Sharon Sha, MD, MS

All Publications

• Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction. Research square Wilson, E., Umans, J., Swarovski, M., Minhas, P., Midttun, Ø., Ulvik, A. A., Shahid-Besanti, M., Linortner, P., Mhatre, S., Wang, Q., Channappa, D., Corso, N., Tian, L., Fredericks, C., Kerchner, G., Plowey, E., Cholerton, B., Ueland, P., Zabetian, C., Gray, N., Quinn, J., Montine, T., Sha, S., Longo, F., Wolk, D., Chen-Plotkin, A., Henderson, V., Wyss-Coray, T., Wagner, A., Mormino, E., Aghaeepour, N., Poston, K., Andreasson, K. 2024

  Abstract

  Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

  View details for DOI 10.21203/rs.3.rs-4980210/v1

  View details for PubMedID 39399688

  View details for PubMedCentralID PMC11469709

• Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation. Alzheimer's & dementia : the journal of the Alzheimer's Association Johns, E., Vossler, H. A., Young, C. B., Carlson, M. L., Winer, J. R., Younes, K., Park, J., Rathmann-Bloch, J., Smith, V., Harrison, T. M., Landau, S., Henderson, V., Wagner, A., Sha, S. J., Zeineh, M., Zaharchuk, G., Poston, K. L., Davidzon, G. A., Mormino, E. C. 2024

  Abstract

  Amyloid positron emission tomography (PET) acquisition timing impacts quantification.In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases.CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan.The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols.Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

  View details for DOI 10.1002/alz.13893

  View details for PubMedID 38962867

• The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias. Cerebellum (London, England) Selvadurai, L. P., Perlman, S. L., Ashizawa, T., Wilmot, G. R., Onyike, C. U., Rosenthal, L. S., Shakkottai, V. G., Paulson, H. L., Subramony, S. H., Bushara, K. O., Kuo, S. H., Dietiker, C., Geschwind, M. D., Nelson, A. B., Gomez, C. M., Opal, P., Zesiewicz, T. A., Hawkins, T., Yacoubian, T. A., Nopoulos, P. C., Sha, S. J., Morrison, P. E., Figueroa, K. P., Pulst, S. M., Schmahmann, J. D. 2024

  Abstract

  The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

  View details for DOI 10.1007/s12311-023-01651-0

  View details for PubMedID 38165578

  View details for PubMedCentralID 4552302

• Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes. Alzheimer's & dementia : the journal of the Alzheimer's Association Abiose, O., Rutledge, J., Moran-Losada, P., Belloy, M. E., Wilson, E. N., He, Z., Trelle, A. N., Channappa, D., Romero, A., Park, J., Yutsis, M. V., Sha, S. J., Andreasson, K. I., Poston, K. L., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Mormino, E. C. 2023

  Abstract

  In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults.We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes.We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = -2.00, p = 0.005, M7: β = -2.39, p < 0.001).In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

  View details for DOI 10.1002/alz.13576

  View details for PubMedID 38146099

• The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort. Alzheimer's & dementia : the journal of the Alzheimer's Association Touroutoglou, A., Katsumi, Y., Brickhouse, M., Zaitsev, A., Eckbo, R., Aisen, P., Beckett, L., Dage, J. L., Eloyan, A., Foroud, T., Ghetti, B., Griffin, P., Hammers, D., Jack, C. R., Kramer, J. H., Iaccarino, L., Joie, R. L., Mundada, N. S., Koeppe, R., Kukull, W. A., Murray, M. E., Nudelman, K., Polsinelli, A. J., Rumbaugh, M., Soleimani-Meigooni, D. N., Toga, A., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J. C., Mendez, M. F., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S., Turner, R. S., Wingo, T. S., Wolk, D. A., Womack, K., Carrillo, M. C., Rabinovici, G. D., Apostolova, L. G., Dickerson, B. C. 2023

  Abstract

  Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker.We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment.The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment.The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD.We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

  View details for DOI 10.1002/alz.13466

  View details for PubMedID 37850549

• Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort. Alzheimer's & dementia : the journal of the Alzheimer's Association Nudelman, K. N., Jackson, T., Rumbaugh, M., Eloyan, A., Abreu, M., Dage, J. L., Snoddy, C., Faber, K. M., Foroud, T., Hammers, D. B., DIAN/DIAN-TU Clinical/Genetics Committee, Taurone, A., Thangarajah, M., Aisen, P., Beckett, L., Kramer, J., Koeppe, R., Kukull, W. A., Murray, M. E., Toga, A. W., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J. C., Mendez, M., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Wingo, T. S., Wolk, D. A., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G., LEADS Consortium 2023

  Abstract

  INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N=299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

  View details for DOI 10.1002/alz.13482

  View details for PubMedID 37801072

• Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Alzheimer's & dementia : the journal of the Alzheimer's Association Cho, H., Mundada, N. S., Apostolova, L. G., Carrillo, M. C., Shankar, R., Amuiri, A. N., Zeltzer, E., Windon, C. C., Soleimani-Meigooni, D. N., Tanner, J. A., Heath, C. L., Lesman-Segev, O. H., Aisen, P., Eloyan, A., Lee, H. S., Hammers, D. B., Kirby, K., Dage, J. L., Fagan, A., Foroud, T., Grinberg, L. T., Jack, C. R., Kramer, J., Kukull, W. A., Murray, M. E., Nudelman, K., Toga, A., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J., Mendez, M., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E. J., Salloway, S., Sha, S., Turner, R. S., Wingo, T. S., Wolk, D. A., Koeppe, R., Iaccarino, L., Dickerson, B. C., La Joie, R., Rabinovici, G. D. 2023

  Abstract

  We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD).We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification.243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants.LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD.72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

  View details for DOI 10.1002/alz.13453

  View details for PubMedID 37690109

• Influence of amyloid and diagnostic syndrome on non-traditional memory scores in early-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association Bushnell, J., Hammers, D. B., Aisen, P., Dage, J. L., Eloyan, A., Foroud, T., Grinberg, L. T., Iaccarino, L., Jack, C. R., Kirby, K., Kramer, J., Koeppe, R., Kukull, W. A., La Joie, R., Mundada, N. S., Murray, M. E., Nudelman, K., Rumbaugh, M., Soleimani-Meigooni, D. N., Toga, A., Touroutoglou, A., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J., Mendez, M., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S., Turner, R. S., Wingo, T. S., Wolk, D. A., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G., Clark, D. G. 2023

  Abstract

  The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD.We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables.Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time.RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores.RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.

