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

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。帕金森病(Parkinson‘s Disease，PD)是第二大常见的神经退行性疾病，虽然经常与运动功能障碍有关，但在ADRD的晚期，痴呆的发生率高达80%，其中大多数都有AD的共同病理。因此，这一人群表现出一系列认知缺陷，这使得人们能够深入了解ADRD的相关机制。这些患者似乎有两种截然不同的认知特征。一种是良性的额部侧写，特征是执行和注意力缺陷，另一种是后部侧写，特征是记忆和视觉空间缺陷，与进展较快的痴呆有关，通常与AD的共同病理有关。这一应用的前提是，识别潜在的额叶和后叶功能的神经回路可能有助于深入了解ADRD发生的结构变化。众所周知，多巴胺能治疗可以改善前额回路功能，但不能改善后回路，这导致了后回路改变是由非多巴胺能病理引起的假说，如AD的共同病理。如果是真的，额叶和后叶受累的模式可能会导致ADRD对当前治疗的不同反应。我计划应用扩散张量束成像技术，这是一种灵敏且广泛使用的MRI技术，来测量大脑区域之间白质(WM)连接的微观结构完整性。我的中心假设是，帕金森病患者前额和后部回路的WM改变(目标1)；这些改变与特定的认知缺陷有关，并与不同的痴呆症进展速度有关(目标2)；额叶和后部损害的比率(F/P比率)调节对治疗的认知反应(例如，左旋多巴、脑深部刺激、目标3)。这些目标将通过利用现有数据集来实现，从而能够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，深入了解其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性的研究思路。我组建了一支世界级的指导团队，他们在与我的研究相关的领域拥有专业知识，并拥有非常成功的指导历史。我为这个项目提供的环境和机构资源非常好，有完善的培训计划，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学的交叉点，并使我能够利用最新的技术进步来解决重要的临床问题。我在神经成像分析和神经心理测试方面探索神经认知回路的新技能，将为我作为一名专注于减轻AD/ADRD负担的独立内科工程师的职业生涯奠定基础。

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.