{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T06:35:02Z","timestamp":1782369302190,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PI21\/00828"],"award-info":[{"award-number":["PI21\/00828"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["PI24\/01018"],"award-info":[{"award-number":["PI24\/01018"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD21\/0002\/0053"],"award-info":[{"award-number":["RD21\/0002\/0053"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD24\/0007\/0013"],"award-info":[{"award-number":["RD24\/0007\/0013"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD24\/0007\/0034"],"award-info":[{"award-number":["RD24\/0007\/0034"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD16\/0015\/0001"],"award-info":[{"award-number":["RD16\/0015\/0001"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD16\/0015\/0002"],"award-info":[{"award-number":["RD16\/0015\/0002"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD16\/0015\/0003"],"award-info":[{"award-number":["RD16\/0015\/0003"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III (ISCIII)","doi-asserted-by":"publisher","award":["RD16\/0015\/0006"],"award-info":[{"award-number":["RD16\/0015\/0006"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["PI21\/00828"],"award-info":[{"award-number":["PI21\/00828"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["PI24\/01018"],"award-info":[{"award-number":["PI24\/01018"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD21\/0002\/0053"],"award-info":[{"award-number":["RD21\/0002\/0053"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD24\/0007\/0013"],"award-info":[{"award-number":["RD24\/0007\/0013"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD24\/0007\/0034"],"award-info":[{"award-number":["RD24\/0007\/0034"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD16\/0015\/0001"],"award-info":[{"award-number":["RD16\/0015\/0001"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD16\/0015\/0002"],"award-info":[{"award-number":["RD16\/0015\/0002"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD16\/0015\/0003"],"award-info":[{"award-number":["RD16\/0015\/0003"]}]},{"name":"La Red Espa\u00f1ola de Enfermedades Inflamatorias (REI)","award":["RD16\/0015\/0006"],"award-info":[{"award-number":["RD16\/0015\/0006"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["PI21\/00828"],"award-info":[{"award-number":["PI21\/00828"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["PI24\/01018"],"award-info":[{"award-number":["PI24\/01018"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD21\/0002\/0053"],"award-info":[{"award-number":["RD21\/0002\/0053"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD24\/0007\/0013"],"award-info":[{"award-number":["RD24\/0007\/0013"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD24\/0007\/0034"],"award-info":[{"award-number":["RD24\/0007\/0034"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD16\/0015\/0001"],"award-info":[{"award-number":["RD16\/0015\/0001"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD16\/0015\/0002"],"award-info":[{"award-number":["RD16\/0015\/0002"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD16\/0015\/0003"],"award-info":[{"award-number":["RD16\/0015\/0003"]}]},{"name":"La Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM)","award":["RD16\/0015\/0006"],"award-info":[{"award-number":["RD16\/0015\/0006"]}]},{"name":"European Union","award":["PI21\/00828"],"award-info":[{"award-number":["PI21\/00828"]}]},{"name":"European Union","award":["PI24\/01018"],"award-info":[{"award-number":["PI24\/01018"]}]},{"name":"European Union","award":["RD21\/0002\/0053"],"award-info":[{"award-number":["RD21\/0002\/0053"]}]},{"name":"European Union","award":["RD24\/0007\/0013"],"award-info":[{"award-number":["RD24\/0007\/0013"]}]},{"name":"European Union","award":["RD24\/0007\/0034"],"award-info":[{"award-number":["RD24\/0007\/0034"]}]},{"name":"European Union","award":["RD16\/0015\/0001"],"award-info":[{"award-number":["RD16\/0015\/0001"]}]},{"name":"European Union","award":["RD16\/0015\/0002"],"award-info":[{"award-number":["RD16\/0015\/0002"]}]},{"name":"European Union","award":["RD16\/0015\/0003"],"award-info":[{"award-number":["RD16\/0015\/0003"]}]},{"name":"European Union","award":["RD16\/0015\/0006"],"award-info":[{"award-number":["RD16\/0015\/0006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset. Biomarkers were quantified using single-molecule array and immunoblotting techniques, and CSF cell subsets were analyzed by flow cytometry. High sNfL z-scores and LS-OCMB positivity were independently associated with increased risk of RAW and aPIRA, collectively termed inflammatory-associated worsening (IAW), while elevated sGFAP levels predicted naPIRA. Patients with both high sNfL and LS-OCMB positivity had the highest risk of IAW. Among LS-OCMB\u2013positive patients, higher regulatory T cell percentages were associated with lower sNfL levels, suggesting a protective role. Conversely, in LS-OCMB\u2013negative patients, sNfL levels correlated with CSF C3 concentrations. These findings support the complementary role of sNfL, sGFAP, and LS-OCMB in identifying distinct mechanisms of disease worsening and may inform early personalized management strategies in MS.<\/jats:p>","DOI":"10.3390\/ijms26146898","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T11:12:34Z","timestamp":1752837154000},"page":"6898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Combining CSF and Serum Biomarkers to Differentiate Mechanisms of Disability Worsening in Multiple Sclerosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3293-0125","authenticated-orcid":false,"given":"Enric","family":"Monreal","sequence":"first","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9148-671X","authenticated-orcid":false,"given":"Jos\u00e9 Ignacio","family":"Fern\u00e1ndez-Velasco","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Sainz de la Maza","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Espi\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2114-8632","authenticated-orcid":false,"given":"Noelia","family":"Villarrubia","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Rold\u00e1n-Santiago","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Aladro","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Getafe, Universidad