{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T15:58:24Z","timestamp":1782057504710,"version":"3.54.5"},"reference-count":47,"publisher":"BMJ","issue":"5","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2026,1,13]]},"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Phase 2 clinical trials in primary progressive multiple sclerosis (PPMS) often use MRI brain volume measures as their primary endpoint. Here, we investigate the longitudinal association between change in MRI outcomes and change in disability over 2 years of follow-up in a large and well-characterised PPMS trial dataset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using the dataset from PROMISE (n=943, mean age of 58.0 years, mean Expanded Disability Status Scale (EDSS) 5.0, and mean disease duration of 10.5 years at baseline), a phase 3 trial of glatiramer acetate in PPMS, we described the change in MRI and disability measures during follow-up and used multivariable logistic regression models to investigate whether change in four MRI outcomes (grey matter volume, white matter volume, brain fraction and total burden of disease) was associated with seven measures of clinical disability worsening (including the EDSS, Timed 25 Foot Walk, Nine-Hole Peg Test and Paced Auditory Serial Addition Test).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found only weak and inconsistent associations between change in MRI and physical and cognitive outcome measures over 2 years of follow-up. Change in MRI measures in year 1 of the trial did not predict change in physical nor cognitive disability in year 2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The association of the investigated volumetric MRI measures and clinical disability outcomes was noticeably weak and inconsistent. Our findings question the suitability of brain volume loss and lesion burden accumulation as functionally relevant trial endpoints in PPMS and inform the design and interpretation of clinical trials in PPMS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jnnp-2025-337940","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T18:20:31Z","timestamp":1769624431000},"page":"422-430","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Breaking the PROMISE: poor association between brain volume loss and clinical disability worsening over 2 years of follow-up in primary progressive 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\/0000-0001-9972-5092","authenticated-orcid":false,"given":"Marcus","family":"Koch","sequence":"first","affiliation":[{"name":"Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jop","family":"Mostert","sequence":"additional","affiliation":[{"name":"Neurology, Rijnstate Hospital Arnhem, Arnhem, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-5864","authenticated-orcid":false,"given":"Eva M","family":"Strijbis","sequence":"additional","affiliation":[{"name":"Neurology, Amsterdam UMC - Locatie VUMC, Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"D\u2019Haeseleer","sequence":"additional","affiliation":[{"name":"Department of Neurology, National MS Center Melsbroek, Melsbroek, Belgium"},{"name":"Neurology, Vrije Universiteit Brussel, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-2866","authenticated-orcid":false,"given":"\u00d8ivind","family":"Torkildsen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Haukeland University Hospital, Bergen, Norway"},{"name":"Department of Clinical Medicine, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacynthe","family":"Comtois","sequence":"additional","affiliation":[{"name":"M\u00e9decine, service de neurologie, H\u00f4pital Cit\u00e9-de-la-Sant\u00e9 de Laval, Laval, Alberta, Canada"},{"name":"Neurosciences, Universit\u00e9 de Montr\u00e9al, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavle","family":"Repovic","sequence":"additional","affiliation":[{"name":"Swedish Neuroscience Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard M J","family":"Uitdehaag","sequence":"additional","affiliation":[{"name":"Neurology, Amsterdam UMC, Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joep","family":"Killestein","sequence":"additional","affiliation":[{"name":"Amsterdam UMC - 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