Investigation of Cognitive Impairment in Parkinson Disease

帕金森病认知障碍的调查

• 批准号: 9752980
• 负责人: John L. O'Donnell
• 金额: $ 6.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752980
• 关键词: Acetylcholine; Address; Affect; Amyloid beta-Protein; Area; Attention; Autopsy; Behavioral; Behavioral Symptoms; Biological Markers; Brain; Climacteric; Clinical; Clinical Research; Cognitive; Cognitive deficits; Cross-Sectional Studies; Data; Dementia; Deposition; Deterioration; Development; Diagnosis; Disease Progression; Dopamine; Dose; Drug Targeting; Early identification; Enzyme-Linked Immunosorbent Assay; Executive Dysfunction; Functional disorder; Future; High Pressure Liquid Chromatography; Image; Impaired cognition; Impairment; Individual; Inflammatory; Investigation; Laboratories; Life; Linear Regressions; Link; Measurement; Measures; Mediating; Memory; Mental Depression; Mentorship; Modeling; Motor; Nerve Degeneration; Neurobehavioral Manifestations; Neuromodulator; Neurotransmitters; Norepinephrine; Output; Parkinson Disease; Participant; Pathologic; Pathologic Processes; Pathology; Patients; Pattern; Pittsburgh Compound-B; Play; Positron-Emission Tomography; Principal Component Analysis; Process; Protein Region; Research Personnel; Role; Scanning; Serotonin; Severities; Signal Transduction; System; Techniques; Testing; Time; Tissues; Tracer; Training; Validation; Visuospatial; abeta accumulation; abeta deposition; alpha synuclein; base; beta amyloid pathology; career; cholinergic; cognitive function; cognitive testing; cohort; disorder control; excitotoxicity; executive function; follow-up; imaging biomarker; in vivo; insight; longitudinal analysis; mild cognitive impairment; motor deficit; neurochemistry; neuroimaging; neuropathology; neuroregulation; novel; pre-clinical research; protein aggregate; recruit; synucleinopathy; tau Proteins; therapy development; uptake

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.

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，淀粉样蛋白β（Aβ）参与PD的皮质病理学，与α-突触核蛋白的积累和神经变性有关。然而，局部Aβ蓄积如何与特定认知领域的下降和局部神经调节递质系统的缺陷相关仍不清楚。本研究将检验以下假设：1）匹兹堡化合物B（Pi B）测定的Aβ与死后蛋白质病相关。2)选定认知领域（执行功能、注意力、视觉空间能力和记忆评分）的缺陷将与PiB和tau、Aβ和α-syn蛋白病的死后测量结果区域相关; 2）PiB成像和认知缺陷将对应于死后组织中的区域神经化学变化; 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，我将使用一个大型的，先前招募的287名PD和对照参与者的队列，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。将使用适当的统计技术和数据驱动、全脑、参数化基于体素的方法评估PiB摄入和选定认知缺陷的横断面分析，以识别与PD驱动的认知障碍相关的区域。将对47例经病理学证实的PD死亡受试者的死后组织进行神经化学和病理生理学分析，这些受试者生前接受过PET PiB扫描，以确定PiB摄取与Aβ和α-突触核蛋白死后沉积之间的关系。然后将在与认知障碍相关的区域中比较生活中PiB摄取与病理性蛋白质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。将使用基线PiB成像和纵向认知数据确定PiB摄取是否可以预测特定认知领域的下降或痴呆发作时间。这项研究和我的导师团队将提供与神经影像学，神经化学和PD的行为表现以及整合递质活动和认知输出问题的分析方法相关的培训。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生涯奠定基础。本研究将有助于阐明PD认知功能障碍与局部病理之间的关系，为PD的治疗确定新的靶点。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，包括抑郁症，冷漠，执行功能障碍或视觉空间功能障碍。