EPIDEMIOLOGY, PATHOLOGY, AND PARKINSONISM IN AGING

这项为期5年的临床科学家发展奖建议使用定量流行病学原理将尸检结果与与衰老相关的神经疾病联系起来。帕金森氏症的一系列症状，包括运动迟缓、僵硬、震颤和步态失衡，在没有帕金森氏病的老年人中很常见，并与发病率和死亡率增加有关。黑质纹状体系统也显示出随年龄变化的频谱。初步数据表明，黑质神经原纤维病变比以前认识到的更常见，并与患有和不患有阿尔茨海默病的老年人的帕金森症状有关。拟议的研究将把黑质神经原纤维病理和黑质纹状体生化变化与阿尔茨海默病和非阿尔茨海默病老年人整体和特定帕金森症状的定量测量联系起来。我们将测试以下假设，即神经纤维病理，特别是在黑质致密部，而不是腹侧被盖或背侧后区，解释了患有和没有AD的老年人的帕金森症状，以及神经纤维病理产生帕金森症状的机制涉及酪氨酸羟基酶基因表达减少和纹状体多巴胺减少，但不是神经元丢失。我们还将确定线粒体突变在神经纤维病理和帕金森症状发病机制中的作用。拟议中的项目将在宗教秩序研究中使用80名没有帕金森氏症的老年人的脑组织，这是一项针对650多名天主教神职人员的纵向研究，这些神职人员同意每年进行检查并在死后捐赠大脑。拟议的研究将为候选人提供与资深同事合作的机会，并允许开发一个独特的研究领域，将临床神经学和神经病理学培训整合在一起。通过这些研究和分析的过程，通过与她的赞助商和顾问的说教会议，以及相关的课程工作，候选人将发展成为一名独立调查人员所需的技能。

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.