Normative Modelling of Brain Volume for Diagnostic and Prognostic Stratification in Multiple Sclerosis

Background. Brain atrophy is a hallmark of multiple sclerosis (MS). For clinical translatability and individual-level predictions, brain atrophy needs to be put into context of the broader population, using reference or normative models. Methods. Reference models of MRI-derived brain volumes were established from a large healthy control (HC) multi-cohort dataset (N=63 115, 51% females). The reference models were applied to two independent MS cohorts (N=362, T1w-scans=953, follow-up time up to 12 years) to assess deviations from the reference, defined as Z-values. We assessed the overlap of deviation profiles and their stability over time using individual-level transitions towards or out of significant reference deviation states (|Z|>1.96). A negative binomial model was used for case-control comparisons of the number of extreme deviations. Linear models were used to assess differences in Z-score deviations between MS and propensity-matched HCs, and associations with clinical scores at baseline and over time. The utilized normative BrainReference models, scripts and usage instructions are freely available. Findings. We identified a temporally stable, brain morphometric phenotype of MS. The right and left thalami most consistently showed significantly lower-than-reference volumes in MS (25% and 26% overlap across the sample). The number of such extreme smaller-than-reference values was 2.70 in MS compared to HC (4.51 versus 1.67). Additional deviations indicated stronger disability (Expanded Disability Status Scale: β=0.22, 95% CI 0.12 to 0.32), Paced Auditory Serial Addition Test score (β=-0.27, 95% CI -0.52 to -0.02), and Fatigue Severity Score (β=0.29, 95% CI 0.05 to 0.53) at baseline, and over time with EDSS (β=0.07, 95% CI 0.02 to 0.13). We additionally provide detailed maps of reference-deviations and their associations with clinical assessments. Interpretation. We present a heterogenous brain phenotype of MS which is associated with clinical manifestations, and particularly implicating the thalamus. The findings offer potential to aid diagnosis and prognosis of MS.