had a higher reported response rate (41%) for stopping relapses when compared to medical abstention (19%). Secondary KLS (n = 18) patients were older and had more frequent and longer episodes, but had clinical symptoms and treatment responses similar to primary cases. In conclusion, KLS is a unique disease which may be more severe in female and secondary cases.

  View details for DOI 10.1093/brain/awh620

  View details for Web of Science ID 000233667500004

  View details for PubMedID 16230322

• CSF hypocretin levels are normal in Huntington's disease patients SLEEP Gaus, S. E., Lin, L., Mignot, E. 2005; 28 (12): 1607-1608

  View details for Web of Science ID 000233734700021

  View details for PubMedID 16408421

• Concomitant loss of dynorphin, NARP, and orexin in narcolepsy NEUROLOGY Crocker, A., Espana, R. A., Papadopoulou, M., SAPER, C. B., Faraco, J., Sakurai, T., Honda, M., Mignot, E., Scammell, T. E. 2005; 65 (8): 1184-1188

  Abstract

  Narcolepsy with cataplexy is associated with a loss of orexin/hypocretin. It is speculated that an autoimmune process kills the orexin-producing neurons, but these cells may survive yet fail to produce orexin.To examine whether other markers of the orexin neurons are lost in narcolepsy with cataplexy.We used immunohistochemistry and in situ hybridization to examine the expression of orexin, neuronal activity-regulated pentraxin (NARP), and prodynorphin in hypothalami from five control and two narcoleptic individuals.In the control hypothalami, at least 80% of the orexin-producing neurons also contained prodynorphin mRNA and NARP. In the patients with narcolepsy, the number of cells producing these markers was reduced to about 5 to 10% of normal.Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and neuronal activity-regulated pentraxin may contribute to the symptoms of narcolepsy.

  View details for Web of Science ID 000232813600010

  View details for PubMedID 16247044

• A link between short sleep and obesity: Building the evidence for causation SLEEP Cizza, G., Skarulis, M., Mignot, E. 2005; 28 (10): 1217-1220

  View details for Web of Science ID 000232461200004

  View details for PubMedID 16295203

• Late-onset narcolepsy presenting as rapidly progressing muscle weakness: Response to plasmapheresis ANNALS OF NEUROLOGY Chen, W., Black, J., Call, P., Mignot, E. 2005; 58 (3): 489-490

  View details for DOI 10.1002/ana.20603

  View details for Web of Science ID 000231679200025

  View details for PubMedID 16130098

• Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury NEUROLOGY Baumann, C. R., Stocker, R., Imhof, H. G., Trentz, O., Hersberger, M., Mignot, E., Bassetti, C. L. 2005; 65 (1): 147-149

  Abstract

  Hypocretin-1 is involved in the regulation of the sleep-wake cycle. The authors prospectively assessed CSF hypocretin-1 levels in 44 consecutive patients with acute traumatic brain injury (TBI). Compared with controls, hypocretin-1 levels were abnormally lower in 95% of patients with moderate to severe TBI and in 97% of patients with posttraumatic brain CT changes. Hypocretin-1 deficiency after TBI may reflect hypothalamic damage and be linked with the frequent development of posttraumatic sleep-wake disorders.

  View details for Web of Science ID 000230427200032

  View details for PubMedID 16009905

• Polymorphisms within the canine MLPH gene are associated with dilute coat color in dogs BMC GENETICS Philipp, U., Hamann, H., Mecklenburg, L., Nishino, S., Mignot, E., Gunzel-Apel, A. R., Schmutz, S. M., Leeb, T. 2005; 6

  Abstract

  Pinschers and other dogs with coat color dilution show a characteristic pigmentation phenotype. The fur colors are a lighter shade, e.g. silvery grey (blue) instead of black and a sandy color (Isabella fawn) instead of red or brown. In some dogs the coat color dilution is sometimes accompanied by hair loss and recurrent skin inflammation, the so called color dilution alopecia (CDA) or black hair follicular dysplasia (BHFD). In humans and mice a comparable pigmentation phenotype without any documented hair loss is caused by mutations within the melanophilin gene (MLPH).We sequenced the canine MLPH gene and performed a mutation analysis of the MLPH exons in 6 Doberman Pinschers and 5 German Pinschers. A total of 48 sequence variations was identified within and between the breeds. Three families of dogs showed co-segregation for at least one polymorphism in an MLPH exon and the dilute phenotype. No single polymorphism was identified in the coding sequences or at splice sites that is likely to be causative for the dilute phenotype of all dogs examined. In 18 German Pinschers a mutation in exon 7 (R199H) was consistently associated with the dilute phenotype. However, as this mutation was present in homozygous state in four dogs of other breeds with wildtype pigmentation, it seems unlikely that this mutation is truly causative for coat color dilution. In Doberman Pinschers as well as in Large Munsterlanders with BHFD, a set of single nucleotide polymorphisms (SNPs) around exon 2 was identified that show a highly significant association to the dilute phenotype.This study provides evidence that coat color dilution is caused by one or more mutations within or near the MLPH gene in several dog breeds. The data on polymorphisms that are strongly associated with the dilute phenotype will allow the genetic testing of Pinschers to facilitate the breeding of dogs with defined coat colors and to select against Large Munsterlanders carrying BHFD.

  View details for DOI 10.1186/1471-2156-6-34

  View details for Web of Science ID 000231069500001

  View details for PubMedID 15960853

  View details for PubMedCentralID PMC1183202

• Emerging therapies in narcolepsy-cataplexy SLEEP Mignot, E., Nishino, S. 2005; 28 (6): 754-763

  Abstract

  In the past, narcolepsy was primarily treated using amphetamine-like stimulants and tricyclic antidepressants. Newer and novel agents, such as the wake-promoting compound modafinil and more selective reuptake inhibitors targeting the adrenergic, dopaminergic, and/or serotoninergic reuptake sites (ie, venlafaxine, atomoxetine) are better-tolerated available alternatives. The development of these agents, together with sodium oxybate (a slow-wave sleep-enhancing agent that consolidates nocturnal sleep, reduces cataplexy, and improves sleepiness), has led to improved functioning and quality of life for many patients with the disorder. However, these treatments are all symptomatically based and do not target hypocretin, a major neurotransmitter involved in the pathophysiology of narcolepsy. In this review, we discuss emerging therapies in the area of narcolepsy. These include novel antidepressant or anticataplectic, wake-promoting, and hypnotic compounds. We also report on novel strategies designed to compensate for hypocretin deficiency and on the use of immunosupression at the time of narcolepsy onset.

  View details for Web of Science ID 000229900500014

  View details for PubMedID 16477963

• Hypocretin deficiency in Prader-Willi syndrome EUROPEAN JOURNAL OF NEUROLOGY Nevsimalova, S., Vankova, J., Stepanova, I., Seemanova, E., Mignot, E., Nishino, S. 2005; 12 (1): 70-72

  Abstract

  Four patients with clinically and genetically confirmed Prader-Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients' age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt-1 in the patients group was down to 164 +/- 46.8 pg/ml (in comparison with 265.8 +/- 48.8 pg/ml in 10 young healthy subjects, P=0.02). The deficiency of CSF Hcrt-1 level correlated in PWS patients with their EDS severity.

  View details for Web of Science ID 000225955700012

  View details for PubMedID 15613151

• HLA expression in narcoleptic hypothalamus 19th Annual Meeting of the Associated-Professional-Sleep-Societies Honda, M., Salehi, A., Hesla, P., Maehlen, J., Gaus, S., Einen, M., Tanaka, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2005: A220–A220

  View details for Web of Science ID 000228906101164

• Cataplexy and frequency of HLA-DQB1*0602 in Korean narcoleptics 19th Annual Meeting of the Associated-Professional-Sleep-Societies Hong, S., Jeong, J., Han, J., Lee, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2005: A218–A218

  View details for Web of Science ID 000228906101157

• History of the Development of Sleep Medicine in the United States JOURNAL OF CLINICAL SLEEP MEDICINE Shepard, J. W., Buysse, D. J., Chesson, A. L., Dement, W. C., Goldberg, R., Guilleminault, C., Harris, C. D., Iber, C., Mignot, E., Mitler, M. M., Moore, K. E., Phillips, B. A., Quan, S. F., Rosenberg, R. S., Roth, T., Schmidt, H. S., Silber, M. H., Walsh, J. K., White, D. P. 2005; 1 (1): 61-82

  Abstract

  Sleep Medicine has only recently been recognized as a specialty of medicine. Its development is based on an increasing amount of knowledge concerning the physiology of sleep, circadian biology and the pathophysiology of sleep disorders. This review chronicles the major advances in sleep science over the past 70 years and the development of the primary organizations responsible for the emergence of Sleep Medicine as a specialty, sleep disorders as a public health concern and sleep science as an important area of research.

  View details for Web of Science ID 000209775200013

  View details for PubMedCentralID PMC2413168

• Angiotensin-converting enzyme, sleep-disordered breathing, and hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Lin, L., Finn, L., Zhang, J., Young, T., Mignot, E. 2004; 170 (12): 1349-1353

  Abstract

  The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism influences ACE activity, cardiovascular risk, blood pressure, and possibly the risk of developing Alzheimer's dementia. We explored the association of the insertion/deletion polymorphism with sleep-disordered breathing (SDB) and hypertension in 1,100 subjects of the Wisconsin Sleep Cohort. The polymorphism did not influence body mass index or the occurrence of SDB, but was dose-dependently associated with blood pressure. Interestingly, SDB and the insertion/deletion polymorphism interacted significantly to modulate blood pressure independently of age, sex, ethnicity, and body mass index. Most specifically, the association of the deletion allele with hypertension was most pronounced in subjects with mild to moderate degrees of sleep apnea (5 < or = apnea-hypopnea index < or = 30). We hypothesize that in the absence of SDB the effect of the deletion allele alone may not be sufficient to increase blood pressure. At severe levels of SDB, the effect of sleep apnea on blood pressure overwhelms any association of the deletion allele with hypertension and occurs independent of any ACE gene genotype.

  View details for DOI 10.1164/rccm.200405-6160C

  View details for Web of Science ID 000225780800014

  View details for PubMedID 15447944

• Sodium oxybate for excessive daytime sleepiness in narcolepsy-cataplexy SLEEP Arnulf, I., Mignot, E. 2004; 27 (7): 1242-1243

  View details for Web of Science ID 000225093100003

  View details for PubMedID 15586777

• APOE epsilon 4 is associated with obstructive sleep apnea/hypopnea - The Sleep Heart Health Study NEUROLOGY Gottlieb, D. J., DeStefano, A. L., Foley, D. J., Mignot, E., Redline, S., Givelber, R. J., Young, T. 2004; 63 (4): 664-668

  Abstract

  Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE epsilon4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE epsilon4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association.A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHI > or = 15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship.At least one APOE epsilon4 allele was present in 25% of subjects, with 1.3% epsilon4/epsilon4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE epsilon4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p = 0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those > or =75 years old (OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE epsilon4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without.The APOE epsilon4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results.

  View details for Web of Science ID 000223493800013

  View details for PubMedID 15326239

• The diurnal rhythm of hypocretin in young and old F344 rats SLEEP Desarnaud, F., Murillo-Rodriguez, E., Lin, L., Xu, M., Gerashchenko, D., Shiromani, S. N., Nishino, S., Mignot, E., Shiromani, P. J. 2004; 27 (5): 851-856

  Abstract

  Hypocretins (HCRT-1 and HCRT-2), also known as orexins, are neuropeptides localized in neurons surrounding the perifornical region of the posterior hypothalamus. These neurons project to major arousal centers in the brain and are implicated in regulating wakefulness. In young rats and monkeys, levels of HCRT-1 are highest at the end of the wake-active period and lowest toward the end of the sleep period. However, the effects of age on the diurnal rhythm of HCRT-1 are not known.To provide such data, cerebrospinal fluid (CSF) was collected from the cisterna magna of young (2-month-old, n = 9), middle-aged (12 months, n = 10), and old (24 months, n = 10) F344 rats at 4-hour intervals, (beginning at zeitgeber [ZT]0, lights on). CSF was collected once from each rat every 4 days at 1 ZT point. After collecting the CSF at all of the time points, the rats were kept awake by gentle handling for 8 hours (ZT 0-ZT8), and the CSF was collected again at the end of the sleep-deprivation procedure. HCRT-1 levels in the CSF were determined by radioimmunoassayBasic neuroscience research lab.Old rats had significantly less HCRT-1 in the CSF versus young and middle-aged rats (P < .002) during the lights-on and lights-off periods and over the 24-hour period. In old rats, significantly low levels of HCRT-1 were evident at the end of the lights-off period (predominantly wake-active period). The old rats continued to have less HCRT-1 even after 8 hours of prolonged waking. Northern blot analysis did not show a difference in pre-proHCRT mRNA between age groups.In old rats there is a 10% decline in CSF HCRT-1 over the 24-hour period. Functionally, if there is less HCRT-1, which our findings indicated, and there is also a decline in HCRT receptor mRNA, as has been previously found, then the overall consequence would be diminished action of HCRT at target sites. This would diminish the waking drive, which in the elderly could contribute to the increased tendency to fall asleep during the normal wake period.

  View details for Web of Science ID 000223451400006

  View details for PubMedID 15453542

  View details for PubMedCentralID PMC1201560

• The effect of hypocretin replacement therapy in a 3-year-old Weimaraner with narcolepsy JOURNAL OF VETERINARY INTERNAL MEDICINE Schatzberg, S. J., Cutter-Schatzberg, K., Nydam, D., Barrett, J., Penn, R., Flanders, J., deLahunta, A., Lin, L., Mignot, E. 2004; 18 (4): 586-588

  View details for Web of Science ID 000222901400025

  View details for PubMedID 15320603

• Locomotor-dependent and -independent components to hypocretin-1 (orexinA) regulation in sleep-wake consolidating monkeys JOURNAL OF PHYSIOLOGY-LONDON Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., Mignot, E. 2004; 557 (3): 1045-1053

  Abstract

  The hypocretin system is involved in the integration of hypothalamic functions with sleep and wake. Hypocretin-1 release peaks at the end of the active period in both diurnal and nocturnal species. A role for hypocretin-1 in the generation of locomotor activity has been suggested by electrophysiological and neurochemical studies in rodents, dogs and cats. These species, however, do not consolidate wake into a single, daily bout and manipulations of locomotion elicit changes in wakefulness, making it difficult to parse the relative contribution of these two factors. We have examined the relationship between locomotion and hypocretin-1 in a wake-consolidating animal, the squirrel monkey (Saimiri sciureus). Strikingly, we found that restricting locomotion to 17% of usual activity had no significant effect on the normal diurnal rise in cerebrospinal fluid (CSF) hypocretin-1, despite an associated increase in CSF cortisol. Increasing locomotion to greater than baseline activity did not significantly increase CSF hypocretin-1 concentrations, but did appear to have a positive modulatory effect on CSF hypocretin-1. In this wake-consolidating animal, locomotion is not necessary for CSF hypocretin-1 to increase throughout the daytime, but high levels of locomotion are likely to provide a small positive feedback onto the hypocretin system.

  View details for DOI 10.1113/jphysiol.2004.061606

  View details for Web of Science ID 000222403700029

  View details for PubMedID 15107479

  View details for PubMedCentralID PMC1665142

• Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin-1 release SLEEP Zhang, S. W., Zeitzer, J. M., Yoshida, Y., Wisor, J. P., Nishino, S., Edgar, D. M., Mignot, E. 2004; 27 (4): 619-627

  Abstract

  Hypocretins (orexins) are involved in the sleep disorder narcolepsy. While hypocretin-1 has a daily oscillation, little is known regarding the relative contribution of circadian and homeostatic components on hypocretin release. The effect of lesions of the suprachiasmatic nucleus (SCN) on hypocretin-1 in the cerebrospinal fluid (CSF) was examined.SCN-ablated (SCNx) and sham-operated control rats were implanted with activity-temperature transmitters. Animals were housed individually under 1 of 3 lighting conditions: 12-hour:12-hour light:dark cycle (LD), constant light (LL), and constant darkness (DD). Lesions were verified histologically and shown not to affect hypocretin-containing cells. Hypocretin-1 concentrations in the CSF were determined every 4 hours using radioimmunoassays.Control animals displayed robust circadian (LL, DD) and diurnal (LD) fluctuations in CSF hypocretin-1, locomotor activity, and temperature. Peak CSF hypocretin-1 was at the end of the active period. Activity, temperature, and CSF hypocretin-1 were arrhythmic in SCNx animals in LL and DD. In LD, a weak but significant fluctuation in activity and temperature but not CSF hypocretin-1 was observed in SCNx animals. We also explored correlations between CSF hypocretin-1, CSF corticosterone, and locomotor activity occurring prior to CSF sampling in arrhythmic SCNx rats under constant conditions. Significant correlations between hypocretin-1 and activity were observed both across and within animals, suggesting that interindividual and time-of-the-day differences in activity have significant effects on hypocretin release in arrhythmic animals. No correlation was found between CSF hypocretin-1 and corticosterone.Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons.

  View details for Web of Science ID 000223169300007

  View details for PubMedID 15282996

• The roles of midbrain and diencephalic dopamine cell groups in the regulation of cataplexy in narcoleptic Dobermans NEUROBIOLOGY OF DISEASE Okura, M., Fujiki, N., Kita, L., Honda, K., Yoshida, Y., Mignot, E., Nishino, S. 2004; 16 (1): 274-282

  Abstract

  Cataplexy, an emotion-triggered sudden loss of muscle tone specific to narcolepsy, is tightly associated with hypocretin deficiency. Using hypocretin receptor 2 gene (hcrtr 2)-mutated narcoleptic Dobermans, we have previously demonstrated that altered dopamine (DA) D(2/3) receptor mechanisms in mesencephalic DA nuclei are important for the induction of cataplexy. In the current study, we also found that the administration of D(2/3) agonists into diencephalic dopaminergic cell groups, including the area dorsal to the ventral tegmental area (DRVTA) and the periventricular gray (PVG) matter of the caudal thalamus (corresponding to area A11), significantly aggravated cataplexy in hcrtr 2-mutated narcoleptic Dobermans. A D(1) agonist and antagonist and a DA uptake inhibitor perfused into the DRVTA had no effect on cataplexy, suggesting an involvement of D(2/3) receptors located on DA cell bodies (i.e., autoreceptors) for the regulation of cataplexy. Because the A11 cell group projects to the spinal ventral horn, the A11 D(2/3) receptive mechanisms may directly modulate the activity of spinal motoneurons and modulate cataplexy.

  View details for DOI 10.1016/j.nbd.2004.02.008

  View details for Web of Science ID 000221365300029

  View details for PubMedID 15207284

• Sleep, sleep disorders and hypocretin (orexin) 1st International Sleep Disorders Forum Mignot, E. ELSEVIER SCIENCE BV. 2004: S2–S8

  Abstract

  Narcolepsy is a disabling neurologic condition affecting 1 in 2000 individuals, characterized by sleepiness, cataplexy, and transitions from wakefulness into rapid-eye-movement sleep. Current treatments include amphetamine-like stimulants and antidepressants. Human narcolepsy is HLA-associated, multigenic, and environmentally influenced. Positional cloning was used to isolate narcolepsy genes in canine families with autosomal recessive narcolepsy transmission. Three mutations in the G-protein-coupled hypocretin (orexin) receptor-2 (Hcrtr-2) gene were identified. In humans, most cases of narcolepsy are not linked to hypocretin (Hcrt) ligand or receptor mutations but are associated with undetectable cerebrospinal fluid Hcrt-1 levels. A single Hcrt gene/narcolepsy mutation was identified in narcoleptic patients. Hcrt-1 is wake-promoting in vivo, and studies in sporadic human narcolepsy indicate a loss of brain Hcrt-1 and Hcrt-2 and a disappearance of Hcrt-1-containing cells in the hypothalamus. Narcolepsy with cataplexy may therefore be due to Hcrt deficiency. The HLA association in humans suggests possible autoimmune activity against hypothalamic Hcrt-containing cells. Hypocretins may also have roles in regulating normal sleep, appetite, neuroendocrine function and energy metabolism, uniquely positioning them as a link between multiple important behaviors. Abnormal Hcrt transmission is also found in neurologic disorders featuring excessive daytime sleepiness and/or hypothalamic abnormalities. Pharmacologic manipulations of Hcrts may have multiple therapeutic applications.

