Effects of Cognitive Training on Everyday Cognitive and Brain Function in Parkinson's Disease

路易体痴呆症(LBD)包括帕金森氏病(PD)痴呆症和路易体痴呆，在美国有100多万人受到困扰。它也是阿尔茨海默病相关痴呆(ADRDS)之一。目前，药物治疗对LBD的症状最多只能提供适度的益处，对于较轻微的认知问题还没有有效的治疗方法。在非痴呆性帕金森病患者中，认知训练计划已经变得流行起来，在接受治疗的认知领域取得了不同程度的成功。然而，这些好处并不是一概而论的，也没有转移到现实生活中的任务。重要的是，这些程序的神经基础在很大程度上是未知的。这项建议旨在制定痴呆症发病前的早期干预措施，以增加认知储备，帮助患者独立管理日常生活的认知需求。它还解决了NIH-ADRD方案的优先事项，即支持认知障碍患者的直接需求。即使在LBD疾病过程的早期阶段，执行和视觉空间功能障碍也是非常常见的，影响日常功能。我们之前使用引导成像训练的工作显示，帕金森病患者特定大脑网络中的运动表现和功能连接性得到改善。在这项工作的基础上，我们现在提出了一项机械性随机临床试验，以确定为期6周的心理意象(MI)训练计划在改善日常任务中目标导向认知技能方面的有效性(目标1)，并使用功能磁共振成像(FMRI)和功能连接性分析(目标2)来研究这种训练的脑机制。可能有执行功能障碍的轻至中度疾病的非痴呆帕金森病患者将被随机分配到试验组(PD-MI)或对照组(PD-CON)。PD-MI组将以有监督的方式和通过家庭作业练习日常任务的MI，而PD-CON组将接受关于PD认知功能和大脑健康的心理教育。我们的MI培训在重要方面不同于现有的认知培训计划：1)专注于在相关现实世界任务中改善认知功能，2)促进个性化和实用技能的发展，这些技能可以灵活地应用于现实生活情景。目标1的主要认知目标参与结果将是日常生活中认知技能自我报告测量的改善。在AIM 2中，主要的神经生物学靶参与结果将是在模仿现实世界需求的自然主义fMRI任务期间，协调的大脑网络交互作用中任务特定的变化。我们还将研究培训后认知功能和功能连接的假定变化是否会持续12周(目标3)。最后，我们将探索功能连接性的变化是否会预测6周和12周时间点的认知结果(探索性目标)。研究结果将为疗效试验提供关键的早期数据，这些试验可能有可能将MI发展为一种个性化的神经认知康复计划，涵盖与LBD相关的一系列认知问题。

Lewy body dementia (LBD) encompasses Parkinson’s disease (PD) dementia and dementia with Lewy bodies and afflicts more than one million people in the US. It is also one of the Alzheimer’s disease-related dementias (ADRDs). Currently, pharmacological treatment provides, at most, modest benefit for symptoms of LBD, and there is no effective treatment for milder cognitive problems. Cognitive training programs in nondemented PD patients have gained popularity with varying degrees of success for the cognitive domain that is treated. However, the benefits have not been generalizable and not transferred to real-life tasks. Importantly, the neural basis of these programs is largely unknown. This proposal aims to develop an early intervention before the onset of dementia to increase cognitive reserve and help patients independently manage the cognitive demands of everyday life. It also addresses the NIH-ADRD programmatic priority of supporting the immediate needs of people living with cognitive impairment. Executive and visuospatial dysfunction is very common even in the early stages of the disease process in LBD affecting everyday functioning. Our previous work using guided imagery training showed improved motor performance and increased functional connectivity in specific brain networks in PD patients. Grounded in that work, we now propose a mechanistic randomized clinical trial to determine the effectiveness of a 6-week mental imagery (MI) training program in improving goal-directed cognitive skills during everyday tasks (Aim 1) and to investigate the brain mechanisms of this training using functional magnetic resonance imaging (fMRI) and functional connectivity analyses (Aim 2) in PD patients. Nondemented PD patients with mild-to-moderate disease, who may have executive dysfunction will be randomly assigned in parallel to either the experimental (PD-MI) or control (PD-Con) group. The PD-MI group will practice MI of everyday tasks in a supervised manner and via homework, whereas the PD-Con group will receive psychoeducation on cognitive functioning and brain health in PD. Our MI training differs from existing cognitive training programs in important ways: It will 1) focus on cognitive functional improvement in relevant real-world tasks and 2) foster the development of personalized and practical skills that can be applied flexibly to real-life situations. The primary cognitive target engagement outcome in Aim 1 will be the improvement in self-reported measures of cognitive skills in daily life. The primary neurobiological target engagement outcome in Aim 2 will be the task-specific changes in coordinated brain network interactions during naturalistic fMRI tasks that will mimic real-world demands. We will also examine whether the putative post-training changes in cognitive function and functional connectivity will be sustained over a 12-week period (Aim 3). Finally, we will explore whether the functional connectivity changes will predict the cognitive outcomes at the 6- and 12-week timepoints (Exploratory Aim). Findings will provide critical early data for efficacy trials that may have the potential to develop MI into a personalized neurocognitive rehabilitation program across a spectrum of cognitive issues related to LBD.