{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T13:41:06Z","timestamp":1787060466148,"version":"build-2736575974"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S026088\/1"],"award-info":[{"award-number":["MR\/S026088\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","award":["A1332"],"award-info":[{"award-number":["A1332"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","award":["PGL21\/10079"],"award-info":[{"award-number":["PGL21\/10079"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Brain Mapping"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n The brain\u2010predicted age difference (brain\u2010PAD) is associated with measures of clinical interest in people with multiple sclerosis (pwMS). Most brain age models rely on 3D T1\u2010weighted scans, which are not routinely acquired in MS clinical practice, limiting their potential for clinical translation. We aimed to develop a model predicting brain age using T2\u2010FLAIR, the core sequence for MS diagnosis and monitoring, and validate the resulting brain\u2010PAD values as a biomarker of MS severity and progression. We collected 3D T2\u2010FLAIR and 3D T1\u2010weighted brain MRI scans to compose (i) a multicentre cohort of healthy participants for brain age modeling, and (ii) a single\u2010centre cohort of pwMS and healthy controls for external validation. We trained and evaluated 3D convolutional neural network models predicting brain age from T2\u2010FLAIR or T1\u2010weighted images. Models were compared using t\u2010tests based on bootstrapped standard errors. Saliency maps were obtained with the SmoothGrad method to visualize regions that were most important for the predictions. Finally, using a linear model framework, we clinically validated the resulting brain\u2010PAD metric by assessing its relationship with diagnosis (MS versus healthy controls), clinical phenotype, disease duration, and physical disability as measured with the Expanded Disability Status Scale (EDSS), adjusting for age and sex. The Inception\u2010ResNet\u2010V2 model based on T2\u2010FLAIR scans yielded accurate brain age predictions (test set MAE\u2009=\u20093.31\u2009years, R\n 2<\/jats:sup>\n =\u20090.944, 5x ensemble MAE\u2009=\u20092.81, R\n 2<\/jats:sup>\n =\u20090.955), which were comparable to those obtained with the T1w\u2010based model (test set MAE\u2009=\u20093.34\u2009years, R\n 2<\/jats:sup>\n =\u20090.942, 5x ensemble MAE\u2009=\u20092.84, R\n 2<\/jats:sup>\n =\u20090.955,\n p<\/jats:italic>\n =\u20090.91). Brain age predictions were mostly driven by subcortical regions, particularly the thalamus. T2\u2010FLAIR\u2010based brain\u2010PAD was higher in pwMS than healthy controls (7.07 vs \u22120.50\u2009years,\n p<\/jats:italic>\n <\u20090.0001). As with T1 brain\u2010PAD, FLAIR brain\u2010PAD correlated with MS disease duration (\n R<\/jats:italic>\n =\u20090.24,\n p<\/jats:italic>\n <\u20090.0001) and EDSS (\n R<\/jats:italic>\n =\u20090.30,\n p<\/jats:italic>\n <\u20090.0001). Brain age predictions relying on T2\u2010FLAIR scans are as accurate as those derived from T1\u2010weighted scans and could be used as an easily obtainable biomarker of MS severity and progression in clinical practice.\n <\/jats:p>","DOI":"10.1002\/hbm.70425","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:06:28Z","timestamp":1773911188000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain Age Estimation on\n T2<\/scp>\n \u2010\n FLAIR<\/scp>\n Scans for Application to Multiple Sclerosis"],"prefix":"10.1002","volume":"47","author":[{"given":"Jordan","family":"Colman","sequence":"first","affiliation":[{"name":"UCL Hawkes Institute, University College London London UK"},{"name":"Department of Neuroradiology King's College Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pontillo","sequence":"additional","affiliation":[{"name":"UCL Hawkes Institute, University College London London UK"},{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation UCL Queen Square Institute of Neurology London UK"},{"name":"MS Center Amsterdam, Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc Amsterdam the Netherlands"},{"name":"Department of Advanced Biomedical Sciences University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Goodkin","sequence":"additional","affiliation":[{"name":"UCL Hawkes Institute, University College London London UK"},{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation UCL Queen Square Institute of Neurology London UK"},{"name":"Bayer Plc Reading 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7209-1736","authenticated-orcid":false,"given":"Gabriel","family":"Gonzalez\u2010Escamilla","sequence":"additional","affiliation":[{"name":"Movement Disorders, Neurostimulation and Neuroimaging University Medicine Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiu","family":"Groppa","sequence":"additional","affiliation":[{"name":"Movement Disorders, Neurostimulation and Neuroimaging University Medicine Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar August","family":"H\u00f8gest\u00f8l","sequence":"additional","affiliation":[{"name":"Department of Neurology Oslo 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek","family":"Yousry","sequence":"additional","affiliation":[{"name":"Lysholm Department of Neuroradiology UCLH National Hospital for Neurology and Neurosurgery London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Prados","sequence":"additional","affiliation":[{"name":"UCL Hawkes Institute, University College London London UK"},{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation UCL Queen Square Institute of Neurology London UK"},{"name":"E\u2010Health Center, Universitat Oberta de Catalunya Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"UCL Hawkes Institute, University College London London UK"},{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation UCL Queen Square Institute of Neurology London 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Rochester NY.\u201dhttps:\/\/papers.ssrn.com\/abstract=4170697.","DOI":"10.2139\/ssrn.4117373"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00450"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0244-7"},{"key":"e_1_2_9_26_1","first-page":"2261","article-title":"Densely Connected Convolutional Networks","author":"Huang G.","year":"2016","journal-title":"Proceedings\u201430th IEEE Conference on Computer Vision and Pattern Recognition, CVPR 2017"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0471-7"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.03.024"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1162\/imag_a_00487"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25011"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf032"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.26599"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25978"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04752-6"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2020.101871"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00861"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209976"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.06.053"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25323"},{"key":"e_1_2_9_40_1","article-title":"SmoothGrad: Removing Noise by Adding Noise","author":"Smilkov D.","year":"2017","journal-title":"arXiv"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2017-021017"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.inffus.2023.03.007"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213349"},{"key":"e_1_2_9_44_1","doi-asserted-by":"crossref","unstructured":"Valverde S. 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