  View details for DOI 10.1002/alz.13434

  View details for PubMedID 37653686

• Lewy Body Dementia: An Overview of Promising Therapeutics. Current neurology and neuroscience reports Skylar-Scott, I. A., Sha, S. J. 2023

  Abstract

  Lewy body dementia (LBD) encompasses dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). This article will emphasize potential disease-modifying therapies as well as investigative symptomatic treatments for non-motor symptoms including cognitive impairment and psychosis that can present a tremendous burden to patients with LBD and their caregivers.We review 11 prospective disease-modifying therapies (DMT) including four with phase 2 data (neflamapimod, nilotinib, bosutinib, and E2027); four with some limited data in symptomatic populations including phase 1, open-label, registry, or cohort data (vodabatinib, ambroxol, clenbuterol, and terazosin); and three with phase 1 data in healthy populations (Anle138b, fosgonimeton, and CT1812). We also appraise four symptomatic therapies for cognitive impairment, but due to safety and efficacy concerns, only NYX-458 remains under active investigation. Of symptomatic therapies for psychosis recently investigated, pimavanserin shows promise in LBD, but studies of nelotanserin have been suspended. Although the discovery of novel symptomatic and disease-modifying therapeutics remains a significant challenge, recently published and upcoming trials signify promising strides toward that aim.

  View details for DOI 10.1007/s11910-023-01292-0

  View details for PubMedID 37572228

  View details for PubMedCentralID 5496518

• Sex and APOE epsilon4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association Nemes, S., Logan, P. E., Manchella, M. K., Mundada, N. S., La Joie, R., Polsinelli, A. J., Hammers, D. B., Koeppe, R. A., Foroud, T. M., Nudelman, K. N., Eloyan, A., Iaccarino, L., Dorsant-Ardon, V., Taurone, A., Thangarajah, M., Dage, J. L., Aisen, P., Grinberg, L. T., Jack, C. R., Kramer, J., Kukull, W. A., Murray, M. E., Rumbaugh, M., Soleimani-Meigooni, D. N., Toga, A., Touroutoglou, A., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J., Mendez, M. F., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Wingo, T. S., Womack, K. B., Wolk, D. A., Rabinovici, G. D., Carrillo, M. C., Dickerson, B. C., Apostolova, L. G., LEADS Consortium 2023

  Abstract

  INTRODUCTION: We used sex and apolipoprotein E epsilon4 (APOE epsilon4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD).METHODS: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE epsilon4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.RESULTS: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE epsilon4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female epsilon4 carriers. EOnonAD female epsilon4 non-carriers also had greater gray matter atrophy than female epsilon4 carriers.DISCUSSION: The effects of sex and APOE epsilon4 must be considered when studying these populations.HIGHLIGHTS: Novel analysis examining the effects of biological sex and apolipoprotein E epsilon4 (APOEepsilon4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE epsilon4 carrier status on pathology burden was the most impactful in females across all cohorts.

  View details for DOI 10.1002/alz.13403

  View details for PubMedID 37496307

• White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Alzheimer's & dementia : the journal of the Alzheimer's Association Eloyan, A., Thangarajah, M., An, N., Borowski, B. J., Reddy, A. L., Aisen, P., Dage, J. L., Foroud, T., Ghetti, B., Griffin, P., Hammers, D., Iaccarino, L., Jack, C. R., Kirby, K., Kramer, J., Koeppe, R., Kukull, W. A., La Joie, R., Mundada, N. S., Murray, M. E., Nudelman, K., Rumbaugh, M., Soleimani-Meigooni, D. N., Toga, A., Touroutoglou, A., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J., Mendez, M. F., Musiek, E., Onyike, C. U., Rogalski, E., Salloway, S., Sha, S., Turner, R. S., Wingo, T. S., Wolk, D. A., Womack, K., Beckett, L., Gao, S., Carrillo, M. C., Rabinovici, G., Apostolova, L. G., Dickerson, B., Vemuri, P., and the LEADS Consortium 2023

  Abstract

  INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study.METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden.RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group.DISCUSSION: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD.HIGHLIGHTS: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

  View details for DOI 10.1002/alz.13402

  View details for PubMedID 37491599

• Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study. Alzheimer's & dementia : the journal of the Alzheimer's Association Dage, J. L., Eloyan, A., Thangarajah, M., Hammers, D. B., Fagan, A. M., Gray, J. D., Schindler, S. E., Snoddy, C., Nudelman, K. N., Faber, K. M., Foroud, T., Aisen, P., Griffin, P., Grinberg, L. T., Iaccarino, L., Kirby, K., Kramer, J., Koeppe, R., Kukull, W. A., La Joie, R., Mundada, N. S., Murray, M. E., Rumbaugh, M., Soleimani-Meigooni, D. N., Toga, A. W., Touroutoglou, A., Vemuri, P., Atri, A., Beckett, L. A., Day, G. S., Graff-Radford, N. R., Duara, R., Honig, L. S., Jones, D. T., Masdeu, J. C., Mendez, M. F., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Wingo, T. S., Wolk, D. A., Womack, K. B., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G., LEADS Consortium 2023

  Abstract

  INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD).METHODS: Cerebrospinal fluid (CSF) concentrations of Abeta1-40, Abeta1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.RESULTS: Biomarkers were correlated with one another. Levels of CSF Abeta42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Abeta42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure.DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

  View details for DOI 10.1002/alz.13399

  View details for PubMedID 37491668

• Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort. Alzheimer's & dementia : the journal of the Alzheimer's Association Polsinelli, A. J., Wonderlin, R. J., Hammers, D. B., Garcia, A. P., Eloyan, A., Taurone, A., Thangarajah, M., Beckett, L., Gao, S., Wang, S., Kirby, K., Logan, P. E., Aisen, P., Dage, J. L., Foroud, T., Griffin, P., Iaccarino, L., Kramer, J. H., Koeppe, R., Kukull, W. A., La Joie, R., Mundada, N. S., Murray, M. E., Nudelman, K., Soleimani-Meigooni, D. N., Rumbaugh, M., Toga, A. W., Touroutoglou, A., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J., Mendez, M. F., Womack, K., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Wingo, T. S., Wolk, D. A., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G., LEADS Consortium 2023

