Digital gait biomarkers, but not clinical ataxia scores, allow to capture 1-year longitudinal change in Spinocerebellar ataxia type 3 (SCA3)

Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross-sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time-frames (e.g. one year). We present the first multi-center longitudinal gait analysis study in spinocerebellar ataxias (SCAs). We performed a combined cross-sectional (n=28) and longitudinal (1-year interval, n=17) analysis in SCA3 subjects (including 7 pre-ataxic mutation carriers). Longitudinal analysis revealed significant change in gait measures between baseline and 1-year follow-up, with high effect sizes (stride length variability: p=0.01, effect size rprb=0.66; lateral sway: p=0.007, rprb=0.73). Sample size estimation for lateral sway reveals a required cohort size of n=43 for detecting a 50% reduction of natural progression, compared to n=240 for the clinical ataxia score SARA. These measures thus present promising motor biomarkers for upcoming interventional studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the European Joint Programme of Neurodegenerative Diseases (JPND) and the European Union Horizon 2020 innovation programme under grant agreement No 643417 (ESMI); and by the European Joint Programme on Rare Diseases under the EJP RD Cofund-EJP No 825575 (PROSPAX, DFG, German Research Foundation) No 441409627 (to M.S. and B.v.d.W). B.v.d.W., T.K., L.S. and M.S. are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. JF is a fellow within the Hertie Network of Excellence in Clinical Neuroscience. ### 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 Univeristy Tuebingen 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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes . Data will be made available upon reasonable request and as patient consent allows. The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary material.