Background and Objectives Gray matter (GM) damage is a key determinant of clinical disability in multiple sclerosis (MS), but its relevance to very long-term outcomes remains insufficiently characterized. We assessed associations between baseline and 12-month MRI measures of GM and white matter (WM) damage and long-term outcomes in relapse-onset MS.Methods We conducted a prospective longitudinal single-center cohort study of relapse-onset MS patients enrolled between 1993 and 1998. Participants underwent clinical and 1.5T brain MRI assessments at baseline and after 12 months. MRI measures included T2-lesion and T1-lesion volumes, GM, WM, and thalamic volume fractions, magnetization transfer ratio (MTR) of GM, thalamus, normal-appearing WM, and WM lesions. Escalation to high-efficacy disease-modifying therapies (HE-DMTs) was recorded. Outcomes included Expanded Disability Status Scale (EDSS) worsening, evolution to a more severe disease stage, MS-related death, and cognitive deterioration. Associations were evaluated using LASSO-regularized logistic regression with internal bootstrap validation.Results Seventy-three relapse-onset MS patients (mean age = 33.0 years; female = 69.9%) were followed for a median of 25.9 years (interquartile range = 18.1-27.1; patients lost during follow-up = 11). EDSS worsening occurred in 79.5% of patients, 72.6% evolved to a more severe disease stage, 24.7% died from MS-related causes, and 39.5% of patients with cognitive data (17/43) experienced cognitive deterioration. EDSS worsening was associated with lower baseline GM fraction (GMF) (standardized-beta = -0.561), escalation to HE-DMTs (standardized-beta = 0.059), lower baseline thalamic fraction (standardized-beta = -0.115), lower baseline normal-appearing WM MTR histogram peak height (standardized-beta = -0.010), and greater 12-month decline in GM MTR histogram peak height (standardized-beta = -0.115) (area under the curve [AUC] = 0.843, 95% CI 0.744-0.941). Evolution to a more severe disease stage was associated with higher 12-month EDSS score change (standardized-beta = 0.167) and lower baseline GMF (standardized-beta = -0.151) (AUC = 0.793, 95% CI 0.670-0.916). MS-related death was associated with male sex (standardized-beta = 0.063), higher baseline EDSS score (standardized-beta = 0.182), lower baseline GMF (standardized-beta = -0.304), lower baseline GM MTR histogram peak height (standardized-beta = -0.050), and greater 12-month decline in mean thalamic MTR (standardized-beta = -0.370) (AUC = 0.887, 95% CI 0.813-0.961). Cognitive deterioration was associated with older baseline age (standardized-beta = 0.197), lower baseline brain parenchymal fraction (standardized-beta = -0.039), and lower baseline mean GM MTR (standardized-beta = -0.376) (AUC = 0.891, 95% CI 0.788-0.994).Discussion Brain GM damage showed consistent associations with disability worsening and evolution, mortality, and cognitive deterioration over 26 years in relapse-onset MS, supporting the long-term clinical relevance of GM-focused MRI markers.
