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

PD 中的前额皮质、认知和言语症状 (PRECIS-PD)

• 批准号: 10283241
• 负责人: Nandakumar Narayanan
• 金额: $ 46.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283241
• 关键词: Acetylcholine; Animals; Applications Grants; Behavior; Behavioral; Biological Markers; Brain; Brain imaging; Calcium; Cells; Cognition; Cognitive; Collaborations; Data; Deep Brain Stimulation; Dehumanization; Diffusion Magnetic Resonance Imaging; Dopamine; Dopamine Receptor; Electroencephalography; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Genetic; Goals; Grant; Human; Image; Impaired cognition; Impairment; Intervention; Iowa; Knowledge; Levodopa; Link; Magnetic Resonance Imaging; Molecular; Morbidity - disease rate; Movement; Mus; Neurons; Nursing Homes; Operative Surgical Procedures; Parkinson Disease; Participant; Patients; Prefrontal Cortex; Process; Publishing; Quality of life; Research; Rodent; Rodent Model; Speech; Structure; Structure of subthalamic nucleus; Symptoms; System; Techniques; Testing; Thinness; Tissue Sample; Universities; Work; analytical tool; awake; cell cortex; cell type; clinical infrastructure; functional electrical stimulation; improved; mortality; motor symptom; multimodality; neuronal circuitry; neurophysiology; neuroregulation; new therapeutic target; non-motor symptom; novel; pre-clinical; recruit; synergism; synuclein; two-photon

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.

抽象的 帕金森病 (PD) 不仅会损害运动，还会损害认知和言语。 认知和言语症状变得越来越普遍，严重影响生活质量 通常会导致丧失独立性并被安置在疗养院，但很少有干预措施可以改善这些情况。 PD 的非人性化方面，以及当前运动症状的治疗方法，例如左旋多巴和深部 脑刺激（DBS）不会改善，甚至会恶化认知和言语。 缺陷，更好地理解导致帕金森病认知和言语异常的基本机制 前额皮质（PFC）对于时间敏感的目标导向规划至关重要。 对于认知和言语至关重要的行为序列在帕金森病患者中，前额皮质变薄，我们的大脑也变薄。 已发表的研究表明，PFC 4 Hz 节律降低，此外，PD 涉及多种因素。 病理生理过程，例如多巴胺、乙酰胆碱和突触核蛋白被破坏。 迫切需要了解帕金森病如何破坏前额皮质并导致认知和言语症状。 这些知识将激发新的生物标志物和针对帕金森病非运动症状的针对性治疗。 拟议的探索性资助的目标是促进新颖的合作，从而实现 Udall 我们将测试减少多巴胺依赖性 PFC 4 Hz 的总体假设。 活动损害帕金森病的认知和言语 我们将确定潜在的细胞和电路机制。 我们将利用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。 互补和融合的尖端技术，例如细胞类型特异性 2 光子成像 行为动物、人类术中神经生理学、脑成像和大脑中的 PFC 常见的研究主题集中在 PD 认知和言语症状中的 PFC， 神经振荡和神经回路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 PD 中断。 我们提议探索性资助项目 1 将重点关注 PFC 4 Hz 的细胞和电路机制。 项目 2 将重点研究人类术中的 PFC 电路和系统。 项目 3 将重点关注人类 PFC 在认知和言语方面的多模态分析。 PD。拟议的研究计划利用了我们在大学的世界一流的临床基础设施。 爱荷华州帕金森基金会卓越中心，促进围绕认知和认知的新协同作用 演讲，这是帕金森病尚未得到充分研究的方面，我们的工作将为治疗帕金森症带来新的靶向治疗。 患有PD的人。