Intrinsic Cortical Networks and Cognitive Dysfunction in Parkinson???s Disease

7.项目摘要/摘要：帕金森氏病(PD)影响着1%的65岁以上成年人。虽然传统上 根据运动症状的定义，高达75%的帕金森氏症患者最终会患上痴呆症，使其成为 在这一人群中安置养老院的原因。尽管目前还没有治愈帕金森病的方法，但我们有能力 自20世纪60年代以来，在我们对运动症状认识的基础上，S的治疗取得了巨大的进步 运动症状神经生理学。我建议帕金森病的治疗和预防痴呆症也可以 通过我们对认知障碍的神经生理学的理解的进步来证明这是可能的。这就做 使用现代网络理论作为这一努力的理论和数学框架。我的长期目标 是为了推进我们对帕金森病认知功能障碍的神经生理学的基本认识 经验可检验的模型、临床相关的生物标记物和新的治疗靶点。中环 这一建议的假设是，皮质功能连接的模式对正常认知功能至关重要 被帕金森病患者的皮质下病理破坏，使这些模式正常化的干预措施将得到改善 认知力。这一假设是基于本提案中提出的初步数据和 其他以前出版过的作品。这项建议的研究目的是加深我们对 皮质连接如何与帕金森病患者的认知功能障碍相关，开发一种新的认知生物标记物 基于皮质生理学的帕金森病患者的功能障碍，并确定皮层连接性的调节 可能会改善帕金森病患者的认知能力。我们将通过三个途径来实现这项提案的目标 具体目标：1)确定图论是否测量功能性皮质活动 脑磁图(MEG)与帕金森病患者认知功能障碍的关系 轻度认知障碍(MCI)；2)开发PD患者认知功能障碍的新的状态定义生物标志物 基于脑磁图特征通过机器学习的方法；以及3)确定重复的效果 经颅磁刺激(RTMS)对脑皮质连接性和认知结果的脑磁图测量 PD-MCI患者。这种方法是创新的，因为它是应用图论进行的第一次研究 帕金森病患者皮质生理学与认知功能障碍关系的研究进展 将机器学习方法应用于认知PD生物标记物开发的研究；以及第一次临床试验 或PD-MCI患者rTMS的机制研究。这项拟议的研究意义重大，因为预计它将 促进我们对帕金森病认知功能障碍的病理生理学的理解，并将提供生物标志物 以及对规划未来治疗干预措施至关重要的试点数据。培训目标及相关内容 该提案的研究活动将提供与高级脑磁图有关的新技能、手稿和试点数据 分析，图论，生物标记物开发和rTMS试验，这是建立我的独立性所必需的 并获得R01资金，以推进这一独特的研究计划。

7. Project Summary/Abstract: Parkinson's disease (PD) affects 1% of adults over age 65. While traditionally defined by motor symptoms, up to 75% of PD patients will eventually develop dementia making it the leading cause of nursing home placement in this population. Although there is currently no cure for PD, our ability to treat motor symptoms has advanced tremendously since the 1960's based on advances in our understanding of motor symptom neurophysiology. I propose that the treatment and prevention of dementia in PD may also prove possible through advances in our understanding of the neurophysiology of cognitive dysfunction. I will use modern network theory as a theoretical and mathematical framework for this endeavor. My long-term goal is to advance our fundamental understanding of the neurophysiology of cognitive dysfunction in PD to provide empirically testable models, clinically relevant biomarkers, and novel therapeutic targets. The central hypothesis of this proposal is that patterns of cortical functional connectivity critical to normal cognitive function are disrupted by subcortical pathology in PD and that interventions which normalize these patterns will improve cognition. This hypothesis has been formulated on the basis of preliminary data presented in this proposal and other previously published work. The research objectives of this proposal are to further our understanding of how cortical connectivity relates to cognitive dysfunction in PD, develop a novel biomarker for cognitive dysfunction in PD based on cortical physiology and to determine whether modulation of cortical connectivity may result in cognitive improvements in PD. We will accomplish the objectives of this proposal through three Specific Aims: 1) Determine whether graph theory measures of functional cortical activity measured with magnetoencephalography (MEG) are associated with cognitive dysfunction in PD subjects with and without mild cognitive impairment (MCI); 2) Develop a novel state-defining biomarker for cognitive dysfunction in PD based on MEG features through a machine learning approach; and 3) Determine the effects of repetitive transcranial magnetic stimulation (rTMS) on MEG measures of cortical connectivity and cognitive outcomes in PD-MCI patients. The approach is innovative because it represents the first study to apply graph theory measures to understanding the relationship of cortical physiology and cognitive dysfunction in PD; the first study to apply machine learning approaches to cognitive PD biomarker development; and the first clinical trial or mechanistic study of rTMS in PD-MCI. The proposed research is significant because it is expected to advance our understanding of the pathophysiology of cognitive dysfunction in PD and will provide biomarkers and pilot data essential to planning future therapeutic interventions. The training objectives and related research activities of this proposal will provide new skills, manuscripts and pilot data related to advanced MEG analysis, graph theory, biomarker development and rTMS trials necessary to establish my independence in these areas and obtain R01 funding to advance this unique research program.