Background Brain atrophy occurs in both normal ageing and in multiple sclerosis (MS), but it occurs at a faster rate in MS, where it is the major driver of disability progression. Here, we employed a neuroimaging biomarker of structural brain ageing to explore how MS influences the brain ageing process.Methods In a longitudinal, multi-centre sample of 3,565 MRI scans in 1,204 MS/clinically isolated syndrome (CIS) patients and 150 healthy controls (HCs) (mean follow-up time: patients 3⋅41 years, HCs 1⋅97 years) we measured ‘brain-predicted age’ using T1-weighted MRI. Brain-predicted age difference (brain-PAD) was calculated as the difference between the brain-predicted age and chronological age. Positive brain-PAD indicates a brain appears older than its chronological age. We compared brain-PAD between MS/CIS patients and HCs, and between disease subtypes. In patients, the relationship between brain-PAD and Expanded Disability Status Scale (EDSS) at study entry and over time was explored.Findings Adjusted for age, sex, intracranial volume, cohort and scanner effects MS/CIS patients had markedly older-appearing brains than HCs (mean brain-PAD 11⋅8 years [95% CI 9⋅1—14⋅5] versus −0⋅01 [−3⋅0—3⋅0], p<0⋅0001). All MS subtypes had greater brain-PAD scores than HCs, with the oldest-appearing brains in secondary-progressive MS (mean brain-PAD 18⋅0 years [15⋅4—20⋅5], p<0⋅05). At baseline, higher brain-PAD was associated with a higher EDSS, longer time since diagnosis and a younger age at diagnosis. Brain-PAD at study entry significantly predicted time-to-EDSS progression (hazard ratio 1⋅02 [1⋅01—1⋅03], p<0⋅0001): for every 5 years of additional brain-PAD, the risk of progression increased by 14⋅2%.Interpretation MS increases brain ageing across all MS subtypes. An older-appearing brain at baseline was associated with more rapid disability progression, suggesting ‘brain-age’ could be an individualised prognostic biomarker from a single, cross-sectional assessment.Funding UK MS Society; National Institute for Health Research University College London Hospitals Biomedical Research Centre.

Accelerated brain ageing and disability in multiple sclerosis