Investigation of Cognitive Impairment in Parkinson Disease

帕金森病(PD)导致进行性运动和非运动障碍，75%的患者在10年后发展为痴呆症。越来越多的证据表明，淀粉样β蛋白(Aβ)参与了帕金森病的皮质病理，与α-突触核蛋白的积聚和神经变性有关。然而，区域Aβ的积累如何与特定认知领域的下降和区域神经调节递质系统的缺陷有关仍不清楚。这项研究将检验以下假设：1)匹兹堡化合物B(PIB)的Aβ测量与死后蛋白病相关。2)特定认知领域(执行功能、注意力、视觉空间能力和记忆得分)的缺陷将与PIB和Tau、Aβ和α-syn蛋白病的死后测量相关；2)PIB成像和认知缺陷将对应于死后组织中的局部神经化学变化；以及3)累积的Aβ预测特定认知领域的恶化和痴呆的时间。为了测试这些问题，我将使用先前招募的287名帕金森病患者和对照组的大型队列，这些参与者接受了PIB的基线PET成像扫描和正在进行的纵向(基线和3年随访)综合认知测试。对PIB摄取和选定的认知缺陷的横断面分析将使用适当的统计技术进行评估，并采用数据驱动、全脑、基于参数体素的方法来确定与PD驱动的认知障碍相关的区域。将对47例经病理证实的帕金森病患者的死后组织进行神经化学和病理生理学分析，以确定活体核素摄取与Aβ和α-突触核蛋白死后沉积的关系。生活中的PIB摄取与病理蛋白聚集体和行为相关神经调节剂(多巴胺、5-羟色胺、去甲肾上腺素和乙酰胆碱)的区域分布变化之间的相关性将在与认知障碍相关的区域进行比较。PIB摄取是否可以预测特定认知领域的下降或痴呆症的发病时间将使用基线PIB成像和纵向认知数据来确定。这项研究和我的指导团队将提供与帕金森病的神经成像、神经化学和行为表现相关的培训，以及整合递质活动和认知输出问题的分析方法。这种培训将通过正式和非正式的专业发展和实验室管理培训，为迈向独立调查员的职业生涯奠定基础。这项研究将有助于阐明帕金森病认知功能障碍与局部病理的关系，为帕金森病的治疗寻找新的靶点。这项研究的发现将为PET示踪剂的开发提供信息，并有助于识别与特定行为症状相关的缺陷，包括抑郁、冷漠、执行功能障碍或视觉空间功能障碍。

Parkinson Disease (PD) causes progressive motor and non-motor deficits with 75% of patients developing dementia after 10 years. A growing body of evidence suggests the involvement of amyloid beta (Aβ) in the cortical pathology of PD that has been linked to accumulation of α-synuclein and neurodegeneration. Yet, how regional Aβ accumulation relates to decline in specific cognitive domains and to deficits in regional neuromodulatory transmitter systems remains unknown. This study will test the hypotheses that 1) Aβ measurements made by Pittsburgh Compound B (PiB) correlate to postmortem proteinopathy. 2) deficits in selected cognitive domains (executive function, attention, visuospatial ability, and memory scores) will correlate regionally to PiB and postmortem measures of tau, Aβ, and α-syn proteinopathy; 2) PiB imaging and cognitive deficits will correspond to regional neurochemical changes in postmortem tissue; and 3) accumulated Aβ predicts deterioration in specific cognitive domains and the time to dementia. To test these questions, I will use a large, previously-recruited cohort of 287 participants with PD and controls that have undergone baseline PET imaging scans of PiB and ongoing longitudinal (baseline and 3-year follow-up) comprehensive cognitive testing. Cross-sectional analyses of PiB uptake and selected cognitive deficits will be assessed using appropriate statistical techniques with a data-drive, whole-brain, parameterized voxel-based approach to identify regions associated with PD-driven cognitive impairment. Neurochemical and pathophysiological analyses will be conducted on postmortem tissue from the 47 deceased participants with pathologically confirmed PD who had PET PiB scans in life to determine the relationship between PiB uptake and post- mortem deposition of Aβ and α-synuclein. Correlations between PiB uptake in life and changes in regional distribution of pathological protein aggregates and behaviorally-relevant neuromodulators (dopamine, serotonin, norepinephrine, and acetylcholine) will then be compared in regions associated with cognitive impairment. Whether PiB uptake can predict decline in specific cognitive domains or time to onset of dementia will be determined using baseline PiB imaging and longitudinal cognitive data. This study and my mentorship team will provide training relating to neuroimaging, neurochemistry, and behavioral manifestations of PD and analytical approaches to integrating questions of transmitter activity and cognitive output. This training will provide the basis for moving forward toward a career as an independent investigator through formal and informal professional development and laboratory management training. This study will help elucidate the relationship between cognitive dysfunction in PD and regional pathology, identifying new targets for treatment in PD. Findings from this study will inform the development of PET tracers and help identify deficits related to specific behavioral symptoms including depression, apathy, executive dysfunction, or visuospatial dysfunction.