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学相关的神经退行性疾病， 进行性认知衰退和帕金森氏病痴呆症（PDD），路易体痴呆症的一种形式。 PD中的认知功能障碍很常见，在病程中影响高达80%的PD患者（PwP）。 PD相关的认知功能下降具有破坏性后果，包括生活质量受损， 照料者负担加重，丧失独立性和生产力，以及机构化风险增加。这导致 造成重大公共卫生和社会负担。PD认知功能障碍的药物治疗包括 通常无效，并且无法阻止PDD的进展。运动有望改善PD患者的认知能力，但 个体PwP的最佳运动处方是未知的。慢波睡眠（SWS）对认知功能非常重要。 由于其参与突触可塑性、皮质重组和胶质淋巴功能，因此具有重要的功能。pi的 初步数据显示，SWS对PwP的认知表现很重要。此外，PI发现， 运动增加PD患者的SWS，只有SWS增加的PwP执行功能有所改善。这 个体间反应的异质性提供了一个机会，定制运动处方，以个人的PwP。 假设是运动会改善PD的认知功能，SWS的变化将作为一种 康复诱导的认知反应的生物标志物和介质。我们的假设是 胶质淋巴功能的效率可能是这些效应的基础。 使用创新的序贯多重分配随机试验（SMART）设计，PI将测试这些 假设在一项随机对照试验中，120名PwP研究1）运动康复的影响 与延迟运动控制对PwP认知的影响（目的1）; 2）确定SWS是否因运动而发生变化 介导PwP中运动诱导的执行功能变化（目的2）; 3）确定胶质淋巴细胞是否 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，参与者将被随机分配到12周的渐进性耐药组。 训练康复（PRT）或延迟运动控制（1：1）。第2个12周阶段的组分配 试验将由前12周内的个体反应决定。具体而言，响应者（ 在试验的第2个12周继续PRT，而无应答者（SWS没有充分增加） 将过渡到第二个12周的耐力训练（ET）。在试验的前12周后， 延迟运动组将在试验的第二个12周进行PRT。该研究涉及优先领域 通过研究1）可以预测个人康复治疗的客观标志物（SWS）来研究NCMRR 反应和2）与身体损害相关的继发性疾病（认知损害）的治疗 （帕金森氏症）。

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).