EPIDEMIOLOGY, PATHOLOGY, AND PARKINSONISM IN AGING

这个为期5年的临床科学家发展奖建议使用定量流行病学原理将死后发现与衰老相关的神经系统疾病联系起来。帕金森氏症的一系列症状，包括运动迟缓、强直、震颤和步态不平衡，在没有帕金森氏症的老年人中很常见，并与发病率和死亡率增加有关。黑质纹状体系统也表现出随年龄变化的谱。初步数据表明，神经纤维病理比以前认识到的更常见，并且与老年痴呆症患者的帕金森症状有关。拟议的研究将神经原纤维病理和生化黑质纹状体变化与老年阿尔茨海默病患者总体和特异性帕金森症状的定量测量联系起来。我们将验证以下假设：神经原纤维病理，特别是在黑质致密部，而不是在腹侧被盖区或脑后区，导致了有或没有AD的老年人的帕金森症状；神经原纤维病理产生帕金森症状的机制涉及酪氨酸羟化酶基因表达的减少和纹状体多巴胺的减少，但不是神经元损失。我们还将确定线粒体突变在神经原纤维病理和帕金森症状的发病机制中的作用。拟议中的项目将在“宗教秩序研究”中使用80名没有帕金森病的老年人的脑组织，这是一项对650多名天主教神职人员的纵向研究，他们同意每年检查一次，并在死后捐赠大脑。拟议的研究将为候选人提供与资深同事一起工作的机会，并允许开发一个独特的研究领域，整合临床神经病学和神经病理学培训。通过这些研究和分析的过程，通过与她的赞助人和顾问的教学会议，以及相关的课程作业，候选人将发展成为一名独立调查员所必需的技能。

This 5-year clinical scientist development award proposes the use of quantitative epidemiologic principles to relate post-mortem findings to neurologic conditions associated with aging. A spectrum of parkinsonian signs, including bradykinesia, rigidity, tremor, and gait imbalance are common in older persons without Parkinson's disease, and are associated with increased morbidity and mortality. The nigrostriatal system also shows a spectrum of change with age. Preliminary data suggest that nigral neurofibrillary pathology is more common than previously recognized and is related to parkinsonian signs in older persons with and without Alzheimer's disease. The proposed studies will relate nigral neurofibrillary pathology and biochemical nigrostriatal changes to quantitative measures of global and specific parkinsonian signs in older persons with and without Alzheimer's disease. We will test the hypotheses that neurofibrillary pathology, specifically within the pars compacta of the substantia nigra, rather than the ventral tegmental or retrorubral areas, accounts for parkinsonian signs in older persons with and without AD, and that the mechanism by which neurofibrillary pathology produces parkinsonian signs involves decreased gene expression of tyrosine hydroxylase and a reduction in striatal dopamine, but not neuronal loss. We will also determine the role of mitochondrial mutations in the pathogenesis of neurofibrillary pathology and parkinsonian signs. The proposed project will use brain tissue of 80 older persons, without Parkinson's disease, in The Religious Order Study, a longitudinal study of over 650 catholic clergy who have agreed to annual examinations and brain donation after death. The proposed study will provide the Candidate in the opportunity to work with senior colleagues and allow the development of a unique research area that integrates the clinical neurology and neuropathology training. Through the course of these studies and analyses, through didactic sessions with her sponsors and consultants, and related course work, the candidate will develop the skills necessary to become an independent investigator.