  View details for Web of Science ID 000222352700002

  View details for PubMedID 15301991

• Undetectable CSF hypocretin-1 in "Hashimoto's encephalopathy" associated with coma NEUROLOGY Castillo, P. R., Mignot, E., Woodruff, B. K., Boeve, B. F. 2004; 62 (10): 1909-1909

  View details for Web of Science ID 000221603900059

  View details for PubMedID 15159515

• Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis NEUROLOGY Overeem, S., Dalmau, J., Bataller, L., Nishino, S., Mignot, E., Verschuuren, J., Lammers, G. J. 2004; 62 (1): 138-140

  Abstract

  Idiopathic narcolepsy is associated with deficient hypocretin transmission. Narcoleptic symptoms have recently been described in paraneoplastic encephalitis with anti-Ma2 antibodies. The authors measured CSF hypocretin-1 levels in six patients with anti-Ma2 encephalitis, and screened for anti-Ma antibodies in patients with idiopathic narcolepsy. Anti-Ma autoantibodies were not detected in patients with idiopathic narcolepsy. Four patients with anti-Ma2 encephalitis had excessive daytime sleepiness; hypocretin-1 was not detectable in their cerebrospinal fluid, suggesting an immune-mediated hypocretin dysfunction.

  View details for Web of Science ID 000188010100037

  View details for PubMedID 14718718

• Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation BRAIN RESEARCH Pedrazzoli, M., D'Almeida, V., Martins, P. J., Machado, R. B., Ling, L., Nishino, S., Tufik, S., Mignot, E. 2004; 995 (1): 1-6

  Abstract

  Rat cisternal (CSF) hypocretin-1 in cerebrospinal fluid was measured after 6 or 96 h of REM sleep deprivation and following 24 h of REM sleep rebound. REM deprivation was found to increase CSF hypocretin-1 collected at zeitgeber time (ZT) 8 but not ZT0. Decreased CSF hypocretin levels were also observed at ZT8 after 24 h of REM sleep rebound. These results suggest that REM sleep deprivation activates and REM sleep rebound inhibits the hypocretin system. Increased hypocretin tone during REM deprivation may be important in mediating some of the effects of REM sleep deprivation such as antidepressant effects, hyperphagia and increased sympathetic activity.

  View details for DOI 10.1016/j.brainres.2003.09.032

  View details for Web of Science ID 000187747400001

  View details for PubMedID 14644464

• Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans AMERICAN JOURNAL OF HUMAN GENETICS Oksenberg, J. R., Barcellos, L. F., Cree, B. A., Baranzini, S. E., Bugawan, T. L., Khan, O., Lincoln, R. R., Swerdlin, A., Mignot, E., Lin, L., Goodin, D., Erlich, H. A., Schmidt, S., Thomson, G., Reich, D. E., Pericak-Vance, M. A., Haines, J. L., Hauser, S. L. 2004; 74 (1): 160-167

  Abstract

  An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

  View details for Web of Science ID 000187723500015

  View details for PubMedID 14669136

  View details for PubMedCentralID PMC1181903

• Genes transcripts relating to the immune response are up-regulated in narcoleptic postmortem hypothalamus using microarray 18th Annual Meeting of the Associated-Professional-Sleep-Societies Honda, M., Salehi, A., Hesla, P., Maehlen, J., Gaus, S., Einen, M., Mignot, E. AMER ACAD SLEEP MEDICINE. 2004: 250–251

  View details for Web of Science ID 000223169400565

• Clinical features and frequency of HLA-DQB1*0602 in Korean narcolepsy patients 18th Annual Meeting of the Associated-Professional-Sleep-Societies Hong, S., Jeong, J., Han, J., Lee, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2004: 242–242

  View details for Web of Science ID 000223169400547

• Diurnal variations of CSF hypocretin (HCRT) and changes in gene expression as detected by microarrays in young and old rats 18th Annual Meeting of the Associated-Professional-Sleep-Societies Desarnaud, F., Murillo-Rodriguez, E., Xu, M., Gerashenko, D., Lu, J., Shiromani, S. N., Lin, L., Nishino, S., Mignot, E., Shiromani, P. AMER ACAD SLEEP MEDICINE. 2004: 382–382

  View details for Web of Science ID 000223169400857

• Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness EUROPEAN NEUROLOGY Baumann, C. R., Dauvilliers, Y., Mignot, E., Bassetti, C. L. 2004; 52 (2): 73-76

  Abstract

  Excessive daytime sleepiness, hallucinations and REM sleep behavior disorder are symptoms reported in both dementia with Lewy bodies (DLB) and narcolepsy. Considering the demonstration of low hypocretin-1/orexin A levels in the cerebrospinal fluid (CSF) of most patients with narcolepsy, we hypothesized the presence of a deficient hypocretinergic transmission in DLB. Hypocretin-1 was tested in the CSF of 10 DLB patients. Levels were found to be in the normal range (mean 521 pg/ml, range 382-667) when compared to controls (n = 20, mean 497 pg/ml, range 350-603) and Alzheimer's disease patients (n = 7, mean 474 pg/ml, range 333-564). In DLB, excessive daytime sleepiness, hallucinations and REM sleep behavior may occur in the absence of a detectable hypocretin deficiency.

  View details for DOI 10.1159/000079749

  View details for Web of Science ID 000224988600002

  View details for PubMedID 15256827

• Effects of IV and ICV hypocretin-1 (Orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog SLEEP Fujiki, N., Yoshida, Y., Ripley, B., Mignot, E., Nishino, S. 2003; 26 (8): 953-959

  Abstract

  Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep.Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 microg/kg) induced significant wakefulness in control dogs. However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans. Only very high intravenously doses of hypocretin-1 (96-384 microg/kg) penetrated the brain, to produce a short-lasting anticataplectic effect in a hypocretin-ligand-deficient animal.Hypocretin-1 administration, by central and systemic routes, does not improve narcoleptic symptoms in Hcrtr2 mutated Dobermans. Systemic hypocretin-1 hardly crosses the blood-brain barrier to produce therapeutic effects. The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans.

  View details for Web of Science ID 000188205200008

  View details for PubMedID 14746374

• Normal hypocretin-1 levels in the cerebrospinal fluid of patients with fatal familial insomnia SLEEP Martinez-Rodriguez, J. E., Sanchez-Valle, R., Saiz, A., Lin, L., Iranzo, A., Mignot, E., Santamaria, J. 2003; 26 (8): 1068-1068

  View details for Web of Science ID 000188205200029

  View details for PubMedID 14746394

• Relationship between CSF hypocretin levels and hypocretin neuronal loss EXPERIMENTAL NEUROLOGY Gerashchenko, D., Munillo-Rodriguez, E., Lin, L., Xu, M., Hallett, L., Nishino, S., Mignot, E., Shiromani, P. J. 2003; 184 (2): 1010-1016

  Abstract

  The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT). Most narcoleptic patients have low to negligible levels of HCRT in the cerebrospinal fluid (CSF), and such measurements serve as an important diagnostic tool. However, the relationship between HCRT neurons and HCRT levels in CSF in human narcoleptics is not known and cannot be directly assessed. To identify this relationship in the present study, the neurotoxin, hypocretin-2-saporin (HCRT2-SAP), was administered to the lateral hypothalamus (LH) to lesion HCRT neurons. CSF was extracted at circadian times (ZT) 0 (time of lights-on) or ZT8 at various intervals (2, 4, 6, 12, 21, 36, 60 days) after neurotoxin administration. Compared to animals given saline in the LH, rats with an average loss of 73% of HCRT neurons had a 50% decline in CSF HCRT levels on day 60. The decline in HCRT levels was evident by day 6 and there was no recovery or further decrease. The decline in HCRT was correlated with increased REM sleep. Lesioned rats that were kept awake for 6 h were not able to release HCRT to match the output of saline rats. As most human narcoleptics have more than 80% reduction of CSF HCRT, the results from this study lead us to conclude that in these patients, virtually all of the HCRT neurons might be lost. In those narcoleptics where CSF levels are within the normal range, it is possible that not all of the HCRT neurons are lost and that the surviving HCRT neurons might be increasing output of CSF HCRT.

  View details for DOI 10.1016/S0014-4886(03)00388-1

  View details for Web of Science ID 000187634400049

  View details for PubMedID 14769395

• CSF hypocretin-1 levels in restless legs syndrome NEUROLOGY Stiasny-Kolster, K., Mignot, E., Ling, L., Moller, J. C., Cassel, W., Oertel, W. H. 2003; 61 (10): 1426-1429

  Abstract

  CSF hypocretin-1 levels at 6 PM did not significantly differ between patients with restless legs syndrome (RLS) and control subjects as measured by direct radioimmunoassay and after acid extraction. The authors did not observe significant differences between early onset and late onset RLS. Hypocretin-1 levels did not correlate with RLS severity or polysomnographic measures. These results contrast with previous findings reporting significantly increased CSF hypocretin-1 in the late evening and mostly in early onset RLS.

  View details for Web of Science ID 000186767800025

  View details for PubMedID 14638970

• Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy SLEEP Hecht, M., Lin, L., Kushida, C. A., Umetsu, D. T., Taheri, S., Einen, M., Mignot, E. 2003; 26 (7): 809-810

  Abstract

  To explore whether acute destruction of hypocretin cells in a patient with narcolepsy could be detected and if the course of the disease could be reversed or altered by the use of prednisone for immunosuppression.Case report.A sleep-clinic population in a tertiary-care hospital.An 8-year-old boy with a very acute recent (< 2 month) onset of sleepiness.Sleep studies; fluid-attenuated inversion recovery and gadolinium magnetic resonance imaging studies with a focus on the hypothalamus; examinations of cerebrospinal fluid for cytology, protein, and hypocretin-1 levels; and HLA typing were performed.A 3-week regimen of 1 mg x kg(-1) x day(-1) of prednisone was administered in an attempt to modify the course of the disease.Sleep evaluations were consistent with a diagnosis of narcolepsy. Hypocretin-1 was absent in the cerebrospinal fluid, and HLA-DQB1*0602 was present. All other results were within normal limits, and prednisone did not have any noticeable effects. Clinical manifestation of narcolepsy might occur when the hypocretin cell damage is too advanced to be reversible.

  View details for Web of Science ID 000186745800007

  View details for PubMedID 14655912

• Narcolepsy: involvement of imprinted, differentially-methylated promotor haplotypes of vesicular monoamine transporter 2 (VMAT2). 53rd Annual Meeting of the American-Society-of-Human-Genetics Drgon, T., Takahashi, M., Walther, D., Lin, Z., Lin, L., Tafti, M., Billiard, M., Thorpy, M., Temple, H., Montplaisir, J., Mignot, E., Uhl, G. R. CELL PRESS. 2003: 332–32

  View details for Web of Science ID 000185599700950

• CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies NEUROLOGY Nishino, S., Kanbayashi, T., Fujiki, N., Uchino, M., Ripley, B., Watanabe, M., Lammers, G. J., Ishiguro, H., Shoji, S., Nishida, Y., Overeem, S., Toyoshima, I., Yoshida, Y., Shimizu, T., Taheri, S., Mignot, E. 2003; 61 (6): 823-825

  Abstract

  CSF hypocretin-1 was measured in 28 Guillain-Barré syndrome (GBS), 12 Miller-Fisher syndrome, 12 chronic inflammatory demyelinating polyneuropathy (CIDP), and 48 control subjects. Seven GBS subjects had undetectably low hypocretin-1 levels (<100 pg/mL). Hypocretin-1 levels were moderately reduced in an additional 11 GBS, 5 Miller-Fisher syndrome, and 1 CIDP subject. Low levels in GBS occurred early in the disease and were associated with upper CNS level abnormalities.

  View details for Web of Science ID 000185460600020

  View details for PubMedID 14504329

• On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy SLEEP Mignot, E., Chen, W., Black, J. 2003; 26 (6): 646-649

  View details for Web of Science ID 000185472200002

  View details for PubMedID 14572113

• Diurnal variation of cerebrospinal fluid hypocretin-1 (orexin-A) levels in control and depressed subjects 16th Annual Meeting of the Associated-Professional-Sleep-Societies Salomon, R. M., Ripley, B., Kennedy, J. S., Johnson, B., Schmidt, D., Zeitzer, J. M., Nishino, S., Mignot, E. ELSEVIER SCIENCE INC. 2003: 96–104

  Abstract

  Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders.We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n=10, three nonresponders) or bupropion (n=5, two nonresponders).Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (-14%) but not bupropion.Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.

  View details for DOI 10.1016/S0006-3223(03)01740-7

  View details for Web of Science ID 000184213800002

  View details for PubMedID 12873798

• Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C SLEEP Vankova, J., Stepanova, I., Jech, R., Elleder, M., Ling, L., Mignot, E., Nishino, S., Nevsimalova, S. 2003; 26 (4): 427-430

  Abstract

  Subjects with Niemann-Pick disease, type C have been reported to display narcolepsylike symptoms, including cataplexy. In this study, 5 patients with juvenile Niemann-Pick disease were evaluted for sleep abnormalities using nocturnal polysomnography, clinical evaluation, and the Multiple Sleep Latency Test. HLA typing and cerebrospinal fluid hypocretin levels were also evaluated in 4 patients. Niemann-Pick disease diagnosis was confirmed in all cases biochemically and by the presence of foam cells in the bone marrow.Deterioration of intellectual function; the presence of pyramidal, dystonic and cerebellar features; and splenomegaly were observed in all cases. Cataplexy was reported in 1 patient. Nocturnal polysomnography revealed disrupted sleep in all patients. Total sleep time, sleep efficiency, rapid eye movement sleep, and delta sleep amounts were decreased when compared to age-matched controls. Altered sleep patterns included sudden increases in muscle tone during delta sleep, electroencephalographic sigma activity connected with rapid eye movements and muscle atonia, atypical K-complexes and spindle activity, and the presence of alpha-delta sleep. All Niemann-Pick disease cases exhibited fragmentary myoclonus. Shortened mean sleep latencies were observed in 3 patients during the Multiple Sleep Latency Test, but sleep-onset rapid eye movement periods were observed only in the case with cataplexy. This patient was HLA DQB1*0602 positive, while the other subjects were HLA negative. Cerebrospinal fluid hypocretin-1 levels were reduced in 2 patients (1 with cataplexy) while in the 2 other patients, the levels were at the lower range of the normal values. Hypocretin levels in the Niemann-Pick disease group (204.8 +/- 39.3 pg/mL) were significantly reduced when compared to controls (265.8 +/- 48.8 pg/mL).The findings suggest that lysozomal storage abnormalities in Niemann-Pick disease patients may impact the hypothalamus and, more specifically, hypocretin-containing cells. These changes might be partially responsible for sleep abnormalities and cataplexy in patients with Niemann-Pick disease.

  View details for Web of Science ID 000183452600006

  View details for PubMedID 12841368

• CSF hypocretin levels in Korean narcoleptic patients 17th Annual Meeting of the Associated-Professional-Sleep-Societies Hong, S., Jeong, J. H., Han, J. H., Lee, S. P., Mignot, E. AMER ACAD SLEEP MEDICINE. 2003: A284–A284

  View details for Web of Science ID 000182841100717

• Investigation of the autoimmune basis of narcolepsy using western blot analysis of lateral hypothalamus protein extract with serum and cerebrospinal fluid (CSF) 17th Annual Meeting of the Associated-Professional-Sleep-Societies Taheri, S., Krempetz, M., Jackson, M., Paterno, J., Mignot, E. AMER ACAD SLEEP MEDICINE. 2003: A285–A285

  View details for Web of Science ID 000182841100720

• Circadian and homeostatic regulation of hypocretin in a primate model: Implications for the consolidation of wakefulness JOURNAL OF NEUROSCIENCE Zeitzer, J. M., Buckmaster, C. L., Parker, K. J., Hauck, C. M., Lyons, D. M., Mignot, E. 2003; 23 (8): 3555-3560

  Abstract

  In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.

  View details for Web of Science ID 000182475200052

  View details for PubMedID 12716965

• Voxel-based morphometry in hypocretin-deficient narcolepsy SLEEP Overeem, S., Steens, S. C., Good, C. D., Ferrari, M. D., Mignot, E., Frackowiak, R. S., van Buchem, M. A., Lammers, G. J. 2003; 26 (1): 44-46

  Abstract

  Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy.We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes.Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London.Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects.We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls.VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.

  View details for Web of Science ID 000181724800010

  View details for PubMedID 12627731

• Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders NATURE NEUROSCIENCE Mignot, E., Taheri, S., Nishino, S. 2002; 5: 1071-1075

  Abstract

  Delineating the basic mechanisms that regulate sleep will likely result in the development of better treatments for sleep disorders. The hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. An increased awareness of the close interaction between sleep and homeostatic systems is also emerging. Progress has occurred in the understanding of narcolepsy--molecular techniques have identified the lateral hypothalamic hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep disorders are now being tackled in the same way and are likely to yield to efforts combining basic and clinical research. Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders.

  View details for DOI 10.1038/nn944

  View details for Web of Science ID 000179041300017

  View details for PubMedID 12403989

• Future of genetics of mood disorders research. Biological psychiatry Merikangas, K. R., Chakravarti, A., Moldin, S. O., Araj, H., Blangero, J. C., Burmeister, M., Crabbe, J., Depaulo, J. R., Foulks, E., Freimer, N. B., Koretz, D. S., Lichtenstein, W., Mignot, E., Reiss, A. L., Risch, N. J., Takahashi, J. S. 2002; 52 (6): 457-477

  Abstract

  This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

  View details for PubMedID 12361664

• Workgroup reports: NIMH strategic plan for mood disorders research - Future of genetics of mood disorders research BIOLOGICAL PSYCHIATRY Merikangas, K. R., Chakravarti, A., Moldin, S. O., Araj, H., Blangero, J., Burmeister, M., Crabbe, J. C., DePaulo, J. R., Foulks, E., Freimer, N. B., Koretz, D. S., Lichtenstein, W., Mignot, E., Reiss, A. L., Risch, N. J., Takahashi, J. S. 2002; 52 (6): 457-477

  Abstract

  This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

  View details for Web of Science ID 000178297000002

• Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome NEUROLOGY Allen, R. P., Mignot, E., Ripley, B., Nishino, S., Earley, C. J. 2002; 59 (4): 639-641

  Abstract

  Hypocretin-1 levels were increased in evening CSF samples from subjects with restless legs syndrome, indicating altered hypocretin transmission in this sleep disorder. Increases in CSF hypocretin-1 levels were most striking in patients with early-onset restless legs syndrome.

  View details for Web of Science ID 000177613500035

  View details for PubMedID 12196669

• HLA and hypocretin studies in Korean patients with narcolepsy SLEEP Hong, S. C., Leen-Kim, Park, S. A., Han, J. H., Lee, S. P., Lin, L., Okun, M., Nishino, S., Mignot, E. 2002; 25 (4): 440-444

  Abstract

  Very few studies have evaluated narcolepsy in Asian countries, outside of Japan. Our goal was to study narcolepsy at the genetic, clinical and pathophysiological level in Korea.Prospective study of consecutive patients and age matched controls. Clinical data ascertained from the Stanford Sleep Inventory, Polysomnography and MSLT data, as well as clinical notes. High resolution DRB1 and DQB1 typing in all subjects and studies of CSF hypocretin-1 was also evaluated in a subset of patients.20 patients diagnosed at St. Vincent and Korea University Hospitals (Seoul, Korea). 21 Korean control subjects.N/A.For narcoleptic subjects, mean age was 28.2 years old and 45% were female. Mean BMI was 23.9+/-3.4 kg/m2, a significantly higher value than that expected in an age- and sex-matched sample (p<0.01). All patients had sleepiness and cataplexy while the prevalence of other symptoms ranged from 60-75%. All but 2 subjects were HLA-DR15 (DR2), DQB1*0602 positive (90%). This high DQB1*0602 percentage compared with 24% DQB1*0602 positivity in 21 control Koreans. Protective effects were observed for the DQB1*0601 and DRB1*0406 alleles, Hypocretin (orexin) CSF studies were also performed in 6 cataplectic subjects, all of which had undetectable CSF hypocretin levels. Two of these subjects had started narcolepsy less than 1 year before analysis yet had undetectable hypocretin levels.These results illustrate the similarity of narcolepsy-cataplexy in Korea in comparisons with other more studied populations. We also identified a new potential HLA protective subtype, HLA-DRB1*0406.

