Investigations of Dementia in Parkinson Disease

帕金森病痴呆症的研究

• 批准号: 10612119
• 负责人: MEGHAN C CAMPBELL
• 金额: $ 233.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612119
• 关键词: Affect; Agreement; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Behavior; Behavioral; Biological Markers; Brain; Brain Pathology; Brain region; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Collection; Complement; Cross-Sectional Studies; Data; Defect; Dementia; Development; Diagnostic; Disease Progression; Economic Burden; Enrollment; Evaluation; Family; Functional disorder; Funding; Impaired cognition; Individual; Investigation; Label; Ligands; Link; Longitudinal Studies; Longitudinal cohort; Magnetic Resonance Imaging; Measures; Methods; Morbidity - disease rate; Neurobiology; Neurodegenerative Disorders; Norepinephrine; North America; Parkinson Disease; Parkinson' s Dementia; Participant; Pathologic; Pathologic Processes; Pathology; Patients; Persons; Pittsburgh Compound-B; Positron-Emission Tomography; Proteins; Quality Control; Research Design; Rest; Scheme; Severities; Site; Societies; Time; Validation; alpha synuclein; amyloid imaging; behavior measurement; behavior prediction; biomarker development; biomarker validation; cholinergic; clinical predictors; cognitive function; cognitive impairment in Parkinson' s; cohort; effective therapy; follow-up; high risk; imaging agent; in vivo; mortality; motor impairment; motor symptom; multimodality; neurochemistry; neuroimaging; neuropathology; neurophysiology; noradrenaline transporter; noradrenergic; novel; novel therapeutics; participant retention; patient stratification; predictive marker; radioligand; regional difference; tau Proteins; therapy development; transport inhibitor; uptake

ABSTRACT This project focuses on dementia in Parkinson disease (PD), one of the Alzheimer Disease Related Dementias. PD produces progressive motor and cognitive impairments leading to dementia in ~75% of patients after 10 years. Development of therapies to slow PD progression requires validated biomarkers of pathologic processes and that predict progression. Such biomarkers could reflect local, regional pathology or disruption of widely distributed networks that cause behavioral deficits. This project focuses on cross-sectional and longitudinal relationships among proteinopathy, cholinergic and noradrenergic deficits, disruption of functional connectivity networks and behavior. We will build upon our findings in a single site (to maximize rigorous quality control and retention of participants) longitudinal cohort of 299 people with PD and controls to extend and expand a multimodal approach to determine the time course of biomarker changes that correspond with and predict cognitive decline in PD. We have the potential to provide in vivo neuroimaging and CSF biomarkers of pathology and pathophysiology that could independently, or in combination, predict clinical manifestations in PD. We will combine PiB (an Aβ amyloid imaging agent), VAT (a vesicular cholinergic transport ligand), and MRB (a norepinephrine transport ligand) PET, CSF protein levels and resting state functional connectivity analyses (FC using advanced analysis methods) measures of pathophysiology with sophisticated behavioral measures focusing on cognition and postmortem brain analyses including quantification of pathologic proteins. We will determine the relationships between PET biomarkers and CSF proteinopathy, and compare these to clinical manifestations. FC, as a measure of brain function, will link brain pathology and neurochemistry with the associated clinical manifestations. In this manner, we will develop a strong mechanistic understanding of changes in these neuroimaging and CSF biomarkers and how this relates to cognitive decline and dementia onset in PD. This project holds great promise for identifying pathophysiological biomarkers for prediction of PD progression, patient stratification for clinical trials, and evaluation of new treatments.

抽象的 该项目侧重于帕金森病（PD）的痴呆症，这是阿尔茨海默氏病与 痴呆症。 PD产生渐进式运动和认知障碍，导致痴呆症约为75％ 10年后的患者。开发降低PD进展的疗法需要经过验证的生物标志物 病理过程和预测进展。这样的生物标志物可以反映本地的区域病理学或 造成行为定义的广泛分布网络的破坏。该项目着重于横截面 以及蛋白质病，胆碱能和去甲肾上腺素能缺乏症之间的纵向关系，破坏 功能连接网络和行为。我们将基于单个站点的发现（以最大化 严格的质量控制和参与者的保留）299人的纵向人群和对照组为 扩展和扩展一种多模式方法，以确定生物标志物变化的时间过程 并预测PD认知能力下降。我们有潜力提供体内神经影像学和CSF 可以独立或结合的病理学和病理生理学生物标志物预测临床 Pd中的表现。我们将结合PIB（Aβ淀粉样蛋白成像剂），增值税（囊泡胆碱能 运输配体）和MRB（一种去甲肾上腺素传输配体）PET，CSF蛋白水平和静止状态 功能连通性分析（使用先进分析方法的FC）衡量病理生理学的测量 精致的行为措施，重点是认知和事后大脑分析 病理蛋白的量。我们将确定宠物生物标志物与CSF之间的关系 蛋白质病，并将其与临床表现进行比较。 FC作为大脑功能的度量，将连接大脑 病理和神经化学与相关的临床表现。通过这种方式，我们将发展一个 对这些神经影像学和CSF生物标志物的变化的强烈机械理解以及这如何相关 PD的认知能力下降和痴呆发作。该项目对识别 预测PD进展，临床试验患者分层的病理生理生物标志物和 评估新疗法。