{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T11:16:01Z","timestamp":1775733361537,"version":"3.50.1"},"posted":{"date-parts":[[2025,9,15]]},"group-title":"Neurology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We constructed age-, sex-, and intracranial volume\u2013adjusted 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 &lt; \u20131.96). 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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\u00b19.7, 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\u20133.30), 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 (\u03b2=0.24, 95% CI 0.14\u20130.34) and longitudinal main effect (\u03b2=0.07, 95% CI 0.02\u20130.13). Lower-than-reference volumes in the thalamus, hippocampus, and putamen were consistently associated with higher disability cross-sectionally (\u03b2\n                    <jats:sub>standardized<\/jats:sub>\n                    = \u20130.17 to \u20130.23) and over time (\u03b2\n                    <jats:sub>standardized<\/jats:sub>\n                    = \u20130.14 to \u20130.18). Deviation-based risk stratification identified patients with modestly higher disability trajectories (\u03b2=0.13, 95% CI 0.03\u20130.24).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.14.25335702","type":"posted-content","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:05:19Z","timestamp":1757981119000},"source":"Crossref","is-referenced-by-count":0,"title":["Normative Modelling of Brain Volume in Multiple Sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8113-2560","authenticated-orcid":false,"given":"Max","family":"Korbmacher","sequence":"first","affiliation":[{"name":"Neuro-SysMed, Department of Clinical Medicine, University of Bergen, Norway"},{"name":"Mohn Medical Imaging and Visualisation centre, Department of Radiology, Haukeland University Hospital, Norway"},{"name":"Department for Radiography, Western Norway University of Applied Sciences, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid Anne","family":"Lie","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin","family":"Wesnes","sequence":"additional","affiliation":[{"name":"Department of Neurology, St. Olav\u2019s Hospital, Trondheim University Hospital, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Westman","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences, and Society Karolinska Institutet, Sweden"},{"name":"The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Espeseth","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Oslo, Norway"},{"name":"Faculty of Psychology, Oslo New University College, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole Andreas","family":"Andreassen","sequence":"additional","affiliation":[{"name":"Center for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Norway"},{"name":"K.G. Jebsen-Centre for Neurodevelopmental disorders, University of Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars T.","family":"Westlye","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Oslo, Norway"},{"name":"Center for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Norway"},{"name":"K.G. Jebsen-Centre for Neurodevelopmental disorders, University of Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stig","family":"Wergeland","sequence":"additional","affiliation":[{"name":"Neuro-SysMed, Department of Clinical Medicine, University of Bergen, Norway"},{"name":"Department of Clinical Medicine, University of Bergen, Norway"},{"name":"Norwegian MS-Registry and Biobank, Helse Bergen, Haukeland University Hospital, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanne Flinstad","family":"Harbo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Norway"},{"name":"Institute for Clinical Medicine, University of Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gro Owren","family":"Nygaard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Norway"},{"name":"Institute for Clinical Medicine, University of Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kjell-Morten","family":"Myhr","sequence":"additional","affiliation":[{"name":"Neuro-SysMed, Department of Clinical Medicine, University of Bergen, Norway"},{"name":"Department of Clinical Medicine, University of Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Einar August","family":"H\u00f8gest\u00f8l","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Norway"},{"name":"Department of Psychology, University of Oslo, Norway"},{"name":"Institute for Clinical Medicine, University of Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00d8ivind","family":"Torkildsen","sequence":"additional","affiliation":[{"name":"Neuro-SysMed, Department of Clinical Medicine, University of Bergen, Norway"},{"name":"Department of Clinical Medicine, University of Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040903350696000_2025.09.14.25335702v6.1","doi-asserted-by":"crossref","first-page":"e211","DOI":"10.1016\/S2589-7500(23)00250-9","article-title":"Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisation","volume":"6","year":"2024","journal-title":"The Lancet Digital Health"},{"key":"2026040903350696000_2025.09.14.25335702v6.2","doi-asserted-by":"crossref","unstructured":"Korbmacher, M. et al. 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