{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:35:19Z","timestamp":1790566519032,"version":"4.1.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":36,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cambridge National Institute for Health and Care Research"},{"name":"Biomedical Centre and Clinical Research Facility"},{"DOI":"10.13039\/501100000381","name":"United Kingdom Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000381","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Enhancing CNS myelin repair (remyelination) is a promising strategy to prevent neurodegeneration and associated progressive disability in multiple sclerosis. Remyelination becomes inefficient with older chronological age, but the relationship between measures of biological age and remyelination has not been previously described in a clinical cohort. Here, we investigated two measures of biological age amongst participants of the Cambridge Centre for Myelin Repair One trial of bexarotene: MRI brain age (BAMRI) and a blood-based biological age (BABlood). In people with radiologically stable multiple sclerosis (n = 44 of 49 total participants), we found that treatment with bexarotene, along with promoting remyelination, was associated with significant decrease in MRI brain age [\u22121.98 years, 95% confidence interval (CI) [\u22123.75, \u22120.21 years] versus placebo over 6 months, P = 0.034]. Whilst BAMRI increased as expected during the trial in the placebo group (+0.92 years, CI [\u22120.41, 2.26]), the brain MRIs of participants treated with bexarotene appeared on average 11 months younger at the end compared to the start of the trial (\u22120.93 years, CI [\u22122.02, 0.17]). The effect of bexarotene on BAMRI was associated with its remyelinating activity in cortical grey matter lesions (\u03b2 = 0.25% units (pu)\/year, CI [0.03, 0.46], P = 0.023) and brainstem lesions (\u03b2 = 0.24\u2005pu\/year, CI [0.09, 0.39], P = 0.003). We also observed some regional trends that the remyelinating response to bexarotene was linked with measures of biological age at baseline. For example, after adjustment for chronological age, remyelination of brainstem lesions assessed by magnetization transfer ratio was reduced by 0.06\u2005pu for each year increase in BAMRI (CI [0.00, 0.13], P = 0.058) and 0.02\u2005pu for each year increase in BABlood (CI [\u22120.01, 0.05], P = 0.17). This is, to the best of our knowledge, the first demonstration that MRI brain age can be therapeutically modulated by a drug in people with a neurological disorder. Overall, these findings highlight that beyond chronological age, biological age may also influence the potential for repair and should be considered when developing treatments for multiple sclerosis.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf032","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T12:55:04Z","timestamp":1738155304000},"source":"Crossref","is-referenced-by-count":6,"title":["Exploratory analysis of biological age measures in a remyelination clinical trial"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8710-0930","authenticated-orcid":false,"given":"Christopher E","family":"McMurran","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0AH ,","place":["UK"]},{"name":"Department of Neuroinflammation, NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London (UCL) Queen Square Institute of Neurology , London, WC1B 5EH ,","place":["UK"]},{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm, SE-171 77 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5531-1111","authenticated-orcid":false,"given":"Ermelinda","family":"de Meo","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London (UCL) Queen Square Institute of Neurology , London, WC1B 5EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7562-2838","authenticated-orcid":false,"given":"Nick G","family":"Cunniffe","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0AH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7737-5834","authenticated-orcid":false,"given":"J William L","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0AH ,","place":["UK"]},{"name":"Department of Neuroinflammation, NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London (UCL) Queen Square Institute of Neurology , London, WC1B 5EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7872-0142","authenticated-orcid":false,"given":"Ferran","family":"Prados","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London (UCL) Queen Square Institute of Neurology , London, WC1B 5EH ,","place":["UK"]},{"name":"Department of Medical Physics and Biomedical Engineering, Centre for Medical Image Computing, University College London , London, WC1V 6LJ ,","place":["UK"]},{"name":"eHealth Center, Universitat Oberta de Catalunya , Barcelona 08018 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2443-8800","authenticated-orcid":false,"given":"Baris","family":"Kanber","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London (UCL) Queen Square Institute of Neurology , London, WC1B 5EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1908-5588","authenticated-orcid":false,"given":"James H","family":"Cole","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Centre for Medical Image Computing, University College London , London, WC1V 6LJ ,","place":["UK"]},{"name":"Dementia Research Centre, Queen Square Institute of Neurology, University College London , London, WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4738-0760","authenticated-orcid":false,"given":"Alasdair J","family":"Coles","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge, CB2 