A glial oxidative signature predicts disability in primary progressive multiple sclerosis and is associated with long-term cognitive decline

Background Progressive multiple sclerosis (MS) involves heterogeneous mechanisms, and primary progressive MS without inflammatory activity (PPMS-NA) is poorly understood. Objective To characterize the immune–oxidative profile of PPMS-NA and assess plasma IL-6, IL-8, IFNα2, and cerebrospinal fluid (CSF) reactive oxygen species (ROS) as predictors of disability and cognitive decline. Methods 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. Results PPMS-NA showed reduced IL-6 and IFNα2 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. Conclusion 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.