Home-based actigraphy to predict disability progression and enhance clinical trials in multiple sclerosis

项目概要/摘要 虽然对于复发缓解型多发性硬化症 (RRMS) 存在有效的免疫疗法，但 进展性多发性硬化症是有限的。在某种程度上，这与进行性多发性硬化症是由于逐渐丧失 中枢神经系统神经元，而不是免疫介导的对其周围髓磷脂的损伤。然而， 缺乏临床残疾的高质量结果衡量标准也阻碍了治疗的发展 MS 的进展。黄金标准扩展残疾状况量表 (EDSS) 的不足之处 扩大渐进式 MS 试验的样本量和长度要求。此外，虽然临床医生可能怀疑 患有 RRMS 的人已过渡到进展过程（继发进展 MS），通常需要 确认使用 EDSS 的年数。因此，这些患者可能是信息最丰富、功能最丰富的患者。 失败，被排除在进行性 MS 试验之外。 2 期进展性多发性硬化症试验通常依赖于全脑萎缩， 通过脑磁共振成像（MRI）测量作为主要结果，但也有局限性。 同时考虑几种神经变性措施可能会提高此类试验的效率。 可穿戴三轴体动记录仪是一种非侵入式、廉价的设备，可以测量家庭中的活动模式。 基于现实世界的设置。使用我们复杂的分析方法，结合了多个维度 活动，我们甚至能够根据 EDSS 评分区分出少数 MS 患者。我们 提议对 255 名确诊、疑似或无明显进展的多发性硬化症患者进行纵向研究， 跟踪 EDSS 和体动记录仪导出的数据长达 4 年。我们将获得基线和后续大脑 MRI 和其他结果传统上用于渐进式 MS 试验，以实现以下目标： 目标 1. 评估体动记录测量是否能够可靠地预测后续 EDSS 确认的残疾 已确定的进展性多发性硬化症患者的进展。 目标 2. 评估体动记录仪衍生的测量是否能够区分疑似和未疑似的 RRMS 患者 进展并预测 EDSS 确认的残疾进展的后续风险。 目标 3. 评估体动记录测量与传统测量相结合时的相对贡献 神经退行性变的成像指标，用于预测随后的临床残疾变化。 直接对应 PA-18-145 的目标，该项目使用尖端的、基于家庭的技术来 预测多发性硬化症患者的轨迹。我们预计体动记录仪测量将预测随后的恶化 EDSS，特别是对于那些明确或疑似 MS 进展的患者，以及添加基于体动记录仪的患者 神经退行性变的影像学测量措施将改善后续的预测，EDSS- 确认残疾进展。如果正确的话，体动记录仪将彻底改变治疗试验的进行 进行性多发性硬化症，这是阻止这种常见的毁灭性疾病中残疾累积的关键一步。

PROJECT SUMMARY/ABSTRACT While effective immunotherapies exist for relapsing-remitting multiple sclerosis (RRMS), therapies for progressive MS are limited. In part, this relates to the fact that progressive MS is caused by gradual loss of central nervous system neurons rather than by immune-mediated injury to the myelin around them. However, therapeutic development has also been hampered by the lack of quality outcome measures of clinical disability progression in MS. The inadequacies of the gold standard, the Expanded Disability Status Scale (EDSS), inflate the sample size and length requirements of progressive MS trials. Further, while clinicians may suspect that a person with RRMS has transitioned to a progressive course (secondary progressive MS), it often takes years to confirm using the EDSS. Thus, these patients, perhaps the most informative with much function to lose, are excluded from progressive MS trials. Phase 2 progressive MS trials often rely on whole brain atrophy, measured by brain magnetic resonance imaging (MRI), as the primary outcome, which also has limitations. Considering several neurodegeneration measures concomitantly may improve the efficiency of such trials. Wearable tri-axial actigraphs are non-invasive, inexpensive devices that measure activity patterns in a home- based, real-world setting. Using our sophisticated analytic approach that incorporates multiple dimensions of activity, we are able to distinguish even small numbers of people with MS based on EDSS score. We propose a longitudinal study of 255 MS patients with confirmed, suspected, or no evident progression, tracking EDSS and actigraphy-derived data for up to 4 years. We will obtain baseline and subsequent brain MRIs and other outcomes traditionally used in progressive MS trials to conduct the following aims: Aim 1. To evaluate if actigraphy-derived measures reliably predict subsequent EDSS-confirmed disability progression in established progressive MS patients. Aim 2. To evaluate if actigraphy-derived measures distinguish RRMS patients with and without suspected progression and predict subsequent risk of EDSS-confirmed disability progression. Aim 3. To evaluate the relative contribution of actigraphy-derived measures, when combined with traditional imaging metrics of neurodegeneration, in predicting subsequent clinical disability change. Corresponding directly to the goal of PA-18-145, this project uses cutting-edge, home-based technology to predict MS patient trajectories. We anticipate that actigraphy measures will predict subsequent worsening on EDSS, particularly in those with definite or suspected MS progression, and that adding actigraphy-based measures to imaging measures of neurodegeneration will improve the prediction of subsequent, EDSS- confirmed disability progression. If correct, actigraphy will revolutionize the conduct of therapeutic trials for progressive MS, a critical step for arresting disability accumulation in this common, devastating disease.