INVESTIGATIONS OF DEMENTIA IN PARKINSON DISEASE

 描述（由申请人提供）：帕金森病（PD）产生进行性运动和认知障碍，导致约75%的患者在10年后出现痴呆。开发减缓PD进展的疗法需要经过验证的病理过程生物标志物和预测进展的生物标志物。这些生物标志物可以反映导致行为缺陷的局部或广泛分布的网络的区域病理生理学和破坏。这个项目集中在蛋白质病，胆碱能缺陷，功能连接网络和行为的破坏之间的横向和纵向关系。我们将在270名PD患者和对照者的单中心纵向队列中建立我们的研究结果，以扩展和扩展多模式方法，以确定与PD认知下降相对应并预测PD认知下降的生物标志物变化的时间过程。我们有可能提供体内神经影像学和CSF病理学和病理生理学生物标志物，可以独立或联合预测PD的临床表现。我们将结合联合收割机PiB（一种Aβ淀粉样蛋白显像剂）和VAT（一种囊泡胆碱能转运配体）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rs-fcMRI）病理生理学指标，以及专注于认知和死后大脑分析（包括病理蛋白定量）的复杂行为指标。我们将确定PET生物标志物和CSF蛋白质病变之间的关系，并将其与临床表现进行比较。Rs-fcMRI作为脑功能的测量，将脑病理学和神经化学与相关的临床表现联系起来。通过这种方式，我们将对这些神经影像学和CSF生物标志物的变化以及这与PD中的认知下降和痴呆的关系有很强的机械理解。该项目对于确定用于预测PD进展的病理生理学生物标志物、用于试验的患者分层和新治疗的评价具有很大的希望。

 DESCRIPTION (provided by applicant): Parkinson disease (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 regional pathophysiology and disruption of local or widely distributed networks that cause behavioral deficits. This project focuses on cross- sectional and longitudinal relationships among proteinopathy, cholinergic deficits, disruption of functional connectivity networks and behavior. We will build upon our findings in a single site longitudinal cohort of 270 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) and VAT (a vesicular cholinergic transport ligand) PET, CSF protein levels and resting state functional connectivity analyses (rs-fcMRI 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. Rs-fcMRI, 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 in PD. This project holds great promise for identifying pathophysiological biomarkers for prediction of PD progression, patient stratification for trials and evaluation of new treatments.