{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T13:11:32Z","timestamp":1768655492468,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,2]]},"group-title":"Neurology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Grey matter (GM) atrophy has been suggested as the most accurate marker of neurodegeneration in multiple sclerosis (MS) progression. However, long-term comparisons between MS and healthy controls (HC) are rare, and the most significantly atrophying brain regions and their clinical importance still need robust and longitudinal validation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    This multi-cohort longitudinal observational study used two relapsing remitting MS (RRMS) cohorts (N=386, T\n                    <jats:sub>1<\/jats:sub>\n                    w-scans=940) sampled for up to 12 years to map grey matter atrophy localisation and disease progression (Expanded Disability Status Scale (EDSS), Paced Auditory Serial Addition Test (PASAT), Fatigue Severity Scale (FSS)). The identified region-specific significant atrophy was compared with 2,163 HCs (T\n                    <jats:sub>1<\/jats:sub>\n                    w-scans=4,326).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The strongest, replicable, significant brain atrophy patterns in RRMS were found in the frontal lobes, specifically, in the superior frontal cortex (SFC, \u03b2\n                    <jats:sub>age<\/jats:sub>\n                    \u2264-0.27), pars orbitalis (\u03b2\n                    <jats:sub>age<\/jats:sub>\n                    \u2264-0.25), and thalami (\u03b2\n                    <jats:sub>age<\/jats:sub>\n                    \u2264-0.20). Across samples, the examined significant atrophy patterns in MS were more pronounced than in a sample of more than 20-years older HCs in the right SFC (Z&gt;2.41, p&lt;0.009), caudal-middle frontal cortex (Z&gt;2.08, p&lt;0.019), caudate (Z&gt;2.09, p&lt;0.019), and the left frontal pole (Z&gt;2.42, p&lt;0.008). The replicability of associations between volumetric and clinical outcome changes was limited and better described by whole-brain than regional volume changes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings indicate accelerated GM atrophy in people with RRMS, specific to the SFL and thalamus and related to disability-progression. These results can inform further studies examining the role of thalamic and SFC atrophy as MS-biomarkers.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Messages<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What is already known on this topic<\/jats:title>\n                    <jats:p>Grey matter atrophy is considered a hallmark of neurodegeneration in multiple sclerosis, with regional atrophy, especially in the thalamus, linked to disability progression. However, few studies have longitudinally examined region-specific atrophy and its clinical relevance or compared MS-related atrophy with normal ageing using large control samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What this study adds<\/jats:title>\n                    <jats:p>This study identifies replicable, region-specific grey matter atrophy in the superior frontal cortex and thalamus across two independent RRMS cohorts. It shows that atrophy in these regions occurs earlier and more rapidly in MS than in healthy controls who are approximately 20 years older. Frontal lobe atrophy was most consistently associated with disability progression. Yet, associations between atrophy and changes in clinical scores were weak and sample dependent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>How this study might affect research, practice or policy<\/jats:title>\n                    <jats:p>Our findings suggest to further explore frontal grey matter atrophy as a potential imaging biomarker for MS progression. This could inform future clinical trials, improve prognostic models, and guide the development of personalized treatment strategies based on region-specific brain changes.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.01.25330635","type":"posted-content","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T13:55:18Z","timestamp":1751464518000},"source":"Crossref","is-referenced-by-count":1,"title":["Accelerated grey matter degeneration in relapsing remitting multiple sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8113-2560","authenticated-orcid":false,"given":"Max","family":"Korbmacher","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid Anne","family":"Lie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin","family":"Wesnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Westman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Espeseth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-3568","authenticated-orcid":false,"given":"Ole Andreas","family":"Andreassen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanne","family":"Harbo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gro Owren","family":"Nygaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8644-956X","authenticated-orcid":false,"given":"Lars Tjelta","family":"Westlye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stig","family":"Wergeland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kjell-Morten","family":"Myhr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Einar August","family":"H\u00f8gest\u00f8l","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00d8ivind","family":"Torkildsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025081800200678000_2025.07.01.25330635v2.1","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1093\/brain\/awy114","article-title":"Can we use regional grey matter atrophy sequence to stage neurodegeneration in multiple sclerosis?","volume":"141","year":"2018","journal-title":"Brain"},{"key":"2025081800200678000_2025.07.01.25330635v2.2","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1001\/jamaneurol.2022.1025","article-title":"Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis","volume":"79","year":"2022","journal-title":"JAMA Neurol"},{"key":"2025081800200678000_2025.07.01.25330635v2.3","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1177\/1352458514543811","article-title":"Cortical thickness and surface area relate to specific symptoms in early relapsing\u2013remitting multiple sclerosis","volume":"21","year":"2015","journal-title":"Mult. 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