  View details for Web of Science ID 000176089100011

  View details for PubMedID 12071546

• Hypocretin stimulates [(35)]GTP gamma S binding in Hcrtr 2-transfected cell lines and in brain homogenate BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Shiba, T., Ozu, M., Yoshida, Y., Mignot, E., Nishino, S. 2002; 294 (3): 615-620

  Abstract

  In vitro functional analyses of hypocretin/orexin receptor systems were performed using [(125)I]hypocretin radioreceptor and hypocretin-stimulated [(35)S]GTP gamma S binding assay in cell lines expressing human or canine (wild-type and narcoleptic-mutation) hypocretin receptor 2 (Hcrtr 2). Hypocretin-2 stimulated [(35)S]GTP gamma S binding in human and canine Hcrtr 2 expressing cell lines, while cell lines expressing the mutated canine Hcrtr 2 did not exhibit specific binding for [(125)I]hypocretin or hypocretin-stimulated [(35)S]GTP gamma S. In rat brain homogenates, regional specific hypocretin-stimulated [(35)S]GTP gamma S binding was also observed. Hypocretin-stimulated [(35)S]GTP gamma S binding, may thus be a useful functional assay for hypocretin receptors in both cell lines and brain tissue homogenates.

  View details for Web of Science ID 000176364700017

  View details for PubMedID 12056812

• CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture PSYCHIATRY RESEARCH Nishino, S., Ripley, B., Mignot, E., Benson, K. L., Zarcone, V. P. 2002; 110 (1): 1-7

  Abstract

  Hypocretins/orexins are newly identified peptides of hypothalamic origin. Hypocretin deficiency is involved in the sleep disorder narcolepsy, suggesting the importance of hypocretin neurotransmission for the regulation of sleep. Hypocretin is known to excite midbrain dopaminergic neurons and to induce hyperactivity and stereotypy in animals. Altered hypocretin neurotransmission might therefore be involved in schizophrenia, since an involvement of dopaminergic mechanisms and an association with sleep disturbance are well demonstrated in patients with schizophrenia. Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). In the current study, we measured CSF hypocretin levels in 12 controls and 13 patients with chronic schizophrenia associated with moderate sleep disturbance, such as longer sleep onset latency, decreased total sleep time and decreased sleep efficacy. No difference in CSF hypocretin levels between schizophrenia and control subjects was found. CSF hypocretin levels were positively correlated with CSF CRH levels in the patient, control and combined subject populations, but the correlation did not reach statistical significance in any population. The hypocretin levels in schizophrenic patients were, however, positively and significantly correlated with sleep latency, one of the most consistent sleep abnormalities seen in schizophrenia. This correlation was not significant in controls, and no other significant correlation between CSF hypocretin levels and any measure of sleep architecture in either patients or controls was observed. Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted.

  View details for Web of Science ID 000176095700001

  View details for PubMedID 12007588

• Diurnal variation of CSF hypocretin-1 (orexin A) levels in control and depressed subjects Salomon, R. M., Ripley, B., Kennedy, J. S., Schmidt, D., Zeitzer, J., Nishino, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2002: A12–A13

  View details for Web of Science ID 000174927200019

• Stimulant medication usage in a large cohort of narcoleptic subjects Okun, M. L., Lopez, A., Colrain, I., Ginney, C., Brooks, S., Mignot, E., Black, J. AMER ACAD SLEEP MEDICINE. 2002: A474–A474

  View details for Web of Science ID 000174927200673

• Clinical aspects of narcolepsy-cataplexy across ethnic groups SLEEP Okun, M. L., Lin, L., Pelin, Z., Hong, S. C., Mignot, E. 2002; 25 (1): 27-35

  Abstract

  The objectives of this study were to compare severity and clinical presentation for narcolepsy-cataplexy across various ethnic groups. A large sample of narcoleptic patients was also used to further describe symptomatology and natural history for this sleep disorder.Retrospective review of clinical data ascertained from the Stanford Sleep Inventory, polysomnography and MSLT data, as well as clinical notes. Ethnicity was narrowly defined as African (Black) Americans, Caucasians, Asians, and Latinos when both parents and the subject identified with a given ethnic group.N/A.We compared the severity and clinical presentation of narcolepsy in 64 African Americans, 353 Caucasians, 32 Asians, 26 Latinos, and 9 subjects of mixed ethnicity. Subjects were recruited through the Stanford center for narcolepsy research.N/A.A striking similarity in symptomatology, age of onset, and disease severity was found across ethnic groups. Mean age of onset for sleepiness, hypnagogic hallucinations, sleep paralysis and cataplexy were 19.20, 19.50, 20.11 and 23.02 years old. We also found that narcoleptic patients have slightly but significantly elevated body mass index relative to normative data (106.6% of matched controls, p<0.005) and are born slightly more frequently during the month of March. A tight correlation between our previously validated cataplexy scale and DQB1*0602 positivity was observed. Two thirds of patients reported having cataplexy with laughing, 92% of those being DQB1*0602 positive independent of ethnicity.These results confirm the similarities in clinical presentation and natural history of narcolepsy-cataplexy in a large number of patients of various ethnic groups and cultural backgrounds.

  View details for Web of Science ID 000173415100006

  View details for PubMedID 11833858

• The role of hypocretins (orexins) in sleep regulation and narcolepsy ANNUAL REVIEW OF NEUROSCIENCE Taheri, S., Zeitzer, J. M., Mignot, E. 2002; 25: 283-313

  Abstract

  The hypocretins (orexins) are two novel neuropeptides (Hcrt-1 and Hcrt-2), derived from the same precursor gene, that are synthesized by neurons located exclusively in the lateral, posterior, and perifornical hypothalamus. Hypocretin-containing neurons have widespread projections throughout the CNS with particularly dense excitatory projections to monoaminergic centers such as the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotoninergic raphe nucleus, and dopaminergic ventral tegmental area. The hypocretins were originally believed to be primarily important in the regulation of appetite; however, a major function emerging from research on these neuropeptides is the regulation of sleep and wakefulness. Deficiency in hypocretin neurotransmission results in the sleep disorder narcolepsy in mice, dogs, and humans. The hypocretins are also uniquely positioned to link sleep, appetite, and neuroendocrine control. The aim of this review is to describe and discuss the current knowledge regarding the hypocretin neurotransmitter system in narcolepsy and normal sleep.

  View details for DOI 10.1146/annurev.neuro.25.112701.142826

  View details for Web of Science ID 000177354800009

  View details for PubMedID 12052911

• Histamine level was decreased in the brain of narcoleptic dogs Sakurai, E., Nishino, S., Kato, M., Fujiki, N., Ripley, B., Mignot, E., Watanabe, T., Yanai, K. JAPANESE PHARMACOLOGICAL SOC. 2002: 195P

  View details for Web of Science ID 000174447700760

• CSF hypocretin/orexin levels in narcolepsy and other neurological conditions NEUROLOGY Ripley, B., Overeem, S., Fujiki, N., Nevsimalova, S., Uchino, M., Yesavage, J., Di Monte, D., DOHI, K., Melberg, A., Lammers, G. J., Nishida, Y., Roelandse, F. W., Hungs, M., Mignot, E., Nishino, S. 2001; 57 (12): 2253-2258

  Abstract

  To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders.A method to measure hypocretin-1 in 100 microL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16-70 years), 48 healthy controls (ages 22-77 years,) and 235 patients with various other neurologic conditions (ages 0-85 years).As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224-653 pg/mL) and all neurologic patients (117-720 pg/mL), with the exception of three patients with Guillain-Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100-194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS.Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.

  View details for Web of Science ID 000172891500018

  View details for PubMedID 11756606

• Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy NEUROLOGY Hungs, M., Lin, L., Okun, M., Mignot, E. 2001; 57 (10): 1893-1895

  Abstract

  Human narcolepsy/cataplexy is associated with reduced hypocretin (orexin) transmission. A common preprophypocretin (HCRT) polymorphism (-909C/T) was identified and tested in 502 subjects (105 trio families, 80 Caucasian narcolepsy cases, and 107 Caucasian control subjects). This polymorphism was not associated with the disease. The promoter and 5' untranslated (5'URT) regions of the HCRT gene (-320 to +21 from ATG) were also sequenced in 281 subjects. None of the subjects carried -22T, a rare 5'UTR polymorphism previously reported to be associated with narcolepsy. The HCRT locus is not a major narcolepsy susceptibility locus.

  View details for Web of Science ID 000172334700029

  View details for PubMedID 11723284

• Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptics dogs NEUROSCIENCE LETTERS Nishino, S., Fujiki, N., Ripley, B., SAKURAI, E., Kato, M., Watanabe, T., Mignot, E., Yanai, K. 2001; 313 (3): 125-128

  Abstract

  A growing amount of evidence suggests that a deficiency in hypocretin/orexin neurotransmission is critically involved in animal and human forms of narcolepsy. Since hypocretin-containing neurons innervate and excite histaminergic tuberomammillary neurons, altered histaminergic neurotransmission may also be involved in narcolepsy. We found a significant decrease in histamine content in the cortex and thalamus, two structures important for histamine-mediated cortical arousal, in Hcrtr-2 mutated narcoleptic Dobermans. In contrast, dopamine and norepinephrine contents in these structures were elevated in narcoleptic animals, a finding consistent with our hypothesis of altered catecholaminergic transmission in these animals. Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy.

  View details for Web of Science ID 000172056000004

  View details for PubMedID 11682143

• A commentary on the neurobiology of the hypocretin/orexin system NEUROPSYCHOPHARMACOLOGY Mignot, E. 2001; 25: S5-S13

  Abstract

  Hypocretins/orexins are rapidly emerging as functionally important neurotransmitters. Two related neuropeptides (Hcrt-1/OXA, Hcrt-2/OXB) encoded by the same precursor gene and two G-protein coupled receptors (Hcrtr1/OXR1, Hcrtr2/OXR2) are currently known. Hypocretin-containing cells are discretely localized within the perifornical hypothalamus but have widespread projections, with generally excitatory postsynaptic effects. Dense excitatory projections to all monoaminergic cell groups have been reported. A major emerging function for this system is likely to be the regulation of sleep. Alterations in hypocretin neurotransmission causes the sleep disorder narcolepsy in mice, dogs and humans. Effects on appetite, neuroendocrine and energy metabolism regulation are also suggested by other studies. Hypocretins are uniquely positioned to link sleep, appetite and neuroendocrine control, three behaviors of major importance in psychiatry. The potential role of this system in regulating the sleep cycle, modulating wakefulness at selected circadian times and in mediating the deleterious effects of sleep deprivation is discussed.

  View details for Web of Science ID 000172066000003

  View details for PubMedID 11682267

• Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities EUROPEAN JOURNAL OF NEUROSCIENCE Yoshida, Y., Fujiki, N., Nakajima, T., Ripley, B., Matsumura, H., Yoneda, H., Mignot, E., Nishino, S. 2001; 14 (7): 1075-1081

  Abstract

  Hypocretins/orexins are neuropeptides implicated in sleep regulation and the sleep disorder narcolepsy. In order to examine how hypocretin activity fluctuates across 24 h with respect to the sleep-wake cycle, we measured changes in extracellular hypocretin-1 levels in the lateral hypothalamus and medial thalamus of freely moving rats with simultaneous sleep recordings. Hypocretin levels exhibited a robust diurnal fluctuation; levels slowly increased during the dark period (active phase), and decreased during the light period (rest phase). Levels were not correlated with the amount of wake or sleep in each period. Although an acute 4-h light-shift did not alter hypocretin levels, 6-h sleep deprivation significantly increased hypocretin release during the forced-wake period. Hypocretin activity is, thus, likely to build up during wakefulness and decline with the occurrence of sleep. These findings, together with the fact that a difficulty in maintaining wakefulness during the daytime is one of the primary symptoms of hypocretin-deficient narcolepsy, suggest that hypocretin activity may be critical in opposing sleep propensity during periods of prolonged wakefulness.

  View details for Web of Science ID 000171795700004

  View details for PubMedID 11683899

• Low cerebrospinal fluid hypocretin levels found in familial narcolepsy SLEEP MEDICINE Hartwig, G., Harsh, J., Ripley, B., Nishino, S., Mignot, E. 2001; 2 (5): 451-453

  Abstract

  This report describes abnormal hypocretin neurotransmission in a case of familial narcolepsy.Narcolepsy is a chronic, often-disabling central nervous system disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep features including cataplexy, a loss of muscle tone triggered by emotion. The cause of human narcolepsy is unknown. Several familial cases have been described, but most cases are sporadic (95%). An abnormality of hypocretin neurotransmission has been found in a majority of sporadic cases.Hypocretin-1 levels were measured in the cerebrospinal fluid of the narcoleptic proband of a family with several affected members.The proband was found to have a hypocretin-1 deficiency.Abnormal hypocretin neurotransmission is found in familial, as well as sporadic, narcolepsy.

  View details for Web of Science ID 000208301200011

• Narcolepsy and the HLA region JOURNAL OF NEUROIMMUNOLOGY Lin, L., Hungs, M., Mignot, E. 2001; 117 (1-2): 9-20

  Abstract

  Narcolepsy was first shown to be tightly associated with HLA-DR2 and DQ1 in 1983, suggesting a possible autoimmune mechanism. Early investigations failed to demonstrate this hypothesis, postulating that HLA-DR2 was only a linkage marker for another, unknown narcolepsy-causing gene. The autoimmune hypothesis is now being re-evaluated under the light of recent results. Like many other autoimmune disorders, narcolepsy usually starts during adolescence, is human leukocyte antigen (HLA)-associated, multigenic and environmentally influenced. Furthermore, HLA-association studies indicated a primary HLA-DQ effect with complex HLA class II allele interactions and a partial contribution of HLA to overall genetic susceptibility. Finally, recent result suggests that human narcolepsy is associated with the destruction of a small number of hypothalamic neurons containing the peptide hypocretins (orexins). This data is consistent with an immune destruction of hypocretin-containing cells as the most common etiology for human narcolepsy.

  View details for Web of Science ID 000170168100002

  View details for PubMedID 11431000

• Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke NEUROLOGY Scammell, T. E., Nishino, S., Mignot, E., SAPER, C. B. 2001; 56 (12): 1751-1753

  Abstract

  Idiopathic narcolepsy usually results from a loss of the hypothalamic neuropeptide orexin (hypocretin), but the cause of secondary narcolepsy resulting from focal brain lesions is unknown. The authors describe a young man who developed narcolepsy after a large hypothalamic stroke. His lesion included much of the hypothalamic region in which orexin is produced, and his CSF concentration of orexin was low. The authors hypothesize that a loss of orexin neurons or their relevant targets may be the specific neuropathology causing this and many other cases of secondary narcolepsy.

  View details for Web of Science ID 000169424200026

  View details for PubMedID 11425947

• Association between apolipoprotein E epsilon 4 and sleep-disordered breathing in adults JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION KADOTANI, H., Kadotani, T., Young, T., Peppard, P. E., Finn, L., Colrain, I. M., Murphy, G. M., Mignot, E. 2001; 285 (22): 2888-2890

  Abstract

  Apolipoprotein E epsilon4(ApoE epsilon4) is a well-known risk factor for Alzheimer disease and cardiovascular disease. Sleep-disordered breathing occurs in Alzheimer disease patients and increases risks for cardiovascular disease. Complex interactions among sleep, brain pathology, and cardiovascular disease may occur in ApoE epsilon4 carriers.To study whether genetic variation at the level of ApoE is associated with sleep-disordered breathing or sleep abnormalities in the general population.Ongoing longitudinal cohort study of sleep disorders at a US university beginning in 1989, providing a population-based probability sample of 791 middle-aged adults (mean [SD] age, 49 [8] years; range, 32-68 years).Nocturnal polysomnography to evaluate apnea-hypopnea index.The probability of moderate-to-severe sleep-disordered breathing (apnea-hypopnea index >/=15%) was significantly higher in participants with epsilon4, independent of age, sex, body mass index, and ethnicity (12.0% vs 7.0%; P =.003). Mean (SEM) apnea-hypopnea index was also significantly higher in participants with ApoE epsilon4 (6.5 [0.6] vs 4.8 [0.3]; P =.01). These effects increased with the number of ApoE epsilon4 alleles carried.A significant portion of sleep-disordered breathing is associated with ApoE epsilon4 in the general population.

  View details for Web of Science ID 000169156300028

  View details for PubMedID 11401610

• Hypocretin levels in sporadic and familial cases of canine narcolepsy NEUROBIOLOGY OF DISEASE Ripley, B., Fujiki, N., Okura, M., Mignot, E., Nishino, S. 2001; 8 (3): 525-534

  Abstract

  Familial and sporadic forms of narcolepsy exist in both humans and canines. Mutations in the hypocretin receptor 2 gene (Hcrtr 2) cause canine familial narcolepsy. In humans, mutations in hypocretin-related genes are rare, but cerebrospinal fluid (CSF) hypocretin-1 is undetectable in most sporadic cases. Using the canine model, we investigated ( 1 ) whether hypocretin deficiency is involved in sporadic cases and ( 2 ) whether alterations in hypocretin neurons or ligand levels also contribute to the phenotype in Hcrtr 2 mutants. We found that hypocretins were undetectable in the brains of three of three and the CSF of two of two sporadic narcoleptic dogs tested. In contrast, hypocretin levels were not altered in brains and CSF of genetically narcoleptic Dobermans, and hypocretin-containing neurons were of normal appearance. Therefore, multiple hypocretin-related etiologies are likely to be involved in canine narcolepsy. The presence of hypocretin peptides in Hcrtr 2-mutated animals suggests that neurotransmission through Hcrtr 1 may be intact, arguing for a preferential importance of Hcrtr 2-mediated function in narcolepsy.

  View details for Web of Science ID 000169459000014

  View details for PubMedID 11442359

• Narcoleptic canines display periodic leg movements during sleep 25th Annual Meeting of the Japanese-Society-of-Sleep-Research (JSSR) Okura, M., Fujiki, N., Ripley, B., Takahashi, S., Amitai, N., Mignot, E., Nishino, S. WILEY-BLACKWELL. 2001: 243–44

  Abstract

  Periodic leg movements during sleep (PLMS) is a high prevalent sleep disorder of unknown etiology. The disease is pharmacologically treated with dopaminergic agonists (i.e. D2/D3 agonists) and opiates. Periodic leg movements during sleep often occur in narcoleptic patients. We observed that narcoleptic canines, like narcoleptic humans, also exhibit jerky, unilateral or bilateral slow leg movements during sleep. The movements in dogs are characterized by repetitive dorsiflexions of the ankle, lasting 0.5-1.5 s, and occur at regular intervals of 3-20 s, thus showing similarities to PLMS in humans. The observation that D2/D3 agonists aggravate cataplexy in narcoleptic dogs suggests that altered dopaminergic regulation in canine narcolepsy may play a critical role in both cataplexy and PLMS. Our canines may therefore be an invaluable resource in PLMS research.

  View details for Web of Science ID 000169754800033

  View details for PubMedID 11422858

• Hypocretin/orexin, sleep and narcolepsy BIOESSAYS Hungs, M., Mignot, E. 2001; 23 (5): 397-408

  Abstract

  The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy and unusually rapid transitions to rapid-eye-movement sleep, opens a new field of investigation in the area of sleep control physiology. Hypocretin-1 and -2 (also called orexin-A and -B) are newly discovered neuropeptides processed from a common precursor, preprohypocretin. Hypocretin-containing cells are located exclusively in the lateral hypothalamus, with widespread projections to the entire neuroaxis. Two known receptors, Hcrtr1 and Hcrtr2, have been reported. The functional significance of the hypocretin system is rapidly emerging in both animals and humans. Hypocretin abnormalities cause narcolepsy in dogs, human and mice. The role of the hypocretin system in normal sleep regulation is more uncertain. We believe hypocretin cells drive cholinergic and monoaminergic activity across the sleep cycle. Input from the suprachiasmatic nucleus to hypocretin-containing neurons may explain the occurrence of clock-dependent alertness. Other functions are suggested by pharmacological and neurochemical experiments. These include regulation of food intake, neuroendocrine function, autonomic nervous system activity and energy balance.

