BACKGROUND AND OBJECTIVES With targeted treatment trials on the horizon, identification of sensitive and valid outcome measures becomes a priority for >100 spastic ataxias. While digital-motor measures, assessed using wearable sensors, are considered prime outcome candidates for spastic ataxias, genotype-specific validation studies are lacking. We here aimed to identify candidate digital-motor outcomes for spastic paraplegia type 7 (SPG7)-one of the most common spastic ataxias-that (1) reflect patient-relevant health aspects, even in mild, trial-relevant disease stages; (2) are suitable for a multicenter setting; and (3) assess mobility also during uninstructed walking simulating real life. METHODS This cross-sectional multicenter study (7 centers, 6 countries) analyzed defined laboratory-based walking and uninstructed "supervised free walking" in patients with SPG7 and healthy controls using 3 wearable sensors (Opal APDM). For the extracted digital gait measures, we assessed effect sizes for the discrimination of patients and controls (Cliff δ) and Spearman correlations with measures of functional mobility and overall disease severity (Spastic Paraplegia Rating Scale [SPRS], including mobility subscore SPRSmobility; Scale for the Assessment and Rating of Ataxia [SARA]) and the activities of daily living subscore of the Friedreich Ataxia Rating Scale (FARS-ADL). RESULTS Gait was analyzed in 65 patients with SPG7 and 50 healthy controls. Among 30 hypothesis-based gait measures, 18 demonstrated at least moderate effect size (δ > 0.5) in discriminating patients from controls and 17 even in mild disease stages (SPRSmobility ≤ 9, n = 41). Spatiotemporal variability measures such as spatial variability measure SPcmp (ρ = 0.67, p < 0.0001) and stride time CV (ρ = 0.67, p < 0.0001) showed the largest correlations with functional mobility (SPRSmobility)-as with overall disease severity (SPRS, SARA) and activities of daily living (FARS-ADL). The correlations of variability measures with SPRSmobility could be confirmed in mild disease stages (e.g., SPcmp: ρ = 0.50, p < 0.0001) and in "supervised free walking" (e.g., stride time CV: ρ = -0.57, p < 0.0001). DISCUSSION We here identified trial-ready digital-motor candidate outcomes for the spastic ataxia SPG7 with proven multicenter applicability, ability to discriminate patients from controls, and correlation with measures of patient-relevant health aspects-even in mild disease stages. If validated longitudinally, these sensor outcomes might inform future natural history and treatment trials in SPG7 and other spastic ataxias.

中文翻译：

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遗传性痉挛性截瘫 7 型临床试验的患者相关指运动结果：一项多中心 PROSPAX 研究。


背景和目标 随着靶向治疗试验的出现，确定敏感和有效的结果指标成为 >100 痉挛性共济失调的优先事项。虽然使用可穿戴传感器评估的数字化运动测量被认为是痉挛性共济失调的主要结果候选者，但缺乏基因型特异性验证研究。我们在这里旨在确定 7 型痉挛性截瘫 （SPG7） 的候选数字运动结果——最常见的痉挛性共济失调之一—— （1） 反映了与患者相关的健康方面，即使在轻微的、与试验相关的疾病阶段;（2） 适合多中心设置;（3） 在模拟现实生活的无指导步行期间也评估活动能力。方法 这项横断面多中心研究 （7 个中心，6 个国家） 使用 3 个可穿戴传感器 （Opal APDM） 分析了 SPG7 患者和健康对照者定义的基于实验室的步行和未经指导的“监督自由行走”。对于提取的数字步态测量，我们评估了区分患者和对照组 （Cliff δ） 的效应大小以及 Spearman 与功能活动度和总体疾病严重程度测量的相关性（痉挛性截瘫评定量表 [SPRS]，包括活动子评分 SPRSmobility;共济失调评估和评级量表 [SARA]） 和弗里德赖希共济失调评定量表 （FARS-ADL） 的日常生活活动子评分。结果 对 65 例 SPG7 患者和 50 例健康对照者的步态进行了分析。在 30 项基于假设的步态测量中，18 项在区分患者与对照组方面表现出至少中等效应量 （δ > 0.5），17 项甚至在轻度疾病阶段 （SPRSmobility ≤ 9，n = 41）。时空变异性测量，例如空间变异性测量 SPcmp （ρ = 0.67， p < 0.0001） 和步幅时间 CV （ρ = 0.67，p < 0.0001）显示与功能移动性 （SPRSmobility） 的相关性最大，与总体疾病严重程度 （SPRS、SARA） 和日常生活活动 （FARS-ADL） 一样。变异性测量与 SPRSmobility 的相关性可以在轻度疾病阶段（例如，SPcmp：ρ = 0.50，p < 0.0001）和“监督自由行走”（例如，步幅时间 CV：ρ = -0.57，p < 0.0001）中得到证实。讨论 我们在这里确定了痉挛性共济失调 SPG7 的试验就绪数字运动候选结果，这些结果具有经过验证的多中心适用性、区分患者与对照组的能力以及与患者相关健康方面的测量相关性——即使在轻度疾病阶段也是如此。如果纵向验证，这些传感器结果可能会为 SPG7 和其他痉挛性共济失调的未来自然史和治疗试验提供信息。