Accelerometry-derived activity fragmentation as a predictor of brain atrophy and disability progression in multiple sclerosis

Background Accelerometry-derived activity fragmentation reflects how frequently active periods are broken by sedentary periods. It has been associated with frailty, mortality, and reduced gait speed in the general population; however, its prognostic significance in multiple sclerosis (MS) remains unknown.

People with MS (PwMS) wore wrist tri-axial accelerometers at three-month intervals, underwent disability assessments biannually and MRI brain approximately annually. We evaluated whether active-to-sedentary transition probability (ASTP) and sedentary-to-active transition probability (SATP) during the 10 most active hours of each 24-hour period (M10) were associated with confirmed disability progression and brain substructure atrophy, by modeling between- and within-person effects.

Among 239 PwMS, 120 had confirmed Expanded Disability Status Scale(EDSS)-plus progression over a mean of 2.9±1.1 years. Within-person increase in ASTP slope during M10 (indicating increasing activity fragmentation throughout M10) was associated with higher risk of subsequent EDSS-plus progression (per 1 SD increase: HR 1.22 [95%CI 1.02,1.46],p=0.03) and lower deep gray matter and thalamic volumes over time (per 1 SD increase: -0.35 [95%CI - 0.58,-0.13],p=0.002, -0.42 [95%CI:-0.68,-0.15],p=0.002 respectively). There were no similar associations for SATP.

Within-person worsening in activity fragmentation was associated with higher risk of neurologic decline. Activity fragmentation may represent an early compensatory strategy for reduced physiologic reserve and serve as an early indicator of MS progression. Competing Interest Statement EMM serves as PI for investigator-initiated studies from Biogen and Genentech and receives royalties for editorial duties on UpToDate and consulting fees from SetPoint Medical. KCF receives consulting fees from SetPoint Medical. Funding Statement This study was supported by R01NR018851 to EMM. AGF is supported by the National Institutes of Health (R25NS065729 and the National Multiple Sclerosis Society (FP-2307-41984 to AGF). KCF is supported by the National Institutes of Health (K01MH121582-04 and the National Multiple Sclerosis Society (TA-1805-31136). We also thank MS4MS for supporting our accelerometry program. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Johns Hopkins gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Study Funding: This study was supported by R01NR018851 to EMM. AGF is supported by the National Institutes of Health (R25NS065729 and the National Multiple Sclerosis Society (FP-2307-41984 to AGF). KCF is supported by the National Institutes of Health (K01MH121582-04 and the National Multiple Sclerosis Society (TA-1805-31136). We also thank MS4MS for supporting our accelerometry program. The authors declare no potential conflicts of interest. Financial Disclosures: AGF, MS, BD, EJ, PGN, YF, SD, CW, EM, VZ report no disclosures. EMM serves as PI for investigator-initiated studies from Biogen and Genentech and receives royalties for editorial duties on UpToDate and consulting fees from SetPoint Medical. KCF receives consulting fees from SetPoint Medical. Data Availability All data produced in the present study are available upon reasonable request to the authors with proper inter-institutional data sharing agreements in place.