  Abstract

  INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n=212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n=70).RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

  View details for DOI 10.1002/alz.13344

  View details for PubMedID 37296082

• Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection. Alzheimer's & dementia : the journal of the Alzheimer's Association Hammers, D. B., Eloyan, A., Taurone, A., Thangarajah, M., Beckett, L., Gao, S., Kirby, K., Aisen, P., Dage, J. L., Foroud, T., Griffin, P., Grinberg, L. T., Jack, C. R., Kramer, J., Koeppe, R., Kukull, W. A., Mundada, N. S., La Joie, R., Soleimani-Meigooni, D. N., Iaccarino, L., Murray, M. E., Nudelman, K., Polsinelli, A. J., Rumbaugh, M., Toga, A., Touroutoglou, A., Vemuri, P., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J., Mendez, M. F., Womack, K., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Wingo, T. S., Wolk, D. A., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G. 2023

  Abstract

  The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point.Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]).Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant.Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

  View details for DOI 10.1002/alz.13160

  View details for PubMedID 37256497

• Learning slopes in early-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association Hammers, D. B., Nemes, S., Diedrich, T., Eloyan, A., Kirby, K., Aisen, P., Kramer, J., Nudelman, K., Foroud, T., Rumbaugh, M., Atri, A., Day, G. S., Duara, R., Graff-Radford, N. R., Honig, L. S., Jones, D. T., Masdeu, J. C., Mendez, M. F., Musiek, E., Onyike, C. U., Riddle, M., Rogalski, E., Salloway, S., Sha, S. J., Turner, R. S., Weintraub, S., Wingo, T. S., Wolk, D. A., Wong, B., Carrillo, M. C., Dickerson, B. C., Rabinovici, G. D., Apostolova, L. G., LEADS Consortium 2023

  Abstract

  OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without beta-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.HIGHLIGHTS: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

  View details for DOI 10.1002/alz.13159

  View details for PubMedID 37243937

• The MVP or the tombstone: is tau the correct target to treat Alzheimer's disease? Brain : a journal of neurology Younes, K., Sha, S. J. 2023

  View details for DOI 10.1093/brain/awad151

  View details for PubMedID 37150887

• Illusory Responses across the Lewy Body Disease Spectrum ANNALS OF NEUROLOGY Shahid, M., Rawls, A., Ramirez, V., Ryman, S., Santini, V. E., Yang, L., Sha, S. J., Hall, J. N., Montine, T. J., Lin, A., Tian, L., Henderson, V. W., Cholerton, B., Yutsis, M., Poston, K. L. 2023

  View details for DOI 10.1002/ana.26574

  View details for Web of Science ID 000925056000001

• Prediction of neuropathologic lesions from clinical data. Alzheimer's & dementia : the journal of the Alzheimer's Association Phongpreecha, T., Cholerton, B., Bhukari, S., Chang, A. L., De Francesco, D., Thuraiappah, M., Godrich, D., Perna, A., Becker, M. G., Ravindra, N. G., Espinosa, C., Kim, Y., Berson, E., Mataraso, S., Sha, S. J., Fox, E. J., Montine, K. S., Baker, L. D., Craft, S., White, L., Poston, K. L., Beecham, G., Aghaeepour, N., Montine, T. J. 2023

  Abstract

  Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life.This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities.Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased.Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

  View details for DOI 10.1002/alz.12921

  View details for PubMedID 36681388

• Research Priorities of Individuals and Caregivers With Lewy Body Dementia A Web-based Survey ALZHEIMER DISEASE & ASSOCIATED DISORDERS Holden, S. K., Bedenfield, N., Taylor, A. S., Bayram, E., Schwilk, C., Fleisher, J., Duda, J., Shill, H., Paulson, H. L., Stacy, K., Wood, J., Corsentino, P., Sha, S. J., Litvan, I., Irwin, D. J., Quinn, J. F., Goldman, J. G., Amodeo, K., Taylor, J., Boeve, B. F., Armstrong, M. J. 2023; 37 (1): 50-58

  Abstract

  Lewy body dementia (LBD) is common, yet under-recognized and under-researched. To plan studies with the highest impact, engagement of the community personally affected by these conditions is essential.A web-based survey of people living with LBD and current and former caregivers of people with LBD queried research priorities through forced ranking and exploration of burden of LBD symptoms. Specific caregiving needs in LBD and perceptions of research participation were also investigated.Between April 7, 2021 and July 1, 2021, 984 responses were recorded. Top research priorities included disease-modifying therapies and improved disease detection and staging. People with LBD were interested in pathophysiology and more bothered by motor symptoms; caregivers were interested in risk factors and symptomatic therapies and more bothered by neuropsychiatric symptoms. Few available LBD treatments and resources were rated as helpful, and many valuable services were never received. Previous participation in LBD research was infrequent, but interest was high.People with LBD and caregivers highlighted the need for research across all aspects of LBD, from pathophysiology and disease modification to prognosis, education, symptomatic treatments, and caregiver support. Funders should increase support for all aspects of LBD research to target the many needs identified by individuals and families living with LBD.

  View details for DOI 10.1097/WAD.0000000000000545

  View details for Web of Science ID 001006680100008

  View details for PubMedID 36821177

  View details for PubMedCentralID PMC9971616

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• Illusory responses across the Lewy body disease spectrum Shahid, M., Rawls, A., Ramirez, V., Ryman, S., Santini, V., Yang, L., Sha, S., Hall, J., Montine, T., Lin, A., Tian, L., Henderson, V., Cholerton, B., Yutsis, M., Poston, K. WILEY. 2022: S364-S365

  Abstract

  To study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions.We studied illusory responses on the Noise Pareidolia Task in 300 participants [38 cognitively-impaired LB, 65 cognitively-unimpaired LB, 51 Alzheimer's disease-spectrum (AD-s), 146 Controls]. Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions.Cognitively-impaired LB participants were 12.3, 4.9, and 4.6 times more likely than Control, cognitively-unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex and education, the probability of endorsing one or more illusory response was 61% in the cognitively-impaired LB group, compared to 26% in AD-s, 25% in cognitively-unimpaired LB, and 12% in Control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least one illusory response.We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. This article is protected by copyright. All rights reserved.

