The Striatum and Hippocampus: "Hubs" of White Matter Connections in Parkinson's Disease Cognitive Decline

纹状体和海马：帕金森病认知衰退中白质连接的“枢纽”

• 批准号: 10295121
• 负责人: Gregory L Brown
• 金额: $ 3.35万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295121
• 关键词: Accounting; Alzheimer' s Disease; Alzheimer' s disease related dementia; Area; Attention; Attentional deficit; Basal Ganglia; Benign; Brain; Brain region; Clinical; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Data Set; Deep Brain Stimulation; Dementia; Development; Diffusion; Digit structure; Disease; Engineering; Environment; Equipment; Exhibits; Extracellular Space; Fiber; Foundations; Functional disorder; Future; Hippocampus (Brain); Impaired cognition; Incidence; Investigation; Knowledge; Lead; Levodopa; Longevity; Longitudinal cohort; Magnetic Resonance Imaging; Measures; Memory; Mentors; Neurocognitive; Neurodegenerative Disorders; Neuropsychological Tests; Neurosciences; Outcome; Parietal; Parkinson Disease; Pathology; Patients; Pattern; Pharmaceutical Preparations; Physicians; Play; Population; Positioning Attribute; Process; Prognosis; Public Health; Recording of previous events; Research; Research Subjects; Resources; Role; Short-Term Memory; Syndrome; Techniques; Testing; Therapeutic; Training; Treatment outcome; Visuospatial; Water; aging population; career; cognitive change; cognitive function; cognitive performance; cohort; cost effective; dementia risk; follow-up; global health; healthy aging; improved; insight; memory recall; motor disorder; neural circuit; neuroimaging; novel; profiles in patients; progression marker; relating to nervous system; response; skills; tractography; treatment response; treatment strategy; white matter; white matter damage

Due to an aging population and increased lifespan, dementia is an increasing clinical and public health issue. The most common and well-known cause is Alzheimer’s disease (AD), but other important disorders are involved in the development of AD-related dementias (ADRD). What is less appreciated is that Parkinson’s disease (PD), the second most common neurodegenerative disease, while often associated with motor dysfunction, contributes to ADRD with an incidence of dementia as high as 80% in late stages in which most have AD co-pathology. Therefore, this population exhibits a range of cognitive deficits that enables insight into mechanisms involved in ADRD. There seem to be two distinct cognitive profiles in these patients. One is a benign frontal profile characterized by executive and attention deficits, whereas the other is a posterior profile characterized by memory and visuospatial deficits that is associated with faster progression to dementia, often with AD co-pathology. The premise of this application is that identifying the neural circuitry underlying frontal and posterior function may provide insight into structural alterations occurring in ADRD. Dopaminergic therapies are known to improve frontal circuitry function, but not posterior circuitry, leading to the hypothesis that posterior circuit alterations are due to non-dopaminergic pathology, such as AD co-pathology. If true, the pattern of frontal-vs-posterior involvement may lead to differential responses to current treatments in ADRD. I plan to apply diffusion tensor tractography, a sensitive and widely available MRI technique, to measure microstructural integrity of white matter (WM) connections between brain regions. My central hypothesis is that WM alterations in frontal and posterior circuitry occurs in PD (Aim 1); that these alterations are associated with specific cognitive deficits and relate to differing rates of progression to dementia (Aim 2); and the ratio of frontal to posterior damage (F/P ratio) modulates the cognitive response to treatment (e.g., levodopa, deep brain stimulation, Aim 3). These aims will be implemented by leveraging existing datasets allowing a cost-effective and impactful investigation. This study immediately will impact knowledge of WM circuits related to dementia with insight into underlying mechanisms and therapeutic strategies, as well as provide the foundational line of research for future study of microstructural signatures of AD/ADRD. I have assembled a world-class mentoring team with expertise in areas related to my research and a history of highly-successful mentoring. The environment and institutional resources available to me for this project are excellent with a well-developed training plan and access to required equipment and research datasets. The proposed project and training plan will position me at the intersection of neuroscience and engineering, and enable me to tackle important clinical problems with the latest technological advancements. My new skills in neuroimaging analysis and neuropsychological testing to probe neurocognitive circuitry will provide a foundation for my career as an independent physician-engineer focused on alleviating the burden of AD/ADRD.

由于人口老龄化和寿命延长，痴呆症是一个日益严重的临床和公共卫生问题。最常见和众所周知的原因是阿尔茨海默病（AD），但其他重要的疾病也参与了AD相关痴呆（ADRD）的发展。不太了解的是，帕金森氏病（PD）是第二常见的神经退行性疾病，虽然通常与运动功能障碍相关，但其导致ADRD，在晚期阶段痴呆的发生率高达80%，其中大多数具有AD共病理学。因此，该人群表现出一系列认知缺陷，使人们能够深入了解ADRD的相关机制。这些患者似乎有两种不同的认知特征。一种是良性的正面轮廓，其特征是执行和注意力缺陷，而另一种是后部轮廓，其特征是记忆和视觉空间缺陷，这与更快地进展为痴呆症有关，通常伴有AD共病理。本申请的前提是，识别额叶和后部功能的神经回路可能会提供对ADRD中发生的结构改变的见解。已知多巴胺能治疗可改善额叶回路功能，但不能改善后回路功能，这导致后回路改变是由于非多巴胺能病理学（如AD共病理学）所致的假设。如果是真的，则前部与后部受累的模式可能导致对ADRD当前治疗的不同反应。我计划应用弥散张量纤维束成像（一种灵敏且广泛使用的MRI技术）来测量大脑区域之间白色物质（WM）连接的微结构完整性。我的中心假设是，额叶和后部回路中的WM改变发生在PD中（目的1）;这些改变与特定的认知缺陷相关，并与进展为痴呆的不同速率相关（目的2）;额叶与后部损伤的比率（F/P比率）调节对治疗的认知反应（例如，左旋多巴，脑深部电刺激，Aim 3）。这些目标将通过利用现有数据集来实现，从而进行具有成本效益和影响力的调查。这项研究将立即影响与痴呆相关的WM回路的知识，深入了解潜在的机制和治疗策略，并为未来AD/ADRD微结构特征的研究提供基础研究。我组建了一个世界级的导师团队，他们在与我的研究相关的领域拥有专业知识，并拥有非常成功的导师历史。我可以为这个项目提供的环境和机构资源非常好，有一个完善的培训计划，并可以获得所需的设备和研究数据集。拟议的项目和培训计划将使我处于神经科学和工程的交叉点，并使我能够利用最新的技术进步解决重要的临床问题。我在神经成像分析和神经心理学测试方面的新技能，以探索神经认知回路，将为我作为一名独立的医生工程师的职业生涯奠定基础，专注于减轻AD/ADRD的负担。