Normative Modeling of Brain Volume in Multiple Sclerosis Using Healthy Controls

Background and ObjectivesInterpretation 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. MethodsWe constructed age-adjusted, sex-adjusted, 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), and fatigue (Fatigue Severity Scale) 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. ResultsModels were trained on 62,444 MRI data sets from healthy individuals across the lifespan (50.8% women, age range 6.0–90.1 years) and applied to 953 longitudinal MRI scans from 362 people with MS (mean age = 38.8 ± 9.7, 70.5% women, 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 2.21–3.30), most prominently in the thalamus (approximately 25% of patients). A higher number of deviations were associated with higher disability (EDSS) indicated by a cross-sectional (β = 0.24, 95% CI 0.14–0.34) and longitudinal main effect (β = 0.07, 95% CI 0.02–0.13). Lower-than-reference volumes in the thalamus, hippocampus, and putamen were consistently associated with higher disability cross-sectionally (βstandardized = −0.17 to −0.23) and over time (βstandardized = −0.14 to −0.18). Deviation-based risk stratification identified patients with modestly higher disability trajectories (β = 0.13, 95% CI 0.03–0.24). DiscussionNormative modelling reveals a heterogeneous morphometric deviation profile in MS, centered on deep gray 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.