  View details for Web of Science ID 000859942301355

  View details for PubMedID 36511519

• Large Collaborative Registries and Real-world Data to Manage Amyloid-Related Imaging Abnormalities-Reply. JAMA neurology Hall, J. N., Sha, S. J. 2022

  View details for DOI 10.1001/jamaneurol.2022.0734

  View details for PubMedID 35467703

• Addition of Vision Impairment to a Life-Course Model of Potentially Modifiable Dementia Risk Factors in the US RESPONSE JAMA NEUROLOGY Hall, J. N., Sha, S. J. 2022; 79 (6): 623-626

  View details for DOI 10.1001/jamaneurol.2022.0723

  View details for Web of Science ID 000788690500002

• Six Recurrent Amyloid-Related Imaging Abnormality Episodes in a Patient Treated With Aducanumab. JAMA neurology Hall, J. N., Mormino, E., Ng, A., Boumis, A., Gaudioso, J. L., Davidzon, G. A., Sha, S. J. 2021

  View details for DOI 10.1001/jamaneurol.2021.3933

  View details for PubMedID 34747986

• Association of CSF Biomarkers with Hippocampal-dependent Memory in Preclinical Alzheimer Disease. Neurology Trelle, A. N., Carr, V. A., Wilson, E. N., Swarovski, M. S., Hunt, M. P., Toueg, T. N., Tran, T. T., Channappa, D. n., Corso, N. K., Thieu, M. K., Jayakumar, M. n., Nadiadwala, A. n., Guo, W. n., Tanner, N. J., Bernstein, J. D., Litovsky, C. P., Guerin, S. A., Khazenzon, A. M., Harrison, M. B., Rutt, B. K., Deutsch, G. K., Chin, F. T., Davidzon, G. A., Hall, J. N., Sha, S. J., Fredericks, C. A., Andreasson, K. I., Kerchner, G. A., Wagner, A. D., Mormino, E. C. 2021

  Abstract

  To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer's disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied 'target' objects, novel 'foil' objects, and perceptually similar 'lure' objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

  View details for DOI 10.1212/WNL.0000000000011477

  View details for PubMedID 33408146

• Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium. Frontiers in neurology Scott, G. D., Arnold, M. R., Beach, T. G., Gibbons, C. H., Kanthasamy, A. G., Lebovitz, R. M., Lemstra, A. W., Shaw, L. M., Teunissen, C. E., Zetterberg, H., Taylor, A. S., Graham, T. C., Boeve, B. F., Gomperts, S. N., Graff-Radford, N. R., Moussa, C., Poston, K. L., Rosenthal, L. S., Sabbagh, M. N., Walsh, R. R., Weber, M. T., Armstrong, M. J., Bang, J. A., Bozoki, A. C., Domoto-Reilly, K., Duda, J. E., Fleisher, J. E., Galasko, D. R., Galvin, J. E., Goldman, J. G., Holden, S. K., Honig, L. S., Huddleston, D. E., Leverenz, J. B., Litvan, I., Manning, C. A., Marder, K. S., Pantelyat, A. Y., Pelak, V. S., Scharre, D. W., Sha, S. J., Shill, H. A., Mari, Z., Quinn, J. F., Irwin, D. J. 2021; 12: 805135

  Abstract

  The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

  View details for DOI 10.3389/fneur.2021.805135

  View details for PubMedID 35173668

• Visual Read Protocols for Clinicians Analyzing 18F-PI-2620 tau PET/MRI Images Koran, M., Shams, S., Adams, P., Toueg, T., Azevedo, C., Hall, J., Corso, N., Sha, S., Fredericks, C., Greicius, M., Wagner, A., Zaharchuk, G., Davidzon, G., Chin, F., Mormino, E. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501466

• Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults. eLife Trelle, A. N., Carr, V. A., Guerin, S. A., Thieu, M. K., Jayakumar, M. n., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hunt, M. P., Litovsky, C. P., Tanner, N. J., Deutsch, G. K., Bernstein, J. D., Harrison, M. B., Khazenzon, A. M., Jiang, J. n., Sha, S. J., Fredericks, C. A., Rutt, B. K., Mormino, E. C., Kerchner, G. A., Wagner, A. D. 2020; 9

  Abstract

  Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

  View details for DOI 10.7554/eLife.55335

  View details for PubMedID 32469308

• Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases. European journal of nuclear medicine and molecular imaging Mormino, E. C., Toueg, T. N., Azevedo, C. n., Castillo, J. B., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hall, J. N., Fan, A. n., Trelle, A. N., Harrison, M. B., Hunt, M. P., Sha, S. J., Deutsch, G. n., James, M. n., Fredericks, C. A., Koran, M. E., Zeineh, M. n., Poston, K. n., Greicius, M. D., Khalighi, M. n., Davidzon, G. A., Shen, B. n., Zaharchuk, G. n., Wagner, A. D., Chin, F. T. 2020

  Abstract

  In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD).Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient.Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

  View details for DOI 10.1007/s00259-020-04923-7

  View details for PubMedID 32572562

• Lewy Body Dementia Association's Research Centers of Excellence Program: Inaugural Meeting Proceedings. Alzheimer's research & therapy Peterson, B., Armstrong, M., Galasko, D., Galvin, J. E., Goldman, J., Irwin, D., Paulson, H., Kaufer, D., Leverenz, J., Lunde, A., McKeith, I. G., Siderowf, A., Taylor, A., Amodeo, K., Barrett, M., Domoto-Reilly, K., Duda, J., Gomperts, S., Graff-Radford, N., Holden, S., Honig, L., Huddleston, D., Lippa, C., Litvan, I., Manning, C., Marder, K., Moussa, C., Onyike, C., Pagan, F., Pantelyat, A., Pelak, V., Poston, K., Quinn, J., Richard, I., Rosenthal, L. S., Sabbagh, M., Scharre, D., Sha, S., Shill, H., Torres-Yaghi, Y., Christie, T., Graham, T., Richards, I., Koehler, M., Boeve, B. 2019; 11 (1): 23

