Investigations of Dementia in Parkinson Disease

帕金森病痴呆症的研究

• 批准号: 10365610
• 负责人: MEGHAN C CAMPBELL
• 金额: $ 157.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365610
• 关键词: Affect; 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; Pittsburgh Compound-B; Positron-Emission Tomography; Proteins; Quality Control; Research Design; Rest; Scheme; Seeds; Severities; Site; Societies; Time; Validation; alpha synuclein; amyloid imaging; base; behavior measurement; biomarker development; cholinergic; clinical predictors; cognitive function; cognitive impairment in Parkinson' s; cohort; disorder control; effective therapy; follow-up; high risk; imaging agent; in vivo; inhibitor/antagonist; mortality; motor impairment; motor symptom; multimodality; neurochemistry; neuroimaging; neuropathology; neurophysiology; noradrenaline transporter; noradrenergic; novel; novel therapeutics; participant retention; patient stratification; radioligand; regional difference; tau Proteins; therapy development; 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.

摘要 该项目的重点是帕金森病（PD），阿尔茨海默病相关的痴呆症 痴呆症PD会产生进行性运动和认知障碍，导致约75%的人患痴呆症。 十年后的病人开发减缓PD进展的疗法需要以下经验证的生物标志物： 病理过程和预测进展。这些生物标志物可以反映局部、区域病理学或免疫学。 破坏广泛分布的网络，导致行为缺陷。该项目侧重于横截面 以及蛋白质病、胆碱能和去甲肾上腺素能缺陷、 功能连接网络和行为。我们将在一个站点上建立我们的发现（以最大化 严格的质量控制和参与者的保留）299名PD患者和对照组的纵向队列， 扩展和扩展多模式方法，以确定生物标志物变化的时间过程， 并预测PD患者的认知能力下降。我们有潜力提供体内神经成像和CSF 病理学和病理生理学的生物标志物可以独立地或组合地预测临床 PD的表现。我们将结合联合收割机PiB（Aβ淀粉样蛋白显像剂）、VAT（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（FC使用高级分析方法）病理生理学指标， 复杂的行为测量，重点关注认知和死后大脑分析，包括 病理蛋白质的定量。我们将确定PET生物标志物和CSF之间的关系， 蛋白质病，并将其与临床表现进行比较。FC，作为大脑功能的衡量标准，将连接大脑 病理学和神经化学以及相关的临床表现。在这种情况下，我们将开发一个 对这些神经影像学和CSF生物标志物的变化及其相关性有较强的机械理解 认知能力下降和痴呆症发作。这个项目很有希望确定 用于预测PD进展的病理生理学生物标志物，用于临床试验的患者分层，以及 评估新疗法。