0AH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2452-1500","authenticated-orcid":false,"given":"Sara","family":"H\u00e4gg","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm, SE-171 77 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-2682","authenticated-orcid":false,"given":"Declan T","family":"Chard","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London (UCL) Queen Square Institute of Neurology , London, WC1B 5EH ,","place":["UK"]},{"name":"National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre , London, W1T 7DN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"issue":"2","key":"2025020812264503300_fcaf032-B1","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1177\/1352458512451510","article-title":"Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis","volume":"19","author":"Tutuncu","year":"2013","journal-title":"Mult Scler"},{"issue":"13","key":"2025020812264503300_fcaf032-B2","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1177\/1352458518800815","article-title":"Age is a critical determinant in recovery from multiple sclerosis relapses","volume":"25","author":"Conway","year":"2019","journal-title":"Mult Scler"},{"key":"2025020812264503300_fcaf032-B3","doi-asserted-by":"crossref","first-page":"577","DOI":"10.3389\/fneur.2017.00577","article-title":"Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments","volume":"8","author":"Weideman","year":"2017","journal-title":"Front Neurol"},{"issue":"1","key":"2025020812264503300_fcaf032-B4","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/S1474-4422(22)00184-3","article-title":"Ageing and multiple sclerosis","volume":"22","author":"Graves","year":"2023","journal-title":"Lancet Neurol"},{"issue":"14","key":"2025020812264503300_fcaf032-B5","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1177\/1352458519884006","article-title":"Remyelination and ageing: Reversing the ravages of time","volume":"25","author":"Neumann","year":"2019","journal-title":"Mult Scler"},{"issue":"1","key":"2025020812264503300_fcaf032-B6","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s00415-019-09421-x","article-title":"Promoting remyelination in multiple sclerosis","volume":"268","author":"Cunniffe","year":"2021","journal-title":"J Neurol"},{"issue":"7","key":"2025020812264503300_fcaf032-B7","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1002\/acn3.51595","article-title":"Remyelination in humans due to a retinoid-X receptor agonist is age-dependent","volume":"9","author":"McMurran","year":"2022","journal-title":"Ann Clin Transl Neurol"},{"issue":"4","key":"2025020812264503300_fcaf032-B8","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/ana.24367","article-title":"Prediction of brain age suggests accelerated atrophy after traumatic brain injury","volume":"77","author":"Cole","year":"2015","journal-title":"Ann Neurol"},{"issue":"12","key":"2025020812264503300_fcaf032-B9","doi-asserted-by":"crossref","first-page":"104859","DOI":"10.1016\/j.msard.2023.104859","article-title":"The NHANES Biological Age Index demonstrates accelerated aging in MS patients","volume":"77","author":"Miner","year":"2023","journal-title":"Mult Scler Relat Disord"},{"key":"2025020812264503300_fcaf032-B10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ebiom.2017.03.046","article-title":"Biological age predictors","volume":"21","author":"Jylh\u00e4v\u00e4","year":"2017","journal-title":"EBioMedicine"},{"issue":"1","key":"2025020812264503300_fcaf032-B11","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/ana.25746","article-title":"Longitudinal assessment of multiple sclerosis with the brain-age paradigm","volume":"88","author":"Cole","year":"2020","journal-title":"Ann Neurol"},{"issue":"6","key":"2025020812264503300_fcaf032-B12","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1002\/acn3.51782","article-title":"Brain age\u201d predicts disability accumulation in multiple sclerosis","volume":"10","author":"Brier","year":"2023","journal-title":"Ann Clin Transl Neurol"},{"issue":"1","key":"2025020812264503300_fcaf032-B13","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.stem.2011.11.019","article-title":"Rejuvenation of regeneration in the aging central nervous system","volume":"10","author":"Ruckh","year":"2012","journal-title":"Cell Stem Cell"},{"issue":"4","key":"2025020812264503300_fcaf032-B14","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.stem.2019.08.015","article-title":"Metformin restores CNS remyelination capacity by rejuvenating aged stem cells","volume":"25","author":"Neumann","year":"2019","journal-title":"Cell Stem Cell"},{"issue":"7772","key":"2025020812264503300_fcaf032-B15","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41586-019-1484-9","article-title":"Niche stiffness underlies the ageing of central nervous system progenitor cells","volume":"573","author":"Segel","year":"2019","journal-title":"Nature"},{"issue":"9","key":"2025020812264503300_fcaf032-B16","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S1474-4422(21)00179-4","article-title":"Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): A randomised, double-blind, placebo-controlled, parallel-group, phase 2a study","volume":"20","author":"Brown","year":"2021","journal-title":"Lancet Neurol"},{"issue":"3","key":"2025020812264503300_fcaf032-B17","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.mad.2005.10.004","article-title":"A new approach to the concept and computation of biological age","volume":"127","author":"Klemera","year":"2006","journal-title":"Mech Ageing