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

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Abstract

BackgroundBrain 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. MethodsReference 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{middle dot}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. FindingsWe 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{middle dot}70 in MS compared to HC (4{middle dot}51 versus 1{middle dot}67). Additional deviations indicated stronger disability (Expanded Disability Status Scale: {beta}=0{middle dot}22, 95% CI 0{middle dot}12 to 0{middle dot}32), Paced Auditory Serial Addition Test score ({beta}=-0{middle dot}27, 95% CI -0{middle dot}52 to -0{middle dot}02), and Fatigue Severity Score ({beta}=0{middle dot}29, 95% CI 0{middle dot}05 to 0{middle dot}53) at baseline, and over time with EDSS ({beta}=0{middle dot}07, 95% CI 0{middle dot}02 to 0{middle dot}13). We additionally provide detailed maps of reference-deviations and their associations with clinical assessments. InterpretationWe 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. FundingNorwegian MS-union, Research Council of Norway (#223273; #324252); the South-Eastern Norway Regional Health Authority (#2022080); and the European Unions Horizon2020 Research and Innovation Programme (#847776, #802998). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSReference values and normative models have yet to be widely applied to neuroimaging assessments of neurological disorders such as multiple sclerosis (MS). We conducted a literature search in PubMed and Embase (Jan 1, 2000-September 12, 2025) using the terms "MRI" AND "multiple sclerosis", with and without the keywords "normative model*" and "atrophy", without language restrictions. While normative models have been applied in psychiatric and developmental disorders, few studies have addressed their use in neurological conditions. Existing MS research has largely focused on global atrophy and has not provided regional reference charts or established links to clinical and cognitive outcomes. Added value of this studyWe provide regionally detailed brain morphometry maps derived from a heterogeneous MS cohort spanning wide ranges of age, sex, clinical phenotype, disease duration, disability, and scanner characteristics. By leveraging normative modelling, our approach enables individualised brain phenotyping of MS in relation to a population based normative sample. The analyses reveal clinically meaningful and spatially consistent patterns of smaller brain volumes, particularly in the thalamus and frontal cortical regions, which are linked to disability, cognitive impairment, and fatigue. Robustness across scanners, centres, and longitudinal follow-up supports the stability and generalisability of these findings to real-world MS populations. Implications of all the available evidenceNormative modelling offers an individualised, sensitive, and interpretable approach to quantifying brain structure in MS by providing individual-specific reference values, supporting earlier detection of neurodegeneration and improved patient stratification. A consistent pattern of thalamic and fronto-parietal deviations defines a distinct morphometric profile of MS, with potential utility for early and personalised diagnosis and disease monitoring in clinical practice and clinical trials.

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