PRL Heterogeneity in Multiple Sclerosis: Pathophysiological and Clinical Implications

BackgroundIn multiple sclerosis (MS), temporal evolution of paramagnetic rim lesions (PRL)-associated tissue damage, and its relationship to clinical disability, serum biomarkers, and treatment response remain incompletely understood.Material and MethodsThis multicentre study combined cross-sectional and longitudinal analyses of data from 182 MS cases (68% relapsing, 64% females; median EDSS 2.5 [range 0-8]). MRI-matched serum neurofilament light chain (sNfL) levels were measured and age corrected. PRL status was assessed on 3-tesla 3D-EPI-phase and lesion T1-times on MP2RAGE-maps. Lesions were classified as short-T1 (<1572ms) or long-T1 (≥1572ms). Longitudinal (~2.5y) lesion T1-time changes were analysed in a subset of pre/post anti-CD20 antibody treated (n=37) and untreated (n=37) cases.ResultsLesion-age assessment in 134 lesions (72 PRL) showed that long-T1 PRL were older than short-T1 PRL (P = 0.015), with no differences in non-PRL. Adjusted analyses showed that short-T1 PRL volume correlated with higher sNfL z-scores (P = 0.026), whereas long-T1 PRL did not. Higher EDSS was associated with greater volume of long-T1 PRL (P = 0.003) but not short-T1 PRL. Pre/post treatment analyses showed significant treatment-related T1 decrease across different lesion subtypes, including short-T1 PRL (P < 0.01), whereas long-T1 PRL showed no detectable treatment effect (P = 0.8).ConclusionPRL show substantial heterogeneity in terms of MRI-measured lesional tissue damage, reflecting differences in the inflammatory/demyelinating and neurodegenerative processes across lesion development stages. Short-T1 PRL, likely representing younger lesions, are characterised by ongoing tissue damage and axonal degeneration, while long-T1 PRL correlate with established clinical disability. Our pre/post anti-CD20 analyses suggest that timely treatment of patients with short- T1 lesions might forestall future disability accrual in MS and that T1 changes in such lesions might serve as a predictive biomarker for this effect.FundingIntramural Research Program of NINDS, NIH; NINDS grants R01NS082347and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Fund for Scientific Research (FNRS); Sanofi Investigator Initiated Trial; Fondation Charcot Stichting Research Fund 2023 and 2025.