Aerobic exercise to improve mobility in multiple sclerosis: optimizing design and execution for a full-scale multimodal remyelination clinical trial

项目摘要/摘要 多发性硬化症(MS)是一种常见的神经系统疾病，可导致严重的活动受限和 参与。MS是由间歇性炎症引起的，导致脱髓鞘和轴突损伤。这个 促进髓鞘再生是一种很有前途的治疗策略，通过以下方式克服和预防MS残疾 提高动作电位的传导速度，为轴突提供神经保护绝缘。 有效的髓鞘再生可能需要多模式的方法，包括康复和药理学。 治疗，以刺激沿神经通路的重新髓鞘形成。在多发性硬化症动物模型中，有氧运动可以 单独或与药物治疗协同促进髓鞘再生。然而，目前还不确定如何 测量MS患者的再髓鞘形成，缺乏可重复和可靠的髓鞘状态测量 是发展髓鞘再生疗法的主要障碍。在成功开发之前 对于大规模的多模式临床试验，迫切需要1)确定最佳结果以评估 重新髓鞘形成的程度，以及2)证明康复有氧运动的可行性和研究设计 干预。 这项研究的中心假设是：1)多发性硬化症患者的脊髓脱髓鞘，通过延长来衡量 躯体感觉诱发电位(SSEP)潜伏期的延长与功能、活动和 多发性硬化症患者的参与，2)有氧静止自行车是一种安全可行的康复 对多发性硬化症患者进行干预，以改善活动能力。除了解决这些假设之外，我们还将收集 有氧运动对SSEP潜伏期、步行速度和其他指标影响的初步数据 主动性和参与性。SSEP是一种理想的客观测量方法，因为它们价格低廉，可重复使用， 并提供了一种反映脊髓髓鞘形成的功能指标。这 拟议的研究将探索由SSEP评估的髓鞘形成与一组 身体结构、功能、活动度和参与度的结果测量，以确定最佳临床结果 以监测髓鞘再生情况。这项研究还将确定24周有氧运动的安全性和可行性。 将静态自行车干预与MS症状教育对照干预进行随机比较， 对多发性硬化症患者进行的单盲平行临床试验一个实验目标是探索有氧静止状态 骑自行车与改善脊髓的活动度和重新髓鞘形成有关，通过测量 SSEP。这项研究的目标是为设计和实施R01资助的未来奠定必要的基础工作， 有氧静止骑行的多模式随机临床试验及药物刺激 多发性硬化症患者的髓鞘再生。

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a common neurologic disease that can result in significant restriction in activity and participation. MS is caused by intermittent inflammation causing demyelination and axonal damage. The promotion of remyelination is a promising therapeutic strategy to overcome and prevent MS disability by improving the conduction velocity of action potentials and providing neuroprotective insulation for the axon. Effective remyelination will likely require a multimodal approach, including rehabilitative and pharmacologic therapies, to stimulate remyelination along neural pathways. In animal models of MS, aerobic exercise can promote remyelination alone or synergistically with pharmacotherapy. However, it is currently uncertain how to measure remyelination in people with MS and this lack of a reproducible and reliable measure of myelin status is a major obstacle to the development of remyelination therapies. Prior to the successful development of large-scale multimodal clinical trials, there is a crucial need to 1) determine the optimal outcomes to assess the extent of remyelination, and 2) demonstrate the feasibility and study design of a rehabilitative aerobic exercise intervention. The central hypotheses of this study are that 1) spinal cord demyelination in MS, as measured by prolongation of somatosensory evoked potential (SSEP) latency, is associated with reduced function, activity and participation in people with MS, and 2) aerobic stationary cycling is a safe and feasible rehabilitative intervention in people with MS to improve mobility. Besides addressing these hypotheses, we will gather preliminary data on the effects of aerobic exercise on SSEP latencies, walking speed, and other measures of activity and participation. SSEPs are an ideal objective measure as they are inexpensive, reproducible, commercially available, and provide a functional measure reflecting myelination in the spinal cord. This proposed study will explore the association between myelination, as assessed by SSEPs, and a panel of outcome measures of body structure, function, activity and participation, to determine optimal clinical outcomes to monitor remyelination. This study will also determine the safety and feasibility of a 24-week aerobic stationary cycling intervention as compared to an MS symptom education control intervention in a randomized, single-blind, parallel clinical trial in people with MS. An experimental aim will explore if aerobic stationary cycling is associated with improvements in mobility and remyelination of the spinal cord, as measured by SSEP. The goal of this study is to lay the ground work needed to design and implement a future, R01-funded, multimodal, randomized clinical trial of aerobic stationary cycling and pharmacotherapy to stimulate remyelination in people with MS.