Project III: Cingulo-Opercular Task Control Network Cholinergic Dysfunction in PD

项目三：概要/摘要 认知缺陷是帕金森病（PD）的一种病态多巴胺替代疗法难治性特征。 PD相关认知缺陷的病理生理学是复杂的，可能涉及相互作用和可变的 几个大脑系统的损伤，特别是在早期到中度疾病。发病率和自然史 PD认知缺陷的发病率是异质性的。了解PD认知障碍的病理生理学是 这对个性化治疗的发展至关重要。PD异质性是有效临床治疗的主要障碍 research.确定PD亚组将通过亚组特异性或 分层临床试验，确定生物标志物，改善临床护理中的预后评估，并协助 病因研究NINDS PD 2014研究的一些“最高优先级建议” 报告呼吁研究认知障碍的病理生理学和PD亚组 识别. U-M Udall中心建立了一个深度表型PD队列， 乙酰胆碱转运蛋白PET配体[18 F]FEOBV，揭示了异质性胆碱能缺陷。胆碱能 扣带-网膜任务控制网络（COTC）节点的终末缺陷-前扣带和岛叶 皮质（AC-I）-与特定领域和整体认知缺陷相关。的重要组成部分 注意-运动接口（AMI;整体组件），COTC有助于紧张性注意，协调 跨不同认知域的网络活动。初步分析表明，早期COTC节点（AC- I）胆碱能缺陷是PD的亚组定义特征，预测更快速的认知下降。中央 项目III的假设是，早期COTC结（AC-I）胆碱能去神经支配显著有助于 早期至中度PD中的认知损害，并确定了具有加速认知下降的PD亚组。 除了我们已建立的Udall受试者队列外，我们还可以访问单独的PD事件受试者队列 通过与格罗宁根大学的合作，使用[18 F]FEOBV PET进行深度表型分析和成像， 进行严格的实验复制和验证我们的主要假设。我们将早期的COTC 结（AC-I）胆碱能去神经支配与认知功能的领域特异性和一般措施。中 前瞻性分析，我们将确定早期COTC结（AC-I）胆碱能去神经支配是否预示着更快的 认知能力下降在与项目I的综合分析中，我们将确定COTC结（AC-I）胆碱能 去神经支配与步态冻结（FoG）相关。在探索性分析中，我们将评估是否更容易获得 MRI或其他测量与COTC结（AC-I）胆碱能去神经支配相关，识别潜在的， COTC结（AC-I）胆碱能去神经支配的可获得生物标志物。项目三将确定一个重要的 PD认知障碍的底物，并确定具有更积极的自然史的PD亚组- a “恶性低胆碱能疾病表型”这些结果将确定潜在的治疗靶点 干预措施和生物标志物开发。

PROJECT III: SUMMARY/ABSTRACT Cognitive deficits are a morbid dopamine replacement therapy-refractory feature of Parkinson disease (PD). The pathophysiology of PD-related cognitive deficits is complex, likely involving interacting and variable impairments of several brain systems, particularly in early to moderate disease. Incidence and natural history of PD cognitive deficits is heterogeneous. Understanding the pathophysiologies of PD cognitive impairments is essential for development of personalized therapies. PD heterogeneity is a major obstacle to effective clinical research. Identifying PD subgroups will enhance discovery of useful interventions through subgroup specific or stratified clinical trials, identify biomarkers, improve prognosis assessment in clinical care, and assist etiopathogenic research. Some of the “highest priority recommendations” of the NINDS PD 2014 Research Report call for research to understand the pathophysiology of cognitive impairments and for PD subgroup identification. The U-M Udall Center established a deeply phenotyped PD cohort imaged with the vesicular acetylcholine transporter PET ligand [18F]FEOBV, revealing heterogeneous cholinergic deficits. Cholinergic terminal deficits in Cingulo-Opercular Task Control network (COTC) nodes – Anterior Cingulate and Insular Cortices (AC-I) – correlate with both domain specific and global cognitive deficits. An important component of the Attentional-Motor Interface (AMI; Overall Component), the COTC subserves tonic attention, coordinating network activities across different cognitive domains. Preliminary analysis suggests that early COTC node (AC- I) cholinergic deficits are a subgroup defining-feature in PD, predicting more rapid cognitive decline. The central hypothesis of Project III is that early COTC node (AC-I) cholinergic denervation contributes significantly to cognitive impairment in early to moderate PD and identifies a PD subgroup with accelerated cognitive decline. In addition to our established Udall subject cohort, we have access to a separate cohort of incident PD subjects through collaboration with the University of Groningen, deeply phenotyped and imaged with [18F]FEOBV PET, for rigorous experimental replication and validation of our primary hypothesis. We will correlate early COTC node (AC-I) cholinergic denervation with domain-specific and general measures of cognitive function. In a prospective analyses, we will determine if early COTC node (AC-I) cholinergic denervation predicts more rapid cognitive decline. In an integrated analysis with Project I, we will determine if COTC node (AC-I) cholinergic denervation is associated with Freezing of Gait (FoG). In exploratory analyses, we will assess if more accessible MRI or other measures correlate with COTC node (AC-I) cholinergic denervation, identifying potential, accessible biomarkers of COTC node (AC-I) cholinergic denervation. Project III will identify an important substrate of PD cognitive impairment and identify a PD subgroup with a more aggressive natural history - a “malignant hypocholinergic disease phenotype.” These results will identify potential targets for therapeutic interventions and biomarker development.