Disability-relevant demyelination in multiple sclerosis: five-year evolution following diagnosis

Improved understanding of how myelin damage contributes to disability in multiple sclerosis (MS) is needed to inform targeted therapeutic strategies and improve clinical trial platforms. Magnetization transfer saturation ( MTsat ) and T 1 relaxometry provide in vivo quantitative MRI measures of myelin integrity, and may offer insights into disability-relevant pathology beyond inflammatory relapse. This longitudinal study explores the relationship between early demyelination and disability progression over the first five years following diagnosis. 62 people with relapsing-remitting (pwRR)MS (≤ 6 months post-diagnosis, 48 female, mean age 38 years) underwent baseline and one-year MRI and Expanded Disability Status Scale (EDSS) assessment. At five-year follow-up, 56/62 (90.3%) completed EDSS and 40/62 additionally completed MRI (64.5%). Disability progression was defined as an increase of ≥ 1.5, ≥ 1.0 or ≥ 0.5 points for a previous EDSS score of < 1.0, 1.0 to 5.5, and ≥ 6.0, respectively. Baseline neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and EBNA1 immunoglobulin (IgG) titres were also measured. MTsat was calculated within normal-appearing white matter (NAWM), white matter lesions (WML), cortical and deep grey matter (GM) structures. Associations between change in MTsat and disability progression were assessed with binomial logistic regression. Interactions with interval disease activity (i.e. new/enlarging lesions [NELs]) were investigated, and comparisons were made with healthy control test-retest data (n = 11). Exploratory analyses were performed for: (prolonged) T 1 ; baseline metrics; blood-derived markers; diffusion-weighted imaging; and, disability-associated differences in five-year microstructural MRI trajectories. Greater baseline-to-one-year decreases in NAWM and WML MTsat were associated with baseline-to-one-year disability progression (adjusted odds ratio [95% confidence interval] = 0.255 [0.078 to 0.602] and 0.261 [0.084 to 0.638]; false discovery rate [FDR]-corrected p -value = 0.015 and 0.015). NELs did not influence these associations (interaction p -values > 0.05). One-to-five-year changes in MTsat were not associated with one-to-five-year disability progression (FDR-corrected p -values > 0.05). Neither baseline nor baseline-to-one-year MTsat changes predicted future disability progression. No exploratory analyses reached FDR-corrected statistical significance. We show for the first time that progressive NAWM and WML demyelination measured with MTsat is associated with early disability progression in recently diagnosed RRMS, independent of radiological inflammatory disease activity. Neither MTsat nor T 1 are associated with longer-term progression over the subsequent four years. MTsat is sensitive to disability-relevant demyelination not visible on conventional MRI, indicates a potential early window of therapeutic opportunity in the year following diagnosis, and is a promising clinically applicable disease stratifier and surrogate endpoint for therapeutic trials.