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

Background and ObjectivesWith 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. MethodsCross-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. ResultsAmong 30 hypothesis-based gait measures, 18 demonstrated at least moderate effect size (Cliffs {delta}>0.5) in discriminating SPG7 patients from controls, and 17 even in mild disease stages (SPRSmobility[&le;]9). Spatiotemporal variability measures such as the spatial variability composite measure SPcmp ({rho}=0.67, p=<0.0001), Stride Time CV ({rho}=0.67, p=<0.0001) and Swing CV ({rho}=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[&le;]9, n=41), Swing CV ({rho}=0.53, p=<0.0001) and SPcmp ({rho}=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 ({rho}=-0.59, p=<0.0001) was highly correlated with SPRSmobility. DiscussionWe 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.