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

帕金森病注意力运动整合和步态功能障碍的胆碱能机制

• 批准号: 10282000
• 负责人: Roger L Albin
• 金额: $ 234万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10282000
• 关键词: Acetylcholine; Affect; Animal Model; Anterior; Attention; Basal Ganglia; Basic Science; Behavioral; Biometry; Brain; Characteristics; Chemicals; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Communities; Corpus striatum structure; Data; Denervation; Diffuse; Disease; Disease Progression; Electrophysiology (science); Equilibrium; Exhibits; Freezing; Functional disorder; Gait; Gait abnormality; Goals; Impaired cognition; Interneurons; Lead; Lesion; Ligands; Link; Mentors; Mentorship; Methods; Michigan; Modeling; Modernization; Motor; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurosciences; Nodal; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pattern; Persons; Physiological; Play; Positioning Attribute; Positron-Emission Tomography; Posture; Pre-Clinical Model; Rattus; Recommendation; Reporting; Research; Research Personnel; Research Project Grants; Resources; Rodent Model; Role; Scientist; Sensory; Signal Transduction; Site; Specific qualifier value; Stimulus; System; Testing; Thalamic structure; Training; Universities; Visual attention; Visuospatial; Work; attentional modulation; basal forebrain; base; brain abnormalities; brain cell; brain dysfunction; career; catalyst; cholinergic; cognitive function; cohort; data management; disease heterogeneity; disorder subtype; dopamine replacement therapy; equilibration disorder; experience; falls; genetic approach; improved; innovation; insight; member; neural circuit; neuroimaging; neurotransmission; next generation; novel strategies; optogenetics; outreach; posture instability; programs; prospective; prospective test; therapeutic target; therapy resistant

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.

总体组成部分：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且致残的 帕金森病 (PD) 的多巴胺替代疗法 (DRT) 耐药特征几乎影响所有患者。 在上一个周期中，密歇根大学尤德尔中心的研究展示了显着的、多方面的、动态的影响 PD 步态和认知异常中的胆碱能系统退化。这些见解引导我们创作了一部小说 PD 病理生理学方法；注意力和运动整合不足的系统神经科学模型 功能。这一概念和我们之前的工作使我们能够追求综合的临床和基础研究测试 注意力运动整合（AMI）网络中断模型中体现的假设。我们的成果 表明多个 AMI 节点内胆碱能神经传递模式的破坏是导致 特征性 PD 步态和平衡异常，纹状体胆碱能中间神经元是重要的整合者 注意力和运动信息，并且关键皮质 AMI 节点的胆碱能去神经具有全局认知 效应并预测疾病更快进展。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以下假设：胆碱能末端的特定区域模式 退化与特定的 PD 步态平衡异常相关。项目 II 将在啮齿动物模型中剖析， 胆碱能神经传递在检测、转移和整合注意力信息中的作用 穿过皮质和纹状体回路。将使用光遗传学和化学遗传学策略来测试是否 操纵皮质或纹状体胆碱能神经传递会影响“双重损伤”（DL）中的跌倒倾向 PD啮齿动物模型跌倒。项目 III 将评估早期前扣带回和岛叶胆碱能去神经是否已 对认知的整体影响，是认知能力更快下降的预测因素。项目一和项目三利用 独特的前瞻性随访 PD 受试者队列。催化剂研究项目将研究细胞 胆碱能信号传导机制及其在关键 AMI 节点（压后皮层）视觉注意力中的作用。 密歇根大学尤德尔中心项目得到行政、临床资源、神经影像资源和 生物统计学和数据管理核心。我们将与太平洋大学和太平洋大学的成员合作 罗彻斯特尤德尔中心。行政核心将监督早期研究人员的指导，包括 尤德尔研究员兼催化剂研究项目负责人。行政核心将指导外展活动 到 PD 社区。我们的创新方法将推进 NINDS 尤德尔中心的目标 卓越计划旨在“确定帕金森病的原因并发现改进的治疗方法。” No other Udall Center 专注于帕金森病的步态和姿势异常、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。拟建的密歇根大学尤德尔中心将 继续在尤德尔中心计划中发挥独特而重要的作用。