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This systematic review aimed to synthesize current evidence on the diagnostic and prognostic utility of fluid biomarkers in distinguishing acute inflammatory injury from chronic neurodegeneration. A comprehensive search of Web of Science, PubMed, and Scopus (January 2020\u2013September 2025) identified 28 eligible studies including 7775 participants (6365 MS patients and 1410 controls). Biomarkers derived from serum, plasma, cerebrospinal fluid (CSF), and stool were evaluated in relation to clinical disability measured using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) outcomes. Neurofilament light chain (NfL) consistently predicted acute inflammatory activity, gadolinium-enhancing lesions, and relapse-associated worsening, but levels were reduced by high-efficacy therapies and did not reliably predict PIRA. In contrast, glial fibrillary acidic protein (GFAP) was associated with astrogliosis, disability progression, and retinal thinning, even in patients with low inflammatory activity. Additional CSF, metabolic, and immunologic markers correlated with neurodegeneration and disease severity. Nevertheless, broader clinical use will require greater assay standardization, improved consistency across cohorts, and validation in prospective longitudinal studies. These findings compel a shift toward a multi-biomarker model to guide personalized therapeutic strategies and develop targeted neuroprotective treatments for progressive multiple sclerosis.<\/jats:p>","DOI":"10.3390\/cells15070610","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:03Z","timestamp":1774878063000},"page":"610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Crossroads of Neuroinflammation and Biomarkers in Multiple Sclerosis: A Systematic Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1849-6923","authenticated-orcid":false,"given":"Maria-Georgiana","family":"Gavril\u0103","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"},{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9603-5860","authenticated-orcid":false,"given":"Carmen Valeria","family":"Albu","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan Cristian","family":"Albu","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"},{"name":"Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Burada","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"},{"name":"Department of Physiology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8707-9768","authenticated-orcid":false,"given":"Raluca Elena","family":"Sandu","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"},{"name":"Department of Biochemistry, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4509-885X","authenticated-orcid":false,"given":"Roxana","family":"Surugiu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","article-title":"Multiple Sclerosis","volume":"372","author":"Compston","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1177\/1352458520970841","article-title":"Rising Prevalence of Multiple Sclerosis Worldwide: Insights from the Atlas of MS, Third Edition","volume":"26","author":"Walton","year":"2020","journal-title":"Mult. 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