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[Preprint]. 2025 Aug 7:2025.01.27.25321205.
doi: 10.1101/2025.01.27.25321205.

Short-term changes in objectively measured activity predict brain atrophy and disability progression in multiple sclerosis

Kathryn C Fitzgerald  1 , Muraleetharan Sanjayan  1 , Blake Dewey  1 , Pratim Guha Niyogi  2 , Nicole Bou Rjeily  1 , Yasser Fadlallah  1 , Alice Delaney  1 , Alexandra Zambriczki Lee  1 , Safiya Duncan  1 , Chelsea Wyche  1 , Ela Moni  1 , Peter A Calabresi  1 , Vadim Zipunnikov  2 , Ellen M Mowry  1
Affiliations

Short-term changes in objectively measured activity predict brain atrophy and disability progression in multiple sclerosis

Kathryn C Fitzgerald et al. medRxiv. .

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.

Keywords: accelerometry; multiple sclerosis; neuroimaging; wearables.

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Conflict of interest statement

Kathryn Fitzgerald receives consulting fees from SetPoint Medical. Ellen Mowry serves as PI for investigator-initiated studies from Biogen and Genentech. She also receives royalties for editorial duties on UpToDate. Peter Calabresi is PI on a grant from Genentech to JHU. He has received consulting fees from Lilly, Idorsia, and Novartis.

Figures

Figure 1.
Figure 1.
Change in accelerometry measures over follow-up overall and by subgroup. Annualized change in accelerometry values for 24-hour activity outcomes (left) and for physical activity and circadian parameters (right). Standardized beta coefficients and 95% CI are obtained from a linear mixed effects model adjusted for age, sex, race, and BMI. 1A includes all participants and 1B include estimates stratified by HEAL-MS subgroup (relapsing-remitting MS [RRMS], progressive MS (PMS), and suspected PMS.
Figure 2.
Figure 2.
Effect estimates for a 1 SD reduction in overall and at specific time periods of the day and rates of subsequent disability progression for within and between (mean) measures. Within-person changes in total activity counts (TAC) or overall activity levels and risk of subsequent disability progression across different time intervals throughout the day. Hazard ratios (HRs) and 95% confidence intervals are shown for three disability outcomes: confirmed progression by EDSS+ (120 events), EDSS (98 events), and Timed 25-Foot Walk (T25FW; 33 events). Each HR reflects the association between a 1 SD decrease in activity overall or for a given period and risk of subsequent disability progression. A reference line at HR = 1 indicates no change in risk. The top panel reflects within-person changes (i.e., individual-level effects) as they correspond to risk whereas the bottom reflects the person-specific overall means (i.e., group-level effects) as they relate to risk. Effect estimates reflect a 1 SD decrease in TAC (and at specific time periods) as they relate to risk of EDSS+. We chose to model a 1 SD decrease as TAC generally decreased on average over follow-up.
Figure 3.
Figure 3.
Effect estimates for a 1 SD reduction in overall and at specific time periods of the day and changes in MRI outcomes for within and between (mean) measures. Within-person changes in total activity counts (TAC) and mean TAC activity levels across different time intervals throughout the day and MRI outcomes. Effect estimates and 95% confidence intervals are shown for three MRI outcomes: whole brain volume (WBV), deep gray matter, and thalamic volume. Each estimates reflects the difference in brain volume for a 1 SD decrease in activity (either within person or in mean overall activity). A reference line at HR = 0 indicates no difference in brain volume. The top panel reflects within-person changes (i.e., individual-level effects) as they correspond to changes in brain volume whereas the bottom reflects the person-specific overall means (i.e., group-level effects) as they relate to brain volumes. Effect estimates reflect a 1 SD decrease in TAC (and at specific time periods) as they relate to brain volumes. We chose to model a 1 SD decrease as TAC generally decreased on average over follow-up.
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