Friederike Held

All Publications

• Complement C4d Informs the Differential Diagnosis of Inflammatory Demyelinating CNS Diseases NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Landt, C., Held, F., Kolotourou, K., Guranda, M., Vakrakou, A. G., Franz, J., Thomas, C., Schmiedeknecht, M., Bergann, K., Wrzos, C., Endmayr, V., Tsaktanis, T., Zechel, S., Ancau, M., Misgeld, T., Hakroush, S., Hametner, S., Rothhammer, V., Hoftberger, R., Hemmer, B., Stadelmann, C., Nessler, S. 2026; 13 (2): e200528

  Abstract

  Complement-targeting therapies are pivotal in managing neuromyelitis optica spectrum disorder (NMOSD), calling for a deeper understanding of complement activation across idiopathic inflammatory demyelinating diseases (IIDDs) of the CNS. C4d, a covalently bound complement split product, offers prolonged detectability at activation sites. This study explores whether C4d immunohistochemistry (IHC) extends the detection window for complement activation in CNS biopsies of IIDDs and evaluates its usefulness as a fluid biomarker.Forty-four IIDD biopsies with active demyelination were analyzed for complement deposition using IHC for C9neo and C4d. C4d levels were also quantified in blood and CSF of patients with IIDDs. The persistence of C4d in CNS tissue was further evaluated in an in vivo NMOSD model.C4d IHC enhanced the sensitivity to detect complement activation, surpassing C9neo by twofold in NMOSD and by sixfold in ADEM, while remaining undetectable in MS biopsies. Exclusive C4d immunopositivity at the glia limitans distinguished NMOSD from ADEM. Furthermore, CSF C4d levels were significantly elevated in both seronegative and seropositive NMOSD compared with MS.C4d detection extends the window for identifying complement activation in CNS biopsies of IIDDs and emerges as a valuable CSF biomarker, enhancing diagnostic precision, autoantibody target identification, and patient stratification for complement-targeting therapies.

  View details for DOI 10.1212/NXI.0000000000200528

  View details for Web of Science ID 001647039300001

  View details for PubMedID 41435221

  View details for PubMedCentralID PMC12735299

• Neurofilament light chain as a surrogate candidate for disease activity in multiple sclerosis (LUMINOUS)-A meta-regression of randomized controlled trials. Multiple sclerosis (Houndmills, Basingstoke, England) Pretzsch, R., El Mahdaoui, S., Johnson, P., Soares, M. D., Koerbel, K., Held, F., Bajrami, A., Pozzilli, V., Lucchini, M., Barbuti, E., Bartels, F., Barket, R., Cordano, C., Hemmer, B., Cagol, A., Schiavetti, I., Sormani, M. P., ECTRIMS Winter School 2024 study group 2026: 13524585251407973

  Abstract

  BACKGROUND/OBJECTIVES: Neurofilament light chain (NfL) is a promising biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). This meta-regression assesses the relationship between treatment effects on serum/plasma NfL (s/pNfL) and clinical and radiological endpoints in randomized controlled trials (RCTs).METHODS: A systematic PubMed search identified RCTs in MS (1999-2023) with ⩾24months' duration and s/pNfL data. Extracted outcomes included treatment effects on s/pNfL, annualized relapse rate (ARR), confirmed disability worsening (CDW), magnetic resonance imaging (MRI) new/enlarging T2 lesions, and percentage brain volume change (PBVC). We evaluated the association of treatment effect on the selected outcomes at the trial level by a meta-regression, weighted by trial size and duration.RESULTS: Fifteen RCTs (n=6814) were included, nine in relapsing MS (RMS, n=5221), and six in progressive MS (PMS, n=1593). Treatment effects on s/pNfL showed a moderate association with treatment effects on MRI new/enlarging T2 lesions (R2=0.42, p=0.01), ARR (R2=0.33, p=0.03) and CDW (R2=0.30, p=0.04), but not with PBVC. In RMS-only trials, association with ARR (R2=0.45, p=0.05) and CDW (R2=0.50, p=0.03) was more pronounced.CONCLUSION: In MS, treatment effects on s/pNfL are moderately associated with therapeutic effects on ARR, MRI new/enlarging T2 lesions, and CDW, whereas no consistent association was observed with PBVC.

