Investigations of Dementia in Parkinson Disease

摘要 这个项目关注的是帕金森病(PD)中的痴呆症，这是与阿尔茨海默病相关的疾病之一 痴呆症。帕金森病会导致进行性运动和认知障碍，导致约75%的人患上痴呆症 10年后的患者。延缓帕金森病进展的治疗方法的开发需要经过验证的生物标志物 可以预测疾病进展的病理过程。这些生物标志物可以反映局部、地区性病理或 广泛分布的网络中断，导致行为缺陷。这个项目的重点是横截面 以及蛋白质病、胆碱能和去甲肾上腺素能缺陷之间的纵向关系， 功能连接网络和行为。我们将在单个站点中建立我们的调查结果(以最大化 严格的质量控制和参与者留住)299名帕金森病患者的纵向队列和对照 扩展和扩展多模式方法以确定对应的生物标志物变化的时间进程 并预测帕金森病患者的认知功能下降。我们有潜力提供活体神经成像和脑脊液 可以独立或联合预测临床的病理学和病理生理学生物标记物 帕金森病的临床表现。我们将结合PIB(一种Aβ淀粉样显像剂)，VAT(一种囊泡胆碱能 转运配体)和MRB(去甲肾上腺素转运配体)PET、脑脊液蛋白水平和静息状态 功能连通性分析(使用高级分析方法)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 病理性蛋白质的定量。我们将确定PET生物标记物和脑脊液之间的关系 蛋白质病，并将其与临床表现进行比较。Fc作为衡量大脑功能的指标，将把大脑联系起来 病理和神经化学以及相关的临床表现。通过这种方式，我们将开发一种 对这些神经影像和脑脊液生物标记物的变化及其相互关系有很强的机械性理解 帕金森病患者认知功能减退和痴呆的发病。这个项目很有希望确定 用于预测PD进展的病理生理生物标记物，临床试验的患者分层，以及 评估新的治疗方法。

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.