Normative Modelling of Brain Volume 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 6.0-90.1) 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 2.21-3.30), 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 (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 (β standardized = -0.17 to -0.23) and over time (β standardized = -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).

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.