Europea de Madrid, 28905 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-8227","authenticated-orcid":false,"given":"Juan Pablo","family":"Cuello","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Ayuso-Peralta","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Pr\u00edncipe de Asturias, 28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3816-2715","authenticated-orcid":false,"given":"Alexander","family":"Rodero-Romero","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6557-912X","authenticated-orcid":false,"given":"Juan Lu\u00eds","family":"Chico-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4567-0177","authenticated-orcid":false,"given":"Fernando","family":"Rodr\u00edguez-Jorge","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Quiroga-Varela","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit, Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), Dr. Josep Trueta University Hospital, 17001 Catalonia, Spain"},{"name":"Department of Medical Sciences, School of Medicine, University of Girona, 17001 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eulalia","family":"Rodr\u00edguez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Pilo de la Fuente","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Getafe, Universidad Europea de Madrid, 28905 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Mart\u00edn-\u00c1vila","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Getafe, Universidad Europea de Madrid, 28905 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Mart\u00ednez-Gin\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5205-3652","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Garc\u00eda-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Llu\u00efsa","family":"Rubio","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Pr\u00edncipe de Asturias, 28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-9121","authenticated-orcid":false,"given":"Sara","family":"Llufriu","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Hospital Clinic Barcelona, Institut d\u2019Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2373-6657","authenticated-orcid":false,"given":"Manuel","family":"Comabella","sequence":"additional","affiliation":[{"name":"Servei de Neurologia, Centre d\u2019Esclerosi M\u00faltiple de Catalunya (Cemcat), Institut de Recerca Vall d\u2019Hebr\u00f3n (VHIR), Hospital Universitari Vall d\u2019Hebr\u00f3n, Universitat Aut\u00f2noma de Barcelona, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0098-9918","authenticated-orcid":false,"given":"Xavier","family":"Montalban","sequence":"additional","affiliation":[{"name":"Servei de Neurologia, Centre d\u2019Esclerosi M\u00faltiple de Catalunya (Cemcat), Institut de Recerca Vall d\u2019Hebr\u00f3n (VHIR), Hospital Universitari Vall d\u2019Hebr\u00f3n, Universitat Aut\u00f2noma de Barcelona, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"\u00c1lvarez-Bravo","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Unit, Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), Dr. Josep Trueta University Hospital, 17001 Catalonia, Spain"},{"name":"Department of Medical Sciences, School of Medicine, University of Girona, 17001 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Lu\u00eds","family":"Veiga-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1329-0943","authenticated-orcid":false,"given":"Jaime","family":"Masjuan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6512-4413","authenticated-orcid":false,"given":"Lucienne","family":"Costa-Frossard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9067-3668","authenticated-orcid":false,"given":"Luisa Mar\u00eda","family":"Villar","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario Ram\u00f3n y Cajal, Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcal\u00e1, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41582-019-0170-8","article-title":"Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis","volume":"15","author":"Rotstein","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","first-page":"101009","article-title":"Fluid biomarkers in multiple sclerosis: From current to future applications","volume":"44","author":"Gaetani","year":"2024","journal-title":"Lancet Reg. Health-Eur."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1093\/brain\/awac016","article-title":"How patients with multiple sclerosis acquire disability","volume":"145","author":"Lublin","year":"2022","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1016\/j.msard.2016.07.003","article-title":"Brain health: Time matters in multiple sclerosis","volume":"9","author":"Giovannoni","year":"2016","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S1474-4422(13)70233-3","article-title":"Body fluid biomarkers in multiple sclerosis","volume":"13","author":"Comabella","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1212\/WNL.59.4.555","article-title":"Intrathecal IgM synthesis predicts the onset of new relapses and a worse disease course in MS","volume":"59","author":"Villar","year":"2002","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/ana.10441","article-title":"Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis","volume":"53","author":"Villar","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1172\/JCI22833","article-title":"Intrathecal synthesis of oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS","volume":"115","author":"Villar","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e1047","DOI":"10.1212\/NXI.0000000000001047","article-title":"Predicting Aggressive Multiple Sclerosis With Intrathecal IgM Synthesis Among Patients With a Clinically Isolated Syndrome","volume":"8","author":"Monreal","year":"2021","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/S1474-4422(22)00009-6","article-title":"Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: A retrospective modelling and validation study","volume":"21","author":"Benkert","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e200052","DOI":"10.1212\/NXI.0000000000200052","article-title":"Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients with Progressive Multiple Sclerosis","volume":"10","author":"Barro","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1001\/jamaneurol.2023.0010","article-title":"Association of Serum Neurofilament Light Chain Levels at Disease Onset With Disability Worsening in Patients With a First Demyelinating Multiple Sclerosis Event Not Treated With High-Efficacy Drugs","volume":"80","author":"Monreal","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4084","DOI":"10.1093\/brain\/awae260","article-title":"Serum biomarkers at disease onset for personalized therapy in multiple sclerosis","volume":"147","author":"Monreal","year":"2024","journal-title":"Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta6100","article-title":"A review of the natural history and epidemiology of multiple sclerosis: Implications for resource allocation and health economic models","volume":"6","author":"Richards","year":"2002","journal-title":"Health Technol. Assess."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple Sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S1474-4422(14)70305-9","article-title":"Role of the innate and adaptive immune responses in the course of multiple sclerosis","volume":"14","author":"Hemmer","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/s41577-022-00718-z","article-title":"The immunology of multiple sclerosis","volume":"22","author":"Attfield","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jneuroim.2009.10.015","article-title":"Role of the innate immune system in the pathogenesis of multiple sclerosis","volume":"221","author":"Gandhi","year":"2010","journal-title":"J. Neuroimmunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lassmann, H. (2019). Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.03116"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri3871","article-title":"Immunopathology of multiple sclerosis","volume":"15","author":"Dendrou","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1001\/jamaneurol.2022.4655","article-title":"Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis","volume":"80","author":"Tur","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_22","first-page":"974","article-title":"Active and non-active progression independent of relapse activity within the first 20 years of relapsing multiple sclerosis","volume":"95","author":"Maarouf","year":"2024","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1439","DOI":"10.1212\/WNL.0000000000008237","article-title":"Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis","volume":"93","author":"Pfuhl","year":"2019","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1001\/jamaneurol.2023.3997","article-title":"Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis","volume":"80","author":"Abdelhak","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/ana.27034","article-title":"Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions","volume":"96","author":"Scalfari","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e200212","DOI":"10.1212\/NXI.0000000000200212","article-title":"Complement Activation Is Associated with Disease Severity in Multiple Sclerosis","volume":"11","author":"Oechtering","year":"2024","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e200361","DOI":"10.1212\/NXI.0000000000200361","article-title":"Aberrant Complement Activation Is Associated with Structural Brain Damage in Multiple Sclerosis","volume":"12","author":"Oechtering","year":"2025","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1177\/1352458507082046","article-title":"Influence of oligoclonal IgM specificity in multiple sclerosis disease course","volume":"14","author":"Villar","year":"2007","journal-title":"Mult. Scler. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jneuroim.2012.03.020","article-title":"Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions","volume":"247","author":"Tzartos","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1487523","DOI":"10.3389\/fimmu.2024.1487523","article-title":"In-depth analysis of serum antibodies against Epstein-Barr virus lifecycle proteins, and EBNA1, ANO2, GlialCAM and CRYAB peptides in patients with multiple sclerosis","volume":"15","author":"Vasilenko","year":"2024","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T Cells and Immune Tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.msard.2018.12.019","article-title":"The proportion of peripheral regulatory T cells in patients with Multiple Sclerosis: A meta-analysis","volume":"28","author":"Li","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e21386","DOI":"10.1371\/journal.pone.0021386","article-title":"T Regulatory Cells Are Markers of Disease Activity in Multiple Sclerosis Patients","volume":"6","author":"Libera","year":"2011","journal-title":"PLoS ONE"},{"key":"ref_34","first-page":"1695","article-title":"Identification of regulatory T cell molecules associated with severity of multiple sclerosis","volume":"27","author":"Rosetti","year":"2020","journal-title":"Mult. Scler. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1001\/jamaneurol.2022.5332","article-title":"Targeting B Cells and Microglia in Multiple Sclerosis with Bruton Tyrosine Kinase Inhibitors","volume":"80","author":"Dybowski","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1001\/jamaneurol.2023.3331","article-title":"Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis","volume":"80","author":"Cagol","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rodero-Romero, A., Monreal, E., Sainz-Amo, R., Dom\u00ednguez, J.M.G., Villarrubia, N., Veiga-Gonz\u00e1lez, J.L., Fern\u00e1ndez-Velasco, J.I., Goicochea-Brice\u00f1o, H., Rodr\u00edguez-Jorge, F., and de la Maza, S.S. (2024). Establishing Normal Serum Values of Neurofilament Light Chains and Glial Fibrillary Acidic Protein Considering the Effects of Age and Other Demographic Factors in Healthy Adults. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147808"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:11:55Z","timestamp":1760033515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146898"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146898","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,18]]}}}