  Abstract

  The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

  View details for PubMedID 30867052

• Positive Attitudes and Therapeutic Misconception Around Hypothetical Clinical Trial Participation in the Huntington's Disease Community. Journal of Huntington's disease Cotter, K. n., Siskind, C. n., Sha, S. n., Hanson-Kahn, A. n. 2019

  Abstract

  New therapies that could modify the disease course of Huntington's disease (HD) are entering clinical trials. However, conceptions about clinical research from the HD community are unknown. This knowledge could help inform patient-clinician discussions surrounding clinical trial participation.The purpose of this study was to assess clinical trial attitudes and understanding in the HD community.We developed a survey incorporating two measures of trial understanding and attitudes and the impact of therapeutic route of administration on hypothetical trial participation. The survey was distributed via emails, flyers, and social media through HD-related organizations.There were 73 responses. Individuals self-reported as clinically diagnosed with HD, gene positive but asymptomatic, or primary caregivers. Respondents viewed clinical trials positively and generally viewed trials as safe. Individuals with prior HD-related research experience were less likely to have negative expectations about trials than those without research experience (p = 0.002), and women had higher information needs than men (p = 0.001) Individuals with HD were more likely than the other groups to experience therapeutic misconception (p = 0.002). All respondents were able to appraise risks and benefits of research but exhibited optimism about trial outcomes. Willingness to participate was highest when the route of administration was minimally invasive.While the HD community views clinical trials positively, patients with HD are at high risk for therapeutic misconception and all groups are optimistic about trial outcomes. Limitations of this study include a small sample that may be inclined to view research positively given past trial participation and interest in participating in HD surveys. However, the findings from this study can be used to strengthen informed consent during HD clinical trial recruitment.

  View details for DOI 10.3233/JHD-190382

  View details for PubMedID 31594242

• Ultra-Low-Dose 18F-Florbetaben Amyloid PET Imaging Using Deep Learning with Multi-Contrast MRI Inputs. Radiology Chen, K. T., Gong, E., de Carvalho Macruz, F. B., Xu, J., Boumis, A., Khalighi, M., Poston, K. L., Sha, S. J., Greicius, M. D., Mormino, E., Pauly, J. M., Srinivas, S., Zaharchuk, G. 2018: 180940

  Abstract

  Purpose To reduce radiotracer requirements for amyloid PET/MRI without sacrificing diagnostic quality by using deep learning methods. Materials and Methods Forty data sets from 39 patients (mean age ± standard deviation [SD], 67 years ± 8), including 16 male patients and 23 female patients (mean age, 66 years ± 6 and 68 years ± 9, respectively), who underwent simultaneous amyloid (fluorine 18 [18F]-florbetaben) PET/MRI examinations were acquired from March 2016 through October 2017 and retrospectively analyzed. One hundredth of the raw list-mode PET data were randomly chosen to simulate a low-dose (1%) acquisition. Convolutional neural networks were implemented with low-dose PET and multiple MR images (PET-plus-MR model) or with low-dose PET alone (PET-only) as inputs to predict full-dose PET images. Quality of the synthesized images was evaluated while Bland-Altman plots assessed the agreement of regional standard uptake value ratios (SUVRs) between image types. Two readers scored image quality on a five-point scale (5 = excellent) and determined amyloid status (positive or negative). Statistical analyses were carried out to assess the difference of image quality metrics and reader agreement and to determine confidence intervals (CIs) for reading results. Results The synthesized images (especially from the PET-plus-MR model) showed marked improvement on all quality metrics compared with the low-dose image. All PET-plus-MR images scored 3 or higher, with proportions of images rated greater than 3 similar to those for the full-dose images (-10% difference [eight of 80 readings], 95% CI: -15%, -5%). Accuracy for amyloid status was high (71 of 80 readings [89%]) and similar to intrareader reproducibility of full-dose images (73 of 80 [91%]). The PET-plus-MR model also had the smallest mean and variance for SUVR difference to full-dose images. Conclusion Simultaneously acquired MRI and ultra-low-dose PET data can be used to synthesize full-dose-like amyloid PET images. © RSNA, 2018 Online supplemental material is available for this article.

  View details for PubMedID 30526350

• Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA neurology Sha, S. J., Deutsch, G. K., Tian, L. n., Richardson, K. n., Coburn, M. n., Gaudioso, J. L., Marcal, T. n., Solomon, E. n., Boumis, A. n., Bet, A. n., Mennes, M. n., van Oort, E. n., Beckmann, C. F., Braithwaite, S. P., Jackson, S. n., Nikolich, K. n., Stephens, D. n., Kerchner, G. A., Wyss-Coray, T. n. 2018

  Abstract

  Young mouse plasma restores memory in aged mice, but, to our knowledge, the effects are unknown in patients with Alzheimer disease (AD).To assess the safety, tolerability, and feasibility of infusions of young fresh frozen plasma (yFFP) from donors age 18 to 30 years in patients with AD.The Plasma for Alzheimer Symptom Amelioration (PLASMA) study randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed by a 6-week washout and crossover to 4 once-weekly infusions of an alternate treatment. Patients and informants were masked to treatment and subjective measurements. After an open-label amendment, 9 patients received 4 weekly yFFP infusions only and their subjective measurements were unmasked. Patients were enrolled solely at Stanford University, a tertiary academic medical center, from September 2014 to December 2016, when enrollment reached its target. Eighteen consecutive patients with probable mild to moderate AD dementia, a Mini-Mental State Examination (score of 12 to 24 inclusive), and an age of 50 to 90 years were enrolled. Thirty-one patients were screened and 13 were excluded: 11 failed the inclusion criteria and 2 declined to participate.One unit of yFFP from male donors/placebo infused once weekly for 4 weeks.The primary outcomes were the safety, tolerability, and feasibility of 4 weekly yFFP infusions. Safety end point analyses included all patients who received the study drug/placebo.There was no difference in the age (mean [SD], 74.17 [7.96] years), sex (12 women [67%]), or baseline Mini-Mental State Examination score (mean [SD], 19.39 [3.24]) between the crossover (n = 9) and open-label groups (n = 9). There were no related serious adverse events. One patient discontinued participation because of urticaria and another because of an unrelated stroke. There was no statistically significant difference between the plasma (17 [94.4%]) and placebo (9 [100.0%]) cohorts for other adverse events, which were mild to moderate in severity. The most common adverse events in the plasma group included hypertension (3 [16.7%]), dizziness (2 [11.1%]), sinus bradycardia (3 [16.7%]), headache (3 [16.7%]), and sinus tachycardia (3 [16.7%]). The mean visit adherence (n = 18) was 86% (interquartile range, 87%-100%) and adherence, accounting for a reduction in the total visit requirement due to early patient discontinuation, was 96% (interquartile range, 89%-100%).The yFFP treatment was safe, well tolerated, and feasible. The study's limitations were the small sample size, short duration, and change in study design. The results warrant further exploration in larger, double-blinded placebo-controlled clinical trials.ClinicalTrials.gov Identifier: NCT02256306.