  View details for Web of Science ID 000168435600005

  View details for PubMedID 11340621

• Identification and functional analysis of mutations in the hypocretin (Orexin) genes of narcoleptic canines (vol 11, pg 531, 2001) GENOME RESEARCH Hungs, M., Fan, J., Lin, L., Lin, X. Y., Grigoriadis, D., Maki, R. A., Mignot, E. 2001; 11 (5): 919

  View details for Web of Science ID 000168501600026

• Physical and radiation hybrid mapping of canine chromosome 12, in a region corresponding to human chromosome 6p12-q12 GENOMICS Li, R., Faraco, J. H., Lin, L., Lin, X. Y., Hinton, L., Rogers, W., Lowe, J. K., Ostrander, E. A., Mignot, E. 2001; 73 (3): 299-315

  Abstract

  The positional cloning of the hypocretin receptor 2, the gene for autosomal recessive canine narcolepsy, has led to the development of a physical map spanning a large portion of canine chromosome 12 (CFA12), in a region corresponding to human chromosome 6p12-q13. More than 40 expressed sequence tags (ESTs) were used in homology search experiments, together with chromosome walking, to build both physical and radiation hybrid maps of the CFA12 13-21 region. The resulting map of bacterial artificial chromosome ends, ESTs, and microsatellite markers represents the longest continuous high-density map of the dog genome reported to date. These data further establish the dog as a system for studying disease genes of interest to human populations and highlight feasible approaches for positional cloning of disease genes in organisms where genomic resources are limited.

  View details for Web of Science ID 000168774400007

  View details for PubMedID 11350122

• Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation NEUROREPORT Fujiki, N., Yoshida, Y., Ripley, B., Honda, K., Mignot, E., Nishino, S. 2001; 12 (5): 993-997

  Abstract

  Hypocretin-1 is consistently detectable in the CSF of healthy human subjects, but is absent in narcoleptics. However, functional roles of CSF hypocretin are largely unknown. We examined fluctuation of CSF hypocretin-1 across 24 h and in response to food restriction in rats. Hypocretin-1 levels were high during the dark period when animals were active, but decreased by 40% toward the end of the light (rest) period. After 72 h food deprivation hypocretin-1 levels during the rest phase increased to concentrations similar to those seen during the baseline active phase; however, no increase in response to food deprivation was observed during the active phase. These results indicate an important link between circadian control of sleep and energy homeostasis via the hypocretin system.

  View details for Web of Science ID 000167905600027

  View details for PubMedID 11303775

• Diagnostic value of low CSF hypocretin/orexin levels in human narcolepsy Nishino, S., Ripley, B., Overeem, S., Nevsimalova, S., Lammers, G. J., Vankova, J., Okun, M., Rogers, W., Brooks, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2001: A95–A96

  View details for Web of Science ID 000168230900157

• The narcolepsy diagnosis: Comparison between the Sleep-EVAL system and clinicians Black, J., Ohayon, M., Okun, M., Guilleminault, C., Mignot, E., Zarcone, V. AMER ACAD SLEEP MEDICINE. 2001: A328–A328

  View details for Web of Science ID 000168230900574

• The comparability of the Stanford Sleep Inventory and the Sleep-EVAL system in narcolepsy diagnosis Okun, M. L., Ohayon, M. M., Mignot, E. AMER ACAD SLEEP MEDICINE. 2001: A328–A329

  View details for Web of Science ID 000168230900575

• Identification and functional analysis of mutations in the Hypocretin (Orexin) genes of narcoleptic canines GENOME RESEARCH Hungs, M., Fan, J., Lin, L., Lin, X. Y., Maki, R. A., Mignot, E. 2001; 11 (4): 531-539

  Abstract

  Narcolepsy is a sleep disorder affecting animals and humans. Exon skipping mutations of the Hypocretin/Orexin-receptor-2 (Hcrtr2) gene were identified as the cause of narcolepsy in Dobermans and Labradors. Preprohypocretin (Hcrt) knockout mice have symptoms similar to human and canine narcolepsy. In this study, 11 sporadic cases of canine narcolepsy and two additional multiplex families were investigated for possible Hcrt and Hcrtr2 mutations. Sporadic cases have been shown to have more variable disease onset, increased disease severity, and undetectable Hypocretin-1 levels in cerebrospinal fluid. The canine Hcrt locus was isolated and characterized for this project. Only one novel mutation was identified in these two loci. This alteration results in a single amino acid substitution (E54K) in the N-terminal region of the Hcrtr2 receptor and autosomal recessive transmission in a Dachshund family. Functional analysis of previously-described exon-skipping mutations and of the E54K substitution were also performed using HEK-293 cell lines transfected with wild-type and mutated constructs. Results indicate a truncated Hcrtr2 protein, an absence of proper membrane localization, and undetectable binding and signal transduction for exon-skipping mutated constructs. In contrast, the E54K abnormality was associated with proper membrane localization, loss of ligand binding, and dramatically diminished calcium mobilization on activation of the receptor. These results are consistent with a loss of function for all three mutations. The absence of mutation in sporadic cases also indicates genetic heterogeneity in canine narcolepsy, as reported previously in humans.

  View details for Web of Science ID 000167885400004

  View details for PubMedID 11282968

• A hundred years of narcolepsy research ARCHIVES ITALIENNES DE BIOLOGIE Mignot, E. 2001; 139 (3): 207-220

  View details for Web of Science ID 000168093800004

  View details for PubMedID 11330202

• Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups AMERICAN JOURNAL OF HUMAN GENETICS Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X. H., Lin, X. Y., Okun, M., Hohjoh, H., Miki, T., Hsu, S. H., Leffell, M. S., GRUMET, F. C., Fernandez-Vina, M., Honda, M., Risch, N. 2001; 68 (3): 686-699

  Abstract

  Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

  View details for Web of Science ID 000166994200013

  View details for PubMedID 11179016

• Narcolepsy: Clinical features, new pathophysiologic insights, and future perspectives JOURNAL OF CLINICAL NEUROPHYSIOLOGY Overeem, S., Mignot, E., van Dijk, J. G., Lammers, G. J. 2001; 18 (2): 78-105

  Abstract

  Narcolepsy is characterized by excessive daytime sleepiness and abnormal manifestations of rapid eye movement sleep such as cataplexy. The authors review the clinical features of narcolepsy, including epidemiology, symptoms, diagnosis, and treatment, in detail. Recent findings show that a loss of hypocretin-producing neurons lies at the root of the signs and symptoms of narcolepsy. The authors review the current state of knowledge on hypocretin anatomy, physiology, and function with special emphasis on the research regarding the hypocretin deficiency in narcolepsy, which may also explain associated features of the disorder, such as obesity. Lastly, they discuss some future perspectives for research into the pathophysiology of sleep/wake disorders, and the potential impact of the established hypocretin deficiency on the diagnosis and treatment of narcolepsy.

  View details for Web of Science ID 000169315700002

  View details for PubMedID 11435802

• Dopaminergic role in stimulant-induced wakefulness JOURNAL OF NEUROSCIENCE Wisor, J. P., Nishino, S., Sora, I., Uhl, G. H., Mignot, E., Edgar, D. M. 2001; 21 (5): 1787-1794

  Abstract

  The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.

  View details for Web of Science ID 000167129700040

  View details for PubMedID 11222668

• The role of histamine in a hypocretin (orexin)-deficient sleep disorder, narcolepsy 5th International Histamine Symposium Nishino, S., Honda, K., Fujiki, N., Wurts, S. W., SAKURAI, E., Kato, M., Watanabe, T., Mignot, E., Yanai, K. ELSEVIER SCIENCE BV. 2001: 247–251

  View details for Web of Science ID 000174224300035

• Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans NEUROSCIENCE RESEARCH Nishino, S., Riehl, J., Hong, J., Kwan, M., REID, M., Mignot, E. 2000; 38 (4): 437-446

  Abstract

  Narcolepsy is a chronic sleep disorder marked by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Since the discovery of sleep onset REM periods (SOREMPs) in narcoleptic patients, narcolepsy has often been regarded as a disorder of REM sleep generation: REM sleep intrudes in active wake or at sleep onset, resulting in cataplexy, sleep paralysis, or hypnagogic hallucinations. However, this hypothesis has not been experimentally verified. In the current study, we characterized the sleep abnormalities of genetically narcoleptic-cataplectic Dobermans, a naturally occurring animal model of narcolepsy, in order to verify this concept. Multiple sleep latency tests during the daytime revealed that narcoleptic Dobermans exhibit a shorter sleep latency and a higher frequency of SOREMPs, compared to control Dobermans. The total amount of time spent in wake and sleep during the daytime is not altered in narcoleptic dogs, but their wake and sleep patterns are fragmented, and state transitions into and from wake and other sleep stages are altered. A clear 30 min REM sleep cyclicity exists in both narcoleptic and control dogs, suggesting that generation of the ultradian rhythm of REM sleep is not altered in narcoleptics. In contrast, cataplexy displays no cyclicity and can be elicited in narcoleptic animals anytime with emotional stimulation and displays no cyclicity. Stimulation of a cholinoceptive site in the basal forebrain induces a long-lasting attack of cataplexy in narcoleptic dogs; however, bursts of rapid eye movements during this state still occur with a 30 min cyclicity. Sites and mechanisms for triggering cataplexy may therefore be different from those for REM sleep. Cataplexy and a dysfunction in the maintenance of vigilance states, but not abnormal REM sleep generation, may therefore be central to narcolepsy.

  View details for Web of Science ID 000166120200013

  View details for PubMedID 11164570

• Sulpiride, a D2/D3 blocker, reduces cataplexy but not REM sleep in canine narcolepsy NEUROPSYCHOPHARMACOLOGY Okura, M., Riehl, J., Mignot, E., Nishino, S. 2000; 23 (5): 528-538

  Abstract

  Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.

  View details for Web of Science ID 000089867500005

  View details for PubMedID 11027918

• DLA-DQB1 alleles and bone marrow transplantation experiments in narcoleptic dogs TISSUE ANTIGENS Wagner, J. L., STORB, R., Storer, B., Mignot, E. 2000; 56 (3): 223-231

  Abstract

  Human narcolepsy is a neurological disorder known to be tightly associated with HLA-DQB1*0602. A clinically similar disorder has been described in various dog breeds. The canine form of the disease is inherited as an autosomal recessive disorder in Labrador retrievers and Doberman pinschers (canarc-1) but occurs sporadically in other breeds, most typically dachshunds and poodles. In this study, we have examined if there is a relationship between the development of narcolepsy and specific dog leukocyte antigen (DLA)-DQB1 alleles. Ninety-nine dogs were typed for DLA-DQB1-31 with narcolepsy and 68 control animals. Recent studies have linked the development of autosomal recessive canine narcolepsy to a disruption of the hypocretin receptor 2 (Hcrtr2) gene on the same chromosome as the canine MHC region (CFA12), but not close to the DLA. Four Hcrtr2-positive families (two Doberman pinscher families, one Labrador retriever family, one dachshund family) were analyzed at the DLA-DQ level. No relationship was found between narcolepsy and DLA in Hcrtr2-mediated narcolepsy but loose genetic linkage was observed (Zmax=2.3 at theta=25%, m= 40). Bone marrow transplantation between two DLA identical affected (Hcrtr2-/-) and unaffected (Hcrtr2+/-) siblings was also performed and found not to be successful neither in transmitting narcolepsy nor in relieving the symptoms in Doberman pinschers. DLA-DQB1 was next studied in 11 dogs with sporadic (non-familial) narcolepsy and in unrelated control animals of the same and different breeds. The allelic and carrier frequencies of various DLA-DQB1 alleles were analyzed. There was no strong positive or negative correlation between the development of narcolepsy and specific DLA-DQB1 alleles. These results do not support the involvement of DLA-DQ in canine narcolepsy, whether of sporadic or familial origin.

  View details for Web of Science ID 000089523200004

  View details for PubMedID 11034558

• Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy NEUROPSYCHOPHARMACOLOGY Riehl, J., Honda, K., Kwan, M., Hong, J., Mignot, E., Nishino, S. 2000; 23 (1): 34-45

  Abstract

  The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of CG-3703 (16 mg/kg) significantly reduced cataplexy and daytime sleep. The anticataplectic effects of CG-3703 were not associated with changes in general behavior, heart rate, blood pressure, rectal temperature, blood chemistry and thyroid function. Although drug tolerance for the effects on cataplexy and sleep were observed during the second week of chronic drug administration, therapeutic efficacy on cataplexy was improved with individual dose adjustment (final dose range: 16 to 28 mg/kg, p.o.). These results suggest that TRH analogs could be a promising new form of treatment for human narcolepsy.

  View details for Web of Science ID 000087772700004

  View details for PubMedID 10869884

• Perspectives in narcolepsy and hypocretin (orexin) research. Sleep medicine Mignot, E. 2000; 1 (2): 87-90

  View details for PubMedID 10767648

• Perspectives in narcolepsy and hypocretin (orexin) research SLEEP MEDICINE Mignot, E. 2000; 1 (2): 87–90

  View details for DOI 10.1016/S1389-9457(00)00013-7

  View details for Web of Science ID 000208300400001

• Narcolepsy: genetic predisposition and neuropharmacological mechanisms. REVIEW ARTICLE. Sleep medicine reviews Nishino, S., Okura, M., Mignot, E. 2000; 4 (1): 57-99

  Abstract

  Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries. Although most cases occur sporadically, familial clustering may be observed; the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602 [most often in combination with HLA-DR2 (DRB1*15)]. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. In addition, environmental factors are involved in disease predisposition; most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Narcolepsy was reported to exist in canines in the early 1970s. Both sporadic and familial cases are also observed in this animal species. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Positional cloning of this gene is in progress, and a human homologue of this gene, or a gene with a functional relationship to canarc-1, might be involved in some human cases. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. These treatments are purely symptomatic and induce numerous side effects. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. The canine model is an invaluable resource for studying the pharmacological and physiological control of EDS and cataplexy. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. Pharmacological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. (See also postscript remarks).

  View details for PubMedID 12531161

• Clinical and polysomnographic features in DQB1*0602 positive and negative narcolepsy patients: results from the modafinil clinical trial SLEEP MEDICINE Hong, S. C., Hayduk, R., Lim, J., Mignot, E. 2000; 1 (1): 33-39

  View details for Web of Science ID 000208300300005

• Narcolepsy: genetic predisposition and neuropharmacological mechanisms SLEEP MEDICINE REVIEWS Nishino, S., Okura, M., Mignot, E. 2000; 4 (1): 57-99

  Abstract

  Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries. Although most cases occur sporadically, familial clustering may be observed; the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602 [most often in combination with HLA-DR2 (DRB1*15)]. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. In addition, environmental factors are involved in disease predisposition; most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Narcolepsy was reported to exist in canines in the early 1970s. Both sporadic and familial cases are also observed in this animal species. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Positional cloning of this gene is in progress, and a human homologue of this gene, or a gene with a functional relationship to canarc-1, might be involved in some human cases. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. These treatments are purely symptomatic and induce numerous side effects. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. The canine model is an invaluable resource for studying the pharmacological and physiological control of EDS and cataplexy. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. Pharmacological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. (See also postscript remarks).

  View details for Web of Science ID 000086058200006

• Hypocretin (orexin) deficiency in human narcolepsy LANCET Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., Mignot, E. 2000; 355 (9197): 39-40

  Abstract

  Alterations in the hypocretin receptor 2 and preprohypocretin genes produce narcolepsy in animal models. Hypocretin was undetectable in seven out of nine people with narcolepsy, indicating abnormal hypocretin transmission.

  View details for Web of Science ID 000085049200016

  View details for PubMedID 10615891

• [Hypocretin (orexin) deficiency in narcolepsy-cataplexy]. Sborník lékar?ský Nevsímalová, S., Vanková, J., Sonka, K., Faraco, J., Rogers, W., Overeem, S., Mignot, E. 2000; 101 (4): 381-386

  Abstract

  A mutation in the HCRT locus was proved in 18-yrs old male suffering from narcolepsy-cataplexy. He has demonstrated cataplectic attacks (brief spells of head dropping provoked by laughter) as well as imperative sleep in spells of several minutes up to one hour since the age of six months. He has suffered from severe bulimia since five years; later hypnagogic hallucinations, sleep paralysis and unquiet nocturnal sleep accompanied by periodic limb movements appeared. Symptoms are partially controlled with methylphenidate and either imipramine, clomipramine or fluoxetine. Periodic leg movements poorly responded to L-DOPA and clonazepam treatment. He is HLA-DQB1*0602 negative. Repeated MSLT (over 16 years followed-up period) showed extremely short latency with predominant SOREMPs and also nocturnal PSG recordings revealed fragmented sleep with SOREMPs. This case report demonstrates that hypocretin (orexin) mutations in human can produce the full narcolepsy phenotype and validates data recently reported in dog and mouse models suggesting a role for hypocretin (orexin) in the pathophysiology of narcolepsy and the regulation of REM sleep.

  View details for PubMedID 11702580

• A polymorphism in the human timeless gene is not associated with diurnal preferences in normal adults. Sleep research online : SRO Pedrazzoli, M., Ling, L., Finn, L., Kubin, L., Young, T., Katzenberg, D., Mignot, E. 2000; 3 (2): 73-76

  Abstract

  The effect of a single nucleotide polymorphism, a glutamine to arginine amino acid substitution in the human Timeless gene (Q831R, A2634G), on diurnal preferences was studied in a random sample of normal volunteers enrolled in a population-based epidemiology study of the natural history of sleep disorders. We genotyped 528 subjects for this single nucleotide polymorphism and determined morningness-eveningness tendencies using the Horne-Ostberg questionnaire. Our results indicate that Q831R Timeless has no influence on morningness- eveningness tendencies in humans.

  View details for PubMedID 11382904

• Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: A study of D- and L-derivatives in canine narcolepsy NEUROSCIENCE Kanbayashi, T., Honda, K., Kodama, T., Mignot, E., Nishino, S. 2000; 99 (4): 651-659

  Abstract

  Using a canine model of narcolepsy and selective DA and NE uptake inhibitors, we have recently shown that DA uptake inhibition promotes wakefulness, while NE uptake inhibition inhibits rapid eye movement sleep and cataplexy. In order to further delineate the respective roles of the dopaminergic and noradrenergic systems in the pharmacological control of symptoms of narcolepsy, we compared the potency of amphetamine isomers (D- and L-amphetamines) and a derivative (L-methamphetamine) on wakefulness and cataplexy. Their respective effects on these narcolepsy symptoms were then compared with their in vivo effects on extracellular DA levels in the caudate and NE levels in the frontal cortex during local drug perfusion in narcoleptic dogs. Polygraphic recordings demonstrated that D-amphetamine was about twice as potent as L-amphetamine, and was six times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep. D-Amphetamine and L-amphetamine were equipotent in reducing rapid eye movement sleep and cataplexy, and L-methamphetamine was about half as potent as L- and D-amphetamines. D-Amphetamine was found to be more potent in increasing DA efflux than L-amphetamine, and L-methamphetamine was found to have little effect on DA efflux; there was no significant difference in the potencies of the three derivatives on NE efflux. The potencies of these amphetamines on wakefulness correlated well with DA, but not NE, efflux in the brain of narcoleptic dogs during local drug perfusion. Our current results further exemplify the importance of the DA system for the pharmacological control of electroencephalogram arousal and suggest that increased DA transmission mediates the wake-promoting effects of amphetamine-like stimulants.

  View details for Web of Science ID 000089250800007

  View details for PubMedID 10974428

• Dopamine D3 agonists into the substantia nigra aggravate cataplexy but do not modify sleep (vol 10, pg 3111, 1999) NEUROREPORT Honda, K., Riehl, J., Mignot, E., Nishino, S. 1999; 10 (17): 3717-3724

  Abstract

  We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.

  View details for Web of Science ID 000083934000001

  View details for PubMedID 10619672

• Dopamine D-3 agonists into the substratia nigra aggravates cataplexy but does not modify sleep NEUROREPORT Honda, K., Riehl, J., Mignot, E., Nishino, S. 1999; 10 (14): 3111-3118

  Abstract

  We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.

  View details for Web of Science ID 000082865500046

  View details for PubMedID 10549832

• A human period gene (HPER1) polymorphism is not associated with diurnal preference in normal adults PSYCHIATRIC GENETICS Katzenberg, D., Young, T., Lin, L., Finn, L., Mignot, E. 1999; 9 (2): 107-109

  Abstract

  Mammalian circadian rhythmicity has recently been shown to be regulated at the genetic level by transcription--translation feed-back loops. Key molecular components such as Clock, Bmal-1, Timeless and three Period proteins have been isolated in mammals. In this study, we hypothesized that polymorphisms at the level of one of these genes--HPER1--could be associated with differential morningness-eveningness tendencies. The sample comprised 463 middle-aged participants enrolled in the Wisconsin Sleep Cohort Study. Diurnal preferences were evaluated using the Horne-Ostberg questionnaire. An A to G synonymous substitution at position 2548 was identified in HPER1 c-DNA sequence by comparing available sequence data. This polymorphism was verified by sequencing and typed using established oligotyping techniques in all subjects, yielding allele frequencies of 0.85 and 0.15 for HPER1 2548G and HPER1 2548A, respectively. Morningness-eveningness scores were then compared between genotype groups. In contrast to data previously published using a Clock polymorphism, scores did not differ significantly across HPER1 groups. These results suggest that polymorphism at the level of HPER1 does not significantly modulate morningness-eveningness tendencies in the general population.