Dev"},{"issue":"6","key":"2025020812264503300_fcaf032-B18","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1093\/gerona\/gls233","article-title":"Modeling the rate of senescence: Can estimated biological age predict mortality more accurately than chronological age?","volume":"68","author":"Levine","year":"2013","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"10111","key":"2025020812264503300_fcaf032-B19","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1016\/S0140-6736(17)32346-2","article-title":"Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): A randomised, controlled, double-blind, crossover trial","volume":"390","author":"Green","year":"2017","journal-title":"Lancet"},{"key":"2025020812264503300_fcaf032-B20","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.neuroimage.2016.06.053","article-title":"A multi-time-point modality-agnostic patch-based method for lesion filling in multiple sclerosis","volume":"139","author":"Prados","year":"2016","journal-title":"Neuroimage"},{"issue":"9","key":"2025020812264503300_fcaf032-B21","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1109\/TMI.2015.2418298","article-title":"Geodesic information flows: Spatially-variant graphs and their application to segmentation and fusion","volume":"34","author":"Cardoso","year":"2015","journal-title":"IEEE Trans Med Imaging"},{"issue":"1","key":"2025020812264503300_fcaf032-B22","doi-asserted-by":"crossref","first-page":"e2413","DOI":"10.1002\/brb3.2413","article-title":"Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups","volume":"12","author":"Clausen","year":"2022","journal-title":"Brain Behav"},{"key":"2025020812264503300_fcaf032-B23","doi-asserted-by":"crossref","first-page":"103175","DOI":"10.1016\/j.nicl.2022.103175","article-title":"Brain-age is associated with progression to dementia in memory clinic patients","volume":"36","author":"Biondo","year":"2022","journal-title":"Neuroimage Clin"},{"issue":"5","key":"2025020812264503300_fcaf032-B24","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/mp.2017.62","article-title":"Brain age predicts mortality","volume":"23","author":"Cole","year":"2018","journal-title":"Mol Psychiatry"},{"issue":"6","key":"2025020812264503300_fcaf032-B25","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1007\/s11357-021-00480-5","article-title":"A toolkit for quantification of biological age from blood chemistry and organ function test data: BioAge","volume":"43","author":"Kwon","year":"2021","journal-title":"Geroscience"},{"issue":"1","key":"2025020812264503300_fcaf032-B26","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/mpr.329","article-title":"Multiple imputation by chained equations: What is it and how does it work?","volume":"20","author":"Azur","year":"2011","journal-title":"Int J Methods Psychiatr Res"},{"issue":"7","key":"2025020812264503300_fcaf032-B27","first-page":"877","article-title":"Heterogeneity of human aging and its assessment","volume":"72","author":"Mitnitski","year":"2017","journal-title":"J Gerontol A Biol Sci Med Sci."},{"issue":"10","key":"2025020812264503300_fcaf032-B28","first-page":"836","article-title":"Effect of ibuprofen on BrainAGE: A randomized, placebo-controlled, dose-response exploratory study","volume":"3","author":"Le","year":"2018","journal-title":"Biol Psychiatry Cogn Neurosci Neuroimaging"},{"key":"2025020812264503300_fcaf032-B29","doi-asserted-by":"crossref","first-page":"e69995","DOI":"10.7554\/eLife.69995","article-title":"Individual variations in \u2018brain age\u2019 relate to early-life factors more than to longitudinal brain change","volume":"10","author":"Vidal-Pineiro","year":"2021","journal-title":"Elife"},{"issue":"20","key":"2025020812264503300_fcaf032-B30","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1161\/CIR.0b013e3182160726","article-title":"Triglycerides and cardiovascular disease: A scientific statement from the American Heart Association","volume":"123","author":"Miller","year":"2011","journal-title":"Circulation"},{"issue":"5","key":"2025020812264503300_fcaf032-B31","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/ana.25592","article-title":"Telomere length is associated with disability progression in multiple sclerosis","volume":"86","author":"Krysko","year":"2019","journal-title":"Ann Neurol"},{"issue":"12","key":"2025020812264503300_fcaf032-B32","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.2217\/epi-2019-0102","article-title":"Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis","volume":"11","author":"Theodoropoulou","year":"2019","journal-title":"Epigenomics"},{"issue":"5","key":"2025020812264503300_fcaf032-B33","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1093\/brain\/aww037","article-title":"Increased cortical grey matter lesion detection in multiple sclerosis with 7 T MRI: A post-mortem verification study","volume":"139","author":"Kilsdonk","year":"2016","journal-title":"Brain"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcaf032\/61668241\/fcaf032.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/7\/1\/fcaf032\/61668241\/fcaf032.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/7\/1\/fcaf032\/61668241\/fcaf032.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T12:27:12Z","timestamp":1739017632000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcaf032\/7986120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,24]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,12,24]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcaf032","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2024,12,24]]},"article-number":"fcaf032"}}