Rest-activity and circadian rhythm parameters relate to cognition and disability outcomes in multiple sclerosis

OBJECTIVE: To prioritize novel measures of disease progression, we examined whether actigraphy-derived rest-activity rhythm (RAR) parameters relate to cognitive performance as well as disability in a multiple sclerosis (MS) cohort enrolled in a prospective brain donation program. METHODS: RAR parameters were assessed using a wrist actigraphy device (AX3 Axivity Actiwatch, Axivity Ltd.) over two weeks. The primary outcome measure was the Symbol Digit Modalities Test (SDMT, N=222). Secondary outcomes included Brixton Spatial Anticipation Test and self-reported disability. In 76 participants, volumetric measures were derived from repurposed clinical magnetic resonance imaging (MRI) data. We applied linear and logistic regression models, adjusting for age, sex, education, time since MS diagnosis, and body mass index. RESULTS: After correction for multiple comparisons, higher intradaily variability (IV) of RAR and lower relative amplitude were associated with worse SDMT performance; higher IV was also associated with greater odds of disability. A broader set of RAR parameters was associated with disability measure. No MRI parameters were related to RAR in the subset of individuals with available MRI data, although we note suggestive associations with hippocampal and choroid plexus volumes warranting further investigation. INTERPRETATION: More robust circadian rhythms were related to better cognition. These results highlight the utility of actigraphy and its more nuanced measures beyond the simple summaries of activity levels that quantitate the extent of motor disability. Selected RAR features may be an effective non-invasive approach to capture clinically relevant quantitative measures of brain function for persons with MS.