Towards patient-relevant, trial-ready digital motor outcomes for SPG7: a cross-sectional prospective multi-center study (PROSPAX)

Background and Objectives With targeted treatment trials on the horizon, identification of sensitive and valid outcome measures becomes a priority for the >100 spastic ataxias. Digital-motor measures, assessed by wearable sensors, are prime outcome candidates for SPG7 and other spastic ataxias. We here aimed to identify candidate digital-motor outcomes for SPG7 – as one of the most common spastic ataxias – that: (i) reflect patient-relevant health aspects, even in mild, trial-relevant disease stages; (ii) are suitable for a multi-center setting; and (iii) assess mobility also during uninstructed walking simulating real-life. Methods Cross-sectional multi-center study (7 centers, 6 countries). Unaided walking was assessed in 65 patients with SPG7 and 50 unrelated healthy controls using 3 wearable sensors (Opal APDM). Digital gait measures were correlated to measures of disease severity (SARA, SPRS; including mobility-relevant subscores SPRS1315291292025, SARAPG) and activities of daily living (FARS-ADL). The task set included lab-based defined gait tasks, complemented by uninstructed ‘supervised free walking’. Results Among 30 hypothesis-based gait measures, 18 demonstrated at least moderate effect size (Cliff’s δ>0.5) in discriminating SPG7 patients from controls, and 17 even in mild disease stages (SPRSmobility≤9). Spatiotemporal variability measures such as the spatial variability composite measure SPcmp (ρ=0.67, p=<0.0001), Stride Time CV (ρ=0.67, p=<0.0001) and Swing CV (ρ=0.64, p=<0.0001) showed the highest correlations with clinician-reported mobility scores (SPRSmobility), and overall disease severity (SPRS, SARA). Overall, top-ranked measures also correlated with patient-relevant functional deficits in everyday life activities (FARS-ADL). In mild disease stages (SPRSmobility≤9, n=41), Swing CV (ρ=0.53, p=<0.0001) and SPcmp (ρ=0.50, p=<0.0001) correlated with SPRSmobility. In the uninstructed ‘supervised free walking’ task, the correlations between spatiotemporal variability measures (Stride Time CV, Stride Length CV, Swing CV) and SPRSmobility could be confirmed; additionally, Gait Speed (ρ=-0.59, p=<0.0001) was highly correlated with SPRSmobility. Discussion We here identified trial-ready digital-motor candidate outcomes for the spastic ataxia SPG7, all characterized by proven multi-center applicability, ability to discriminate patients from controls, and correlation with measures of disease severity – even in mild disease stages –, and patient-relevant everyday function. If validated longitudinally, these sensor outcomes might inform future natural history and treatment trials in SPG7 and other spastic ataxias. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the DFG under the frame of EJP-RD network PROSPAX (No 441409627; to R.S., M.S., IR, FMS) and by the Clinician Scientist program "PRECISE.net" funded by the Else Kroener-Fresenius-Stiftung (to L.B., A.T., and M.S.). The study was further funded by the German Ministry for Education and Research (BMBF) via funding for the TreatHSP network (01GM1905 to R.S. and S.K.; 01GM2209A to R.S.). J.S. was supported by the International Max Planck Research School for Intelligent Systems (IMPRS-IS) and the Else Kroener-Fresenius-Stiftung Medical Scientist programme "ClinbrAIn". A.T. received funding from the University of Tuebingen, medical faculty, for the Clinician Scientist Program Grant #439-0-0. I.R. is supported in part by the Italian Ministry of Health (Ricerca Finalizzata RF-2019-12370417; Ricerca Corrente 2023, RC 5x1000). A.N.B. is supported by TUBITAK (grant no: 319S063). B.vdW. is supported by ZonMw (the Netherlands Organization for Scientific Research; 463002002). ### 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: The Institutional Review Board of the University of Tuebingen gave ethical approval for this work (AZ 824/2019BO2) 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 Data will be made available upon reasonable request and as patient consent allows.