Partnered Dance Aerobic Exercise as a neuroprotective, motor and cognitive intervention in Parkinson's disease

帕金森氏病（PD）是一种损害运动和认知功能的顽固性疾病， 通过药物和手术大多数PD患者的两个优先问题是关闭时间和认知 损伤即使在最好的医疗管理下，74%的PD患者也会经历与以下因素相关的“关闭时间”： 与药物相关的运动波动，严重影响生活质量和认知1。认知 即使在新诊断的PD患者中也发现了缺陷，并且非常难以治疗2。然而，我们的坚强 初步数据表明，舞蹈-有氧运动相结合可减少休息时间（Cohens标准化 d=1.09），基于运动障碍协会统一帕金森病评定量表-IV，MDS-MRS-IV），以及 改善其他疾病特征5-8，在PDAE后至少一个月保持益处。这些数据 推动这项提案。PDAE在一个即兴的，认知参与的康复物理过程中提供AE 活动认知参与是PDAE的一个重要组成部分，它有益于空间认知（d=.76）。 与这些发现相一致，我们有强有力的初步证据，通过功能磁共振获得 根据功能磁共振成像（fMRI），每两周一次的PDAE训练增加了与认知有关的大脑区域的活动。虽然 运动有益于运动和认知症状，可能对PD具有神经保护作用，3，4使用稳健的 人类神经保护的生物标志物非常罕见。我们建议进行一项随机对照试验， 诊断为PD的退伍军人和非退伍军人，以比较PDAE与步行AE（WAE）的疗效， 关闭时间，认知和神经保护。重要的是，我们将评估新的神经黑色素的神经保护作用- 敏感MRI（NM-MRI）和铁敏感（R2*）MRI序列，以量化神经黑色素损失和铁 在黑质神经节（SNc）中的蓄积3，8 9.我们将使用这些生物标志物， 和铁的积累，作为工具，以图表与PD患者的神经变性的过程中， 长期（16个月）干预。我们的总体假设是，PDAE -一种认知参与AE - 在减少关闭时间和改善认知方面比WAE更有效。与WAE类似，我们 认为PDAE在PD中具有神经保护作用。我们将102名患有轻中度PD的退伍军人随机分配到16名 PDAE或WAE的月份。需要16个月的观察期来稳健地评估神经保护， 影像学结果。创新的16个月干预期将包括之前确定的培训 （3个月的双周疗程）和新的维持（13个月的每周疗程）阶段。我们将评估 基线、3个月（培训后即刻）和16个月（维持后即刻）时的受试者 以及行为和生理上测量的认知。我们将获得NM-MRI和R2* 成像 基线和16个月时的数据，以评估神经保护。我们将：1.检查培训的效果， PDAE与WAE在关断时间上的维持阶段; 2.比较3个月和16个月时的PDAE与WAE， 空间认知的行为和fMRI测量;以及3.比较PDAE与WAE对 神经变性目标1的主要结果指标将是运动障碍协会统一 帕金森病评定量表第IV部分评分，测定MRMF。空间的主要结局指标 目标2的认知将是科西块。我们将首次使用前景广阔的尖端成像技术 技术，以揭示PDAE，作为长期运动，是否减缓PD的神经退行性变超过 走路了解药物疗效和运动方式之间的关系将使临床医生能够 更好地治疗PD。了解通过PDAE改善认知的机制将决定PDAE， 一个可扩展的，现成的治疗，是一个强大的模型，同时身体/心理训练，以解决CI在 警局该项目结合了以患者为中心的临床科学和机械目的，以改善退伍军人的健康 在乎

Parkinson’s disease (PD), an intractable condition impairing motor and cognitive function, is imperfectly treated by drugs and surgery. Two priority issues for a majority of people with PD are OFF-time and Cognitive impairment. Even under best medical management, 74% of people with PD experience “OFF-time” related to medication-related motor fluctuations, which severely impacts both quality of life and cognition 1. Cognitive deficits are found even in newly diagnosed people with PD and are very difficult to treat 2. However, our strong preliminary data demonstrate that partnered dance-aerobic exercise reduces OFF-time (Cohens standardized d=1.09), on the Movement Disorders Society Unified Parkinson Disease Rating Scale-IV, MDS-UPDRS-IV) and ameliorates other disease features 5-8, with retention of benefits for at least one month post-PDAE. These data motivate this proposal. PDAE provides AE during an improvisational, cognitively-engaging rehabilitative physical activity. Cognitive engagement is a critical component of PDAE, which has benefitted spatial cognition (d=.76). Consistent with these findings, we have strong preliminary evidence, obtained via functional magnetic resonance imaging (fMRI), that biweekly PDAE training increases activity in brain regions implicated in cognition. Although exercise benefits motor and cognitive symptoms and may be neuroprotective for PD, 3,4 studies using robust biomarkers of neuroprotection in humans are quite rare. We propose to perform a randomized, controlled trial in veterans and non-veterans with diagnosed PD to compare the efficacy of PDAE versus walking AE (WAE) for OFF-time, cognition, and neuroprotection. Importantly, we will assess neuroprotection with novel neuromelanin- sensitive MRI (NM-MRI) and iron-sensitive (R2*) MRI sequences to quantify neuromelanin loss and iron accumulation in substantia nigra pars compacta (SNc) 3,8 9. We will use these biomarkers, neuromelanin loss and iron accumulation, as tools to chart the course of neurodegeneration in patients with PD who have undergone long-term (16 months) intervention. Our overall hypothesis is that PDAE – a cognitively engaging AE – is more effective at reducing OFF-time and improving cognition than WAE. However, similar to WAE, we believe PDAE is neuroprotective in PD. We will randomly assign 102 veterans with mild-moderate PD to 16 months of PDAE or WAE. The 16-month observation period is required to robustly assess neuroprotection with imaging outcomes. The innovative 16-month intervention period will consist of previously established Training (3 months of biweekly sessions) and novel Maintenance (13 months of weekly sessions) phases. We will assess participants at baseline, 3 months (immediately post-Training), and 16 months (immediately post-Maintenance) for OFF-time and behaviorally and physiologically measured cognition. We will acquire NM-MRI and R2* imaging data at baseline and 16 months to assess neuroprotection. We will: 1. examine effects of Training and Maintenance phases of PDAE vs. WAE on OFF-time; 2. compare PDAE vs WAE at 3 and 16 months on behavioral and fMRI measures of spatial cognition; and 3. compare PDAE vs. WAE for effects on rates of neurodegeneration. The primary outcome measure of Aim 1 will be the Movement Disorders Society Unified Parkinson Disease Rating Scale Part IV score, which assays MRMF. The primary outcome measure for spatial cognition of Aim 2 will be the Corsi blocks. For the first time, we will use promising, cutting edge imaging techniques to reveal whether PDAE, used as long-term exercise, slows neurodegeneration in PD more than walking. Understanding the relationships between drug efficacy and exercise modalities will allow clinicians to better treat PD. Understanding the mechanisms for improving cognition via PDAE will determine whether PDAE, a scalable, readily available treatment, is a robust model of concurrent physical/mental training to address CI in PD. This project combines patient-centered, clinical science and mechanistic aims to improve veteran health care.