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: 10672404
• 负责人: Roger L Albin
• 金额: $ 233.42万
• 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/10672404
• 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; Collaborations; Communities; Corpus striatum structure; Data; Denervation; Diffuse; Disease; Disease Progression; Electrophysiology (science); Equilibrium; Exhibits; Freezing; Functional disorder; Gait; Gait abnormality; Genetic; 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.

总体组件：摘要/摘要 进行性步态平衡困难，相关的跌倒和认知障碍很常见且残疾 多巴胺替代疗法（DRT）的帕金森病（PD）耐药性，几乎所有患者。 在先前的周期中，U-M UDALL中心研究表明，显着，多方面和动态影响 PD步态和认知异常的胆碱能系统变性。这些见解使我们成为了一本小说 PD病理生理学的方法；注意力不足和电机整合的系统神经科学模型 功能。这个概念以及我们先前的工作位置我们进行综合的临床和基础研究测试 在这种注意运动集成（AMI）网络中断的模型中所体现的假设。我们的结果 表明多个AMI节点内胆碱能神经传递的破坏模式负责 特征性的PD步态和平衡异常，纹状体胆碱能中间神经元是关键的集成剂 注意力和运动信息，以及关键皮质AMI节点的胆碱能神经化具有全球认知 影响和预测更快的疾病进展。项目我将使用胆碱能宠物配体[18F] FEOBV 在PD中，前瞻性检验胆碱能末端的特定区域模式的假设 变性与特定的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，转移和整合注意信息时的作用 遍历皮质和纹状体电路。光和化学遗传策略将用于测试是否是否 操纵皮质或纹状体胆碱能神经传递会影响“双重病变”（DL）的跌倒承诺 PD瀑布的啮齿动物模型。项目III将评估早期的前扣带回和岛状胆碱能神经的神经 全球对认知的影响，是认知能力下降更快的预测指标。 I和III的项目利用 前瞻性遵循PD主题队列的独特之处。催化剂研究项目将研究细胞 胆碱能信号传导的机制及其在关键AMI节点（泛胞胞胞菌皮质）中的视觉注意力中的作用。 U-M UDALL中心项目得到行政，临床资源，神经影像资源的支持， 生物统计学和数据管理核心。我们将与太平洋和大学成员合作 罗切斯特乌德尔中心。行政核心将监督早期调查人员的心态，包括 UDALL研究员和Catalyst研究项目负责人。行政核心将指导外展 到PD社区。我们的创新方法将促进Ninds Udall中心的目标 卓越计划“定义并发现改进的PD治疗方法”。没有其他Udall中心 专注于PD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定义PD亚组。拟议的U-M Udall中心将 继续在Udall Centers计划中扮演独特而重要的角色。

项目成果

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.

• DOI: 10.1007/s00213-021-05822-x
• 发表时间: 2021-07
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Kucinski A;Sarter M
• 通讯作者: Sarter M

Make a Left Turn: Cortico-Striatal Circuitry Mediating the Attentional Control of Complex Movements.

• DOI: 10.1002/mds.28532
• 发表时间: 2021-03
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Sarter M;Avila C;Kucinski A;Donovan E
• 通讯作者: Donovan E

Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal.

• DOI: 10.3389/fneur.2023.1123290
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROLOGY
• 影响因子: 3.4
• 作者: Bohnen, Jeffrey L. B.;Albin, Roger L.;Bohnen, Nicolaas I.
• 通讯作者: Bohnen, Nicolaas I.

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches.

• DOI: 10.1016/s1474-4422(21)00377-x
• 发表时间: 2022-04
• 期刊: The Lancet. Neurology
• 作者: Bohnen NI;Yarnall AJ;Weil RS;Moro E;Moehle MS;Borghammer P;Bedard MA;Albin RL
• 通讯作者: Albin RL

Cholinergic centro-cingulate network in Parkinson disease and normal aging.

• DOI: 10.18632/aging.205209
• 发表时间: 2023-10-27
• 期刊: Aging