  View details for PubMedID 30383097

• An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. Alzheimer's & dementia (New York, N. Y.) Sha, S. J., Miller, Z. A., Min, S., Zhou, Y., Brown, J., Mitic, L. L., Karydas, A., Koestler, M., Tsai, R., Corbetta-Rastelli, C., Lin, S., Hare, E., Fields, S., Fleischmann, K. E., Powers, R., Fitch, R., Martens, L. H., Shamloo, M., Fagan, A. M., Farese, R. V., Pearlman, R., Seeley, W., Miller, B. L., Gan, L., Boxer, A. L. 2017; 3 (4): 507–12

  Abstract

  Introduction: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers.Methods: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints.Results: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2±10.9% in plasma and -10.2±7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period.Discussion: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

  View details for DOI 10.1016/j.trci.2017.08.002

  View details for PubMedID 29124108

• Egocentric and allocentric visuospatial working memory in premotor Huntington's disease: A double dissociation with caudate and hippocampal volumes. Neuropsychologia Possin, K. L., Kim, H., Geschwind, M. D., Moskowitz, T., Johnson, E. T., Sha, S. J., Apple, A., Xu, D., Miller, B. L., Finkbeiner, S., Hess, C. P., Kramer, J. H. 2017; 101: 57-64

  Abstract

  Our brains represent spatial information in egocentric (self-based) or allocentric (landmark-based) coordinates. Rodent studies have demonstrated a critical role for the caudate in egocentric navigation and the hippocampus in allocentric navigation. We administered tests of egocentric and allocentric working memory to individuals with premotor Huntington's disease (pmHD), which is associated with early caudate nucleus atrophy, and controls. Each test had 80 trials during which subjects were asked to remember 2 locations over 1-sec delays. The only difference between these otherwise identical tests was that locations could only be coded in self-based or landmark-based coordinates. We applied a multiatlas-based segmentation algorithm and computed point-wise Jacobian determinants to measure regional variations in caudate and hippocampal volumes from 3T MRI. As predicted, the pmHD patients were significantly more impaired on egocentric working memory. Only egocentric accuracy correlated with caudate volumes, specifically the dorsolateral caudate head, right more than left, a region that receives dense efferents from dorsolateral prefrontal cortex. In contrast, only allocentric accuracy correlated with hippocampal volumes, specifically intermediate and posterior regions that connect strongly with parahippocampal and posterior parietal cortices. These results indicate that the distinction between egocentric and allocentric navigation applies to working memory. The dorsolateral caudate is important for egocentric working memory, which can explain the disproportionate impairment in pmHD. Allocentric working memory, in contrast, relies on the hippocampus and is relatively spared in pmHD.

  View details for DOI 10.1016/j.neuropsychologia.2017.04.022

  View details for PubMedID 28427989

• Early-onset Alzheimer's disease versus frontotemporal dementia: resolution with genetic diagnoses? Neurocase Sha, S. J., Khazenzon, A. M., Ghosh, P. M., Rankin, K. P., Pribadi, M., Coppola, G., Geschwind, D. H., Rabinovici, G. D., Miller, B. L., Lee, S. E. 2016; 22 (2): 161-167

  Abstract

  We report a diagnostically challenging case of a 64-year-old man with a history of remote head trauma who developed mild behavioral changes and dyscalculia. He was diagnosed with clinical Alzheimer's disease (AD), with additional features consistent with behavioral variant frontotemporal dementia. Structural magnetic resonance imaging revealed atrophy in bilateral frontal and parietal cortices and hippocampi on visual inspection and left frontal pole and bilateral anterior temporal encephalomalacia, suspected to be due to head trauma. Consistent with the diagnosis of Alzheimer's pathology, positron emission tomography (PET) with Pittsburgh compound B suggested the presence of beta-amyloid. Fluorodeoxyglucose PET demonstrated hypometabolism in bilateral frontal and temporoparietal cortices. Voxel-based morphometry showed atrophy predominant in ventral frontal regions (bilateral orbitofrontal cortex, pregenual anterior cingulate/medial superior frontal gyrus), bilateral mid cingulate, bilateral lateral temporal cortex, and posterior insula. Bilateral caudate, thalamus, hippocampi, and cerebellum were prominently atrophied. Unexpectedly, a pathologic hexanucleotide repeat expansion in C9ORF72 was identified in this patient. This report underscores the clinical variability in C9ORF72 expansion carriers and the need to consider mixed pathologies, particularly when imaging studies are inconsistent with a single syndrome or pathology.

  View details for DOI 10.1080/13554794.2015.1080283

  View details for PubMedID 26304661

• Frontotemporal Dementia and Psychiatric Illness: Emerging Clinical and Biological Links in Gene Carriers AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Block, N. R., Sha, S. J., Karydas, A. M., Fong, J. C., De May, M. G., Miller, B. L., Rosen, H. J. 2016; 24 (2): 107-116

  Abstract

  To describe psychiatric presentations in individuals with genetic mutations causing frontotemporal dementia (FTD).Case descriptions from five carriers of FTD-related gene mutations with symptoms associated with non-neurodegenerative psychiatric disease.A comprehensive research program investigating genetic and non-genetic FTD at the University of California, San Francisco Memory and Aging Center.Three proband and two non-proband gene carriers.Medical history and neurological examination, neuropsychological testing, magnetic resonance and/or positron emission tomography imaging, and a genetic analysis to screen for dementia-related mutations. Genetic status was unknown at the time of initial evaluation.The chosen cases are illustrative of the variety of presentations of psychiatric symptoms in FTD gene carriers. In some cases, a non-neurodegenerative psychiatric illness was diagnosed based on specific symptoms, but the diagnosis may have been inappropriate based on the overall syndrome. In other cases, symptoms closely resembling those seen in non-neurodegenerative psychiatric illness did occur, in some cases immediately preceding the development of dementia, and in other cases developing a decade prior to dementia symptoms.Psychiatric symptoms in FTD gene carriers can be very similar to those seen in non-neurodegenerative psychiatric illness. Psychiatric symptoms with atypical features (e.g., late-life onset, insidiously worsening course) should prompt careful assessment for neurodegenerative disease. Guidelines for such an assessment should be established.

