Accelerated Brain Aging Identifies Functional Vulnerability Beyond Chronological Age in Multiple Sclerosis

Chronological age incompletely captures neurodegenerative burden and functional vulnerability in multiple sclerosis (MS). Brain-predicted age difference (Brain-PAD; predicted minus chronological age) provides an MRI-derived index of accelerated brain aging, but links to mobility and real-world behavior remain unclear. Forty-three adults with MS completed structural MRI, mobility testing, and six months of free-living physical activity monitoring. Brain age was estimated using PyBrainAge applied to FreeSurfer-derived cortical thickness and subcortical volumes. Hierarchical regressions tested whether Brain-PAD explained additional variance in mobility (Mini-BESTest total and subscores; forward/backward walking velocity) and moderate-to-vigorous physical activity (MVPA) beyond age and disability (PDDS). Predicted brain age exceeded chronological age (Brain-PAD = 8.4 ± 11.1 years; p < 0.001). After accounting for age and PDDS, Brain-PAD explained additional variance in Mini-BESTest total (ΔR² = 0.05, p = 0.042) and anticipatory control (ΔR² = 0.08, p = 0.034), with a trend for sensory orientation. Brain-PAD was not associated with walking velocity beyond PDDS. Higher Brain-PAD was associated with lower MVPA (β = -0.91, p = 0.005) and explained additional variance (ΔR² = 0.19). Brain-PAD is elevated in MS and relates to balance control and real-world physical activity beyond age and disability, highlighting its potential to identify functional vulnerability.