  View details for DOI 10.1177/13524585251407973

  View details for PubMedID 41574448

• Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis. Journal of neurology, neurosurgery, and psychiatry Abdelhak, A., Bachhuber, F., Ning, K., Benkert, P., John Boscardin, W., Maleska Maceski, A., Schaedelin, S., Achtnichts, L., Finkener, S., Lalive, P. H., Uginet, M., Pot, C., Du Pasquier, R., Hoepner, R., Chan, A., Gobbi, C., Zecca, C., Müller, S., Roth, P., Granziera, C., Chitnis, T., Madill, E., Weiner, H. L., Green, A. J., Hauser, S. L., Cree, B. A., Kümpfel, T., Havla, J., Skripuletz, T., Gingele, S., Senel, M., Vardakas, I., Taranu, D., Ziemann, U., Kowarik, M. C., Kleiter, I., Hoshi, M. M., Zettl, U. K., Haarmann, A., Thebault, S., Freedman, M. S., Bergman, H. P., Iacobaeus, E., Khademi, M., Ferraro, D., Cardi, M., Mariotto, S., Comabella, M., Montalban, X., Vilaseca-Jolonch, A., Strijbis, E. M., Wessels, M. H., Killestein, J., Hemmer, B., Held, F., Sellebjerg, F., Højsgaard Chow, H., Alvarez-Lafuente, R., Domínguez-Mozo, M. I., Hegen, H., Berek, K., Deisenhammer, F., Thouvenot, E., Agherbi, H., Rejdak, K., Gąsior, M., Tzanetakos, D., Tzartos, J. S., Sormani, M. P., Dujmovic Basuroski, I., Arrambide, G., Khalil, M., Piehl, F., Teunissen, C. E., Kuhle, J., Tumani, H. 2025; 96 (11): 1046-1052

  Abstract

  Biologically informative markers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) may help predict confirmed disability worsening (CDW) in multiple sclerosis (MS). However, data on the prognostic value of their blood concentrations in progressive MS (PMS) are limited, and there are substantial discrepancies in the published literature. This international collaboration uses individual participant data to define the prognostic value of serum GFAP and NfL in people with PMS (pwPMS).Data were collected from BioMS-eu network centres and collaborating cohorts. pwPMS with primary progressive MS (PPMS) or secondary progressive MS (SPMS) with at least one GFAP value and at least three follow-up expanded disability status scale (EDSS) scores were included. The prognostic value of serum GFAP and NfL age- and sex-adjusted Z-scores for future CDW was evaluated using Cox regression models, accounting for sex, age, baseline disease duration and EDSS, and dominant treatment during follow-up.1058 participants and 7530 encounters were included (median age 53 years (IQR: 44 to 59), 57% female, follow-up 4.6 years (2.9 to 8.4)) with median baseline GFAP of 0.74 (-0.10 to 1.55) and NfL of 0.64 (-0.36 to 1.51). 723 CDW events were recorded. Each GFAP Z-score increase was associated with ~10% higher CDW risk (adjusted HR (aHR) 1.107 (1.001 to 1.225), p=0.049). Results were mainly driven by SPMS participants (n=613, aHR 1.242 (1.073 to 1.438), p=0.004). Higher NfL Z-scores predicted CDW only in PPMS participants (1.236 (1.092 to 1.399), p=0.001).GFAP was a prognostic indicator for future CDW in pwPMS, especially in pwSPMS. On the other hand, NfL was predictive of CDW only in pwPPMS.

