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

项目总结/摘要 虽然复发缓解型多发性硬化症（RRMS）存在有效的免疫疗法，但治疗 渐进性MS是有限的。在某种程度上，这与进行性MS是由代谢产物的逐渐丧失引起的事实有关。 中枢神经系统的神经元，而不是通过免疫介导的损伤髓鞘周围。然而，在这方面， 由于缺乏临床残疾的质量结果测量， 金标准的不足，扩展残疾状态量表（EDSS）， 扩大渐进性MS试验的样本量和长度要求。此外，虽然临床医生可能怀疑 一个患有RRMS的人已经过渡到一个渐进的过程（二级渐进MS），通常需要 使用EDSS确认。因此，这些病人，也许是最翔实的，有很多功能， 失败，被排除在渐进性MS试验之外。2期进展性MS试验通常依赖于全脑萎缩， 通过脑磁共振成像（MRI）测量，作为主要结局，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。 可穿戴式三轴活动记录仪是一种非侵入性、廉价的设备，可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，包括多个维度， 活动，我们能够区分即使是少数人与MS的基础上EDSS评分。我们 建议对255例确诊、疑似或无明显进展的MS患者进行纵向研究， 追踪EDSS和活动记录仪数据长达4年。我们将获得基线和随后的大脑 MRI和传统上用于进行性MS试验的其他结局，以实现以下目标： 目标1.评价腕动记录仪衍生的测量值是否可靠地预测随后经EDSS证实的残疾 在已确诊的进展性MS患者中进展。 目标二。评价腕动描记术衍生的测量值是否可区分有和无可疑RRMS的患者 进展并预测EDSS证实的残疾进展的后续风险。 目标3：评价腕动计衍生测量与传统测量相结合时的相对贡献。 神经变性的成像指标，在预测随后的临床残疾的变化。 与PA-18-145的目标直接对应，该项目使用尖端的家庭技术， 预测MS患者的轨迹。我们预计，腕动记录测量将预测随后的恶化， EDSS，特别是在明确或疑似MS进展的患者中， 神经退行性变的成像测量的措施将改善随后的EDSS的预测， 确认残疾进展。如果正确的话，活动记录仪将彻底改变治疗试验的进行， 进行性MS，这是阻止这种常见的毁灭性疾病的残疾积累的关键步骤。

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.