OBJECTIVE: During the natural course of MS, the brain is exposed to ageing as well as disease effects. Brain ageing can be modelled statistically; the so-called 'brain-age' paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression and future outcomes. METHODS: In a longitudinal, multi-centre sample of 3,565 MRI scans, in 1,204 MS and clinically-isolated syndrome (CIS) patients and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured 'brain-predicted age' using T1-weighted MRI. We compared brain-PAD between MS and CIS patients and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored. RESULTS: MS patients had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years [95% CI 8.5, 12.1] versus 4.3 years [-2.1, 6.4], p < 0.001). The highest brain-PADs were in secondary-progressive MS (+19.4 years [17.1, 21.9]). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02 [1.01, 1.03], p < 0.001); though normalised brain volume was a stronger predictor. Greater annualised brain-PAD increases were associated with greater annualised EDSS score (r = 0.26, p < 0.001). INTERPRETATION: The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, 'brain-age' could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrolment. This article is protected by copyright. All rights reserved