  View details for DOI 10.1136/jnnp-2025-335831

  View details for PubMedID 40506119

• Distinct Reactivity Patterns to EBV Nuclear Proteins and CNS Antigens Distinguish CNS Demyelinating Disorders from Systemic Autoimmunity Sattarnezhad, N., Held, F., Babaei, M., Gawde, S., Ho, P., Barrett, A., Wijerante, T., Comanescu, A., Parsafar, S., Bartels, F., McDonald, J., Kipp, L., Van Haren, K., Chaichian, Y., Lock, C., Han, M., Baker, M., Dunn, J., Steinman, L., Lanz, T., Robinson, W. SAGE PUBLICATIONS LTD. 2025: 309-310

  View details for Web of Science ID 001603659901013

• Real-World Practices and Challenges of Radiologically Isolated Syndrome (RIS): Results of a Cross-Sector Survey by the DACH MS Guidelines Group Held, F., Bayas, A., Berthele, A., Christe, K., Dettmers, C., Domurath, B., Ebert, J., Fasshauer, E., Flachenecker, P., Gaertner, J., Hasanbasic, D., Heesen, C., Hegen, H., Thomas, H., Huppke, P., Khalil, M., Kirschner-Hermanns, R., Korn, T., Kuempfel, T., Lamprecht, S., Luessi, F., Meier, U., Hoerste, G., Maeurer, M., Oertel, F., Pot, C., Proebstel, A., Rostasy, K., Salmen, A., Scheiderbauer, J., Schmidt, M., Stark, E., Trebst, C., Trollmann, R., Warnke, C., Wattjes, M. P., Benedikt, W., Wildemann, B., Zimmermann, U., Gehring, K., Hemmer, B. SAGE PUBLICATIONS LTD. 2025: 138-140

  View details for Web of Science ID 001603659900152

• Prognostic Factors for Multiple Sclerosis Symptoms in Radiologically Isolated Syndrome. JAMA neurology Fissolo, N., Schaedelin, S., Villar, L. M., Lünemann, J. D., Correale, J., Rejdak, K., Schwab, N., Vilaseca, A., Held, F., García-Merino, A., Bittner, S., Trojano, M., Furlan, R., Tumani, H., Pérez-Miralles, F., Rosenstein, I., Galimberti, D., Álvarez-Bravo, G., Thouvenot, E., Llufriu, S., Khoury, S. J., Hoepner, R., Martínez-Yélamos, S., Hegen, H., Drulovic, J., Téllez-Lara, N., Khalil, M., Oechtering, J., Pérez-Sempere, Á., Rodríguez-Antigüedad, A., Enrique-Martínez, J., Strijbis, E., Killestein, J., Eichau, S., Colombo, E., Schaller-Nagengast, J., Midaglia, L., Sánchez-López, A. J., Monreal, E., Chan, A., Paul, F., Rovira, À., Tintoré, M., Lycke, J., Zipp, F., Hemmer, B., Kuhle, J., Montalban, X., Comabella, M. 2025; 82 (7): 722-733

