Normative MRI modelling identifies critical brain volume deviations associated with disability in multiple sclerosis.

Background and Objectives: Interpretation of brain atrophy in multiple sclerosis (MS) relies on group level research and lacks individualized reference standards. Normative modelling can enable patient level assessments of regional brain volumes relative to population expectations. Methods: We constructed age, sex, and intracranial volume adjusted normative models of regional cortical and subcortical FreeSurfer estimated brain volumes and applied to data from a concluded clinical trial and routine hospital examinations to derive regional deviation Z scores and counts of critical deviations (Z > |1.96|). Associations with disability (Expanded Disability Status Scale [EDSS]), cognitive performance (Paced Auditory Serial Addition Test [PASAT]), and fatigue (Fatigue Severity Scale [FSS]) were examined cross sectionally and longitudinally using fixed and random effects models. A deviation based stratification rule was evaluated for disability progression and relapse risk using survival analyses. Results: Models were trained on 62,444 MRI datasets from healthy individuals across the lifespan (50.8% females, age range 6.0 to 90.1) and applied to 953 longitudinal MRI scans from 362 people with MS (mean age = 38.8 (9.7), 70.5% females, follow up up to 12 years). People with MS exhibited a higher number of critical deviations than matched controls (incidence rate ratio 2.70, 95% CI 2.21 to 3.30), most prominently in the thalamus (approximately 25% of patients). A higher number of deviations was associated with higher disability (EDSS) indicated by a cross sectional ({beta}=0.24, 95% CI 0.14 to 0.34) and longitudinal main effect ({beta}=0.07, 95% CI 0.02 to 0.13). Lower than reference volumes in the thalamus, hippocampus, and putamen were consistently associated with higher disability cross sectionally ({beta}standardized=-0.17 to -0.23) and over time ({beta}standardized=-0.14 to -0.18). Deviation based risk stratification identified patients with modestly higher disability trajectories ({beta}=0.13, 95% CI 0.03 to 0.24). Discussion: Normative modelling reveals a heterogeneous morphometric deviation profile in MS, centred on deep grey matter structures and associated with disability accumulation. These findings support the use of population referenced MRI metrics for individual level phenotyping in MS and warrant validation in independent cohorts.