Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease

帕金森病步态功能障碍的胆碱能机制

• 批准号: 9196496
• 负责人: WILLIAM T. DAUER
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196496
• 关键词: Acetylcholine; Animal Model; Behavioral; Biometry; Brain; Brain Stem; Caregivers; Caring; Cell Nucleus; Cerebellum; Clinical; Clinical Trials; Cognition; Cognitive; Communities; Complex; Corpus striatum structure; Data; Denervation; Development; Disease; Dopa; Dopamine; Education and Outreach; Educational Activities; Equilibrium; Exhibits; Fall prevention; Family; Financial compensation; Force of Gravity; Functional disorder; Future; Gait; Gait abnormality; Goals; Heterogeneity; Hip Fractures; Hospitalization; Intervention; Joints; Lead; Lesion; Levodopa; Ligands; Locomotion; Longitudinal Studies; Mediating; Methods; Michigan; Mission; Modeling; Molecular Target; Motor; Musculoskeletal Equilibrium; National Institute of Neurological Disorders and Stroke; Nerve; Nicotinic Receptors; Nursing Homes; Pacific Northwest; Parkinson Disease; Pathogenesis; Patients; Pattern; Pennsylvania; Pharmacodynamics; Play; Positron-Emission Tomography; Posture; Prevention strategy; Publishing; Recommendation; Reporting; Research; Research Personnel; Resistance; Resolution; Resources; Rodent Model; Role; Scientist; Sensory; Series; Skilled Nursing Facilities; Subgroup; Symptoms; System; TNFRSF5 gene; Testing; Therapeutic; Time; Training; Translational Research; Universities; Work; basal forebrain; base; brain cell; cholinergic; cholinergic neuron; cognitive function; data management; disabling symptom; effective therapy; equilibration disorder; falls; human subject; improved; innovation; insight; interdisciplinary approach; lens; member; neural circuit; neurochemistry; neuroimaging; neuron loss; neurotransmission; next generation; novel; novel strategies; outreach; personalized medicine; programs; public health relevance; response; treatment strategy

 DESCRIPTION (provided by applicant): Multiple neurochemical systems degenerate in PD, and several common and profoundly disabling symptoms are largely levodopa resistant. Progressive gait and balance difficulties, and associated falls, are among the most common levodopa resistant symptoms, eventually occurring in nearly all patients. The gravity of this problem is underscored by a lack of any effective therapy, leading the authors of the NINDS PD 2014 Research Report to list as "highest priority recommendations" studies aimed at understanding the neural circuit mechanisms of gait and balance disorders in PD, and developing effective treatments for these dopa-resistant symptoms (Clinical recommendations 2, 3 & 4; Translational recommendation 1 & 6; Basic recommendation 3). Our team has made a series of discoveries in human subjects with PD and in a novel PD animal model that strongly implicate degeneration of cholinergic projections in the pathogenesis of gait dysfunction in PD. The central themes of the proposed University of Michigan (U-M) Udall Center research program are the role of cholinergic lesions in gait and balance abnormalities in PD and the development of novel treatment strategies targeted at cholinergic neurotransmission. Considerable recent data indicates that gait and postural control are not purely "motor" functions but require complex integration of motor, sensory, and cognitive functions. Defining the relationship between cholinergic dysfunction and gait abnormalities requires a multidisciplinary approach in which investigators view the relationship between cholinergic function, gait, and cognition through different lenses, share insights and challenge each other in ways that yield progress far beyond that achievable were each project pursued separately. We have assembled such a team, making our proposed work ideally suited for support under the P50 Udall Center mechanism. Our team has developed preliminary data that lead us to propose a "3-Hit" model of gait dysfunction in PD which posits that the typical clinical progression of gait and postural abnormalities in PD is caused by the interaction of striatal dopamine loss with degeneration of cholinergic neurons in the basal forebrain (BF) and pedunculopontine (PPN) nucleus. The proposed research program will test the 3-Hit hypothesis and seek to develop proof-of-principle evidence for a novel cholinergic-based therapy for falls in PD. Project I will further develop and mechanistically dissect a recently published unique rodent model of PD gait abnormalities mimicking the combined cholinergic and dopaminergic lesions that occur in PD. These studies will define the cognitive-motoric impact of loss of PPN cholinergic neurons, alone and in combination with BF cholinergic and striatal dopaminergic loss and, in connection with Project III, examine the therapeutic benefit and circuit mechanism of action of stimulation of a defined molecular target (α4β2* nicotinic receptors). Project II will employ a novel PET ligand in PD patients that provides previously unattainable resolution of cholinergic nerve terminals; this ligand will enable, for the first time, delineation of PPN cholinergic projections that have been implicated in gait abnormalities in PD. Our preliminary data demonstrate that PD patients exhibit considerable heterogeneity of cholinergic degeneration, suggesting the presence of subgroups that may exhibit unique responses to pharmacological interventions. Utilizing a "personalized medicine" approach assessing only hypo-cholinergic subjects identified in Project II, Project III will employ novel PET and gait assessment methods in pilot target engagement/pharmacodynamic studies assessing the therapeutic potential and mechanism of action α4β2* nAChR stimulation. This innovative approach is critical for a highly heterogeneous disease like PD. The proposed research program is synergistic with the Pacific Northwest Udall Center, two members of which are consultants for our proposed Center, and is supported by Administrative, Clinical Resource, and Biostatistics and Data Management Cores. Our proposed Center is also strongly committed to educating researchers, PD caregivers, PD patients and their families, and to pursuing outreach to traditionally underserved communities that suffer disproportionally from PD. These activities will be shared by the Administrative Core and an Education and Outreach Core, which will undertake joint educational activities with the University of Pennsylvania Udall Center, further integrating the Udall Center network. Together, our innovative approaches will provide much needed insight into a devastating yet understudied symptom of PD and advance the goal of the NINDS Udall Centers of Excellence program to "define the causes of and discover improved treatments for PD". No current Udall Center is focused on gait and postural abnormalities in PD, or on cholinergic deficits. The proposed U-M Udall Center will therefore play a unique and important role within the NINDS Udall Center program.

