{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:30:44Z","timestamp":1788582644586,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T00:00:00Z","timestamp":1711152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Brain Mapping"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain\u2010age paradigm to assess whether FD patients' brains appear older than normal and to validate brain\u2010predicted age difference (brain\u2010PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1\u2010weighted brain scans of healthy subjects from eight publicly available sources (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20092160; mean age\u2009=\u200933\u2009years [range 4\u201386]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain\u2010age predictions in the internal cohort. Within a linear modeling framework, brain\u2010PAD was tested for age\/sex\u2010adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel\u2010level neuroimaging measures. We studied 52 FD patients (40.6\u2009\u00b1\u200912.6\u2009years; 28F) and 58 HC (38.4\u2009\u00b1\u200913.4\u2009years; 28F). The brain\u2010age model achieved accurate out\u2010of\u2010sample performance (mean absolute error\u2009=\u20094.01\u2009years,\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u2009.90). FD patients had significantly higher brain\u2010PAD than HC (estimated marginal means: 3.1 vs. \u22120.1,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.01). Brain\u2010PAD was associated with FASTEX score (\n                    <jats:italic>B<\/jats:italic>\n                    \u2009=\u20090.10,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.02), brain parenchymal fraction (\n                    <jats:italic>B<\/jats:italic>\n                    \u2009=\u2009\u2212153.50,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.001), white matter hyperintensities load (\n                    <jats:italic>B<\/jats:italic>\n                    \u2009=\u20090.85,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain\u2010PAD correlates with FD\u2010related multi\u2010organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.\n                  <\/jats:p>","DOI":"10.1002\/hbm.26599","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T09:59:01Z","timestamp":1711187941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Assessing brain involvement in Fabry disease with deep learning and the brain\u2010age paradigm"],"prefix":"10.1002","volume":"45","author":[{"given":"Alfredo","family":"Montella","sequence":"first","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4451-4746","authenticated-orcid":false,"given":"Mario","family":"Tranfa","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Scaravilli","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation UCL Institute of Neurology  London UK"},{"name":"Department of Radiology and Nuclear Medicine MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Centre for Medical Image Computing University College London  London UK"},{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1908-5588","authenticated-orcid":false,"given":"James","family":"Cole","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing University College London  London UK"},{"name":"Dementia Research Centre UCL Queen Square Institute of Neurology, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Gravina","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Information Technology (DIETI) University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Marrone","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Information Technology (DIETI) University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Riccio","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Information Technology (DIETI) University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Riccio","sequence":"additional","affiliation":[{"name":"Department of Public Health, Nephrology Unit University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Sansone","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Information Technology (DIETI) University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Petracca","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Reproductive and Odontostomatological Sciences University \u201cFederico II\u201d  Naples Italy"},{"name":"Department of Human Neurosciences Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[{"name":"Department of Public Health, Nephrology Unit University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0300-5160","authenticated-orcid":false,"given":"Sirio","family":"Cocozza","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-1890","authenticated-orcid":false,"given":"Giuseppe","family":"Pontillo","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences University \u201cFederico II\u201d  Naples Italy"},{"name":"NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation UCL Institute of Neurology  London UK"},{"name":"Department of Radiology and Nuclear Medicine MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Department of Electrical Engineering and Information Technology 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