  View details for Web of Science ID 000081591900010

  View details for PubMedID 10412192

• Construction and characterization of an eightfold redundant dog genomic bacterial artificial chromosome library GENOMICS Li, R., Mignot, E., Faraco, J., KADOTANI, H., Cantanese, J., Zhao, B., Lin, X., Hinton, L., Ostrander, E. A., Patterson, D. F., de Jong, P. J. 1999; 58 (1): 9-17

  Abstract

  A large insert canine genomic bacterial artificial chromosome (BAC) library was built from a Doberman pinscher. Approximately 166,000 clones were gridded on nine high-density hybridization filters. Insert analysis of randomly selected clones indicated a mean insert size of 155 kb and predicted 8.1 coverage of the canine genome. Two percent of the clones were nonrecombinant. Chromosomal fluorescence in situ hybridization studies of 60 BAC clones indicated no chimerism. The library was hybridized with dog PCR products representing eight genes (ADA, TNFA, GCA, MYB, HOXA, GUSB, THY1, and TOP1). The resulting positive clones were characterized and shown to be compatible with an eightfold redundant library.

  View details for Web of Science ID 000080706600002

  View details for PubMedID 10331940

• Nocturnal sleep and daytime sleepiness in normal subjects with HLA-DQB1*0602 SLEEP Mignot, E., Young, T., Lin, L., Finn, L. 1999; 22 (3): 347-352

  Abstract

  Narcolepsy, a neurological disorder characterized by excessive daytime sleepiness and abnormal REM sleep, is known to be tightly associated with the Human Leukocyte Antigen (HLA) DQ allele DQB1*0602. In this study, we have explored the possibility that normal subjects carrying this HLA allele (25% of the general population) could display subclinical REM sleep abnormalities and increased daytime sleepiness. Data from 525 middle-aged adults enrolled in the Wisconsin Sleep Cohort study were used for this analysis. Nocturnal polysomnography, sleep latency during the multiple sleep latency test (MSLT), and questionnaire items pertaining to excessive daytime sleepiness were compared between DQB1*0602 positive (n = 132) and negative (n = 393) participants. Results indicate shorter REM latency whether or not the latency was adjusted for wake after sleep onset (p = 0.003) and p = 0.02 respectively), increased sleep efficiency (p = 0.06) and decreased percent time spent in stage I sleep (p = 0.02) during nocturnal polysomnography in DQB1*0602 subjects. Data gathered using the Multiple Sleep Latency Test or the Epworth and Stanford sleepiness scales did not differentiate between DQB1*0602 positive and negative subjects. These results support the hypothesis that polymorphisms at the level of HLA DQ modulates sleep tendencies in humans.

  View details for Web of Science ID 000082053300008

  View details for PubMedID 10341385

• Genetic studies in narcolepsy, a disorder affecting REM sleep International Workshop on Canine Genetics - The Map, the Genes, the Diseases Faraco, J., Lin, X., Li, R., Hinton, L., Lin, L., Mignot, E. OXFORD UNIV PRESS INC. 1999: 129–32

  Abstract

  Narcolepsy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal manifestations of rapid eye movement (REM) sleep including cataplexy, sleep paralysis, and hypnagogic hallucinations. It is known to be a complex disorder, with both genetic predisposition and environmental factors playing a role. In humans, susceptibility to narcolepsy is tightly associated with a specific HLA allele, DQB1*0602. In humans and canines, most cases are sporadic. In Doberman pinschers and Labrador retrievers, however, the disease is transmitted as an autosomal recessive gene canarc-1 with full penetrance. This gene is not linked with the dog leukocyte antigen complex, but is tightly linked with a marker with high homology to the human mu-switch immunoglobulin gene. We have isolated several genomic clones encompassing the canarc-1 marker and the variable heavy chain immunoglobulin region in canines. These have been partially sequenced and have been mapped onto specific dog chromosomes by fluorescence in situ hybridization (FISH). Our results indicate that the mu-switch-like marker is not part of the canine immunoglobulin machinery. We are continuing to extend the genomic contig using a newly developed canine BAC library and attempting to identify the corresponding human region of conserved synteny.

  View details for Web of Science ID 000078225400026

  View details for PubMedID 9987919

• Neuronal degeneration in canine narcolepsy JOURNAL OF NEUROSCIENCE Siegel, J. M., Nienhuis, R., Gulyani, S., Ouyang, S., Wu, M. F., Mignot, E., Switzer, R. C., McMurry, G., Cornford, M. 1999; 19 (1): 248-257

  Abstract

  Narcolepsy is a lifelong illness characterized by persistent sleepiness, hypnagogic hallucinations, and episodes of motor paralysis called cataplexy. We have tested the hypothesis that a transient neurodegenerative process is linked to symptom onset. Using the amino-cupric silver stain on brain sections from canine narcoleptics, we found elevated levels of axonal degeneration in the amygdala, basal forebrain (including the nucleus of the diagonal band, substantia innominata, and preoptic region), entopeduncular nucleus, and medial septal region. Reactive neuronal somata, an indicator of neuronal pathology, were found in the ventral amygdala. Axonal degeneration was maximal at 2-4 months of age. The number of reactive cells was maximal at 1 month of age. These degenerative changes precede or coincide with symptom onset. The forebrain degeneration that we have observed can explain the major symptoms of narcolepsy.

  View details for Web of Science ID 000077839400028

  View details for PubMedID 9870955

• Locus coeruleus neurons: Cessation of activity during cataplexy NEUROSCIENCE Wu, M. F., Gulyani, S. A., Yau, E., Mignot, E., Phan, B., Siegel, J. M. 1999; 91 (4): 1389-1399

  Abstract

  Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, emotionally significant stimuli. We now report that locus coeruleus neurons cease discharge throughout cataplexy periods in canine narcoleptics. Locus coeruleus discharge rates during cataplexy were as low as or lower than those seen during rapid-eye-movement sleep. Prazosin, an alpha1 antagonist, and physostigmine, a cholinesterase inhibitor, both of which precipitate cataplexy, decreased locus coeruleus discharge rate. Our results are consistent with the hypothesis that locus coeruleus activity contributes to the maintenance of muscle tone in waking, and that reduction in locus coeruleus discharge plays a role in the loss of muscle tone in cataplexy and rapid-eye-movement sleep. Our results also show that the complete cessation of locus coeruleus activity is not sufficient to trigger rapid-eye-movement sleep in narcoleptics.

  View details for Web of Science ID 000080437600019

  View details for PubMedID 10391445

• Neuronal activity in the cholinoceptive basal forebrain of freely moving narcoleptic dobermans NEUROREPORT Nishino, S., Honda, K., Riehl, J., Okura, M., Mignot, E. 1998; 9 (16): 3653-3661

  Abstract

  Cholinergic stimulation in the basal forebrain (BF) triggers cataplexy in canine narcolepsy. Extracellular single unit recordings in the BF were carried out in freely moving narcoleptic dogs to study the neuronal mechanisms mediating cataplexy induction in the BF. Among the 64 recorded neurons, 12 were wake-active, three were slow wave sleep (SWS)-active, 17 were wake-/REM-active, 11 were REM sleep-active, three were cataplexy-active, and the other 18 were state-independent. Systemic administration of physostigmine, a cholinesterase inhibitor, induces status cataplecticus, decreases SWS and increases acetylcholine levels in the BF. Firing of most of the state-dependent neurons in the BF was significantly modified by physostigmine. Some of these neurons may thus mediate sleep stage changes or the effect on cataplexy observed after cholinergic stimulation in the BF.

  View details for Web of Science ID 000077493400021

  View details for PubMedID 9858375

• A CLOCK polymorphism associated with human diurnal preference SLEEP Katzenberg, D., Young, T., Finn, L., Lin, L., King, D. P., Takahashi, J. S., Mignot, E. 1998; 21 (6): 569-576

  Abstract

  A single nucleotide polymorphism located in the 3' flanking region of the human CLOCK gene was investigated as a predictor of diurnal preference in a population-based random sample of 410 normal adults. Morningness-eveningness preferences were determined using the 19-item Home-Ostberg questionnaire. Subjects carrying one of the two CLOCK alleles, 3111C, had a significantly lower mean Horne-Ostberg score. The distribution of scores was clearly shifted toward eveningness for these subjects. The score difference was independent of age, sex and ethnic heritage, thus making population stratification effects unlikely to explain this difference. These subjects had a substantial 10- to 44-minute delay in preferred timing for activity or sleep episodes. We suggest that the identified polymorphism or another tightly linked polymorphism within the CLOCK gene or its regulatory elements may be responsible for the finding.

  View details for Web of Science ID 000076046000003

  View details for PubMedID 9779516

• Development of cataplexy in genetically narcoleptic Dobermans EXPERIMENTAL NEUROLOGY Riehl, J., Nishino, S., Cederberg, R., Dement, W. C., Mignot, E. 1998; 152 (2): 292-302

  Abstract

  Forty-two genetically narcoleptic Doberman puppies [20 pure narcoleptic (N) puppies (from four narcoleptic x narcoleptic crosses) and 22 backcross narcoleptic (BN) puppies (from six narcoleptic x heterozygous crosses)] were systematically observed during the developmental period (4-24 weeks) to assess the age at onset and severity of cataplexy, a pathological manifestation of REM sleep atonia seen in narcolepsy. The mean age of onset of cataplexy was 9.69 +/- 1.15 weeks, with a median age of 7 weeks. The severity of cataplexy increased with age and reached a plateau at around 16-24 weeks. The effects of cross type (N vs BN) and sex on the development of cataplexy were analyzed. There was no difference in severity between N and BN puppies (P = 0.51). However, females had more severe cataplexy than males (P = 0.01), and this trend was preserved in five of the six litters that had both male and female puppies. These results suggest that the pathophysiological process in genetic canine narcolepsy emerges during the early developmental period and that it may involve a differential development in males and females. Furthermore, our results revealed that cataplexy onset corresponds to the emergence of adult-like REM sleep and to previously reported neuroanatomical and neurochemical abnormalities in canine narcolepsy.

  View details for Web of Science ID 000075698200014

  View details for PubMedID 9710528

• Microsatellite single nucleotide polymorphisms in the HLA-DQ region TISSUE ANTIGENS Lin, L., Jin, L., Lin, X., Voros, A., Underhill, P., Mignot, E. 1998; 52 (1): 9-18

  Abstract

  Sequencing studies were performed in three previously described microsatellite and minisatellite markers located within the HLA-DQ region, DQCAR, DQCARII and G51152. Multiple nucleotide substitutions that did not change size polymorphisms were observed in all three markers. In all loci, the number of core repeats did not correlate with neighboring DQ allele sequence motifs while single nucleotide changes within or flanking the microsatellite sequence did. This result indicates higher mutation rates for microsatellite expansions/contractions than for nucleotide substitutions in these loci. Further analysis indicated an almost complete phylogenetic correspondence between DQCAR single nucleotide polymorphisms (SNPs) and DQB1 sequences on one side (1.0-1.5 kb apart) and a complete relationship between DQCARII and DQA1 sequences on the other (4.5 kb apart). In contrast, G51152 sequences did not correspond perfectly with DQB1 allelic sequences, thus suggesting the existence of several ancestral crossovers between this marker and DQB1 (20-25 kb). Sequencing microsatellites might be useful in disease mapping studies by increasing marker informativeness and by helping in the interpretation of association study results. It is also proposed that SNPs within the flanking region of CA repeats could be used to develop biallelic markers from already available mapped microsatellite markers.

  View details for Web of Science ID 000074956100002

  View details for PubMedID 9714469

• Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture PSYCHIATRY RESEARCH Nishino, S., Mignot, E., Benson, K. L., Zarcone, V. P. 1998; 78 (3): 141-150

  Abstract

  Sleep abnormalities have been consistently observed in patients with schizophrenia. Elevated levels of corticotropin releasing factor (CRF) and prostaglandins (PGs) in the cerebrospinal fluid (CSF) of patients with schizophrenia have been reported, and these neurochemical substances, known to modulate sleep in experimental animals, may play a role in these sleep abnormalities. In this study, we measured PGD2, PGE2, PGF2alpha and CRF levels in the CSF of 14 unmedicated schizophrenic patients and 14 age- and sex-matched control subjects. Polysomnographic recordings were also carried out for each subject. As expected, the sleep of the schizophrenic subjects significantly differed from that of the controls; schizophrenic subjects had a longer sleep onset latency, slept less, spent fewer minutes in stage 2 sleep and had a lower sleep efficiency. We could not, however, detect any differences in CSF CRF and PG levels between normal and schizophrenic subjects, nor could we find any correlation between CSF variables and sleep parameters in the schizophrenic subjects and the non-psychiatric controls. These results do not favor the hypothesis of a role for CRF or PGs in the pathophysiology of sleep disturbances in schizophrenia.

  View details for Web of Science ID 000074238900003

  View details for PubMedID 9657418

• Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines EXPERIMENTAL NEUROLOGY Reid, M. S., Nishino, S., Tafti, M., Siegel, J. M., Dement, W. C., Mignot, E. 1998; 151 (1): 89-104

  Abstract

  Basal forebrain (BF) cholinergic regulation of cataplexy was investigated in narcoleptic canines. Specific cholinergic agonists and antagonists, and excitatory or inhibitory amino acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the BF of narcoleptic canines. Cataplexy was monitored using the food-elicited cataplexy test (FECT) and recordings of electroencephalogram, electrooculogram, and electromyogram. In narcoleptic canines, carbachol and oxotremorine (10(-5)-10(-3) M), but not McN-A-343 or nicotine (10(-4)-10(-3) M), produced a dose-dependent increase in cataplexy. In addition, N-methyl-d-aspartate (10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effects, while muscimol (10(-3) M) produced a weak (P < 0.10) increase in cataplexy. In control canines, carbachol (10(-5)-10(-3) M), but not oxotremorine (10(-4)-10(-3) M), produced muscle atonia after the highest concentration in one of three animals. Carbachol (10(-3) M)-induced cataplexy in narcoleptic canines was blocked by equimolar perfusion with the muscarinic antagonists atropine, gallamine, and 4-DAMP but not pirenzepine. These findings indicate that carbachol-stimulated cataplexy in the BF of narcoleptic canines is mediated by M2, and perhaps M3, muscarinic receptors. The release of acetylcholine in the BF was also examined during FECT and non-FECT behavioral stimulation in narcoleptic and control canines. A significant increase in acetylcholine release was found in both narcoleptic and control BF during FECT stimulation. In contrast, simple motor activity and feeding, approximating that which occurs during an FECT, did not affect acetylcholine release in the BF of narcoleptic canines. These findings indicate that BF acetylcholine release is enhanced during learned emotion/reward associated behaviors in canines.

  View details for Web of Science ID 000073593600008

  View details for PubMedID 9582257

• Reduction of REM sleep latency associated with HLA-DQB1*0602 in normal adults LANCET Mignot, E., Young, T., Lin, L., Finn, L., Palta, M. 1998; 351 (9104): 727-727

  View details for Web of Science ID 000072463800017

  View details for PubMedID 9504524

• Neurobiology of narcolepsy NEUROSCIENTIST Nishino, S., Mignot, E. 1998; 4 (2): 133-143

  View details for Web of Science ID 000072594700016

• Genetic and familial aspects of narcolepsy Roundtable Discussion on Current Issues in the Diagnosis and Management of Narcolepsy Mignot, E. LIPPINCOTT WILLIAMS & WILKINS. 1998: S16–S22

  Abstract

  Narcolepsy-cataplexy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal REM sleep. The development of human narcolepsy involves environmental factors acting on a specific genetic background. The importance of environmental factors is evidenced by the reported 25 to 31% of monozygotic twins who are concordant for narcolepsy. One of the predisposing genetic factors is located in the MHC DQ region. More than 85% of all narcoleptic patients with definite cataplexy share a specific HLA allele, HLA DQB1*0602 (most often in combination with HLA DR2), compared with 12 to 38% of the general population, as evaluated in various ethnic groups. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1 to 2% of the first-degree relatives of narcolepsy patients manifest the disorder, compared with 0.02 to 0.18% in the general population. Studies using a canine model of narcolepsy illustrate the importance of non-MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait, canarc-1. In spite of an association with immune-related polymorphisms, narcolepsy does not appear to be a classic autoimmune disease. Other pathophysiologic models involving the microglia and the release of specific cytokines in the CNS may be involved and are being explored. This approach, together with positional cloning studies in humans and canines, should reveal the cause of narcolepsy and open new therapeutic avenues.

  View details for Web of Science ID 000072168200004

  View details for PubMedID 9484418

• Breeding history of the Stanford colony of narcoleptic dogs VETERINARY RECORD Cederberg, R., Nishino, S., Dement, W. C., Mignot, E. 1998; 142 (2): 31-36

  Abstract

  Narcolepsy is a disabling sleep disorder of unknown aetiology. In humans, the disease is mostly sporadic, with a few familial cases having been reported. In 1973 a sporadic case of narcolepsy was reported in a poodle, and in 1975 familial cases of narcolepsy occurred in dobermanns. As with human narcoleptics, these narcoleptic dogs exhibited excessive daytime sleepiness and cataplexy. A colony of narcoleptic dogs was established at Stanford University in 1976 to study the pathophysiology of the disease. Between 1976 and 1995, a total of 669 animals of various breeds were born, of which 487 survived. Dobermanns accounted for 78 per cent of the total. The narcolepsy genotype in dobermanns had no significant influence on puppy mortality rate (numbers of stillborn and survival rate). The sex, maternal parity or the age of the sire or dam had no significant effect. The percentage of stillborn puppies increased from 6.1 per cent in outbred litters to 15.4 per cent in inbred litters (P = 0.10). Birth season also had a significant effect, and the highest survival rate (P = 0.02), and the lowest percentage of stillborn puppies (P = 0.09) occurred between April and June.

  View details for Web of Science ID 000071662300006

  View details for PubMedID 9481825

• HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups TISSUE ANTIGENS Pelin, Z., Guilleminault, C., Risch, N., GRUMET, F. C., Mignot, E. 1998; 51 (1): 96-100

  Abstract

  Narcolepsy is a neurological disorder known to be tightly associated with HLA-DQA1*0102 and DQB1*0602. In this study, we have examined if homozygosity for DQB1*0602 increases disease susceptibility and/or severity. Patients diagnosed at Stanford University (n=160) or enrolled in a multicenter clinical trial (n=509) were included in this analysis. In both African-Americans and Caucasian-Americans with or without cataplexy, a significantly higher than expected number of subjects were DQB1*0602 homozygotes. Relative risks were 2-4 times higher in DQB1*0602 homozygotes vs heterozygotes across all patient groups. In contrast, symptom severity did not differ between DQB1*0602 homozygous and heterozygous subjects. These results indicate that HLA-DQB1*0602 homozygosity increases susceptibility to narcolepsy but does not appear to influence disease severity.

  View details for Web of Science ID 000071134000012

  View details for PubMedID 9459509

• The role of genetic factors in the development of narcolepsy and hypersomnia in childhood 9th European Congress of Clinical Neurophysiology (ECCN 98) Nevsimalova, S., Mignot, E. MONDUZZI EDITORE. 1998: 63–68

  View details for Web of Science ID 000076658100010

• Characterization of 12 microsatellite loci of the human MHC in a panel of reference cell lines IMMUNOGENETICS Martin, M. P., Harding, A., Chadwick, R., Kronick, M., Cullen, M., Lin, L., Mignot, E., Carrington, M. 1998; 47 (2): 131-138

  Abstract

  The human genome contains a large number of interspersed microsatellite repeats which exhibit a high degree of polymorphism and are inherited in a Mendelian fashion, making them extremely useful genetic markers. Several microsatellites have been described in the HLA region, but allele nomenclature, a set of broadly distributed controls, and typing methods have not been standardized, which has resulted in discrepant microsatellite data between laboratories. In this report we present a detailed protocol for genotyping microsatellites using a semi-automated fluorescence-based method. Twelve microsatellites within or near the major histocompatibility complex (MHC) were typed in the 10th International Histocompatibility Workshop homozygous typing cell lines (HTCs) and alleles were designated based on size. All loci were sequenced in two HTCs providing some information on the level of complexity of the repeat sequence. A comparison of allele size obtained by genotyping versus that obtained by direct sequencing showed minor discrepancies in some cases, but these were not unexpected given the technical differences in the methodologies. Fluorescence-based typing of microsatellites in the MHC described herein is highly efficient, accurate, and reproducible, and will allow comparison of results between laboratories.

