{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:47:27Z","timestamp":1777265247074,"version":"3.51.4"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Progressive multiple sclerosis (MS) involves heterogeneous mechanisms, and primary progressive MS without inflammatory activity (PPMS-NA) is poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To characterize the immune\u2013oxidative profile of PPMS-NA and assess plasma IL-6, IL-8, IFN\u03b12, and cerebrospinal fluid (CSF) reactive oxygen species (ROS) as predictors of disability and cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a multicenter longitudinal study with two cohorts. Cohort 1 included participants across MS phenotypes (n = 146 baseline; n = 36 follow-up) and other neurological disorders, measuring plasma cytokines and CSF ROS. Cohort 2 included 40 people with MS, followed for 10 years to assess associations with cognition. Outcomes were analyzed with multivariate models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PPMS-NA showed reduced IL-6 and IFN\u03b12 but elevated CSF ROS versus RRMS and OND, reflecting low systemic inflammation and central oxidative stress. IL-8 increased, predicting disability and 10-year processing speed decline. IL-6 had time- and domain-specific effects: initially linked to attention, later inversely with visuospatial and working memory. CSF ROS correlated with atrophy, supporting oxidative stress as neurodegeneration driver.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PPMS-NA is a progressive MS subtype driven by oxidative and glial processes. IL-8 and CSF ROS are biomarkers for early stratification, and IL-6 relates to cognition, supporting therapies targeting oxidative stress and glia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1802339","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:27:28Z","timestamp":1777264048000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A glial oxidative signature predicts disability in primary progressive multiple sclerosis and is associated with long-term cognitive decline"],"prefix":"10.3389","volume":"17","author":[{"given":"Albert","family":"Miguela","sequence":"first","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joana Maria","family":"Huertas-Pons","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e0udia","family":"Coll-Martinez","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]},{"name":"Department of Neurology, Girona Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital and Santa Caterina Hospital","place":["Girona\/Salt, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariadna","family":"Gifreu-Fraixin\u00f3","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Department of Neurology, Girona Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital and Santa Caterina Hospital","place":["Girona\/Salt, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Salavedra-Pont","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Department of Neurology, Girona Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital and Santa Caterina Hospital","place":["Girona\/Salt, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Comabella","sequence":"additional","affiliation":[{"name":"Servei de Neurologia, Centre d\u2019Esclerosi M\u00faltiple de Catalunya (Cemcat), Institut de Recerca Vall d\u2019Hebron (VHIR), Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona","place":["Barcelona, Spain"]},{"name":"Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) - Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa Mar\u00eda","family":"Villar","sequence":"additional","affiliation":[{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]},{"name":"Department of Immunology, Hospital Ram\u00f3n y Cajal, Ramon y Cajal Institute for Health Research (IRYCIS), Spain","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Gich","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]},{"name":"Department of Neurology, Girona Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital and Santa Caterina Hospital","place":["Girona\/Salt, Spain"]},{"name":"Department of Medical Sciences, Faculty of Medicine, University of Girona","place":["Girona, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"\u00c1lvarez-Bravo","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]},{"name":"Department of Neurology, Girona Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital and Santa Caterina Hospital","place":["Girona\/Salt, Spain"]},{"name":"Department of Medical Sciences, Faculty of Medicine, University of Girona","place":["Girona, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Llu\u00eds","family":"Rami\u00f3-Torrent\u00e0","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]},{"name":"Department of Medical Sciences, Faculty of Medicine, University of Girona","place":["Girona, Spain"]},{"name":"Medical Management Department, Fundaci\u00f3 Hospital d\u2019Olot i Comarcal de la Garrotxa","place":["Olot, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Quiroga-Varela","sequence":"additional","affiliation":[{"name":"Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBGI-CERCA)","place":["Salt, Spain"]},{"name":"Red de Enfermedades Inflamatorias, Carlos III Health Institute (ISCIII)","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25168751","article-title":"Primary progressive multiple sclerosis\u2014a key to understanding and managing disease progression","volume":"25","author":"Sempik","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.22074\/cellj.2016.4867","article-title":"Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy","volume":"19","author":"Ghasemi","year":"2017","journal-title":"Cell J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.46.4.907","article-title":"Defining the clinical course of multiple sclerosis: the 2013 revisions","volume":"83","author":"Lublin","year":"2014","journal-title":"Neurology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/122.10.1941","article-title":"The natural history of multiple sclerosis: a geographically based study. 5. 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