  Abstract

  Understanding the risk factors for symptom development will allow clinicians to stratify people with radiologically isolated syndrome (pwRIS) more effectively and tailor their management strategies accordingly.To identify prognostic factors at radiologically isolated syndrome (RIS) diagnosis associated with the development of multiple sclerosis (MS) symptoms.This cohort study was performed in samples collected between July 2004 and September 2022 and included 33 MS centers. All pwRIS who meet the 2017 McDonald criteria for dissemination in space with a sample collected near the diagnostic magnetic resonance imaging were included. No patients who met eligibility criteria were excluded. The data were analyzed from July 2024 to November 2024.Body fluid biomarkers and environmental factors in pwRIS.The main outcome was the development of MS symptoms. Analyses involved univariable and multivariable Cox proportional hazards models, including age, sex, and treatment following RIS diagnosis, as additional independent variables.The study included 273 pwRIS (mean age, 38.6 [SD 11.6] years; 207 women [75.8%] and 66 men [24.2%]) with a median follow-up of 5.0 [IQR, 2.5-7.7] years. A total of 101 pwRIS developed MS symptoms (37.0%). The presence of immunoglobulin G oligoclonal bands (OBs) (hazard ratio [HR], 5.09; 95% CI, 2.36-10.97; P < .001), immunoglobulin M OBs (HR, 2.58; 95% CI, 1.61-4.14; P < .001), and a κ free light chain index of 6.1 or more (HR, 2.79; 95% CI, 1.37-5.67; P = .005) were associated with MS symptoms. High cerebrospinal fluid neurofilament light chain (NfL) levels (HR, 1.31; 95% CI, 1.18-1.45; P < .001) and high serum NfL z scores (HR, 1.42; 95% CI, 1.16-1.72; P = .005) were also associated with an increased risk of MS symptoms. In contrast, high anti-cytomegalovirus titers (HR, 0.59; 95% CI, 0.38-0.93; P = .02) and high ultraviolet radiation exposure in the year before (HR, 0.52; 95% CI, 0.37-0.74; P < .001) and the year after (HR, 0.54, 95% CI, 0.38-0.75; P < .001) diagnosis reduced the risk of MS symptoms. For all these prognostic factors, the multivariable analysis yielded similar results. The combination of high serum NfL z scores and positive immunoglobulin G OBs conferred a 5-year risk of clinical symptoms of 58.3% (95% CI, 45.9-67.9). This risk increased to 81.6% (95% CI, 60.9-91.4) in pwRIS who were younger and positive for immunoglobulin M OBs.The study elucidates the prognostic factors that significantly impact the risk of developing MS symptoms in pwRIS at diagnosis, thereby, enhancing the potential for tailored clinical interventions.

  View details for DOI 10.1001/jamaneurol.2025.1481

  View details for PubMedID 40455494

  View details for PubMedCentralID PMC12131171

• Single-cell analysis of cerebrospinal fluid reveals common features of neuroinflammation. Cell reports. Medicine Jacobs, B. M., Gasperi, C., Kalluri, S. R., Al-Najjar, R., McKeon, M. O., Else, J., Pukaj, A., Held, F., Sawcer, S., Ban, M., Hemmer, B. 2025; 6 (1): 101733

  Abstract

  Neuroinflammation is often characterized by immune cell infiltrates in the cerebrospinal fluid (CSF). Here, we apply single-cell RNA sequencing to explore the functional characteristics of these cells in patients with various inflammatory, infectious, and non-inflammatory neurological disorders. We show that CSF is distinct from the peripheral blood in terms of both cellular composition and gene expression. We report that the cellular and transcriptional landscape of CSF is altered in neuroinflammation but is strikingly similar across different neuroinflammatory disorders. We find clonal expansion of CSF lymphocytes in all disorders but most pronounced in inflammatory diseases, and we functionally characterize the transcriptional features of these cells. Finally, we explore the genetic control of gene expression in CSF lymphocytes. Our results highlight the common features of immune cells in the CSF compartment across diverse neurological diseases and may help to identify new targets for drug development or repurposing in multiple sclerosis (MS).

  View details for DOI 10.1016/j.xcrm.2024.101733

  View details for PubMedID 39708811

  View details for PubMedCentralID PMC11866449

• Proteomics Reveals Age as Major Modifier of Inflammatory CSF Signatures in Multiple Sclerosis. Neurology(R) neuroimmunology & neuroinflammation Held, F., Makarov, C., Gasperi, C., Flaskamp, M., Grummel, V., Berthele, A., Hemmer, B. 2025; 12 (1): e200322

