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 该项目重点关注帕金森病 (PD) 中的痴呆症，帕金森病是阿尔茨海默病相关疾病之一 痴呆症会导致进行性运动和认知障碍，导致约 75% 的人患上痴呆症。 开发减缓 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的生物标志物可以反映局部、区域病理或进展。 导致行为缺陷的广泛分布的网络的破坏该项目侧重于横截面。 蛋白质病、胆碱能和去甲肾上腺素能缺陷、破坏 我们将在单个站点中建立功能连接网络和行为的基础（以最大化）。 严格的质量控制和参与者保留）由 299 名 PD 患者组成的纵向队列和对照 扩展和扩展多模式方法来确定对应的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和脑脊液检查。 病理学和病理生理学的生物标志物可以独立或组合预测临床 我们将结合 PiB（一种 Aβ 淀粉样蛋白显像剂）、VAT（一种囊泡胆碱能药物）。 转运配体）和 MRB（去甲肾上腺素转运配体）PET、CSF 蛋白水平和静息状态 功能连接分析（使用先进分析方法的 FC）病理生理学测量 专注于认知和死后大脑分析的复杂行为测量，包括 我们将确定 PET 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，作为大脑功能的衡量标准，将大脑联系起来。 通过这种方式，我们将开发一种病理学和神经化学以及相关的临床表现。 对这些神经影像和脑脊液生物标志物的变化及其相互关系有深入的了解 该项目对于识别帕金森病中的认知能力下降和痴呆症有着巨大的希望。 用于预测 PD 进展的病理生理学生物标志物、临床试验的患者分层以及 新疗法的评估。