Cholinergic mechanisms of attentional-motor integration and gait dysfunction in Parkinson Disease

整体组件：总结/摘要 进行性步态平衡困难，相关的福尔斯，认知障碍是常见的和致残的 多巴胺替代疗法（DRT）是帕金森病（PD）的耐药特征，几乎影响所有患者。 在上一个周期，U-M Udall中心的研究表明， PD步态和认知异常中的胆碱能系统变性。这些见解使我们想到了一部小说 帕金森病病理生理学研究方法：注意力和运动整合不足的系统神经科学模型 功能协调发展的这一概念和我们先前的工作使我们能够追求综合的临床和基础研究测试 注意-运动整合（AMI）网络中断模型中体现的假设。我们的结果 提示多个AMI节点内胆碱能神经传递中断的模式负责 特征性PD步态和平衡异常，纹状体胆碱能中间神经元是帕金森病的关键整合者。 注意力和运动信息，关键皮层AMI节点的胆碱能去神经支配具有全局认知功能， 影响并预测更快的疾病进展。项目I将使用胆碱能PET配体[18F]FEOBV 在PD受试者中，前瞻性地检验胆碱能末梢的特定区域模式 与特定PD步态平衡异常相关的变性。项目二将在啮齿动物模型中解剖， 胆碱能神经传递在检测、传递和整合注意力信息中的作用， 穿过皮层和纹状体回路光遗传学和化学遗传学策略将用于测试 操纵皮质或纹状体胆碱能神经传递影响“双重损伤”（DL）中的跌倒倾向 PD福尔斯的啮齿动物模型。项目III将评估早期前扣带回和岛叶胆碱能去神经支配是否 对认知的整体影响，并且是更快速认知衰退的预测因素。项目一和项目三利用 唯一前瞻性随访的PD受试者队列。催化剂研究项目将研究蜂窝 胆碱能信号机制及其在AMI关键节点压后皮质视觉注意中的作用。 U-M Udall中心项目由行政，临床资源，神经影像资源和 生物统计学和数据管理核心。我们将与太平洋地区的成员国和大学合作， 罗切斯特尤德尔中心。行政核心将监督对早期调查人员的指导，包括 Udall研究员和催化剂研究项目负责人。行政核心将指导外联工作 PD社区。我们的创新方法将推进NINDS Udall中心的目标， 卓越计划，以“定义的原因，并发现改善治疗PD。”没有其他Udall中心 主要关注PD患者的步态和姿势异常，认知和运动功能的整合，胆碱能 缺陷，或使用病理学预测因子来定义PD亚组。U-M Udall中心将 继续在Udall中心计划中发挥独特而重要的作用。

OVERALL COMPONENT: SUMMARY/ABSTRACT Progressive gait-balance difficulties, associated falls, and cognitive impairments are common and disabling dopamine replacement therapy (DRT)-resistant features of Parkinson disease (PD), affecting nearly all patients. In the prior cycle, U-M Udall Center research demonstrated prominent, multifaceted, and dynamic impacts of cholinergic systems degeneration in PD gait and cognitive abnormalities. These insights led us to a novel approach to PD pathophysiology; a systems neuroscience model of deficient integration of attentional and motor functions. This concept and our prior work position us to pursue integrated clinical and basic research testing hypotheses embodied in this model of Attentional-Motor Integration (AMI) network disruption. Our results suggest that patterns of disrupted cholinergic neurotransmission within multiple AMI nodes are responsible for characteristic PD gait and balance abnormalities, that striatal cholinergic interneurons are crucial integrators of attentional and motor information, and that cholinergic denervation of key cortical AMI nodes has global cognitive effects and predicts more rapid disease progression. Project I will employ the cholinergic PET ligand [18F]FEOBV in PD subjects to prospectively test the hypothesis that specific regional patterns of cholinergic terminal degeneration associate with specific PD gait-balance abnormalities. Project II will dissect, in a rodent model, the role of cholinergic neurotransmission in detecting, transferring, and integrating attentional information as it traverses cortical and striatal circuits. Opto- and chemo-genetic strategies will be used to test whether manipulating cortical or striatal cholinergic neurotransmission affects fall propensity in the “Dual Lesion” (DL) rodent model of PD falls. Project III will assess if early anterior cingulate and insular cholinergic denervation has global effects on cognition and is a predictor of more rapid cognitive decline. Projects I and III take advantage of unique prospectively followed PD subject cohorts. The Catalyst Research Project will study cellular mechanisms of cholinergic signaling and its role in visual attention in a key AMI node, the retrosplenial cortex. U-M Udall Center projects are supported by Administrative, Clinical Resource, Neuroimaging Resource and Biostatistics and Data Management Cores. We will collaborate with members of the Pacific and University of Rochester Udall Centers. The Administrative Core will oversee mentorship of early stage investigators, including a Udall Research Fellow and the Catalyst Research Project Lead. The Administrative Core will direct outreach to the PD community. Our innovative approaches will advance the goal of the NINDS Udall Centers of Excellence program to “define the causes of and discover improved treatments for PD.” No other Udall Center is focused on gait and postural abnormalities in PD, on integration of cognitive and motor functions, on cholinergic deficits, or on use of a pathological predictor to define PD subgroups. The proposed U-M Udall Center will continue to play a unique and important role within the Udall Centers program.