Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease

 描述（由申请人提供）：PD中多种神经化学系统退化，几种常见和严重致残的症状主要是左旋多巴耐药。进行性步态和平衡困难以及相关的福尔斯是最常见的左旋多巴耐药症状，最终几乎发生在所有患者中。由于缺乏任何有效的治疗方法，这一问题的严重性得到了强调，导致NINDS PD 2014研究报告的作者将旨在了解PD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耐药症状的研究列为“最高优先级建议”。（临床建议2、3和4;翻译建议1和6;基本建议3）。我们的团队在PD患者和新型PD动物模型中取得了一系列发现，这些发现强烈暗示了PD步态功能障碍发病机制中胆碱能投射的退化。密歇根大学（U-M）Udall中心研究计划的中心主题是胆碱能病变在PD步态和平衡异常中的作用，以及针对胆碱能神经传递的新型治疗策略的开发。相当多的最近的数据表明，步态和姿势控制不是纯粹的“运动”功能，但需要复杂的运动，感觉和认知功能的整合。确定胆碱能功能障碍和步态异常之间的关系需要一个多学科的方法，其中研究人员通过不同的镜头查看胆碱能功能，步态和认知之间的关系，分享见解和相互挑战的方式，产生的进展远远超出可实现的是每个项目分别追求。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P50 Udall中心机制下的支持。我们的团队已经开发了初步数据，使我们提出了PD步态功能障碍的“3-Hit”模型，该模型假定PD步态和姿势异常的典型临床进展是由纹状体多巴胺丢失与基底前脑（BF）和脚桥（PPN）核中胆碱能神经元变性的相互作用引起的。拟议的研究计划将测试3次击中假设，并寻求开发一种新的基于胆碱能药物的治疗PD福尔斯的原则性证据。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PD中发生的胆碱能和多巴胺能病变。这些研究将确定PPN胆碱能神经元损失（单独和联合BF胆碱能和纹状体多巴胺能损失）对认知运动的影响，并结合项目III，检查刺激确定的分子靶点（α4β2* 烟碱受体）的治疗获益和回路作用机制。项目II将采用一种新的PET配体在PD患者，提供以前无法达到的分辨率的胆碱能神经末梢;这种配体将使，第一次，描绘PPN胆碱能预测，已牵连在步态异常的PD。我们的初步数据表明，PD患者表现出相当大的异质性胆碱能变性，这表明存在亚组，可能表现出独特的反应，药物干预。利用仅评估项目II中确定的低胆碱能受试者的“个性化医学”方法，项目III将在试点靶点接合/药效学研究中采用新型PET和步态评估方法，评估α4β2* nAChR刺激的治疗潜力和作用机制。这种创新的方法对于PD等高度异质性疾病至关重要。拟议的研究计划是协同与西北太平洋尤德尔中心，其中两名成员是我们拟议的中心顾问，并由行政，临床资源，生物统计学和数据管理核心的支持。我们建议的中心还坚定地致力于教育研究人员，PD护理人员，PD患者及其家属，并寻求推广到传统上服务不足的社区，这些社区遭受PD的折磨。这些活动将由行政核心和教育和外联核心共享，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。总之，我们的创新方法将为PD的破坏性但未充分研究的症状提供急需的洞察力，并推进NINDS Udall卓越中心计划的目标，即“确定PD的原因并发现PD的改进治疗方法”。目前没有Udall中心专注于PD的步态和姿势异常或胆碱能缺陷。因此，拟议中的U-M Udall中心将在NINDS Udall中心计划中发挥独特而重要的作用。

 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.