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.

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Publication Details

Journal
Neurology Open Access
Published
2026-08-25
DOI
https://doi.org/10.1212/wn9.0000000000000153
Primary Topic
Multiple Sclerosis Research Studies
Type
article
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0.00

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article

Normative Modeling of Brain Volume in Multiple Sclerosis Using Healthy Controls

Einar August Høgestøl, Lars Tjelta Westlye, Winnie Kwang, Payam Mahboubi et al.
Neurology Open Access
Multiple Sclerosis Research Studies
article

Normative Modeling of Brain Volume in Multiple Sclerosis Using Healthy Controls

Einar August Høgestøl, Lars Tjelta Westlye, Winnie Kwang, Payam Mahboubi, Juliet Fockler, Øivind Torkildsen, Ole A. Andreassen, for Alzheimer’s Disease Neuroimaging Initiative, Andrew J. Saykin, Yuliana Cabrera, Ingrid Anne Lie, D Flenniken, Gro Owren Nygaard, Max Korbmacher, Jeremy Pizzola, Diana Truran Sacrey, Kristin Wesnes, Taylor Clanton, Thomas Espeseth, Kaori Kubo Germano, Hanne F. Harbo, Kjell‐Morten Myhr, Stig Wergeland, Lindsey Hergesheimer, Eric Westman, Shaniya Parkins, Mai Seng Thao, Kedir Adem Hussen, Joel Felmlee Jr., Vanessa Guzman, Catherine Conti, Adeyinka Ajayi, Cat Conti, Justin Robison, Ozioma Okonkwo, Sarah Walterc, Miriam Ashford, Richard J. Perrin, Adrienne Kormos, Cecily Jenkins, Pallavi Sachdev, Rachel Nosheny, Rema Raman, Virginia Boatwright, Ronald Petersen, Hannatu Amaza, Matt Glittenberg, Tom Montine, Joe Strong, Stephanie Smith, Caileigh Zimmerman, Trinity Weisensel, Danielle Harvey, Elizabeth Shaffer, Monica Rivera-Mindt, Robert C. Green, William Jagust, Edward B. Lee, Laurel Beckett, Michael Donohue, Erin Drake, Adam Diaz, Jennifer Salazar, Melanie J. Miller, Paul Aisen, Gustavo Jimenez, Kwangsik Nho, Susan Landau, Sheila Ogwang, Joseph Di Benedetto, Isabella Hoang, Michael W. Weiner, Olusegun Adegokec, Omobolanle Ayo, Andrea Fidell, Naomi Saito, Duygu Tosun, Chengshi Jin, Sandra Talavera, Lisa Thomas, Michael Rafii, Leslie M. Shaw, Caitlin Webb, Clifford R. Jack, Fabiola Magana, Arthur W. Toga
article en

Abstract

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.

Neurology Open AccessVol. 2(3)
Oslo University Hospital (NO), OsloMet – Oslo Metropolitan University (NO), University of Oslo (NO), Haukeland University Hospital (NO), Karolinska Institutet (SE), Public Health England (GB), St Olav's University Hospital (NO), NeuroDevelopment Center (US), Western Norway University of Applied Sciences (NO), University of Bergen (NO), Imperial College London (GB)
U.S. Department of Defense, Bristol-Myers Squibb, Eli Lilly and Company, Biogen, Eisai, Norges Forskningsråd, H. Lundbeck A/S, IXICO, National Institutes of Health, Genentech, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Dental and Craniofacial Research
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