Investigation of Cognitive Impairment in Parkinson Disease

帕金森病（PD）导致进行性运动和非运动缺陷，75%的患者在10年后发展为痴呆。越来越多的证据表明β淀粉样蛋白（Aβ）参与PD的皮质病理，与α-突触核蛋白的积累和神经变性有关。然而，区域Aβ积累与特定认知领域的下降和区域神经调节递质系统的缺陷之间的关系尚不清楚。本研究将验证以下假设：1)匹兹堡化合物B （PiB）测定的Aβ与死后蛋白病变相关。2)某些认知领域的缺陷（执行功能、注意力、视觉空间能力和记忆分数）与PiB和死后tau、Aβ和α-syn蛋白病的测量具有区域相关性；2) PiB成像和认知缺陷与死后组织的局部神经化学变化相对应；3)积累的Aβ可预测特定认知领域的退化和痴呆的时间。为了测试这些问题，我将使用先前招募的287名PD患者和对照组的大型队列，他们接受了PiB的基线PET成像扫描和持续的纵向（基线和3年随访）综合认知测试。PiB摄取的横断面分析和选择的认知缺陷将使用适当的统计技术进行评估，采用数据驱动、全脑、基于参数化体素的方法来识别与pd驱动的认知障碍相关的区域。研究人员将对47例经病理证实的PD患者的死后组织进行神经化学和病理生理分析，以确定PiB摄取与死后Aβ和α-突触核蛋白沉积之间的关系。生活中PiB摄取与病理性蛋白聚集体和行为相关神经调节剂（多巴胺、血清素、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认知障碍相关区域进行比较。PiB摄取是否可以预测特定认知领域的下降或痴呆发病时间，将通过基线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有关PD的神经影像学、神经化学和行为表现的培训，以及整合递质活动和认知输出问题的分析方法。该培训将通过正式和非正式的专业发展和实验室管理培训，为独立研究者的职业发展提供基础。本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。这项研究的结果将为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.