  View details for Web of Science ID 000071336100004

  View details for PubMedID 9396859

• DQ microsatellite association studies in three ethnic groups TISSUE ANTIGENS Lin, L., Jin, L., Kimura, A., Carrington, M., Mignot, E. 1997; 50 (5): 507-520

  Abstract

  Polymorphism at the level of three microsatellite markers (DQCAR, DQCARII, G51152) located in the HLA-DQ region was characterized in 78 10th International Histocompatibility Workshop B-cell lines, 718 random Japanese Asians, 99 Norwegian Caucasians and 95 New Guinean Aborigines with established HLA-DRB1, -DQA1 and -DQB1 typing. DQCAR, DQCARII, and G51152 result in 13, 13, and 11 alleles respectively. All three markers were in tight linkage disequilibrium with HLA-DRB1, -DQA1 and -DQB1. DRB1, DQA1, DQCARII, DQCAR, DQB1, and G51152 haplotypes could be defined for all subjects. In fact, DQ microsatellite typing data could predict DQA1 and DQB1 genotypes with high accuracy and may be used as a simple first pass HLA-DQ typing method. The haplotype data was also used to determine recombination in the DRB1-DQA1 (about 80 kb), DQA1-DQCARII (about 4.5 kb), DQCARII-DQCAR (about 7.5 kb), DQCAR-DQB1 (about 1-1.5 kb) and DQB1-G51152 (about 20-25 kb) genomic segments and the relative rate of slippage microsatellite mutations for DQCAR, DQCARII, and G51152. This led us to conclude that recombination is more frequent in the DRB1-DQA1 and DQCAR-DQCARII segments, thus suggesting cross-overs within small genomic segments are not proportional to genetic distance. We also observed that DQCAR had a higher mutation rate than DQCARII or G51152 and that 1 or 2 CA slippage mutations were arising more frequently from large size microsatellite alleles.

  View details for Web of Science ID A1997YC43900012

  View details for PubMedID 9389326

• HLA class II haplotype and sequence analysis support a role for DQ in narcolepsy IMMUNOGENETICS Ellis, M. C., Hetisimer, A. H., Ruddy, D. A., Hansen, S. L., Kronmal, G. S., McClelland, E., Quintana, L., Drayna, D. T., Aldrich, M. S., Mignot, E. 1997; 46 (5): 410-417

  Abstract

  A systematic haplotype and sequencing analysis of the HLA-DR and -DQ region in patients with narcolepsy was performed. Five new (CA)n microsatellite markers were generated and positioned on the physical map across the HLA-DQB1-DQA1-DRB1 interval. Haplotypes for these new markers and the three HLA loci were established using somatic cell hybrids generated from patients. A four-marker haplotype surrounding the DQB1(*)0602 gene was found in all narcolepsy patients, and was identical to haplotypes observed on random chromosomes harboring the DQB1(*)0602 allele. Eighty-six kilobases of contiguous genomic sequence across the region did not reveal new genes, and analysis of this sequence for single nucleotide polymorphisms did not reveal sequence variation among DQB1(*)0602 chromosomes. These results are consistent with other studies, suggesting that the HLA-DQ genes themselves are among the predisposing factors in narcolepsy.

  View details for Web of Science ID A1997XX03100006

  View details for PubMedID 9271631

• Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy JOURNAL OF NEUROSCIENCE Nishino, S., Arrigoni, J., Shelton, J., Kanbayashi, T., Dement, W. C., Mignot, E. 1997; 17 (16): 6401-6408

  Abstract

  The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

  View details for Web of Science ID A1997XU78100037

  View details for PubMedID 9236248

• HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy NEUROLOGY Rogers, A. E., Meehan, J., Guilleminault, C., GRUMET, F. C., Mignot, E. 1997; 48 (6): 1550-1556

  Abstract

  Narcolepsy is considered a homogeneous clinical entity when excessive daytime sleepiness and cataplexy are present. Cataplexy is a polymorphic symptom that can be very mild and is thus subjectively defined. The Multiple Sleep Latency Test (MSLT) is widely used as a diagnostic test for narcolepsy. A short mean sleep latency and multiple sleep onset REM periods (SOREMPs) are typically observed in narcoleptic patients. The discovery of a tight association of narcolepsy with HLA class II antigens offers a unique opportunity to explore the respective value of the MSLT or of the presence of clear-cut cataplexy in defining an etiologically homogeneous group of narcoleptic patients. In this study, we carried out HLA typing for DR15(DR2) and DQB1*0602 in 188 narcoleptic patients with cataplexy in three ethnic groups (24 Asians, 61 Blacks, and 103 Caucasians). These results confirm the importance of DQB1*0602 typing rather than DR15 (DR2) typing in Black narcoleptic patients and demonstrate that the presence of clear-cut cataplexy is a better predictor for DQB1*0602 positivity than the presence of abnormal MSLT results.

  View details for Web of Science ID A1997XE09100015

  View details for PubMedID 9191765

• Genetics of narcolepsy and other sleep disorders AMERICAN JOURNAL OF HUMAN GENETICS Mignot, E. 1997; 60 (6): 1289-1302

  View details for Web of Science ID A1997XE29400005

  View details for PubMedID 9199548

  View details for PubMedCentralID PMC1716121

• Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy TISSUE ANTIGENS Mignot, E., Kimura, A., Lattermann, A., Lin, X., Yasunaga, S., MUELLERECKHARDT, G., Rattazzi, C., Lin, L., Guilleminault, C., Dement, W. C., Underhill, P. 1997; 49 (4): 329-341

  Abstract

  Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narcolepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0102 and DQB1*0602, a DQ1 subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.

  View details for Web of Science ID A1997WV41100002

  View details for PubMedID 9151385

• Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog JOURNAL OF COMPARATIVE NEUROLOGY Tafti, M., Nishino, S., Liao, W., Dement, W. C., Mignot, E. 1997; 379 (2): 185-197

  Abstract

  Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations.

  View details for Web of Science ID A1997WL65800002

  View details for PubMedID 9050784

• HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients SLEEP Mignot, E., Hayduk, R., Black, J., GRUMET, F. C., Guilleminault, C. 1997; 20 (11): 1012-1020

  Abstract

  Narcolepsy is a sleep disorder associated with HLA DR15 (DR2) and DQB1*0602. We HLA typed 509 patients enrolled in a clinical trial for the drug modafinil and analyzed the results in relation to cataplexy, a symptom of narcolepsy characterized by muscle weakness triggered by emotions. The patients were either subjects with cataplexy who had a mean sleep latency (SL) of less than 8 minutes and two or more sleep onset rapid eye movement (REM) periods (SOREMPs) during a multiple sleep latency test, or narcoleptic patients without cataplexy but with a mean SL shorter than 5 minutes and two or more SOREMPs. The respective values of DRB1*15 (DR2) and DQB1*0602 as markers for narcolepsy were first compared in different ethnic groups and in patients with and without cataplexy. DQB1*0602 was found to be a more sensitive marker for narcolepsy than DRB1*15 across all ethnic groups. DQB1*0602 frequency was strikingly higher in patients with cataplexy versus patients without cataplexy (76.1% in 421 patients versus 40.9% in 88 patients). Positivity was highest in patients with severe cataplexy (94.8%) and progressively decreased to 54.2% in patients with the mildest cataplexy. A voluntary 50-item questionnaire focusing on cataplexy was also analyzed in 212 of the 509 HLA-typed patients. Subjects with definite cataplexy as observed by an experienced clinician were more frequently HLA DQB1*0602-positive than those with doubtful cataplexy, and the manifestations of cataplexy were clinically more typical in DQB1*0602-positive patients. These results show that the HLA association is as tight as previously reported (85-95%) when cataplexy is clinically typical or severe. We also found that patients with mild, atypical, or no cataplexy have a significantly increased DQB1*0602 frequency (40-60%) in comparison with ethnically matched controls (24%). These results could be explained by increased disease heterogeneity in the noncataplexy group or by a direct effect of the HLA DQB1*0602 genotype on the clinical expression of narcolepsy.

  View details for Web of Science ID 000071355600011

  View details for PubMedID 9456467

• HLA class II studies in non DRB1*1501 patients with narcolepsy-cataplexy 12th International Histocompatibility Workshop - HLA Mignot, E., Kimura, A., Lattermann, A., GRUMET, F. C., Mayer, G., Thorsby, E., HESLA, P. E., Mueller-Eckhardt, G. EDITIONS EDK. 1997: 436–441

  View details for Web of Science ID 000071716700074

• Familial aspects of narcolepsy-cataplexy in the Czech Republic SLEEP Nevsimalova, S., Mignot, E., Sonka, K., Arrigoni, J. L. 1997; 20 (11): 1021-1026

  Abstract

  A group of 153 probands with narcolepsy included 38 subjects (24.8%) with a familial incidence of excessive daytime sleepiness (EDS). In 15 cases (9.8%), at least one additional family member suffered from narcolepsy-cataplexy; only EDS was present in the remaining 23 cases (15.0%). One thousand eighty-two relatives were evaluated. The percentage of first degree relatives affected with narcolepsy-cataplexy was 2.28% (1.20% if only clinically confirmed cases were accounted); the adequate value for second degree relatives was 1.49%. The occurrence of EDS exceeded these values several times (4.28% in first degree relatives, 6.57% in second degree relatives). The vertical mode of transmission was found in most families. Human leukocyte antigen (HLA) typing was performed in six families with multiple-case incidence of narcolepsy. Forty-one blood samples were analyzed (12 patients with narcolepsy, 7 with only EDS, 2 with sleep apnea syndrome, and 20 healthy relatives). HLA DR2+ and DQB1*0602+ were found in only 8 out of 12 narcoleptic patients with cataplexy and in six out of seven patients with isolated attacks of sleepiness. These findings support the hypothesis that there is a common genetic basis for narcolepsy associated with cataplexy and "monosymptomatic" forms of narcolepsy and suggest the existence of non-major histocompatibility complex (MHC) susceptibility factors for narcolepsy.

  View details for Web of Science ID 000071355600012

  View details for PubMedID 9456468

• The natural history of a microsatellite located in the HLA DQ region 12th International Histocompatibility Conference - HLA Mignot, E., Macaubas, C., Jin, L., Hallmayer, J., Kimura, A., GRUMET, F. C. EDITIONS EDK. 1997: 121–124

  View details for Web of Science ID 000071717200022

• Mutation rate varies among alleles at a microsatellite locus: Phylogenetic evidence PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jin, L., Macaubas, C., Hallmayer, J., Kimura, A., Mignot, E. 1996; 93 (26): 15285-15288

  Abstract

  The understanding of the mutational mechanism that generates high levels of variation at microsatellite loci lags far behind the application of these genetic markers. A phylogenetic approach was developed to study the pattern and rate of mutations at a dinucleotide microsatellite locus tightly linked to HLA-DQB1 (DQCAR). A random Japanese population (n = 129) and a collection of multiethnic samples (n = 941) were typed at the DQB1 and DQCAR loci. The phylogeny of DQB1 alleles was then reconstructed and DQCAR alleles were superimposed onto the phylogeny. This approach allowed us to group DQCAR alleles that share a common ancestor. The results indicated that the DQCAR mutation rate varies drastically among alleles within this single microsatellite locus. Some DQCAR alleles never mutated during a long period of evolutionary time. Sequencing of representative DQCAR alleles showed that these alleles lost their ability to mutate because of nucleotide substitutions that shorten the length of uninterrupted CA repeat arrays; in contrast, all mutating alleles had relatively longer perfect CA repeat sequences.

  View details for Web of Science ID A1996WC20400055

  View details for PubMedID 8986803

• Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine BRAIN RESEARCH Reid, M. S., Tafti, M., Nishino, S., Sampathkumaran, R., Siegel, J. M., Mignot, E. 1996; 733 (1): 83-100

  Abstract

  Cataplexy in the narcoleptic canine may be modulated by systemic administration of monoaminergic compounds. In the present study, we have investigated the effects of monoaminergic drugs on cataplexy in narcoleptic canines when perfused locally via microdialysis probes in the amygdala, globus pallidus/putamen, basal forebrain, pontine reticular formation and ventral tegmental area of narcoleptic and control Doberman pinchers. Cataplexy was quantified using the Food-Elicited Cataplexy Test and analyzed by electroencephalogram, electroculogram and electromyogram. Local perfusion with the monoaminergic agonist quinpirole, 7-OH-DPAT and BHT-920, into the ventral tegmental area produced a dose-dependent increase in cataplexy without significantly reducing basal muscle tone. Perfusion with the antagonist raclopride in the same structure produced a moderate reduction in cataplexy. Local perfusion with quinpirole, 7-OH-DPAT and BHT-920 into the globus pallidus/putamen also produced an increase, while raclopride produced a decrease, in cataplexy in narcoleptic canines. In control animals, none of the above drugs produced cataplexy or muscle atonia when perfused into either the ventral tegmental area or the globus pallidus/putamen. Other monoaminergic drugs tested in these two brain areas; prazosin, yohimbine, amphetamine, SKF 38393 and SCH 23390 had no effects on cataplexy. Local perfusion with each of the above listed drugs had no effect on cataplexy in any of the other brain regions examined. These findings show that cataplexy may be regulated by D2/D3 dopaminergic receptors in the ventral tegmental area and perhaps the globus pallidus/ putamen. It is suggested that neurons in the mesolimbic dopamine system of narcoleptics are hypersensitive to dopaminergic autoreceptor agonists.

  View details for Web of Science ID A1996VJ89400011

  View details for PubMedID 8891251

• Thalidomide, a hypnotic with immune modulating properties, increases cataplexy in canine narcolepsy NEUROREPORT Kanbayashi, T., Nishino, S., Tafti, M., Hishikawa, Y., Dement, W. C., Mignot, E. 1996; 7 (12): 1881-1886

  Abstract

  Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.

  View details for Web of Science ID A1996VP15900002

  View details for PubMedID 8905685

• Major histocompatibility class II molecules in the CNS: Increased microglial expression at the onset of narcolepsy in a canine model JOURNAL OF NEUROSCIENCE Tafti, M., Nishino, S., Aldrich, M. S., Liao, W. N., Dement, W. C., Mignot, E. 1996; 16 (15): 4588-4595

  Abstract

  Human narcolepsy is a neurological disorder known to be closely associated with HLA-DR2 and DQB1*0602. Because most autoimmune diseases are HLA-associated, a similar mechanism has been proposed for narcolepsy. However, neither systemic nor CNS evidence of an autoimmune abnormality has ever been reported. In this study, major histocompatibility (MHC) class I and class II expression was studied in the CNS of human and canine narcoleptics using immunohistochemistry and Northern analysis. Results indicated that canine narcolepsy is associated with a significant increase of MHC class II expression by the microglia. Moreover, the highest values were found between 3 and 8 months of age, strikingly concomitant to the development of narcolepsy in the canine model. In humans, class II expression was not found significantly different between control and narcoleptic subjects. This result could be explained by the old age of the subjects (69.86 +/- 5.31 and 68.36 +/- 4.74 years in narcoleptics and controls, respectively), because class II expression is significantly correlated with age in both humans and dogs. For the first time, this study demonstrated that the expression of MHC class II molecules in the CNS is age-dependent and that a consistent increase of their expression by the microglia might be critically involved in the development of narcolepsy.

  View details for Web of Science ID A1996UX95500006

  View details for PubMedID 8764647

• IgH (mu-switch and gamma-1) region restriction fragment length polymorphism in human narcolepsy JOURNAL OF CLINICAL IMMUNOLOGY Singh, S. M., George, C. F., OTT, R. N., Rattazzi, C., Guilleminault, C., Dement, W. C., Mignot, E. 1996; 16 (4): 208-215

  Abstract

  Predisposition to narcolepsy involves genetic factors both in humans and in a canine model of the disorder. In humans, narcolepsy is strongly associated with HLA DR15 and DQB1*0602. In Dobermans and Labradors, narcolepsy is transmitted as a single autosomal recessive gene with full penetrance (canarc-1). Canine narcolepsy is not linked with DLA, the canine equivalent of HLA, but co-segregates with a DNA segment with high homology with the mu immunoglobulin heavy-chain (IgH) switch-like region (S mu). To determine if the IgH locus is involved in genetic predisposition to human narcolepsy, restriction fragment length polymorphisms specific for the IgM and IgG cluster within this locus were studied in sporadic cases of the disease, as well as in five families with two or more affected individuals. Comparisons were made between control populations and both familial and sporadic cases and for patients with and without HLA-DR15 and DQB1*0602. RFLP analysis at the S mu and gamma-1 loci, which cover over 200 kb of 14q32.3, indicates that there is no evidence for any association between the IgH region and human narcolepsy.

  View details for Web of Science ID A1996VA01500004

  View details for PubMedID 8840222

• The natural history of a microsatellite located in the HLA DQ region Mignot, E., Macaubas, C., Jin, L., Hallmayer, J., Kimura, A., GRUMET, F. C. ELSEVIER SCIENCE INC. 1996: O09–O09

  View details for Web of Science ID A1996UM45500009

• Thalidomide, immune modulation and narcolepsy SLEEP Kanbayashi, T., Nishino, S., Tafti, M., Hishikawa, Y., Dement, W. C., Mignot, E. 1996; 19 (2): 116-116

  View details for Web of Science ID A1996UC74600005

  View details for PubMedID 8855033

• Some genetic aspects of narcolepsy CESKA A SLOVENSKA NEUROLOGIE A NEUROCHIRURGIE Nevsimalova, S., Mignot, E., Sonka, K., Arrigoni, J. L. 1996; 59 (4): 210-215

  View details for Web of Science ID A1996VC57500007

• Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs SLEEP Shelton, J., Nishino, S., Vaught, J., Dement, W. C., Mignot, E. 1995; 18 (10): 817-826

  Abstract

  The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.

  View details for Web of Science ID A1995TQ23600001

  View details for PubMedID 8746387

• DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases. Tissue antigens Mignot, E., Kimura, A., Abbal, M., Thorsby, E., Lin, X., Voros, A., Macaubas, C., Bouissou, F., Sollid, L. M., Cambon-Thomsen, A. 1995; 46 (4): 299-304

  Abstract

  DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA1*0302, DQB1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB1*0701, DQA1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3,DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4,DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7,DQ2-DQCAR 111-121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.