 描述(申请人提供)：帕金森病的多种神经化学系统退化，一些常见的和严重的残疾症状在很大程度上是左旋多巴耐药的。进行性步态和平衡困难，以及相关的跌倒，是最常见的左旋多巴抵抗症状，最终几乎在所有患者中都会发生。这个问题的严重性因缺乏任何有效的治疗而突显出来，导致NINDS PD 2014研究报告的作者将旨在了解帕金森病步态和平衡障碍的神经回路机制并开发有效治疗这些多巴抵抗症状的研究列为“最优先建议”(临床建议2、3和4；翻译建议1和6；基本建议3)。我们的团队已经在帕金森病患者和一种新的帕金森病动物模型中取得了一系列发现，该模型强烈地表明胆碱能投射的退化与帕金森病步态障碍的发病机制有关。密歇根大学(U-M)Udall中心拟议的研究计划的中心主题是胆碱能损伤在帕金森病步态和平衡异常中的作用，以及针对胆碱能神经传递的新治疗策略的开发。最近的大量数据表明，步态和姿势控制不是纯粹的“运动”功能，而是需要运动、感觉和认知功能的复杂整合。确定胆碱能功能障碍和步态异常之间的关系需要多学科的方法，研究人员通过不同的透镜来看待胆碱能功能、步态和认知之间的关系，分享见解并相互挑战，从而产生远远超出每个项目单独追求的进展。我们已经组建了这样一个团队，使我们提出的工作非常适合在P50 Udall中心机制下提供支持。我们的团队已经开发了初步数据，导致我们提出了帕金森病患者步态功能障碍的“三次打击”模型，该模型假设帕金森病患者步态和姿势异常的典型临床进展是纹状体多巴胺丢失与基底前脑(BF)和脚桥核(PPN)胆碱能神经元变性的相互作用所致。拟议的研究计划将检验三击假说，并寻求为一种基于胆碱能的新疗法治疗帕金森病发展原则证据。项目I将进一步开发和机械解剖最近发表的PD步态异常的独特啮齿动物模型，模拟发生在PD中的胆碱能和多巴胺能联合损害。这些研究将确定PPN胆碱能神经元丢失的认知-运动影响，单独或与BF胆碱能和纹状体多巴胺能损失结合在一起，并结合项目III，检查刺激特定分子靶标(α4β2*烟碱受体)的治疗益处和电路作用机制。项目二将在帕金森病患者中使用一种新的PET配体，它可以提供以前无法获得的胆碱能神经末梢的分辨率；这种配体将首次能够描绘与帕金森病患者步态异常有关的PPN胆碱能投射。我们的初步数据显示，帕金森病患者表现出相当大的胆碱能变性的异质性，这表明存在可能对药物干预表现出独特反应的亚群。利用只评估项目II中确定的低胆碱能受试者的“个性化医学”方法，项目III将在试点目标参与/药效学研究中使用新的正电子发射计算机断层扫描和步态评估方法，评估α4β2*nAChR刺激的治疗潜力和机制。这种创新的方法对于像帕金森氏症这样高度异质性的疾病至关重要。拟议的研究计划与太平洋西北Udall中心协同工作，其中两名成员是我们拟议中心的顾问，并得到行政、临床资源、生物统计和数据管理核心的支持。我们拟建的中心也坚定地致力于教育研究人员、PD护理人员、PD患者及其家人，并致力于向患有不成比例的PD的传统服务不足的社区提供服务。这些活动将由行政核心和一个教育和外联核心共同开展，后者将与宾夕法尼亚大学尤德尔中心开展联合教育活动，进一步整合尤德尔中心网络。我们的创新方法将为我们提供对破坏性但研究不足的帕金森氏症症状的迫切需要的洞察，并推进NINDS Udall卓越中心计划的目标，即“确定帕金森氏症的原因并发现改进的治疗方法”。目前没有Udall中心关注帕金森病患者的步态和姿势异常，或胆碱能缺陷。因此，拟议的U-M Udall中心将在NINDS Udall中心计划中发挥独特和重要的作用。