{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:35:19Z","timestamp":1790566519440,"version":"4.1.0"},"reference-count":36,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"\n Importance<\/jats:title>\n Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA).<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18\u202f629 measurements).<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n Clinical data and NfL and GFAP\n z<\/jats:italic>\n scores, collected and calculated every 6 or 12 months.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The SMSC and EPIC cohorts consisted of 1709 (13\u202f375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (\n z<\/jats:italic>\n score &amp;gt;1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71;\n P<\/jats:italic>\n \u2009=\u2009.01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP\n z<\/jats:italic>\n score unit reduction during the first 2 years receiving fingolimod or B-cell\u2013depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84;\n P<\/jats:italic>\n \u2009=\u2009.01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), respectively.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2026.2500","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:00:52Z","timestamp":1785769252000},"page":"894","source":"Crossref","is-referenced-by-count":1,"title":["Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis"],"prefix":"10.1001","volume":"83","author":[{"given":"Maximilian","family":"Einsiedler","sequence":"first","affiliation":[{"name":"Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience, Neurology Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Sandgren","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience, Neurology Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Schaedelin","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience, Neurology Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiarra","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Maleska Maceski","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience, Neurology Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Oechtering","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience, Neurology Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Cordano","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California, San 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