  View details for DOI 10.1016/j.jagp.2015.04.007

  View details for Web of Science ID 000370787800002

  View details for PubMedID 26324540

  View details for PubMedCentralID PMC4686378

• Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. Alzheimer's research & therapy Sha, S. J., Ghosh, P. M., Lee, S. E., Corbetta-Rastelli, C., Jagust, W. J., Kornak, J., Rankin, K. P., Grinberg, L. T., Vinters, H. V., Mendez, M. F., Dickson, D. W., Seeley, W. W., Gorno-Tempini, M., Kramer, J., Miller, B. L., Boxer, A. L., Rabinovici, G. D. 2015; 7 (1): 8-?

  Abstract

  Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer's disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer's disease neuropathology) in patients presenting with CBS.In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal).A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen's kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD).Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.

  View details for DOI 10.1186/s13195-014-0093-y

  View details for PubMedID 25733984

  View details for PubMedCentralID PMC4346122

• Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion BRAIN Lee, S. E., Khazenzon, A. M., Trujillo, A. J., Guo, C. C., Yokoyama, J. S., Sha, S. J., Takada, L. T., Karydas, A. M., Block, N. R., Coppola, G., Pribadi, M., Geschwind, D. H., Rademakers, R., Fong, J. C., Weiner, M. W., Boxer, A. L., Kramer, J. H., Rosen, H. J., Miller, B. L., Seeley, W. W. 2014; 137: 3047-3060

  Abstract

  Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

  View details for DOI 10.1093/brain/awu248

  View details for Web of Science ID 000346760900026

  View details for PubMedID 25273996

• Quantitative 7T Phase Imaging in Premanifest Huntington Disease AMERICAN JOURNAL OF NEURORADIOLOGY Apple, A. C., Possin, K. L., Satris, G., JOHNSON, E., Lupo, J. M., Jakary, A., Wong, K., Kelley, D. A., Kang, G. A., SHA, S. J., Kramer, J. H., Geschwind, M. D., Nelson, S. J., Hess, C. P. 2014; 35 (9): 1707-1713

  Abstract

  In vivo MR imaging and postmortem neuropathologic studies have demonstrated elevated iron concentration and atrophy within the striatum of patients with Huntington disease, implicating neuronal loss and iron accumulation in the pathogenesis of this neurodegenerative disorder. We used 7T MR imaging to determine whether quantitative phase, a measurement that reflects both iron content and tissue microstructure, is altered in subjects with premanifest Huntington disease.Local field shift, calculated from 7T MR phase images, was quantified in 13 subjects with premanifest Huntington disease and 13 age- and sex-matched controls. All participants underwent 3T and 7T MR imaging, including volumetric T1 and 7T gradient recalled-echo sequences. Local field shift maps were created from 7T phase data and registered to caudate ROIs automatically parcellated from the 3T T1 images. Huntington disease-specific disease burden and neurocognitive and motor evaluations were also performed and compared with local field shift.Subjects with premanifest Huntington disease had smaller caudate volume and higher local field shift than controls. A significant correlation between these measurements was not detected, and prediction accuracy for disease state improved with inclusion of both variables. A positive correlation between local field shift and genetic disease burden was also found, and there was a trend toward significant correlations between local field shift and neurocognitive tests of working memory and executive function.Subjects with premanifest Huntington disease exhibit differences in 7T MR imaging phase within the caudate nuclei that correlate with genetic disease burden and trend with neurocognitive assessments. Ultra-high-field MR imaging of quantitative phase may be a useful approach for monitoring neurodegeneration in premanifest Huntington disease.

  View details for DOI 10.3174/ajnr.A3932

  View details for Web of Science ID 000341639900011

  View details for PubMedID 24742810

• Executive Functions in Premanifest Huntington's Disease MOVEMENT DISORDERS You, S. C., Geschwind, M. D., Sha, S. J., Apple, A., Satris, G., Wood, K. A., Johnson, E. T., Gooblar, J., Feuerstein, J. S., Finkbeiner, S., Kang, G. A., Miller, B. L., Hess, C. P., Kramer, J. H., Possin, K. L. 2014; 29 (3): 405-409

  Abstract

  We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington's disease (HD).Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall executive composite score, plus working memory, cognitive control, and fluency scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects.The premanifest HD subjects scored significantly lower on the working memory score. The executive composite positively correlated with striatal volumes, and the working memory score negatively correlated with disease burden. The cognitive control and fluency scores did not differ between the groups or correlate significantly with the disease markers.The NIH EXAMINER executive composite and working memory scores are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD.

  View details for DOI 10.1002/mds.25762

  View details for Web of Science ID 000332823000022

  View details for PubMedID 24375511

  View details for PubMedCentralID PMC4029327

• Interrater reliability of the new criteria for behavioral variant frontotemporal dementia NEUROLOGY LaMarre, A. K., Rascovsky, K., Bostrom, A., Toofanian, P., Wilkins, S., Sha, S. J., Perry, D. C., Miller, Z. A., Naasan, G., Laforce, R. J., Hagen, J., Takada, L. T., Tartaglia, M. C., Kang, G., Galasko, D., Salmon, D. P., Farias, S. T., Kaur, B., Olichney, J. M., Park, L. Q., Mendez, M. F., Tsai, P., Teng, E., Dickerson, B. C., Domoto-Reilly, K., McGinnis, S., Miller, B. L., Kramer, J. H. 2013; 80 (21): 1973-1977

  Abstract

  To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD).Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings.The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; κ = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy.The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

  View details for Web of Science ID 000319332900015

  View details for PubMedID 23635967

• Frontotemporal dementia due to C9ORF72 mutations Clinical and imaging features NEUROLOGY Sha, S. J., Takada, L. T., Rankin, K. P., Yokoyama, J. S., Rutherford, N. J., Fong, J. C., Khan, B., Karydas, A., Baker, M. C., DeJesus-Hernandez, M., Pribadi, M., Coppola, G., Geschwind, D. H., Rademakers, R., Lee, S. E., Seeley, W., Miller, B. L., Boxer, A. L. 2012; 79 (10): 1002-1011

  Abstract

  To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion.A total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS).All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers.Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.