  Abstract

  BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) can start as relapsing or progressive. While their clinical features and treatment responses are distinct, it has remained uncertain whether their pathomechanisms differ. A notable age-related effect on MS phenotype and response to immunotherapies is well acknowledged, but the underlying pathophysiologic reasons are yet to be fully elucidated. We aimed to identify disease-specific and age-related proteomic signatures using a comprehensive targeted proteomic analysis.METHODS: In our retrospective cohort study, we analyzed the CSF and serum proteome of age-matched individuals with treatment-naive relapsing-remitting and primary progressive MS, neurologic controls (NC), and individuals with neuroborreliosis using targeted proteomics and validated findings in an independent cohort. Proteomic results were integrated with clinical and laboratory covariates.RESULTS: Among 2,500 proteins, 47 CSF proteins were distinct between individuals with MS (n = 60) and NC (n = 20), with a subset also differing from those with neuroborreliosis (n = 8). We identified MS-associated proteins, including novel candidate biomarkers such as LY9 and JCHAIN, and putative treatment targets, such as SLAMF7, BCMA, and IL5RA, for which drugs are already licensed in other indications. The CSF proteome differences between relapsing and progressive MS were minimal, but major changes were noted in individuals older than 50 years, indicating a shift from MS-associated inflammatory to age-related protein signature. NEFL was the only serum protein that differed between individuals with MS and controls.DISCUSSION: This study unveils a unique CSF proteomic signature in MS, providing new pathophysiologic insights and identifying novel biomarker candidates and potential therapeutic targets. Our findings highlight similar immunologic mechanisms in relapsing and progressive MS and underscore aging's profound effect on the intrathecal immune response. This aligns with the observed lower efficacy of immunotherapies in the elderly, thus emphasizing the necessity for alternative therapeutic approaches in treating individuals with MS beyond the age of 50.

  View details for DOI 10.1212/NXI.0000000000200322

  View details for PubMedID 39536291

• A Genetic Risk Variant for Multiple Sclerosis Severity is Associated with Brain Atrophy. Annals of neurology Gasperi, C., Wiltgen, T., McGinnis, J., Cerri, S., Moridi, T., Ouellette, R., Pukaj, A., Voon, C., Bafligil, C., Lauerer, M., Andlauer, T. F., Held, F., Aly, L., Shchetynsky, K., Stridh, P., Harroud, A., Wiestler, B., Kirschke, J. S., Zimmer, C., Baras, A., Piehl, F., Berthele, A., Granberg, T., Kockum, I., Hemmer, B., Mühlau, M. 2023; 94 (6): 1080-1085

  Abstract

  The minor allele of the genetic variant rs10191329 in the DYSF-ZNF638 locus is associated with unfavorable long-term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080-1085.

