{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:35:11Z","timestamp":1793198111175,"version":"4.5.0"},"reference-count":42,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017147","name":"International Progressive MS Alliance","doi-asserted-by":"publisher","award":["PA-1412-02420"],"award-info":[{"award-number":["PA-1412-02420"]}],"id":[{"id":"10.13039\/100017147","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2026,1,19]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Brain atrophy is increasingly used as an outcome measure in clinical trials in relapsing-remitting multiple sclerosis (RRMS), but little is known about how chronological age interacts with MS-specific effects. For instance, while annual brain atrophy rates typically increase with age in healthy individuals, MS patients tend to exhibit decreasing atrophy rates over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the relationship between age and brain volume in a large dataset of 4241 trial participants with RRMS. We used pooled individual-participant data from phase 3 clinical trials with 96 weeks follow-up, which included both active treatment and placebo\/comparator arms. Participants were categorised into seven groups based on chronological age (18\u201324 years, 25\u201330 years, 31\u201335 years, 36\u201340 years, 41\u201345 years, 46\u201350 years, 51\u201356 years). We performed multilevel linear mixed-effects regression analyses to examine differences between age groups in normalised whole brain volume (NWBV), thalamus grey matter volume (NThGMV), grey matter volume (NGMV) and white matter volume at baseline and their changes over follow-up. We also studied how disease duration influenced these relationships using similar models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Older participants showed significantly lower NWBV, NGMV and NThGMV at baseline than younger participants. Most importantly, older participants exhibited lower rates of atrophy during follow-up, particularly in the thalamus. This association was consistent across all disease duration subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Older participants had more severe atrophy when enrolled into trials, but slower (thalamic) atrophy rates, independent of disease duration over time. Together, these findings emphasise that age should be taken into account when designing clinical trials that use brain atrophy as an outcome measure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jnnp-2025-337779","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T18:20:24Z","timestamp":1770229224000},"page":"581-590","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Brain atrophy rates vary with age in relapsing-remitting multiple sclerosis"],"prefix":"10.1136","volume":"97","clinical-trial-number":[{"clinical-trial-number":"nct04260711","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04225312","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05296161","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6695-2667","authenticated-orcid":false,"given":"Sezgi","family":"Ka\u00e7ar","sequence":"first","affiliation":[{"name":"MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands"},{"name":"MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"van Nederpelt","sequence":"additional","affiliation":[{"name":"MS Center Amsterdam, Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia R","family":"Jelgerhuis","sequence":"additional","affiliation":[{"name":"MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5673-9996","authenticated-orcid":false,"given":"Eline M E","family":"Coerver","sequence":"additional","affiliation":[{"name":"MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joep","family":"Killestein","sequence":"additional","affiliation":[{"name":"MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6892-104X","authenticated-orcid":false,"given":"Maria Pia","family":"Sormani","sequence":"additional","affiliation":[{"name":"Department of Health Sciences (DISSAL), University of Genova, Genova, Italy"},{"name":"Ospedale Policlinico San Martino IRCCS, Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7485-1367","authenticated-orcid":false,"given":"Olga","family":"Ciccarelli","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK"},{"name":"National Institute for Health and Care Research (NIHR) University College Hospitals (UCLH) Biomedical Research Centre (BRC), London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-0106","authenticated-orcid":false,"given":"Douglas L","family":"Arnold","sequence":"additional","affiliation":[{"name":"NeuroRx Research and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada"},{"name":"McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9557-5381","authenticated-orcid":false,"given":"Zo\u00e9 L E","family":"van Kempen","sequence":"additional","affiliation":[{"name":"MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B M J","family":"Uitdehaag","sequence":"additional","affiliation":[{"name":"MS Center Amsterdam, Neurology, Vrije 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