Abstract
BACKGROUND AND OBJECTIVES: The brain-predicted age difference (brain-PAD) is a novel marker of neurodegeneration in multiple sclerosis (MS). Brain-PAD has been associated with clinical disability in heterogeneous MS patient cohorts of varying ages and disease durations. In this study, we investigate the relation between clinical disability and brain-PAD in a unique birth-year cohort of people with MS (pwMS) and healthy controls (HCs) of the same age all born in 1966, eliminating age as a confounding factor. METHODS: This was a cross-sectional cohort study conducted in the Netherlands. Disability was quantified using the expanded disability status scale (EDSS), 9-hole peg test (9HPT), and the timed 25-foot walk test (T25FWT). Cognition was assessed using the Minimal Assessment of Cognitive Function in MS battery. The brain-PAD was calculated by subtracting the person's chronological age from the predicted brain age derived from 3-dimensional T1-weighted brain MRI scans using machine learning (brainageR software). Brain-PAD for HCs and MS subtypes (relapsing remitting, secondary progressive, and primary progressive) were compared using a generalized linear model. The relation between brain-PAD and disease duration and disability and cognitive measures were tested using univariate linear regression. In addition, the clinical explanatory value added by brain-PAD to those of brain parenchymal fraction (BPF) and T2 lesion volume was investigated. RESULTS: The study included 116 HC (mean age 52.9 ± 1.1 years, 61% female) and 237 pwMS (mean age 52.9 ± 0.9 years, median disease duration 16.3 years [interquartile range 8.2-24.4] and a median EDSS of 3.5 [interquartile range 2.5-4.0]). Brain-PAD was higher in pwMS compared with HC by 9.7 years (SE = 0.82, p < 0.0001). Longer disease duration was associated with a higher brain-PAD (β = 0.21, p < 0.001). A higher brain-PAD was associated with worse performance on the T25FWT (β = 0.0063, p < 0.05), 9HPT (β = 0.0074, p < 0.001), and EDSS (β = 0.028, p < 0.05). Brain-PAD was higher for cognitively impaired people with MS, compared with cognitively preserved pwMS and HC (p < 0.0001). Brain-PAD had added explanatory value over BPF in clinical outcome measures. DISCUSSION: In a cohort unbiased by age differences, greater brain ageing was associated with worse performance on disability and cognitive tests, underscoring the potential of brain-PAD as a marker for neurodegeneration and disease severity in MS.