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Advanced magnetic resonance imaging (MRI) biomarkers like the central vein sign, cortical lesions and paramagnetic rim lesions are highly specific to multiple sclerosis and could potentially improve diagnostic accuracy. In this study, we applied machine learning techniques to a retrospective, multicentric dataset of 322 multiple sclerosis\/multiple sclerosis-mimic (204\/118) and 84 prodromal multiple sclerosis\/non-multiple sclerosis (43\/41) adult patients, incorporating the central vein sign, cortical lesions and paramagnetic rim lesions. We compared (5 \u00d7 2 cross-validation combined F-test) the diagnostic performance of 71 machine learning models, each corresponding to a distinct combination of full-count or simplified biomarker inputs, against the baseline dissemination in space McDonald criteria. The aim was to evaluate the multiple sclerosis diagnostic power of combining these biomarkers in an MRI-only diagnostic framework. 51 of the 71 models significantly outperformed the dissemination in space criterion (P &amp;lt; 0.05), with balanced accuracy improvements up to 13.0% (confidence interval: [+10.5; +17.0]). The best overall model (random forest, using full-count assessments) achieved 95.7% (confidence interval: [93.2; 99.7]) balanced accuracy; the best simplified model (logistic regression, using only simplified assessments) reached 94.7% with no significant difference with the former (P = 0.29). Notably, 12\/51 high-performing models used only simplified assessments. To further investigate the models\u2019 generalizability, external validation on two out-of-distribution test sets using bootstrapping (1000 resamples) confirmed these results and highlighted a more robust generalization for the best model using solely simplified biomarkers. On the first external test set (n = 37, Verona), the simplified model achieved 97.2% balanced accuracy, while the full-count model reached 93.3% (versus 83.3% for baseline). On the second test set (n = 84, prodromal cases), the simplified model achieved 92.6% (versus 60.1% for baseline) showing competitive performance against the full-count model (93.9%). Both models improved all key performance metrics\u2014balanced accuracy, sensitivity, specificity, precision and F1 score\u2014over the baseline on both test sets (all P &amp;lt; 0.0001). Within a non-invasive MRI-only diagnostic framework, these results show that the incorporation of advanced imaging biomarkers into the multiple sclerosis-MRI diagnostic criteria significantly enhances the diagnostic accuracy\u2014a statement holding true even when using simplified central vein sign, cortical lesions and paramagnetic rim lesions assessments. The study also provides a publicly available online diagnostic tool, facilitating further interaction, validation and clinical support (https:\/\/www.msdiagnostictool.org).<\/jats:p>","DOI":"10.1093\/braincomms\/fcag079","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T12:43:09Z","timestamp":1773146589000},"source":"Crossref","is-referenced-by-count":0,"title":["Machine learning-based combination of the central vein sign, cortical lesions and paramagnetic rim lesions: a web-based tool for the diagnosis of multiple sclerosis"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6603-982X","authenticated-orcid":false,"given":"Maxence","family":"Wynen","sequence":"first","affiliation":[{"name":"ICTEAM Institute, Universit\u00e9 Catholique de Louvain , 1348 Louvain-la-Neuve ,","place":["Belgium"]},{"name":"Neuroinflammation Imaging Lab (NIL), Universit\u00e9 Catholique de Louvain , 1200 Brussels ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2210-1625","authenticated-orcid":false,"given":"Colin","family":"Vanden Bulcke","sequence":"additional","affiliation":[{"name":"ICTEAM Institute, Universit\u00e9 Catholique de Louvain , 1348 Louvain-la-Neuve ,","place":["Belgium"]},{"name":"Neuroinflammation Imaging Lab (NIL), Universit\u00e9 Catholique de Louvain , 1200 Brussels ,","place":["Belgium"]},{"name":"Department of Neurology, Cliniques Universitaires Saint-Luc (CUSL), Universit\u00e9 Catholique de Louvain , 1200 Brussels ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Neuroinflammation Imaging Lab (NIL), Universit\u00e9 Catholique de Louvain , 1200 Brussels ,","place":["Belgium"]},{"name":"Department of Neurology, H\u00f4pital Erasme, H\u00f4pital Universitaire de Bruxelles, Universit\u00e9 Libre de Bruxelles , 1070 Brussels ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5305-3104","authenticated-orcid":false,"given":"Pedro M","family":"Gordaliza","sequence":"additional","affiliation":[{"name":"CIBM Center for Biomedical Imaging , CH-1015 Lausanne ,","place":["Switzerland"]},{"name":"Radiology Department, Lausanne University Hospital (CHUV) and University of Lausanne , CH-1011 Lausanne ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0880-0267","authenticated-orcid":false,"given":"Anna","family":"St\u00f6lting","sequence":"additional","affiliation":[{"name":"Neuroinflammation Imaging Lab (NIL), Universit\u00e9 Catholique de Louvain , 1200 Brussels ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-0840","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Guisset","sequence":"additional","affiliation":[{"name":"Neuroinflammation Imaging Lab (NIL), Universit\u00e9 Catholique de Louvain , 1200 Brussels ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e9ment","family":"Cordier","sequence":"additional","affiliation":[{"name":"ICTEAM Institute, Universit\u00e9 Catholique de Louvain , 1348 Louvain-la-Neuve ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Sofia","family":"Martire","sequence":"additional","affiliation":[{"name":"Neurology Unit, IRCCS San Raffaele Hospital , 20132 Milan ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnese","family":"Tamanti","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Biomedicine and Movement, The Multiple Sclerosis Center of University Hospital of Verona , 37129 Verona ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benoit","family":"Macq","sequence":"additional","affiliation":[{"name":"ICTEAM Institute, Universit\u00e9 Catholique de Louvain , 1348 Louvain-la-Neuve ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6763-0125","authenticated-orcid":false,"given":"Pascal","family":"Sati","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cedars-Sinai Medical Center , 90048 Los Angeles, CA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-0479","authenticated-orcid":false,"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Neurology Unit, IRCCS San Raffaele Hospital , 20132 Milan ,","place":["Italy"]},{"name":"Vita-Salute San Raffaele University , Milan ,","place":["Italy"]},{"name":"Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute , 20132 Milan ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimiliano","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Biomedicine and Movement, The Multiple Sclerosis Center of University Hospital of Verona , 37129 Verona ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Absinta","sequence":"additional","affiliation":[{"name":"Experimental Neuropathology Lab, IRCCS Humanitas Research Institute , 20132 Milan ,","place":["Italy"]},{"name":"Department of Biomedical Sciences, Humanitas University , 20072 Milan ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2628-4334","authenticated-orcid":false,"given":"Daniel 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