  View details for PubMedID 8560448

• DQCAR MICROSATELLITE POLYMORPHISMS IN 3 SELECTED HLA CLASS II-ASSOCIATED DISEASES TISSUE ANTIGENS Mignot, E., Kimura, A., Abbal, M., Thorsby, E., Lin, X., Voros, A., Macaubas, C., Bouissou, F., Sollid, L. M., CAMBONTHOMSEN, A., Yasunaga, S., GRUMET, F. C. 1995; 46 (4): 299-304

  View details for Web of Science ID A1995RZ63900003

• TRACKING THE EVOLUTION OF A MICROSATELLITE LOCUS LOCATED IN THE HLA-DQA1/DQB1 CLASS-II REGION Macaubas, C., Jin, L., Hallmayer, J., Kimura, A., Mignot, E. CELL PRESS. 1995: 953–53

  View details for Web of Science ID A1995RW68700954

• MUSCLE ATONIA IS TRIGGERED BY CHOLINERGIC STIMULATION OF THE BASAL FOREBRAIN - IMPLICATION FOR THE PATHOPHYSIOLOGY OF CANINE NARCOLEPSY JOURNAL OF NEUROSCIENCE Nishino, S., Tafti, M., Reid, M. S., Shelton, J., Siegel, J. M., Dement, W. C., Mignot, E. 1995; 15 (7): 4806-4814

  Abstract

  Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep-related symptoms, such as cataplexy. The exact pathophysiology underlying the disease is unknown but may involve central cholinergic systems. It is known that the brainstem cholinergic system is activated during REM sleep. Furthermore, REM sleep and REM sleep atonia similar to cataplexy can be triggered in normal and narcoleptic dogs by stimulating cholinergic receptors within the pontine brainstem. The pontine cholinergic system is, therefore, likely to play a role in triggering cataplexy and other REM-related abnormalities seen in narcolepsy. The other cholinergic system that could be involved in the pathophysiology of narcolepsy is located in the basal forebrain (BF). This system sends projections to the entire cerebral cortex. Since acetylcholine release in the cortex is increased both during REM and wake, the basocortical cholinergic system is believed to be involved in cortical desynchrony. In the current study, we analyzed the effect of cholinergic compounds injected into the forebrain structures of narcoleptic and control dogs. We found that carbachol (a cholinergic agonist) injected into the BF triggers cataplexy in narcoleptic dogs while it increases wakefulness in control dogs. Much higher doses of carbachol bilaterally injected in the BF were, however, shown to trigger muscle atonia even in control dogs. These results suggest that a cholinoceptive site in the BF is critically implicated in triggering muscle atonia and cataplexy. Together with similar results previously obtained in the pontine brainstem, it appears that a widespread hypersensitivity to cholinergic stimulation may be central to the pathophysiology of canine narcolepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995RJ66200008

  View details for PubMedID 7623112

• EXTENSIVE POLYMORPHISM OF A (CA)(N) MICROSATELLITE LOCATED IN THE HLA-DQA1/DQB1 CLASS-II REGION HUMAN IMMUNOLOGY Macaubas, C., Hallmayer, J., Kalil, J., Kimura, A., Yasunaga, S., GRUMET, F. C., Mignot, E. 1995; 42 (3): 209-220

  Abstract

  A highly polymorphic (CA)n microsatellite marker (DQCAR), located between the DQA1 and the DQB1 genes, was characterized in four ethnic groups. Based on length polymorphism, 12 alleles could be defined. The marker is located 1- to 2-kb telomeric to the DQB1 gene and 10 kb centromeric to the DQA1 gene and was shown to be in tight linkage disequilibrium with HLA-DQ. Analysis of the linkage disequilibrium pattern revealed little additional diversity in DQ1-associated haplotypes. Almost all DQ1 subjects examined were DQCAR 103 or DQCAR 107 (13 and 15 CA repeats, respectively). In contrast, significant haplotypic diversity was observed for most DQ2-, DQ3-, and DQ4-associated haplotypes. These haplotypes often had longer allele sizes (DQCAR > 111, more than 17 CA repeats) and more DQCAR alleles per haplotype. These haplotypes also carried DQCAR alleles of different sizes, even though they bore the same DQA1 and DQB1 alleles, and sometimes the same DRB1 allele as well. These results indicate that DQCAR could be a useful marker to better define disease associations with HLA. Our results are also consistent with the hypothesis that CAR alleles with higher numbers of repeats have higher mutation rates and that recombination within the HLA-DR/DQ region is haplotype dependent.

  View details for Web of Science ID A1995QL39300004

  View details for PubMedID 7759308

• EFFECT OF 5-HT1A RECEPTOR AGONISTS AND ANTAGONISTS ON CANINE CATAPLEXY JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Nishino, S., Shelton, J., RENAUD, A., Dement, W. C., Mignot, E. 1995; 272 (3): 1170-1175

  Abstract

  Pharmacological studies using a canine model of narcolepsy have demonstrated that adrenergic rather than serotonergic or dopaminergic uptake inhibition is the primary mode of action of antidepressants on cataplexy, a pathological manifestation of rapid eye movement (REM) sleep atonia that occurs in narcolepsy. This result is in line with the known involvement of adrenergic systems in the regulation of REM sleep. However, the lack of anticataplectic effects of selective serotonergic compounds was puzzling as serotonergic neurons of the dorsal raphe nuclei are known to decrease activity during the REM sleep in a manner similar to the adrenergic neurons of the locus coeruleus. To further explore the role of serotonergic systems, we tested the effect on canine cataplexy of six 5-HT1A agonists and five 5-HT1A antagonists. Results indicate that 5-HT1A agonists significantly suppress cataplexy in correlation with their in vitro affinities to the canine central 5-HT1A receptors. Anticataplectic effects were, however, accompanied by various behavioral changes, such as flattened body posture, increased panting and agitation. In contrast, the selective 5-HT1A antagonist did not aggravate cataplexy, although a 5-HT1A antagonist was able to block the anticataplectic effect of a 5-HT1A agonist. These results suggest that the anticataplectic effects of 5-HT1A agonists are truly mediated by 5-HT1A receptor stimulation. It is, however, likely that anticataplectic effects occur due to the behavioral side effects rather than the direct involvement of this receptor subtype in the regulation of cataplexy. Further studies are therefore necessary to address the question of whether these 5-HT1A agonists hold promise in the pharmacological treatment of human cataplexy.

  View details for Web of Science ID A1995QL99500028

  View details for PubMedID 7891329

• A NEW DRB1(ASTERISK)1202 ALLELE (DRB1(ASTERISK)12022) FOUND IN ASSOCIATION WITH DQA1(ASTERISK)0102 AND DQB1(ASTERISK)0602 IN 2 BLACK NARCOLEPTIC SUBJECTS IMMUNOGENETICS Behar, E., Lin, X. Y., GRUMET, F. C., Mignot, E. 1995; 41 (1): 52-52

  View details for Web of Science ID A1995PV36000010

  View details for PubMedID 7528725

• NARCOLEPSY AND IMMUNITY ADVANCES IN NEUROIMMUNOLOGY Mignot, E., Tafti, M., Dement, W. C., GRUMET, F. C. 1995; 5 (1): 23-37

  Abstract

  Narcolepsy is a neurological disorder known to be associated with human leukocyte antigen (HLA)-DQB1*0602 in humans. In a canine model, the disorder is also genetically linked to a gene of high homology with the human mu-switch-like immunoglobulin (Ig) gene (current LOD score 13.6 at 0% recombination). Since association with HLA or other immune function polymorphic genes (T cell receptor of Ig, mainly) is a hallmark of most autoimmune diseases, it is proposed that autoimmunity may also play a role in the development of narcolepsy. Arguments for and against this hypothesis are reviewed. It is shown that both on the basis of the most recent molecular studies, and because of some of its clinical features, narcolepsy may be an autoimmune disorder. However, neither systemic nor central nervous system (CNS) evidence of any autoimmune abnormality have ever been found. To reconcile this discrepancy, it is suggested that the pathological immune process involved in narcolepsy could be difficult to detect because it is restricted to a very small region of the brain or targets a low abundance neuroeffector. Alternatively, it is possible that a more fundamental relationship is involved between sleep generation and immune regulation. The pathophysiology of narcolepsy may then involve new CNS-immune mechanisms that may shed new light on the sleep process itself.

  View details for Web of Science ID A1995QP30900004

  View details for PubMedID 7795891

• CONTROVERSIES IN THE DIAGNOSIS OF NARCOLEPSY 4th International Conference on Narcolepsy Guilleminault, C., Mignot, E., Partinen, M. AMER SLEEP DISORDERS ASSOC. 1994: S1–S6

  Abstract

  The diagnosis of narcolepsy can be problematic. Most sleep laboratories use polygraphic testing to establish the diagnosis. One polygraphic recording followed by a single multiple sleep latency test (MSLT) is used to differentiate the causes of syndromes with complaints of daytime somnolence. Prospective investigations have demonstrated that patients with periodic leg movements or upper airway resistance syndrome may present abnormal sleep latencies and more than one sleep onset rapid eye movement period (SOREMP) during MSLT. On the other hand, investigations of patients with daytime sleepiness and cataplexy have shown that the MSLT may not show more than one SOREMP. The combination of history of cataplexy and more than one SOREMP during MSLT is the best clinical determinant of narcolepsy. History of daytime sleepiness and presence of more than one SOREMP during MSLT, however, is a poorer discriminant of narcolepsy than history of cataplexy, particularly in an aging population.

  View details for Web of Science ID A1994QD08100002

  View details for PubMedID 7701189

• NEUROPHARMACOLOGY AND NEUROCHEMISTRY OF CANINE NARCOLEPSY 4th International Conference on Narcolepsy Nishino, S., Reid, M. S., Dement, W. C., Mignot, E. AMER SLEEP DISORDERS ASSOC. 1994: S84–S92

  Abstract

  It is believed that narcolepsy involves abnormalities of rapid eye movement (REM) sleep, especially of REM sleep atonia. Compelling evidence suggests that the regulation of REM sleep and REM sleep atonia involves a reciprocal interaction of cholinergic and monoaminergic systems. Using our canine model of narcolepsy and a pharmacological approach, we have previously demonstrated a similar interaction in the regulation of cataplexy. Global activation of cholinergic or monoaminergic transmission aggravates or suppresses canine cataplexy, respectively. We have also identified the subtypes of monoaminergic and cholinergic receptors specifically involved in this interaction. Cataplexy is aggravated by activation of the cholinergic system via M2 stimulation, as well as deactivation of the catecholaminergic systems by either blockade of postsynaptic alpha-1b receptors or stimulation of alpha-2 or D2 inhibitory autoreceptors. These pharmacological results correspond to previously identified neurochemical abnormalities in canine narcolepsy, such as significant increases in M2 receptors in the pons, alpha-1 receptors in the amygdala, alpha-2 receptors in the locus coeruleus and D2 receptors in the amygdala and nucleus accumbens, when compared to control animals. Using local perfusion of active compounds, we have further demonstrated that cholinoceptive sites in the pontine reticular formation, as well as in the basal forebrain, are involved in the regulation of cataplexy. Although the specific sites of action of the monoaminergic compounds remain unknown, the results of our pharmacological and neurochemical studies to date suggest that a widespread hyperactivity of cholinergic systems within the central nervous system together with a hypoactivity of catecholaminergic systems underlie the pathophysiology of narcolepsy.

  View details for Web of Science ID A1994QD08100016

  View details for PubMedID 7701206

• AN IMMUNOGLOBULIN SWITCHLIKE SEQUENCE IS LINKED WITH CANINE NARCOLEPSY 4th International Conference on Narcolepsy Mignot, E., Bell, R. A., Rattazzi, C., LOVETT, M., GRUMET, F. C., Dement, W. C. AMER SLEEP DISORDERS ASSOC. 1994: S68–S76

  Abstract

  Canine narcolepsy is an animal model of the human disorder that is transmitted as a single autosomal recessive gene with full penetrance (canarc-1) in Dobermans and Labradors. In previous experiments, we have identified a very tight linkage marker for canarc-1. This marker, a 0.85-kb band cross reacting with a human mu-switch Heavy-Chain Immunoglobulin probe (maximum logarithm of odds [LOD] score Zmax = 10.8 at 0% recombination), has now been cloned and sequenced. The gene, composed of GC rich repeats, is 75% homologous to the human mu-switch gene and is similar in organization to immunoglobulin switch genes. Curiously, however, this mu-switchlike segment appears to be unlinked with other switchlike polymorphisms detected at high stringency with the human mu-switch probe. Because in most animal species all switch genes are located within 300-500 kb and show tight linkage in families, this result suggests two possible hypotheses: 1) Our 0.85 kb is a true immunoglobulin switch segment, but the map of the canine Variable Heavy-Chain loci is organized in unlinked clusters, or 2) our 0.85-kb segment is not an immunoglobulin switch segment and is located elsewhere in the genome in all species. We are now using chromosome walking and Yeast Artificial Chromosome Cloning techniques, together with corresponding studies in humans to identify the pathological gene.

  View details for Web of Science ID A1994QD08100014

  View details for PubMedID 7701203

• DQB1-ASTERISK-0602 AND DQA1-ASTERISK-0102 (DQ1) ARE BETTER MARKERS THAN DR2 FOR NARCOLEPSY IN CAUCASIAN AND BLACK-AMERICANS 4th International Conference on Narcolepsy Mignot, E., Lin, X., Arrigoni, J., Macaubas, C., Olive, F., Hallmayer, J., Underhill, P., Guilleminault, C., Dement, W. C., GRUMET, F. C. AMER SLEEP DISORDERS ASSOC. 1994: S60–S67

  Abstract

  In the present study, we tested 19 Caucasian and 28 Black American narcoleptics for the presence of the human leucocyte antigen (HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction (PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501 and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75% of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501 positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical and polygraphic results for this patient were typical, thus confirming the existence of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups.

  View details for PubMedID 7701202

• CHOLINERGIC REGULATION OF CATAPLEXY IN CANINE NARCOLEPSY IN THE PONTINE RETICULAR-FORMATION IS MEDIATED BY M2 MUSCARINIC RECEPTORS SLEEP Reid, M. S., Tafti, M., Nishino, S., Siegel, J. M., Dement, W. C., Mignot, E. 1994; 17 (5): 424-435

  Abstract

  Both rapid eye movement sleep and cataplexy in the narcoleptic canine have been shown to increase after both systemic and local administration of cholinergic agonists in the pontine reticular formation. Furthermore, binding studies indicate an increase in the number of M2 muscarinic receptors in the pontine reticular formation of narcoleptic canines. In the present study we have investigated the receptor subtypes involved in mediating the cholinergic stimulation of cataplexy, as defined by brief periods of hypotonia induced by emotions, within the pontine reticular formation of narcoleptic canines. Specific cholinergic and monoaminergic agonists and antagonists, and excitatory or inhibitory amino-acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of narcoleptic canines, and cataplexy was monitored using the Food-Elicited Cataplexy Test and recordings of electroencephalogram, electrooculogram and electromyogram. In narcoleptic canines, bilateral perfusion with oxotremorine (M2 muscarinic) (10(-5)-10(-3) M) in the pontine reticular formation produced a dose-dependent increase in cataplexy, which reached complete muscle atonia (status cataplecticus) during the highest concentration. In control canines bilateral perfusion with oxotremorine (10(-5)-10(-3) M) did not produce any cataplectic attacks, but did produce muscle atonia after the highest concentration. Bilateral perfusion with either McN-A-343 (M1 muscarinic) or nicotine (both 10(-5)-10(-3) M) did not have any effect on cataplexy in either narcoleptic or control canines. The increase in cataplexy in narcoleptic canines produced by local perfusion with carbachol (10(-4) M) followed by equimolar perfusion with a muscarinic antagonist was rapidly reversed by atropine (muscarinic) and gallamine (M2 muscarinic), partially reversed by 4-DAMP (M3/M1 muscarinic) and completely unaffected by pirenzepine (M1 muscarinic). Bilateral perfusion with excitatory, glutamatergic receptor agonists N-methyl-D-aspartate, AMPA (both at 10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effect on cataplexy, whereas bilateral perfusion with the inhibitory GABAergic receptor agonist muscimol (10(-4)-10(-3) M) produced a moderate increase in cataplexy in the narcoleptic canines. Bilateral perfusion with numerous monoaminergic compounds, BHT-920 (alpha-2 agonist), yohimbine (alpha-2 antagonist), propranolol (beta antagonist) and prazosin (alpha-1 antagonist), did not have any effect on cataplexy. These findings demonstrate that cholinergic regulation of cataplexy in the narcoleptic canine at the level of the pontine reticular formation is mediated by M2, and possibly M3, muscarinic receptors. The effects of muscimol indicate that the stimulation of cataplexy might be elicited by local neuronal inhibition.

  View details for Web of Science ID A1994PE28600005

  View details for PubMedID 7991953

• MODAFINIL BINDS TO THE DOPAMINE UPTAKE CARRIER SITE WITH LOW-AFFINITY SLEEP Mignot, E., Nishino, S., Guilleminault, C., Dement, W. C. 1994; 17 (5): 436-437

  View details for Web of Science ID A1994PE28600006

  View details for PubMedID 7991954

• STABILITY OF CATAPLEXY OVER SEVERAL MONTHS - INFORMATION FOR THE DESIGN OF THERAPEUTIC TRIALS SLEEP Gelb, M., Guilleminault, C., Kraemer, H., Lin, S., Moon, S., Dement, W. C., Mignot, E. 1994; 17 (3): 265-273

  Abstract

  Twenty-seven narcoleptic patients severely affected with cataplexy completed four symptom diaries over a 4-month period in order to clarify some of the controversies surrounding assessment of anticataplectic medications. The home diary method was found to be a viable model for the assessment of anticataplectic activity. Assessment of reliability in 1-, 2-, 3-, 4-, 5- and 10-day intervals indicated that reliability increases with the number of days included. A 10-day design was found to be optimal. Reliability decreased, however, with each successive diary over the 4-month period. Power analysis indicates that two groups of 30-40 subjects in a parallel design, or one group of 30-40 subjects in a crossover design, would be sufficient to demonstrate a significant therapeutic anticataplectic effect in most cases. A "first diary effect" was observed, suggesting that a training period prior to the actual trial might improve reliability. Whether the patient was treated or untreated with stimulant medications did not affect severity or fluctuation of cataplexy, suggesting that both groups of patients could be included in therapeutic trials. No time-of-day fluctuation was observed in the daily distribution of cataplexy attacks. Sudden increases in cataplexy were often, although not always, caused by unusual emotional events or sleepiness. The finding of a long-lasting "precataplectic" feeling or "aura" pointed to the need to carefully clarify the symptom prior to beginning a therapeutic trial.

  View details for Web of Science ID A1994NQ80400010

  View details for PubMedID 7939127

• CHOLINERGIC MECHANISMS IN CANINE NARCOLEPSY .1. MODULATION OF CATAPLEXY VIA LOCAL-DRUG ADMINISTRATION INTO THE PONTINE RETICULAR-FORMATION NEUROSCIENCE Reid, M. S., Tafti, M., GEARY, J. N., Nishino, S., Siegel, J. M., Dement, W. C., Mignot, E. 1994; 59 (3): 511-522

  Abstract

  Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.

  View details for Web of Science ID A1994NF79800003

  View details for PubMedID 8008205

• CHOLINERGIC MECHANISMS IN CANINE NARCOLEPSY .2. ACETYLCHOLINE-RELEASE IN THE PONTINE RETICULAR-FORMATION IS ENHANCED DURING CATAPLEXY NEUROSCIENCE Reid, M. S., Siegel, J. M., Dement, W. C., Mignot, E. 1994; 59 (3): 523-530

  Abstract

  Cataplexy in the narcoleptic canine has been shown to increase after local administration of carbachol into the pontine reticular formation. Rapid eye movement sleep has also been shown to increase after local administration of carbachol in the pontine reticular formation, and furthermore, acetylcholine release in the pontine tegmentum was found to increase during rapid eye movement sleep in rats. Therefore, in the present study we have investigated acetylcholine release in the pontine reticular formation during cataplexy in narcoleptic canines. Extracellular acetylcholine levels were measured in the pontine reticular formation of freely moving narcoleptic and control Doberman pinschers using in vivo microdialysis probes. Cataplexy was induced by the Food-Elicited Cataplexy Test and monitored using recordings of electroencephalogram, electrooculogram and electromyogram. Basal levels of acetylcholine in the microdialysis perfusates were approximately 0.5 pmol/10 min in both control and narcoleptic canines. Local perfusion with tetrodotoxin (10(-5) M) or artificial cerebrospinal fluid without Ca2+ produced a decrease, while intravenous injections of physostigmine (0.05 mg/kg) produced an increase in acetylcholine levels, indicating that the levels of acetylcholine levels measured are derived from neuronal release. During cataplexy induced by the Food-Elicited Cataplexy Test, acetylcholine levels increased by approximately 50% after four consecutive tests in narcoleptic canines, but did not change after four consecutive tests in control canines. Motor activity and feeding behavior, similar to that occurring during a Food-Elicited Cataplexy Test, had no effect on acetylcholine levels in the narcoleptic canines.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1994NF79800004

  View details for PubMedID 8008206

• DESMETHYL METABOLITES OF SEROTONERGIC UPTAKE INHIBITORS ARE MORE POTENT FOR SUPPRESSING CANINE CATAPLEXY THAN THEIR PARENT COMPOUNDS SLEEP Nishino, S., Arrigoni, J., Shelton, J., Dement, W. C., Mignot, E. 1993; 16 (8): 706-712

  Abstract

  Our series of pharmacological studies on canine narcolepsy has suggested that the adrenergic systems are more critically involved in the regulation of cataplexy than the serotonergic and dopaminergic systems. This, however, is an apparent contradiction to data obtained in human patients, which show that chronic oral administration of serotonergic uptake inhibitors, such as clomipramine, zimelidine and fluoxetine, is effective in reducing cataplexy. To explore this discrepancy, we have assessed the anticataplectic effects of various serotonergic uptake inhibitors and their active desmethyl metabolites on canine cataplexy. We found that the anticataplectic effect of the desmethyl metabolites, which are usually more potent for in vitro adrenergic uptake inhibition, was more potent and developed more rapidly than the effect of the parent compounds. Furthermore, the anticataplectic potency was positively correlated to the adrenergic uptake inhibition and was negatively correlated with serotonergic uptake inhibition among the 10 compounds tested. These results are consistent with our hypothesis of a preferential involvement of the adrenergic system in the control of cataplexy. Our results also suggest that the anticataplectic effect of "selective" serotonergic uptake inhibitors in human narcolepsy might be mediated by their less selective active metabolites.

