Abstract:
OBJECTIVES: With disease-modifying drugs for degenerative ataxias on the horizon, ecologically valid measures of motor performance that can detect patient-relevant changes in short, trial-like time frames are highly warranted. In this 2-year longitudinal study, we aimed to unravel and evaluate measures of ataxic gait which are sensitive to longitudinal changes in patients{\textquoteright} real life by using wearable sensors. METHODS: We assessed longitudinal gait changes of 26 participants with degenerative cerebellar disease (SARA:9.4{\textpm}4.1) at baseline, 1-year and 2-year follow-up assessment using 3 body-worn inertial sensors in two conditions: (1) laboratory-based walking (LBW); (2) real-life walking (RLW) during everyday living. In the RLW condition, a context-sensitive analysis was performed by selecting comparable walking bouts according to macroscopic gait characteristics, namely bout length and number of turns within a two-minute time interval. Movement analysis focussed on measures of spatio-temporal variability, in particular stride length variability, lateral step deviation, and a compound measure of spatial variability (SPCmp). RESULTS: Gait variability measures showed high test-retest reliability in both walking conditions (ICC \> 0.82). Cross-sectional analyses revealed high correlations of gait measures with ataxia severity (SARA, effect size ρ >= 0.75); and in particular with patients{\textquoteright} subjective balance confidence (ABC score, ρ>=0.71), here achieving higher effect sizes for real-life than lab-based gait measures (e.g. SPCmp: RLW ρ=0.81 vs LBW ρ=0.71). While the clinician-reported outcome SARA showed longitudinal changes only after two years, the gait measure SPCmp revealed changes already after one year with high effect size (rprb=0.80). In the subgroup with spinocerebellar ataxia type 1, 2 or 3 (SCA1/2/3), the effect size was even higher (rprb=0.86). Based on these effect sizes, sample size estimation for the gait measure SPCmp showed a required cohort size of n=42 participants (n=38 for SCA1/2/3 subgroup) for detecting a 50\% reduction of natural progression after one year by a hypothetical intervention, compared to n=254 for the SARA. CONCLUSIONS: Gait variability measures revealed high reliability and sensitivity to longitudinal change in both laboratory-based constrained walking as well as in real-life walking. Due to their ecological validity and larger effect sizes, characteristics of real-life gait recordings are promising motor performance measures as outcomes for future treatment trials.Competing Interest StatementDr Ilg received consultancy honoraria by Ionis Pharmaceuticals, unrelated to the present work. Mr Seemann reports no disclosures. Mrs Beyme reports no disclosures. Mrs John reports no disclosures. Mr Harmuth reports no disclosures. Prof Giese reports no disclosures. Prof Schoels served as advisor for Alexion, Novartis and Vico. He participates as a principal investigator in clinical studies sponsored by Vigil Neuroscience (VGL101-01.001; VGL101-01.002), Vico Therapeutics (VO659-CT01), PTC Therapeutics (PTC743-NEU-003-FA) and Stealth BioTherapeutics (SPIMD-301), all unrelated to the present work. Prof Timmann reports no disclosures. Prof Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Biogen, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, and Solaxa, all unrelated to the present manuscript. Funding StatementThis work was supported by the International Max Planck Research School for Intelligent Systems (IMPRS-IS) (to J.S.) and the Else Kroener-Fresenius-Stiftung Medical Scientist programme ClinbrAIn (to W.I. and M.G.). as well as the Else Kroener-Fresenius Stiftung Clinician Scientist program PRECISE.net (to M.S.). In addition, this work was supported by the European Union, project European Rare Disease Research Alliance (ERDERA, $\#$ 101156595) (to M.S.).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee/IRB of University Tuebingen, Germany gave ethical approval for this workI 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.YesI 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.YesData will be made available upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary material. Raw data regarding human participants (e.g. clinical data) are not shared freely to protect the privacy of the human participants involved in this study; no consent for open sharing has been obtained.
