Abstract
OBJECTIVE: To evaluate how within-person changes in accelerometry-derived activity patterns translate to brain atrophy and disability worsening in people with multiple sclerosis (PwMS). METHODS: We included PwMS aged ≥40 years with approximately annual brain MRI who wore GT9X Actigraph accelerometers every three months over three years. Accelerometry-derived indices included total and 2-hour specific activity, sedentary time, and circadian rhythm parameters. Confirmed disability worsening was characterized using the composite Expanded Disability Status Scale-plus (EDSS+) and whole brain segmentation used SLANT-CRUISE. We modeled within- and between-person effects using Cox (for EDSS+) and linear mixed effects (for MRI) multivariable-adjusted models adjusted for age, sex, and body mass index that included only accelerometry measures obtained prior to EDSS+. RESULTS: Among 239 PwMS (mean age 54.8, 29% male), 120 experienced EDSS+-confirmed progression over a mean 2.9 years (SD: 1.1 years). Participants wore accelerometers an average of 7.4 times over 67 days. Total activity declined an average of 48,694 activity counts ((~)0.10 SD per year; 95% CI: -33092, -64297; p=1.21x10(-9)), and people with progressive MS exhibited more pronounced declines in total activity relative to RRMS (p=2.34x10(-5)). Within-person decreases in daytime activity (particularly 8:00-14:00) were significantly associated with higher risk of EDSS+. For example, a 1 SD decrease in within-person (individual-level) activity from 8:00-10:00, 10:00-12:00 and 12:00-14:00 was associated with a respective 1.20 (95% CI: 1.04, 1.39; p=0.01), 1.22 (95% CI: 1.04, 1.41; p=0.008), and 1.23 (95% CI: 1.07, 1.42; p=0.007) higher risk of confirmed disability progression by EDSS+. MRI also models demonstrated that within-person declines in morning activity (8:00-10:00) were associated with greater whole brain, deep gray matter and thalamic volume loss (for whole brain -0.16%; 95% CI: -0.29, -0.04; p=0.009; deep gray: -0.32%; 95% CI: -0.13, -0.51; p=0.0009; thalamic: -0.30%; 95% CI: -0.52, -0.08; p=0.007). Lower between-person mean MVPA was associated with lower brain volumes over time but was not associated with EDSS+. INTERPRETATION: Within-person reductions in daytime activity patterns precede clinical disability worsening and brain atrophy in PwMS. Longitudinal accelerometry may offer sensitive, non-invasive biomarkers of subclinical disease progression in MS.