EPIDEMIOLOGY, PATHOLOGY, AND PARKINSONISM IN AGING

这个为期5年的临床科学家发展奖提出了使用定量流行病学原则，将死后发现与衰老相关的神经系统疾病联系起来。一系列帕金森症状，包括运动迟缓、僵硬、震颤和步态不平衡，在无帕金森病的老年人中很常见，并与发病率和死亡率增加相关。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，黑质神经系统病理学比以前认识到的更常见，并且与老年人（有或无阿尔茨海默病）的帕金森症状有关。拟议的研究将涉及黑质神经病理学和生化黑质纹状体的变化，以量化措施的全球和具体的帕金森氏症的迹象，在老年人与阿尔茨海默氏症。我们将测试的假设，神经病理学，特别是在黑质，而不是腹侧被盖或红核后区，占帕金森病的迹象，在老年人与AD和无，神经病理学产生帕金森病的迹象的机制涉及酪氨酸羟化酶的基因表达减少和纹状体多巴胺的减少，但不是神经元的损失。我们还将确定线粒体突变在神经病理学和帕金森症状发病机制中的作用。拟议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，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相结合。通过这些研究和分析的过程中，通过教学会议与她的赞助商和顾问，以及相关的课程工作，候选人将开发必要的技能，成为一个独立的调查员。

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.