Prefrontal Cortex, Cognition, and Speech Symptoms in PD (PRECIS-PD)

摘要 帕金森病（PD）不仅损害运动，而且损害认知和言语。随着PD的进展， 认知和言语症状变得越来越普遍，严重影响生活质量， 常常导致丧失独立性并被安置在疗养院。很少有干预措施能改善这些问题。 PD的非人性化方面，以及目前用于运动症状的治疗，如左旋多巴和深 脑刺激（DBS）不会改善，甚至会恶化认知和语言。降低该等 缺陷，更好地了解导致PD患者认知和言语异常的基本机制 是必要的。前额叶皮层（PFC）对于时间敏感的目标导向计划至关重要。 对认知和言语至关重要的行为序列。在PD患者中，PFC变薄，我们的 已发表的工作表明PFC 4 Hz节律降低。此外，PD涉及多种 病理生理过程，如多巴胺、乙酰胆碱和突触核蛋白被破坏。有一个 迫切需要了解PD如何破坏PFC并导致认知和言语症状。这 知识将激发新的生物标志物和针对PD非运动症状的靶向治疗。 提议的探索性资助的目标是促进新的合作，这将导致Udall 卓越中心。我们将检验多巴胺依赖性PFC 4 Hz降低 活动损害PD的认知和言语。我们将识别潜在的细胞和电路机制， 临床前啮齿动物模型和人类PD患者中的PFC功能和功能障碍。我们将利用 互补和会聚的尖端技术，如细胞类型特异性双光子成像， 行为动物中的PFC，人类术中神经生理学，脑成像和脑 连通性。常见的研究主题集中在帕金森病认知和言语症状中的PFC， 神经振荡和神经回路。项目之间的具体协同作用包括我们的分子- 定义的电路，共享的分析工具，以及认知和言语功能的时间组织 在PD中中断。 我们提出了一个探索补助金。项目1将集中在细胞和电路机制的PFC 4赫兹 啮齿类动物的节律项目2将专注于人类术中PFC电路和系统 神经生理学项目3将重点关注人类前额叶皮层在认知和言语方面的多模态分析 警局拟议的研究计划利用了我们世界一流的临床基础设施在大学 爱荷华州帕金森基金会卓越中心，并催化围绕认知和 言语，这是PD的严重不足的方面。我们的工作将导致新的靶向治疗， 患有PD的人。

Abstract Parkinson’s disease (PD) impairs not only movement, but also cognition and speech. As PD progresses, cognitive and speech symptoms become increasingly prevalent, heavily compromising quality of life and often leading to loss of independence and placement in nursing homes. Few interventions improve these dehumanizing aspects of PD, and current therapies for motor symptoms, such as levodopa and deep brain stimulation (DBS), do not improve, and can even worsen cognition and speech. To mitigate these deficits, a better understanding of the basic mechanisms leading to abnormal cognition and speech in PD is needed. The prefrontal cortex (PFC) is critical for goal-directed planning of temporally sensitive behavioral sequences essential for cognition and speech. In PD patients, the PFC is thinned, and our published work demonstrates that PFC 4 Hz rhythms are decreased. Furthermore, PD involves diverse pathophysiological processes such as disrupted dopamine, acetylcholine, and synuclein. There is a critical need to understand how PD disrupts the PFC and leads to cognitive and speech symptoms. This knowledge will inspire new biomarkers and targeted treatments for non-motor symptoms of PD. The goal of the proposed Exploratory Grant is to catalyze novel collaborations that will lead to an Udall Center of Excellence. We will test the overall hypothesis that decreased dopamine-dependent PFC 4 Hz activity impairs cognition and speech in PD. We will identify cellular and circuit mechanisms underlying PFC function and dysfunction in preclinical rodent models and in human PD patients. We will harness complementary and convergent cutting-edge techniques, such as cell-type-specific 2-photon imaging of the PFC in behaving animals, human intraoperative neurophysiology, brain imaging, and brain connectivity. Common research themes focus on the PFC in cognitive and speech symptoms of PD, neuronal oscillations, and neuronal circuits. Specific synergies among projects include our molecularly- defined circuits, shared analytic tools, and the temporal organization of cognitive and speech functions disrupted in PD. We propose an Exploratory Grant. Project 1 will focus on cellular and circuit mechanisms of PFC 4 Hz rhythms in rodents. Project 2 will focus on PFC circuits and systems in human intraoperative neurophysiology. Project 3 will focus on Multi-modal analysis of human PFC in cognition and speech in PD. The proposed research plan leverages our world-class clinical infrastructure at The University of Iowa Parkinson’s Foundation Center of Excellence and catalyzes new synergies around cognition and speech, which are greatly understudied facets of PD. Our work will lead to new targeted therapies for those suffering from PD.