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Here, we aimed to identify the most informative MRI and serum biomarkers for predicting clinical outcomes in people with MS (pwMS), including disability severity, cognitive impairment, disease phenotype, and risk of PIRA. We applied a machine learning\u2013based feature selection approach to cross\u2010sectional and longitudinal data from two independent pwMS cohorts. Cohort 1 (n = 120) included 57 MRI biomarkers, incorporating advanced quantitative MRI (qMRI). Cohort 2 (n = 279) included 35 MRI biomarkers derived from conventional MRI. Both cohorts obtained serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) measurements. Spinal cord atrophy consistently emerged as the strongest predictor of disability severity and predicted PIRA, along with cortical thinning and subcortical atrophy \u2013 particularly in deep gray matter. sNfL, sGFAP, and qMRI metrics independently contributed to the prediction of PIRA and progressive disease phenotype. In conclusion, our findings show that spinal cord atrophy and cortical degeneration are the most robust and consistent predictors of MS severity and progression. Serum biomarkers of neuroaxonal and astrocytic damage, together with qMRI\u2010derived tissue metrics, provide independent and complementary value for outcome prediction.<\/jats:p>","DOI":"10.1002\/advs.202512946","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:28:01Z","timestamp":1768292881000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Assessing the Relative Importance of Imaging and Serum Biomarkers in Capturing Disability, Cognitive Impairment, and Clinical Progression in Multiple Sclerosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7703-0553","authenticated-orcid":false,"given":"Alessandro","family":"Cagol","sequence":"first","affiliation":[{"name":"Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering Faculty of Medicine University Hospital Basel and University of Basel  Basel 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