Parkinson's Disease and Dementia

宾夕法尼亚大学佩雷尔曼医学院的总体组成部分。尤德尔 帕金森病卓越研究中心：“帕金森病和痴呆症” Udall中心主任：J.Q.特罗亚诺夫斯基 Udall中心摘要/摘要：竞争性续签申请的目标是为大学 宾夕法尼亚州（Penn）Perelman医学院Udall中心将阐明渐进性 帕金森病（PD）的神经变性，特别是那些导致PD认知障碍的神经变性 无痴呆和有痴呆（PDD）和路易体痴呆（LB）或DLB（项目I/II），我们参考 统称为LB病症或LBD。Udall中心的研究人员假设LBD导致神经元 由病理性α-突触核蛋白（a-syn）菌株的差异传播导致的功能障碍和死亡 导致路易体（LB）和神经突（LN）的形成及其神经毒性作用。理解 LBD的进展及其从分子水平到患者水平的异质性将提高我们开发LBD的能力。 精准医学方法来治疗和管理LBD。因此，项目III/IV试图阐明 PD、PDD和DLB基础菌株与多系统基础菌株相比， 萎缩（MSA），其特征在于由错误折叠的a-syn形成的胶质细胞胞质内含物（GCI），而项目I 旨在更好地临床管理可能由这些菌株引起的LBD内表型的多样性 差异，项目II将我们对表型多样性的分析扩展到认知的重要领域， 下降与最近RFA中描述的Udall中心的使命一致， Penn Udall中心关于更新期的声明旨在阐明PD从正常 PDD患者的认知障碍、执行功能障碍和痴呆以及疾病进展 在DLB中，除了由病理性a-syn的进行性积累介导的神经变性之外，的 在a-syn基因中发现PD致病性突变的里程碑式发现，病理性a-syn基因的发现， 在PD/PDD/DLB中形成LB/LN的疾病蛋白以及在MSA中形成GCI的疾病蛋白， a-syn菌株的细胞间传播将a-syn置于理解LBD/MSA机制的中心阶段。 Penn Udall中心的更新旨在解决四个核心支持的四个项目中的这些关键问题 包括：行政核心A：核心领导者（CL）- John Q。Trojanowski;临床核心B：CL -丹尼尔 Weintraub，合作研究者（Co-Is）- Lama Chahine、Nabila Dahodwala、James莫利、Alice Chen-Plotkin; 神经病理学和遗传学核心C：CL -约翰Q。Trojanowski; Co-Core Leaders - Edward B.李，薇薇安娜 货车Deerlin;数据管理、生物统计学和生物信息学核心D：CL - Sharon Xie，Co-I - Li-San 王.这些核心支持以下项目，以实现Udall中心更新的目标：项目I “帕金森病精准医学框架”：项目负责人（PL）- Alice Chen Plotkin; Co-I - Dan Weintraub; Project II“Executive Difficulty in Parkinson's Dementia”：PL - Murray Grossman; 共同研究者：Rizwan Akhtar、大卫、欧文、Corey McMillan;项目III“病理性A-syn 传输”：PL -弗吉尼亚M.- Y. Lee;项目IV“病理性A-syn菌株和多样性 Synucleinopathies”：PL-John Q. Trojanowski; Co-Is - Virginia M.- Y.李先生，陆先生。

Overall Component for the University of Pennsylvania Perelman School of Medicine Morris K. Udall Parkinson's Disease Research Center of Excellence: “Parkinson's Disease and Dementia” Udall Center Director: J.Q. Trojanowski Udall Center Summary/Abstract: The goals of the competing renewal application for the University of Pennsylvania (Penn) Perelman School of Medicine Udall Center are to elucidate mechanisms of progressive neurodegeneration in Parkinson's disease (PD), especially those that underlie cognitive impairments in PD without and with dementia (PDD) and in dementia with Lewy bodies (LBs) or DLB (Projects I/II) that we refer to collectively as LB disorders or LBD. Udall Center investigators hypothesize that LBD leads to neuron dysfunction and death resulting from the differential transmission of pathologic alpha-synuclein (a-syn) strains leading to the formation of Lewy bodies (LBs) and neurites (LNs) and their neurotoxic effects. Understanding LBD progression and its heterogeneity from molecular to patient levels will advance our ability to develop a precision medicine approach to LBD care and management. Thus, Projects III/IV seek to elucidate the conformationally distinct strains underlying PD, PDD and DLB compared to those underlying multiple system atrophy (MSA) characterized by glial cytoplasmic inclusions (GCIs) formed by misfolded a-syn, while Project I seeks to better clinically manage the diversity of phenotypes within LBD that may result from these strain differences, and Project II extends our analysis of phenotypic diversity to the important area of cognitive decline. Consistent with the mission of the Udall Centers described in the most recent RFA, the vision statement of the Penn Udall Center for the renewal period is to elucidate the progression of PD from normal cognition to cognitive impairment, executive dysfunction and dementia in PDD, as well as disease progression in DLB in addition to neurodegeneration mediated by progressive accumulations of pathological a-syn. The landmark discovery of mutations pathogenic for PD in the a-syn gene, the discovery of pathological a-syn as the disease protein that forms LBs/LNs in PD/PDD/DLB as well as GCI in MSA in addition to evidence for the cell-to-cell spread of a-syn strains places a-syn at center stage for understanding mechanisms of LBD/MSA. The Penn Udall Center renewal seeks to address these key issues in four Projects supported by four Cores including: Administrative Core A: Core Leader (CL) - John Q. Trojanowski; Clinical Core B: CL - Daniel Weintraub, Co-Investigators (Co-Is) - Lama Chahine, Nabila Dahodwala, James Morley, Alice Chen-Plotkin; Neuropathology & Genetics Core C: CL - John Q. Trojanowski; Co-Core Leaders - Edward B. Lee, Vivianna Van Deerlin; Data Management, Biostatistics & Bioinformatics Core D: CL - Sharon Xie, Co-I - Li-San Wang. These Cores support the following Projects to achieve the goals of the Udall Center renewal: Project I “A Framework for Precision Medicine in Parkinson's Disease”: Project Leader (PL) - Alice Chen Plotkin; Co-I - Dan Weintraub; Project II “Executive Difficulty in Parkinson's Dementia”: PL - Murray Grossman; Co-Is: Rizwan Akhtar, David Irwin, Corey McMillan; Project III “Mechanisms of Pathological A-syn Transmission”: PL - Virginia M.-Y. Lee; Project IV “Pathologic A-syn Strains & Diverse Synucleinopathies”: PL - John Q. Trojanowski; Co-Is - Virginia M.-Y. Lee, Kelvin Luk.