Cognitive Biomarker Targets for Treatment in Veterans with Parkinson's Disease

 产品说明： 超过100，000名患有帕金森病（PD）的退伍军人目前正在接受VA的PD相关护理和服务。PD的管理包括运动和非运动症状的治疗。轻度认知功能障碍（PD-MCI）是PD患者常见的非运动症状，对功能产生负面影响，是生活质量的主要决定因素，也是发展为痴呆的危险因素。在平民人群中，超过四分之一的PD患者患有PD-MCI;退伍军人的估计数字不详。也不知道战斗相关的风险因素是否影响PD-MCI的性质（即，严重程度或认知领域的类型），因此研究退伍军人的PD-MCI可能特别重要。平民中PD-MCI的治疗选择有限，并且可能需要为患有PD-MCI的退伍军人量身定制治疗，这使得这成为一个重要的研究课题。了解PD-MCI可以在认知能力下降的最早阶段提供对大脑机制的深入了解。例如，认知功能由包括神经网络的大脑区域支持。这些网络在功能上是连接的，即使当认知任务没有被执行时（即，当一个人处于静止状态时）。认知网络的静息状态功能连接（rsFC）的变化与认知功能的变化相关。了解与PD-MCI相关的认知网络rsFC的独特差异将有助于阐明这种情况的神经生物学。这些信息可用于制定早期康复干预措施，如重复经颅磁刺激（rTMS），重点是预防或延迟PD-D的发作。rTMS是一种非药理学和非侵入性刺激技术，可以在目标脑区域和网络中诱导神经元可塑性。rTMS显示出作为神经系统疾病患者认知增强工具的前景。目前CDA 2提案的目的是加强我们对PD退伍军人中最常见的轻度认知缺陷的理解，并确定支持认知功能的关键脑区的rsFC改变。关于这些大脑和行为关系的信息将用于指导使用rTMS进行认知康复干预的方案的开发。为了实现这些目标，将招募患有PD的退伍军人，并使用神经心理学测试表征认知行为。将使用先进的功能性磁共振成像（fMRI）技术和rsFC分析表征行为的潜在神经生物学。将采用多种方法进行功能连接性分析。具体地，将确定与认知损害相关的认知网络内或之间的区域的功能连接的中断。将共同评价这些大脑和行为表征，以制定rTMS方案，从而确定皮质刺激部位以及刺激参数。将进行一项初步随机对照试验，以确定rTMS改善认知功能的安全性、可行性和有效性。参与者将接受活性或 在两周的过程中，每天进行10次假rTMS。预计这一创新项目将为我们的基础知识提供一个缺失的基本要素，没有它，就无法理解患有PD的退伍军人的轻度认知障碍。这些知识的获得对于开发和优化患有PD-MCI的退伍军人的认知康复治疗至关重要，最终目标是提高生活质量。与CDA 2提案相关的发现可能会为MCI和痴呆发生的其他情况的神经康复提供信息。

 DESCRIPTION: More than 100,000 Veterans living with Parkinson's disease (PD) currently receive PD-related care and services from the VA. Management of PD includes treatment of both motor and non-motor symptoms. Mild cognitive impairment (PD-MCI) is a common non-motor symptom in PD that negatively impacts functioning, is a main determinant of quality of life, and is a risk factorfor developing dementia. In the civilian population, over a quarter of PD patients have PD-MCI; estimates are unknown in Veterans. It is also unknown if combat- related risk factors impact the nature PD-MCI (i.e., severity or types of cognitive domains), thus studying PD- MCI in Veterans may be particularly important. Limited treatment options for PD-MCI in the civilian population and the possible need to tailor treatments to Veterans with PD-MCI makes this an important research topic. Understanding PD-MCI can offer insight into the brain mechanisms at the earliest stage of cognitive decline. For example, cognitive function is supported by brain regions that comprise neural networks. These networks are functionally connected even when a cognitive task is not being performed (i.e., when a person is at rest). Changes in the resting state functional connectivity (rsFC) of cognitive networks are associated with changes in cognitive function. Understanding unique differences in the rsFC of cognitive networks associated with PD-MCI will aid in elucidating the neurobiology of this condition. Such information can be used to develop early rehabilitation interventions, such as repetitive transcranial magnetic stimulation (rTMS), that focus on preventing or delaying the onset of PD-D. rTMS is a non-pharmacological and non- invasive stimulation technique that can induce neuronal plasticity in targeted brain regions and networks. rTMS shows promise as a tool for cognitive enhancement in people with neurological conditions. The objectives of the current CDA2 proposal are to enhance our understanding of the mild cognitive deficits that most frequently occur in Veterans with PD and to determine the altered rsFC of critical brain regions that support cognitive function. Information gained about these brain and behavior relationships will be used to guide the development of a protocol for a cognitive rehabilitation intervention using rTMS. To carry out these objectives, Veterans with PD will be recruited and cognitive behavior will be characterized using neuropsychological tests. The underlying neurobiology of the behavior will be characterized using advanced functional magnetic resonance imaging (fMRI) techniques and rsFC analysis. Multiple approaches for functional connectivity analyses will be undertaken. Specifically, disruptions in functional connectivity of regions within or between cognitive networks that are correlated with cognitive impairment will be determined. These brain and behavior characterizations will be evaluated collectively to develop an rTMS protocol such that a cortical stimulation site as well as stimulation parameters will be determined. A pilot randomized control trial to determine safety, feasibility and efficacy of rTMS to improve cognitive function will be conducted. Participants will be treated with either active or sham rTMS for 10 daily sessions over the course of two weeks. It is expected that this innovative project will contribute a missing, fundamental element to our base knowledge, without which mild cognitive impairment in Veterans with PD cannot be understood. The acquisition of such knowledge is critical for developing and optimizing cognitive rehabilitation treatments for Veterans with PD-MCI, with an ultimate goal of improving quality of life. Findings related to this CDA2 proposal will potentially inform neurorehabilitation of other conditions in which MCI and dementia occur.