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，但治疗方法并不完善 通过药物和手术。对于大多数帕金森病患者来说，两个优先问题是非工作时间和认知 减损。即使在最好的医疗管理下，74%的帕金森病患者经历了与 与药物有关的运动波动，严重影响生活质量和认知1.认知 即使在新诊断的帕金森氏症患者中也发现了缺陷，而且很难治疗2。然而，我们的强者 初步数据表明，结伴跳舞-有氧运动减少了休息时间(Cohens标准化 D=1.09)，在运动障碍协会统一帕金森病评定量表-IV上)和 改善其他疾病特征5-8，在PDAE后至少保留一个月的益处。这些数据 激励这项提议。PDAE在即兴的、认知参与的康复物理中提供AE 活动。认知投入是PDAE的一个重要组成部分，它有利于空间认知(d=0.76)。 与这些发现一致，我们有强有力的初步证据，通过功能磁共振获得 成像(FMRI)，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 运动可以改善运动和认知症状，并可能对帕金森病起到神经保护作用，3，4项研究使用Robust 人类神经保护的生物标志物相当罕见。我们建议进行一项随机对照试验 退伍军人与非退伍军人诊断为帕金森病的疗效比较 业余时间、认知和神经保护。重要的是，我们将使用新的神经黑色素来评估神经保护- 敏感MRI(NM-MRI)和铁敏感(R2*)MRI序列用于量化神经黑素丢失和铁 黑质致密部蓄积(SNC)3，8，9。我们将使用这些生物标记物，神经黑素丢失 和铁的积累，作为工具来描绘患有帕金森病的帕金森病患者的神经变性过程 接受长期(16个月)干预。我们的总体假设是，PDAE-一种认知参与的AE -在减少休息时间和改善认知方面比WAE更有效。然而，与WAE类似，我们 相信PDAE对帕金森病有神经保护作用。我们将102名患有轻中度帕金森病的退伍军人随机分配到16名 几个月的PDAE或WAE。需要16个月的观察期来有力地评估神经保护 成像结果。创新的16个月干预期将包括先前确定的培训 (3个月的双周会议)和新的维护(13个月的每周会议)阶段。我们将评估 参与者在基线、3个月(培训后立即)和16个月(维护后立即) 用于非工作时间以及行为和生理测量的认知。我们将获得NM-MRI和R2*成像 在基线和16个月时评估神经保护的数据。我们将：1.检查培训的效果和 PDAE的维护阶段与WAE的关闭时间；2.比较PDAE与WAE在3个月和16个月的维护阶段 空间认知的行为和功能磁共振测量；以及3.比较PDAE和WAE对 神经退行性变。目标1的主要结果衡量标准将是运动障碍社会统一 帕金森病评定量表第四部分评分，分析MRMF。空间的主要结果衡量标准 对目标2的认知将是Corsi区。我们将首次使用前景看好的尖端成像技术 揭示作为长期运动的PDAE是否比其他方法更能延缓帕金森病患者的神经变性 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 最好给警局治病。了解通过PDAE改善认知的机制将决定PDAE是否， 一种可扩展的、随时可用的治疗方法，是同时进行身体/心理训练的强大模型，可用于解决脑梗塞 警察。该项目结合了以患者为中心、临床科学和机械学的目标，旨在改善退伍军人的健康 关心。

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.