  View details for Web of Science ID 000308674000015

  View details for PubMedID 22875087

  View details for PubMedCentralID PMC3430713

• Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Khan, B. K., Yokoyama, J. S., Takada, L. T., Sha, S. J., Rutherford, N. J., Fong, J. C., Karydas, A. M., Wu, T., Ketelle, R. S., Baker, M. C., Hernandez, M., Coppola, G., Geschwind, D. H., Rademakers, R., Lee, S. E., Rosen, H. J., Rabinovici, G. D., Seeley, W. W., Rankin, K. P., Boxer, A. L., Miller, B. L. 2012; 83 (4): 358-364

  Abstract

  Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described.384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable.C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.

  View details for DOI 10.1136/jnnp-2011-301883

  View details for Web of Science ID 000301296600003

  View details for PubMedID 22399793

• Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease ALZHEIMERS RESEARCH & THERAPY Takada, L. T., Sha, S. J. 2012; 4 (5)

  Abstract

  Earlier reports of chromosome 9p-linked frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) kindreds observed psychosis as a prominent feature in some patients. Since the discovery of chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansions as a cause of FTD and ALS, research groups and consortia around the world have reported their respective observations of the clinical features associated with this mutation. We reviewed the recent literature on C9orf72-associated FTD and ALS with focus on the neuropsychiatric features associated with this mutation, as well as the experience at University of California, San Francisco. The results and methodologies varied greatly across studies, making comparison of results challenging. Four reports found that psychotic features (particularly delusions) were frequent among mutation carriers, particularly when present early during the disease course, suggesting that this symptom category may be a marker for the mutation. Disinhibition and apathy were the most commonly reported early behavioral symptoms, but these may not be helpful in distinguishing carriers and noncarriers because of the symptoms' frequency in sporadic behavioral variant FTD. Other neuropsychiatric features were reported in different frequencies across studies, suggesting either a similar behavioral phenotype in carriers and noncarriers or reflecting the heterogeneity in clinical presentation of behavioral variant FTD due to C9orf72 expansions. Further studies with larger cohorts will be necessary to determine the neuropsychiatric presentation associated with this mutation.

  View details for DOI 10.1186/alzrt141

  View details for Web of Science ID 000315195500004

  View details for PubMedID 23034079

• Treatment implications of C9ORF72 ALZHEIMERS RESEARCH & THERAPY Sha, S. J., Boxer, A. 2012; 4 (6)

  Abstract

  Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.

  View details for DOI 10.1186/alzrt149

  View details for Web of Science ID 000315195900003

  View details for PubMedID 23186535

• Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases? NATURE CLINICAL PRACTICE NEUROLOGY Sha, r. S., Hou, C., Viskontas, I. V., Miller, B. L. 2006; 2 (12): 658-665

  Abstract

  New findings relating to the clinical, genetic and molecular bases of neurodegenerative disorders have led to a shift away from traditional nomenclatures of clinical syndromes. Historically, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were classified on the basis of distinct clinical and pathological features. In recent years, however, advances in molecular and genetic research have led clinicians to suggest that the similar etiologies of the three disorders warrant their amalgamation into a single disorder with three subtypes. In this Review, we consider the utility and validity of combining FTLD, CBD and PSP. The earliest reports of these disorders demonstrate their distinctiveness, whereas recent findings challenge traditional nomenclatures by showing etiological overlap. For example, tau inclusions have been confirmed in patients with CBD and those with PSP, and in some patients with FTLD, implying that all three disorders are 'tauopathies'. Furthermore, most patients with progressive nonfluent aphasia, a subtype of FTLD, show PSP or CBD post-mortem. Even tau-related cases of FTLD, CBD and PSP are distinguishable on the basis of other criteria, however, and many FTLD cases do not show tau pathology. We argue, therefore, that FTLD, CBD and PSP should be considered as pathologically similar but distinct syndromes. New research criteria for CBD and PSP should note that progressive nonfluent aphasia is often a precursor of these conditions.

  View details for DOI 10.1038/ncpneuro0357

  View details for Web of Science ID 000242169100009

  View details for PubMedID 17117169

• Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cognitive and behavioral neurology Kramer, J. H., Jurik, J., Sha, S. J., Rankin, K. P., Rosen, H. J., Johnson, J. K., Miller, B. L. 2003; 16 (4): 211-218

  Abstract

  To assess the ability of a brief neuropsychological bedside screening battery to discriminate between Alzheimer disease, frontotemporal dementia, and semantic dementia.Subjects were 21 patients with frontotemporal dementia, 14 patients with semantic dementia, and 30 patients with Alzheimer disease comparable in terms of Mini Mental Status Examination score, age, and education. Frontotemporal dementia and semantic dementia diagnoses were made clinically using the consensus criteria of Neary et al. 1 Subjects were administered a brief neuropsychological screening assessing episodic memory, working memory, executive function, naming, spatial ability, abstract reasoning, and calculations.Both the Alzheimer disease and semantic dementia groups were significantly impaired relative to the frontotemporal dementia group on verbal memory, whereas only the Alzheimer disease group was impaired on visual memory. Frontotemporal dementia patients performed significantly worse on backward digit span and made significantly more executive errors than Alzheimer disease and semantic dementia patients. Semantic dementia patients were more impaired than Alzheimer disease and frontotemporal dementia patients on confrontation naming. Discriminant function analyses identified the 5 most discriminating variables that correctly classified 89.2% of cases.Frontotemporal dementia, semantic dementia, and Alzheimer disease are associated with distinct neuropsychological profiles that classify these dementia syndromes with considerable success. The neuropsychological profiles highlight the distinctiveness between the 3 syndromes, are consistent with the known loci of neuropathology in these conditions, and can potentially serve as an adjunct to the current clinical criteria.

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