MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA

项目2(格拉博夫斯基)：摘要 帕金森病相关认知障碍和遗传性APOE或GBA变异的磁共振系统成像。 新的证据表明，帕金森病(PD)认知障碍的变异性在一定程度上反映了 基本的生物异质性。我们假设差额是由差额调节的。 固有皮质系统的损害，以及功能连接功能磁共振成像将显示特定的 神经生理关系中的系统水平变化取决于特定的分子 疾病的驱动力。载脂蛋白ε4和gba变异体是痴呆的可靠遗传预测因子 帕金森病，以及他们可能会改变认知障碍的特征，从基因上证明了关注这些- 已定义的组。我们将在APOEε4中应用新的动态和已建立的功能连接性功能磁共振方法 和GBA变异携带者，以及健康对照对象。这些分析将在实践中进行 多巴胺能关闭状态。我们预计APOEε4对内存相关系统的影响不成比例 包括默认模式网络的顶层和时间部分，而GBA变体加速 前额内侧壁和基底节多巴胺能靶点的病理效应及其意义 功能完整的额顶外侧网络。使用相同的基因定义的参与者，我们将 测试以下假设：动态功能连通性和网络核心分析、我们拥有的方法 为静息和任务状态功能磁共振而开发，可以灵敏地预测 帕金森病患者的认知功能障碍。这些分析将使用多巴胺能神经元的功能磁共振数据进行。 药物治疗。我们还将评估功能连接性是否可以预测认知诊断和/或 进展与多巴胺能替代状态不变。最后，我们将研究大脑皮层的轮廓 认知障碍不同病理生理机制相关生物标志物的系统变化 在警局。我们的初步研究表明，系统中断的综合和区域措施在#年增加 与脑脊液中α-突触核蛋白或Aβ42浓度(病理性)降低的比例。我们将复制这一点 在一组单独的PD参与者中发现，并继续分析综合和区域措施是否 脑脊液皮质病理生物标志物与认知之间的关系在系统紊乱中起中介作用。在……里面 二次分析由该中心的其他项目提供信息，我们将把这一新方法扩展到其他项目 疾病机制的标记物：SAI(胆碱能张力的测量，项目3)和定量分子 病理学，项目1。在这个项目中获得的新知识将为精确医学奠定基础 帕金森病患者认知障碍的不同分子驱动因素。

PROJECT 2 (GRABOWSKI): ABSTRACT MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA. Emerging evidence indicates that variability in cognitive impairment in Parkinson Disease (PD) in part reflects fundamental biological heterogeneity. We hypothesize that the difference is mediated by differential compromise of intrinsic cortical systems, and that functional connectivity fMRI will demonstrate specific systems-level alternations in neurophysiologic relationships that vary depending upon the specific molecular driver of disease. The findings that APOE ε4 and GBA variants are robust genetic predictors of dementia in PD, and that they may modify the profile of the cognitive impairment, justify a focus on these genetically- defined groups. We will apply novel dynamic and established functional connectivity fMRI methods in APOE ε4 and GBA variant carriers, and healthy comparison subjects. These analyses will be conducted in the practical dopaminergic OFF state. We expect that APOE ε4 disproportionately affects memory-related systems including the parietal and temporal components of the default mode network, while GBA variants accelerate pathological effects on dopaminergic targets in the mesial frontal wall and the basal ganglia, and their functionally integrated lateral frontoparietal networks. Using the same genetically-defined participants, we will test the hypothesis that dynamic functional connectivity and network kernel analyses, approaches we have developed for both resting and task state fMRI, can sensitively predict the development and progression of cognitive impairment in PD. These analyses will be conducted with fMRI data taken ON dopaminergic medication. We will also evaluate whether functional connectivity predicting cognitive diagnosis and/or progression are invariant to dopaminergic replacement status. Finally we will investigate profiles of cortical systems change associated with biomarkers of different pathophysiologic mechanisms of cognitive impairment in PD. Our preliminary studies establish that omnibus and regional measures of system disruption increase in proportion to the (pathologic) reduction of α-synuclein or Aβ42 concentration in CSF. We will replicate this finding in a separate group of PD participants and go on to analyze whether omnibus and regional measures of system disruption mediate the relationship between CSF biomarkers of cortical pathology and cognition. In secondary analyses informed by the other Projects in this Center, we will extend this novel approach to other markers of disease mechanisms: SAI (a measure of cholinergic tone, Project 3) and quantitative molecular pathology, Project 1. The new knowledge gained in this Project will be foundational to precision medicine for different molecular drivers of cognitive impairment in PD.