  View details for Web of Science ID A1993MV96900004

  View details for PubMedID 8165384

• FURTHER CHARACTERIZATION OF THE ALPHA-1 RECEPTOR SUBTYPE INVOLVED IN THE CONTROL OF CATAPLEXY IN CANINE NARCOLEPSY JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Nishino, S., Fruhstorfer, B., Arrigoni, J., Guilleminault, C., Dement, W. C., Mignot, E. 1993; 264 (3): 1079-1084

  Abstract

  We have demonstrated previously that central noradrenergic mechanisms, especially postsynaptic alpha-1 receptors, are critically involved in the regulation of cataplexy, a pathological manifestation of rapid eye movement sleep atonia in narcolepsy. However, it has been shown recently that alpha-1 receptors constitute a heterogeneous population of binding sites, which is encoded by several distinct genes. In light of these findings, we investigated the possibility that the effect of alpha-1 compounds on cataplexy found in our previous study is mediated more specifically by certain alpha-1 receptor subtypes than by other subtypes. We therefore examined the effects of eight selective alpha-1 antagonists and five agonists on canine cataplexy and compared these with the affinities of the same compounds for the canine central alpha-1a and alpha-1b subtypes. The affinities of the compounds for the alpha-1 receptor subtypes were assessed by using [3H]prazosin receptor binding in combination with a 5-methylurapidil (an alpha-1a selective ligand) mask. Six of the eight alpha-1 antagonists tested exacerbated canine cataplexy, whereas all five agonists tested suppressed cataplexy. Furthermore, the potency (ED50 values) of the compounds on cataplexy significantly correlated with the affinity of the compounds for the alpha-1b binding site. These results are consistent with our earlier implication of the alpha-1 receptor mechanisms in the control of cataplexy and further suggest a specific involvement of the alpha-1b receptor subtype in these mechanisms.

  View details for Web of Science ID A1993KT84600009

  View details for PubMedID 8095546

• PHARMACOLOGICAL CONTROL OF NARCOLEPSY AND REM-SLEEP SYMP ON ENDOCRINE AND NUTRITIONAL CONTROL OF BASIC BIOLOGICAL FUNCTIONS Mignot, E., Guilleminault, C. HOGREFE & HUBER PUBLISHERS. 1993: 307–314

  View details for Web of Science ID A1993BY66S00036

• DQB1-0602 (DQW1) IS NOT PRESENT IN MOST NONDR2 CAUCASIAN NARCOLEPTICS SLEEP Mignot, E., Lin, X., Kalil, J., George, C., Singh, S., Billiard, M., Montplaisir, J., Arrigoni, J., Guilleminault, C., Dement, W. C., GRUMET, F. C. 1992; 15 (5): 415-422

  Abstract

  Human narcolepsy is a genetically determined disorder of sleep strongly associated with the human leucocyte antigens (HLA) DR2 and DQw1. In black narcoleptic patients, susceptibility for narcolepsy is more closely related to a specific gene subtype of DQw1, DQB1-0602, than to DR2. About 30% of black narcoleptic patients are nonDR2, but all carry the HLA DQB1-0602 gene. In the present study, we have tested caucasian nonDR2 cataplectic patients (6 sporadic cases and 7 familial cases from 3 multiplex families) for the presence of the HLA DQB1-0602 and DQA1-0102 (DQw1) using a specific polymerase chain reaction (PCR)-oligotyping technique. None of the patients was DQB1-0602 or DQA1-0102 positive, thus proving that, in caucasians, DQB1-0602 and DQA1-0102 (DQw1) are not prerequisites for the diagnosis of narcolepsy. Further studies with more patients are warranted to exclude the possibility that a few caucasian patients carry rare haplotypes with DQB1-0602 independently of DR2.

  View details for PubMedID 1455124

• MONOAMINERGIC UPTAKE IN SYNAPTOSOMES PREPARED FROM FROZEN BRAIN-TISSUE SAMPLES OF NORMAL AND NARCOLEPTIC CANINES BRAIN RESEARCH VALTIER, D., Dement, W. C., Mignot, E. 1992; 588 (1): 115-119

  Abstract

  Canine narcolepsy, a model of the human disorder, is associated with altered catecholamine but not serotonin (5-HT) metabolism in some brain areas, particularly the amygdala. A possible explanation for these global changes could be the existence of specific defects in monoamine uptake processes. We have studied the uptake of [3H]norepinephrine (NE), [3H]dopamine (DA) and [3H]5-HT in synaptosomes prepared from cortex and amygdala of narcoleptic and control Doberman pinscher brains. Since narcoleptic canines are relatively few in number, we have used a specific brain freezing procedure that has been reported to allow restoration of metabolically functional tissue upon thawing. Preliminary studies comparing monoamine uptake in fresh and frozen brain samples of both groups of dogs were carried out and demonstrated that this procedure significantly altered serotoninergic but not noradrenergic and dopaminergic uptake. All further investigations were then done on synaptosomes prepared from frozen samples. Our results demonstrate that synaptosomal uptake of [3H]NE, [3H]DA and [3H]5-HT in cortex and amygdala are not altered in narcolepsy.

  View details for Web of Science ID A1992JL38700014

  View details for PubMedID 1393561

• ACTIVITY OF MEDIAL MESOPONTINE UNITS DURING CATAPLEXY AND SLEEP-WAKING STATES IN THE NARCOLEPTIC DOG JOURNAL OF NEUROSCIENCE Siegel, J. M., Nienhuis, R., Fahringer, H. M., Chiu, C., Dement, W. C., Mignot, E., Lufkin, R. 1992; 12 (5): 1640-1646

  Abstract

  Narcolepsy has been hypothesized to be a disease of rapid eye movement (REM) sleep. According to this hypothesis, cataplexy is a result of the triggering during waking of the mechanism that normally serves to suppress muscle tone in REM sleep. REM sleep control mechanisms have been localized to the pons. Narcoleptic dogs have increased numbers of cholinergic receptors in the medial pons. These findings suggest that neurons mediating the triggering of cataplexy might be located in medial pontine regions. In the present study, this hypothesis has been investigated by recording the discharge of units in the medial mesopontine region of the narcoleptic dog. Unit activity was examined in the nucleus reticularis pontis oralis, caudalis, and central gray, with each cell being recorded during both cataplexy and sleep states. Maximal discharge rates were observed, in all of these regions, during active waking states (mean rate, 45.3/sec) and REM sleep (16.0/sec), with minimal discharge rates in non-REM sleep (8.3/sec). Unit discharge was reduced in cataplexy relative to precataplexy periods. Cataplexy discharge rates were 8.3/sec, 52% of the mean REM sleep rate. Cataplexy discharge rates were also significantly lower than those at REM sleep onset. Cataplexy discharge rates were comparable to rates in quiet waking and non-REM sleep. While medial mesopontine neurons discharge at high rates in REM sleep, they have little or no activity in cataplexy. We interpret the lack of activation of medial mesopontine units in cataplexy as indicating that the characteristic phasic motor activation of REM sleep does not occur in this state.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992HT83700007

  View details for PubMedID 1578258

• STRATEGIES FOR THE DEVELOPMENT OF NEW TREATMENTS IN SLEEP DISORDER MEDICINE WORKSHOP ON TARGET RECEPTORS FOR ANXIOLYTICS AND HYPNOTICS : FROM MOLECULAR PHARMACOLOGY TO THERAPEUTICS Mignot, E., Edgar, D. M., Miller, J. D., Prosser, R. A., VANGELDER, R. N., Nishino, S., Dement, W. C. KARGER. 1992: 129–150

  View details for Web of Science ID A1992BW57Z00015

• DOPAMINE-D2 MECHANISMS IN CANINE NARCOLEPSY JOURNAL OF NEUROSCIENCE Nishino, S., Arrigoni, J., VALTIER, D., Miller, J. D., Guilleminault, C., Dement, W. C., Mignot, E. 1991; 11 (9): 2666-2671

  Abstract

  Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D2 antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D2 agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D2 antagonist) and the R(+) enantiomer of 3-PPP (a D2 agonist). There was also a significant correlation between the in vivo pharmacological potency and in vitro drug affinity for D2 receptors (but not for D1 and alpha 2 receptors) among the seven central D2 antagonists tested. Selective D1 compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D2-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D2 antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D2 agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D2 compounds on cataplexy is mediated secondarily via the noradrenergic systems.

  View details for Web of Science ID A1991GE83100004

  View details for PubMedID 1831837

• NEURONAL-ACTIVITY IN NARCOLEPSY - IDENTIFICATION OF CATAPLEXY-RELATED CELLS IN THE MEDIAL MEDULLA SCIENCE Siegel, J. M., Nienhuis, R., Fahringer, H. M., Paul, R., Shiromani, P., Dement, W. C., Mignot, E., Chiu, C. 1991; 252 (5010): 1315-1318

  Abstract

  Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.

  View details for Web of Science ID A1991FN85700043

  View details for PubMedID 1925546

• GENETIC-LINKAGE OF AUTOSOMAL RECESSIVE CANINE NARCOLEPSY WITH A MU-IMMUNOGLOBULIN HEAVY-CHAIN SWITCH-LIKE SEGMENT PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mignot, E., Wang, C., Rattazzi, C., Gaiser, C., LOVETT, M., Guilleminault, C., Dement, W. C., GRUMET, F. C. 1991; 88 (8): 3475-3478

  Abstract

  Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog an as-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-1 were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human mu-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-1 in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at theta = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z less than -2 at theta less than 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease.

  View details for Web of Science ID A1991FG91300106

  View details for PubMedID 1673032

• RADIOLIGAND BINDING TO ADENOSINE RECEPTORS AND ADENOSINE UPTAKE SITES IN DIFFERENT BRAIN-REGIONS OF NORMAL AND NARCOLEPTIC DOGS PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR Hawkins, M., OCONNOR, S., Radulovacki, M., Bowersox, S., Mignot, E., Dement, W. 1991; 38 (1): 1-6

  Abstract

  The present study compares the characteristics of radioligand binding to adenosine receptors and adenosine uptake sites in 100- and 50-day-old normal and narcoleptic dogs. Binding to A1 receptors was quantified using a selective A1 agonist ([3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine, [3H]R-PIA) and an antagonist ([3H]dipropyl-8-cyclopentyl-xanthine, [3H]CPX). Differences in the binding of [3H]R-PIA and that of [3H]5'-ethylcarboxamide adenosine ([3H]NECA), which binds to both A1 and A2 receptors with similar affinities, were used to quantify A2 receptors. Nucleoside transport sites were labeled with [3H]nitrobenzylthioinosine ([3H]NBTI), a potent inhibitor of nucleoside transport systems. The present study offered no evidence that either adenosine A1 receptors and adenosine uptake sites in the frontal cortex or adenosine A2 receptors in the putamen were altered in narcoleptic dogs. However, we found that adenosine A1 receptors in the dog exist in different affinity states and that the affinity state in which the receptor is found depends on the brain region examined. A characterization of these low- and high-affinity sites was performed and results indicated that these sites cannot be explained by a single interaction of the A1 receptor with a single G-protein population.

  View details for Web of Science ID A1991EQ55300001

  View details for PubMedID 1901994

• EFFECTS OF CENTRAL ALPHA-2 ADRENERGIC COMPOUNDS ON CANINE NARCOLEPSY, A DISORDER OF RAPID EYE-MOVEMENT SLEEP JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Nishino, S., Haak, L., Shepherd, H., Guilleminault, C., Sakai, T., Dement, W. C., Mignot, E. 1990; 253 (3): 1145-1152

  Abstract

  Recent experiments have demonstrated that pharmacological activation of central noradrenergic systems by monoaminergic stimulators or uptake blockers or through the stimulation of alpha-1 adrenergic receptors improved cataplexy, a major symptom of narcolepsy. In order to further the understanding of the control of cataplexy by noradrenergic mechanisms, the involvement of central alpha-2 adrenoceptors was examined in genetically narcoleptic Doberman pinschers using in vivo pharmacology. Yohimbine (1.5-96.0 micrograms/kg i.v.) and seven other selective and centrally acting alpha-2 adrenoceptor antagonists (rauwolscine: 1.5-96 micrograms/kg i.v.; atipemazole: 1.5-96 micrograms/kg i.v.; Wy-25309: 1.5-386 micrograms/kg i.v.; CGS-7525A: 1.5-386 micrograms/kg i.v.; idazoxan, 6-1536 micrograms/kg i.v.; piperoxan, 6-1536 micrograms/kg i.v.; and mianserin, 6-1536 micrograms/kg i.v.) significantly suppressed cataplexy. The alpha-2 mediation of this effect was demonstrated by a close correlation between drug affinities (Ki) toward the alpha-2 site (defined using [3H]yohimbine in canine cortex) and the ability of these drugs to reduce cataplexy [ED50 in nanomoles per kilogram i.v.) (r2 = 0.71, n = 8, P less than .01). The effects of six centrally acting alpha-2 agonists on canine cataplexy were also examined and two groups of compounds were distinguished on the basis of their pharmacological profile. Classical alpha-2 agonists such as clonidine (0.0625-4.0 micrograms/kg i.v.), p-aminoclonidine (0.0625-4.0 micrograms/kg i.v.) and guanfacine (0.0625-4.0 micrograms/kg i.v.) had no effect on cataplexy whereas BHT-920 (0.01875-3.0 micrograms/kg i.v.), BHT-933 (16.0-258 micrograms/kg i.v.) and xylazine (16.0-258 micrograms/kg i.v.) dramatically aggravated cataplexy.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990DK70200035

  View details for PubMedID 1972749

• NORADRENERGIC AND CHOLINERGIC CONTROL OF CATAPLEXY - PHARMACOLOGICAL EVIDENCE 2ND INTERNATIONAL SYMP ON ENDOGENOUS SLEEP FACTORS Mignot, E., Nishino, S., Guilleminault, C., Dement, W. C. S P B ACADEMIC PUBL. 1990: 203–215

  View details for Web of Science ID A1990BT19L00021

• RECEPTOLOGY IN NARCOLEPSY 1ST EUROPEAN CONGRESS OF NEUROLOGY / INTERNATIONAL SYMP ON NEUROLOGICAL EMERGENCIES Mignot, E., Guilleminault, C. JOHN LIBBEY & CO. 1990: 521–530

  View details for Web of Science ID A1990BR70B00096

• EFFECTS OF INTRAVENOUS ADMINISTRATION OF PROSTAGLANDINS ON CANINE NARCOLEPSY 2ND INTERNATIONAL SYMP ON ENDOGENOUS SLEEP FACTORS Nishino, S., Mignot, E., Fruhstorfer, B., Kilduff, T. S., Ueno, R., Hayaishi, O., Dement, W. C. S P B ACADEMIC PUBL. 1990: 77–83

  View details for Web of Science ID A1990BT19L00009

• FAMILIAL PATTERNS OF NARCOLEPSY LANCET Guilleminault, C., Mignot, E., GRUMET, F. C. 1989; 2 (8676): 1376-1379

  Abstract

  Familial patterns of narcolepsy were investigated in a clinic population of 334 unrelated narcoleptic patients. 40% of probands had at least 1 family member with an isolated daytime sleepiness complaint and 6% had a positive family history of narcolepsy. Multicase families were rare; only two families were found with 3 or more affected relatives. Family members often shared the same HLA-DR2 haplotype as the proband but did not have narcolepsy. However, the risk of disease for first-degree relatives was six to eighteen times greater than that for unrelated individuals. Although most patients were HLA-DR2+, 2 new HLA-DR2- individuals were found. The data predict that as many as 9% of unrelated North-American white patients with narcolepsy will be DR2-. Analysis of these and other data indicates that although strongly associated with disease, the HLA-DR2 haplotype is neither sufficient nor necessary for the development of narcolepsy.

  View details for Web of Science ID A1989CD35200012

  View details for PubMedID 2574313

• EVIDENCE FOR MULTIPLE [H-3] PRAZOSIN BINDING-SITES IN CANINE BRAIN MEMBRANES BRAIN RESEARCH Mignot, E., Bowersox, S. S., Maddaluno, J., Dement, W., CIARANELLO, R. 1989; 486 (1): 56-66

  Abstract

  Two classes of alpha 1 adrenoceptors were identified in canine brain and liver using conventional radioligand binding methods. Scatchard plots of specific [3H]prazosin binding to brain and liver membranes prepared from 100-150-day-old Doberman pinscher dogs were consistently curvilinear and best fit a two-site binding model (frontal cortex, Kd1 = 57.7 +/- 10.0 pM, Bmax1 = 64.6 +/- 17.1 fmol/mg protein, Kd2 = 1.5 +/- 0.5 nM, Bmax2 = 159 +/- 37.6 fmol/mg protein; liver, Kd1 = 82.6 +/- 36 pM, Bmax1 = 7.0 +/- 5.1 fmol/mg protein, Kd2 = 0.8 +/- 0.2 nM, Bmax2 = 62.1 +/- 8.7 fmol/mg protein). Kinetically derived affinity constants from association and dissociation experiments agreed with those obtained by Scatchard analyses of equilibrium binding data. Binding sites were saturable, heat labile, bound ligand reversibly, and appeared to be appropriately distributed in relation to endogenous catecholamine. [3H]Prazosin also bound with high affinity to two classes of binding site in porcine and bovine brain membrane but [3H]prazosin binding in monkey and rat brain was best described by a single-site binding model. Affinities obtained were in between values obtained for high and low affinity Kds in the other species. Competitions for [3H]prazosin binding sites in canine frontal cortex were conducted with the following antagonists: WB-4101, corynanthine, phentolamine, benoxathian, phenoxybenzamine, chlorethylclonidine, thymoxamine, prazosin, yohimbine and agonists: methoxamine, (-)-norepinephrine, and clonidine. All ligands but prazosin, norepinephrine and clonidine competed for specific [3H]prazosin binding in a statistically significant biphasic manner. Benoxathian and WB-4101 displayed the highest affinities (benoxathian: Ki1 = 0.26 nM, WB-4101: Ki1 = 0.20 nM) and selectivity (high affinity/low affinity: benoxathian = 1640, WB-4101 = 13204) for the high affinity [3H]prazosin binding site; chlorethylclonidine had highest affinity (Ki2 = 91 nM) and selectivity (low affinity/high affinity = 405) for the lower affinity [3H]prazosin binding site. As defined, the two sites were similar to the alpha 1a and alpha 1b recently described in the rat and rabbit. A noticeable difference was that the subtypes described in dog brain had a 30-fold difference in affinity for prazosin.

  View details for Web of Science ID A1989U375200007

  View details for PubMedID 2541871

• PROSTAGLANDIN-E2 AND ITS METHYL-ESTER REDUCE CATAPLEXY IN CANINE NARCOLEPSY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nishino, S., Mignot, E., Fruhstorfer, B., Dement, W. C., Hayaishi, O. 1989; 86 (7): 2483-2487

  Abstract

  The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.

  View details for Web of Science ID A1989U042300075

  View details for PubMedID 2928344

• ROLE OF CENTRAL ALPHA-1 ADRENOCEPTORS IN CANINE NARCOLEPSY JOURNAL OF CLINICAL INVESTIGATION Mignot, E., Guilleminault, C., Bowersox, S., Rappaport, A., Dement, W. C. 1988; 82 (3): 885-894

  Abstract

  The role of central alpha-1 adrenergic receptors in cataplexy was investigated in genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with 25-600 micrograms/kg prazosin, a selective alpha-1 adrenergic receptor blocker, exacerbated cataplexy, whereas treatment with the alpha-1 agonist, methoxamine, ameliorated it. Subsequent studies showed that the beneficial effects of classical treatments of human narcolepsy (amphetamines and tricyclic antidepressants) are antagonized by prazosin, suggesting that these drugs are active through an indirect alpha-1 stimulation (via an increase of norepinephrine in the synaptic cleft). Other studies confirmed that the observed effects were not due to peripheral alpha-1 cardiovascular involvement. Atropine, a central anticholinergic agent, but not methylatropine, a peripheral one, completely suppressed the prazosin effect, which suggests that adrenergic and cholinergic systems act sequentially and not independently to generate cataplexy. Little is known about the physiological role of central alpha-1 adrenoceptors. This series of experiments implicates these receptors in narcolepsy-cataplexy.

  View details for Web of Science ID A1988Q160600022

  View details for PubMedID 2843574