  View details for DOI 10.1002/ana.26807

  View details for PubMedID 37753809

  View details for PubMedCentralID PMC11303986

• Locus for severity implicates CNS resilience in progression of multiple sclerosis NATURE Harroud, A., Stridh, P. J., McCauley, J. H., Saarela, J., van den Bosch, A. M. R., Engelenburg, H., Beecham, A., Alfredsson, L., Alikhani, K., Amezcua, L., Andlauer, T. F. M., Ban, M., Barcellos, L., Barizzone, N., Berge, T., Berthele, A., Bittner, S., Bos, S., Briggs, F. B. S., Caillier, S., Calabresi, P., Caputo, D., Carmona-Burgos, D., Cavalla, P., Celius, E., Cerono, G., Chinea, A., Chitnis, T., Clarelli, F., Comabella, M., Comi, G., Cotsapas, C., Cree, B. C. A., D'Alfonso, S., Dardiotis, E., De Jager, P., Delgado, S., Dubois, B., Engel, S., Esposito, F., Fabis-Pedrini, M., Filippi, M., Fitzgerald, K., Gasperi, C., Gomez, L., Gomez, R., Hadjigeorgiou, G., Hamann, J., Held, F., Henry, R., Hillert, J., Huang, J., Huitinga, I., Islam, T., Isobe, N., Jagodic, M., Kermode, A. L., Khalil, M., Kilpatrick, T., Konidari, I., Kreft, K., Lechner-Scott, J., Leone, M., Luessi, F., Malhotra, S., Manouchehrinia, A., Manrique, C., Martinelli-Boneschi, F., Martinez, A., Martinez-Maldonado, V., Mascia, E., Metz, L., Midaglia, L., Montalban, X., Oksenberg, J., Olsson, T., Oturai, A., Paakkonen, K., Parnell, G. P., Patsopoulos, N., Pericak-Vance, M., Piehl, F., Rubio, J., Santaniello, A., Santoro, S., Schaefer, C., Sellebjerg, F., Shams, H., Shchetynsky, K., Silva, C., Siokas, V., Sondergaard, H., Sorosina, M., Taylor, B., Vandebergh, M., Vasileiou, E., Vecchio, D., Voortman, M., Weiner, H., Wever, D., Yong, V., Hafler, D., Stewart, G., Compston, A., Zipp, F., Harbo, H., Hemmer, B., Goris, A., Smolders, J., Hauser, S., Kockum, I., Sawcer, S., Baranzini, S., Jonsdottir, I., Blanco, Y., Llufriu, S., Madireddy, L., Saiz, A., Villoslada, P., Stefansson, K., Harbo, H. F., Hemmer, B., Goris, A., Kockum, I., Sawcer, S. J., Baranzini, S. E. 2023: 323-331

  Abstract

  Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

  View details for DOI 10.1038/s41586-023-06250-x

  View details for Web of Science ID 001023900900003

  View details for PubMedID 37380766

  View details for PubMedCentralID 7720355

• The impact of disease-modifying therapies on immunoglobulin blood levels in patients with multiple sclerosis: a retrospective cross-sectional study. Therapeutic advances in neurological disorders Klein, A., Flaskamp, M., Berthele, A., Held, F., Muratovic, H., Hemmer, B. 2023; 16: 17562864231162661

  Abstract

  Although disease-modifying therapies (DMTs) in multiple sclerosis (MS) are known to target the immune system, mechanisms of action, efficacy, safety, and tolerability profiles differ. The long-term impact of DMTs on the immune system and its relation to infectious complications is still poorly understood.To analyze the effect of DMTs on serum immunoglobulin (Ig) levels under consideration of patient demographics and therapy duration.We included 483 patients on DMTs, 69 patients without DMTs, and 51 controls in this retrospective cross-sectional study.IgG, IgM, and IgG subclass 1-4 levels of patients with MS under treatment with DMTs were compared with treatment naive MS patients and controls by multivariate linear regression. Further, Ig levels stratified by DMTs were analyzed regarding therapy duration.MS patients treated with fingolimod (FG), natalizumab, and B-cell depleting therapies (BCDT) demonstrated significantly lower IgG and IgM levels than healthy controls after a median treatment of 37, 31, and 23 months, respectively (p < 0.05). Treatment with dimethyl fumarate (DMF) and teriflunomide was associated with lower IgG, but not IgM levels. DMF and BCDT were also associated with lower IgG1 levels, while FG led to a reduction of IgG2. Treatment with interferon-beta (IFN) and glatiramer acetate (GA) had no impact on Ig levels. Analysis of subgroups by linear regression also showed a time-dependent decrease of Igs levels in patients treated with BCDT with a median annual reduction of IgG of 3.2% and IgM of 6.2%.Treatment with DMTs, except GA and IFN, was associated with a decrease in Ig levels. DMTs differed in the extent of decreasing Ig levels but also in their differential effects on Ig subclasses. Monitoring of Ig levels should be considered in patients on long-term treatment with DMTs, particularly those on BCDT, to identify patients at risk of low immunoglobulin levels.

