Slow wave sleep as a biomarker of rehabilitation-induced cognitive improvement in Parkinson's disease

摘要 帕金森病(PD)是一种与路易体病理相关的神经退行性疾病，可导致 到进行性认知衰退和帕金森氏病痴呆(PDD)，路易体痴呆的一种形式。 认知功能障碍在帕金森病中很常见，高达80%的帕金森病患者(PWP)在整个病程中受到影响。 与帕金森病相关的认知能力下降会造成毁灭性的后果，包括生活质量受损， 照顾者的负担，丧失独立性和生产力，以及更大的制度化风险。这将导致 严重的公共卫生和社会负担。帕金森病患者认知功能障碍的药物治疗 通常无效，且无一能阻止进展为PDD。锻炼有望改善帕金森病患者的认知能力，但 对于个人PWP来说，最好的运动处方是未知的。慢波睡眠(SWS)对认知功能有重要作用 由于它参与突触可塑性、皮质重组和淋巴功能而发挥作用。少年派的 初步数据表明，主观幸福感对PWP的认知成绩有重要影响。此外，私家侦探发现， 运动增加帕金森病患者的SWS，只有SWS增加的PWP才能改善执行功能。这 个体间反应的异质性提供了为个体PWP量身定做运动处方的机会。 假设运动将改善帕金森病患者的认知功能，而SWS的变化将作为一种 康复认知反应的生物标志物和介体。我们的探索性假设是 淋巴功能的效率可能是这些效应的基础。 使用创新的顺序多分配随机试验(SMART)设计，PI将测试这些 120例PWP随机对照试验的假设：1)运动康复的效果 PWP中延迟运动控制对认知的影响(目标1)；2)确定运动是否会引起主观幸福感的变化 调节运动诱发的PWP的执行功能改变(目标2)；以及3)确定是否有淋巴反应 功能预测运动引起的认知变化(探索性目的)。 研究设计：在试验的第一阶段，参与者将随机接受12周的渐进性抵抗 训练康复(PRT)或延迟运动控制(1：1)。第二个为期12周的阶段的ARM分配 试验将在头12周内根据个人反应确定。具体地说，响应者(那些增加的 在SWS中)将在试验的第二个12周内继续PRT，而无响应者(SWS中没有足够的增加) 将过渡到第二个12周的耐力训练(ET)。在试验的前12周后，参与者在 延迟运动组将在试验的第二个12周进行PRT。这项研究涉及优先领域 通过调查1)可以预测个体康复治疗的客观标志(SWS)来评估NCMRR 反应和2)与身体损伤相关的继发性疾病(认知障碍)的治疗 (帕金森氏病)。

ABSTRACT Parkinson’s disease (PD) is a neurodegenerative disorder associated with Lewy Body pathology that can lead to progressive cognitive decline and Parkinson’s disease dementia (PDD), a form of Lewy Body Dementia. Cognitive dysfunction in PD is common, affecting up to 80% of persons with PD (PwP) over the disease course. PD-associated cognitive decline has devastating consequences, including quality of life impairment, increase in caregiver burden, loss of independence and productivity, and increased risk of institutionalization. This results in significant public health and societal burden. Pharmacologic treatments for cognitive dysfunction in PD are often ineffective and none prevent progression to PDD. Exercise has promise for improving cognition in PD, but the best exercise prescription for individual PwP is unknown. Slow wave sleep (SWS) is important for cognitive function due to its involvement in synaptic plasticity, cortical reorganization, and glymphatic function. The PI’s preliminary data show that SWS is important for cognitive performance in PwP. Further, the PI found that exercise increases SWS in PD and only PwP with increased SWS had improvement in executive function. This interindividual response heterogeneity provides an opportunity to tailor exercise prescriptions to individual PwP. The hypothesis is that exercise will improve cognitive function in PD and that changes in SWS will serve as a biomarker and mediator of rehabilitation-induced cognitive response. Our exploratory hypothesis is that efficiency of glymphatic function may underlie these effects. Using an innovative Sequential Multiple Assignment Randomized Trial (SMART) design, the PI will test these hypotheses in a randomized, controlled trial of 120 PwP to investigate 1) the effects of exercise rehabilitation versus delayed-exercise control on cognition in PwP (Aim 1); 2) determine if changes in SWS due to exercise mediate the exercise-induced changes in executive function in PwP (Aim 2); and 3) determine if glymphatic function predicts exercise-induced changes in cognition (Exploratory Aim). Study design: In the first phase of the trial, participants will be randomized to 12-weeks of progressive resistance training rehabilitation (PRT) or delayed-exercise control (1:1). Arm assignment in the 2nd 12-week phase of the trial will be determined by individual response in the first 12 weeks. Specifically, responders (those with increases in SWS) will continue PRT for the 2nd 12 weeks of the trial while non-responders (no sufficient increase in SWS) will transition to endurance training (ET) for the 2nd 12 weeks. After the 1st 12 weeks of the trial, participants in the delayed-exercise group will perform PRT for the 2nd 12 weeks of the trial. The study addresses priority areas of NCMRR by investigating 1) an objective marker (SWS) that may predict individual rehabilitation treatment response and 2) treatment for secondary conditions (cognitive impairment) associated with physical impairment (Parkinson’s disease).