Friederike Held

All Publications

• 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. R., Engelenburg, H., Beecham, A., Alfredsson, L., Alikhani, K., Amezcua, L., Andlauer, T. M., Ban, M., Barcellos, L., Barizzone, N., Berge, T., Berthele, A., Bittner, S., Bos, S., Briggs, F. 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. 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