  View details for DOI 10.1177/17562864231162661

  View details for PubMedID 37114068

  View details for PubMedCentralID PMC10126592

• Frequency of myelin oligodendrocyte glycoprotein antibodies in a large cohort of neurological patients. Multiple sclerosis journal - experimental, translational and clinical Held, F., Kalluri, S. R., Berthele, A., Klein, A. K., Reindl, M., Hemmer, B. 2021; 7 (2): 20552173211022767

  Abstract

  Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD) is recognized as a distinct nosological entity. IgG antibodies against MOG (MOG-Ab) overlap with neuromyelitis optica spectrum disorders (NMOSD) phenotype in adults. However, an increasing number of clinical phenotypes have been reported to be associated with MOG-Ab.To investigate the seroprevalence of MOG-Ab under consideration of demographics, disease entities and time course in a large cohort of unselected neurological patients.Blood samples of 2.107 consecutive adult neurologic patients admitted to our department between 2016-2017 were tested for MOG-Ab using a cell-based assay. MOG-Ab persistence was analyzed in follow-up samples. External validation was performed in two independent laboratories.We found MOG-Ab in 25 of 2.107 (1.2%) patients. High antibody ratios were mostly associated with NMOSD and MOG-AD phenotype (5/25). Low ratios occurred in a wide range of neurological diseases, predominantly in other demyelinating CNS diseases (5/25) and stroke (6/25). MOG-Ab persistence over time was not confined to NMOSD and MOG-AD phenotype.The present study demonstrates the occurrence of MOG-Ab in a wide range of neurological diseases. Only high MOG-Ab ratios were associated with a defined clinical phenotype, but low MOG-Ab ratios were not. The diagnostic value of low MOG-Ab is thus highly limited.

  View details for DOI 10.1177/20552173211022767

  View details for PubMedID 34262784

  View details for PubMedCentralID PMC8246507

• Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis. Annals of neurology Vandebergh, M., Andlauer, T. F., Zhou, Y., Mallants, K., Held, F., Aly, L., Taylor, B. V., Hemmer, B., Dubois, B., Goris, A. 2021; 89 (5): 884-894

  Abstract

  Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date.We performed a genomewide association study (GWAS) in a discovery cohort and investigated the genomewide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2,231 relapses occurring before the start of any immunomodulatory treatment in 991 patients. For assessing time to relapse, we applied a survival analysis utilizing Cox proportional hazards models. We also investigated the association between MS genetic risk scores and relapse hazard and performed a gene ontology pathway analysis.The low-frequency genetic variant rs11871306 within WNT9B reached genomewide significance in predicting relapse hazard and replicated (meta-analysis hazard ratio (HR) = 2.15, 95% confidence interval (CI) = 1.70-2.78, p = 2.07 × 10-10 ). A pathway analysis identified an association of the pathway "response to vitamin D" with relapse hazard (p = 4.33 × 10-6 ). The MS genetic risk scores, however, were not associated with relapse hazard.Genetic factors underlying disease heterogeneity differ from variants associated with MS susceptibility. Our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence. The present study highlights these cross-talking pathways as potential modulators of MS disease activity. ANN NEUROL 2021;89:884-894.

  View details for DOI 10.1002/ana.26061

  View details for PubMedID 33704824

  View details for PubMedCentralID PMC8252032

• Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease. Clinical science (London, England : 1979) Held, F., Morris, A. W., Pirici, D., Niklass, S., Sharp, M. M., Garz, C., Assmann, A., Heinze, H. J., Schreiber, F., Carare, R. O., Schreiber, S. 2017; 131 (10): 1001-1013

  Abstract

  Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of β-amyloid (Aβ) transport and degradation. We analyzed BM changes and the pattern of deposition of Aβ in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immunostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular Aβ was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous Aβ deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular β-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous Aβ. Impaired β-amyloid clearance along perivascular and endothelial pathways and failure of extracellular Aβ degradation may be the key mechanisms connecting non-amyloid CSVD and CAA.

  View details for DOI 10.1042/CS20170004

  View details for PubMedID 28348005