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

总体构成：摘要/摘要 进行性步态平衡困难、相关跌倒和认知障碍是常见的和致残的。 帕金森病(PD)的多巴胺替代疗法(DRT)抵抗特征，几乎影响到所有患者。 在之前的周期中，U-M Udall中心的研究显示出显著、多方面和动态的影响 帕金森病步态和认知异常的胆碱能系统退化。这些洞察力将我们引向了一部小说 帕金森病的病理生理学探讨注意与运动缺乏整合的系统神经科学模型 功能。这一概念和我们之前的工作定位于我们追求临床和基础研究测试的一体化 注意-运动整合(AMI)网络中断模型中体现的假说。我们的结果 提示多个急性心肌梗死结节内胆碱能神经传递受阻的模式是 特征性帕金森病步态和平衡异常，纹状体胆碱能中间神经元是 注意和运动信息，关键皮层急性心肌梗死结节胆碱能去神经具有全局认知 影响和预测更快的疾病进展。项目I将采用胆碱能PET配体[18F]FEOBV 在帕金森病受试者中前瞻性地检验假设胆碱能终末的特定区域模式 变性与特定的帕金森病步态平衡异常有关。项目二将在啮齿动物模型中进行解剖， 胆碱能神经传递在检测、传递和整合注意信息中的作用 穿过大脑皮层和纹状体回路。将使用光遗传和化学遗传策略来测试 操纵皮质或纹状体胆碱能神经传递对“双重损伤”(DL)跌倒倾向的影响 帕金森病跌倒的啮齿动物模型。项目III将评估早期前扣带回和胰岛胆碱能去神经是否有 对认知的全局性影响，是认知衰退更快的预测指标。项目I和项目III利用 独一无二的前瞻性跟踪PD受试者队列。催化剂研究项目将研究细胞 急性心肌梗死关键结节--脾后皮质胆碱能信号的机制及其在视觉注意中的作用。 U-M Udall中心项目由行政、临床资源、神经成像资源和 生物统计学和数据管理核心。我们将与太平洋地区的成员和加州大学合作 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 给警局社区。我们的创新方法将推动NINDS Udall中心 卓越计划，以“确定帕金森病的原因并发现改进的治疗方法。”没有其他的Udall中心 重点是帕金森病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，或使用病理预测因子来定义PD亚组。拟议的U-M Udall中心将 继续在尤德尔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.