Neural Substrates of Cognitive Decline in Aging Monkeys

描述(由申请人提供)：恒河猴是正常人类衰老的模型，它使认知测试之后能够为多学科研究最佳地保存脑组织。拟议中的研究将检验这一假设，即与年龄相关的认知下降是从中年早期开始的一系列轻微退行性变化的结果，白质发炎和损伤导致轴突功能变化，并进展为神经元的功能和结构变化。我们将对三组猴子进行研究，以检验这一假设的各个方面。第一批36只猴子将用于一项横断面研究，研究对象包括5至30岁的成年猴子。在行为测试之后，核磁共振扫描之后将进行体内神经生理学和新的两阶段灌流固定，以提供新鲜和固定的组织，以确定认知能力下降背后的大脑变化。第二个由6只中年猴子组成的队列将被视为第一个队列，只是它们将被用混合醛灌流固定，用于电子显微镜检查，以补充现有样本，并能够识别超微结构变化，这些变化是中年时出现的第一个与认知能力下降有关的变化。第三组12只中年早期猴子(年龄13-15岁)将被纵向跟踪4年以上，进行重复的行为测试、脑部核磁共振扫描以及血液和脑脊液样本。由于认知障碍的患病率在13-15岁时较低，但在20岁时较高，行为数据将确定单个猴子的认知特征和下降速度。纵向核磁共振将揭示体内大脑结构的同步变化，脑脊液和血液样本将允许跟踪生物标记物。对于第1组和第3组，在灌流固定之前，将对复合动作电位进行体内神经生理学评估。然后，接下来将进行两个阶段的灌流，以便在大脑其余部分固定之前，立即从一个大脑半球收集未固定的样本。新鲜组织将用于突触电流和动作电位的体外神经生理学，用于单细胞聚合酶链式反应，以及用于潜在机制的生化和分子研究。固定的组织将用于解剖学研究，包括神经元数量的体视学研究，以及炎症和其他退化过程的免疫细胞化学研究。 关于单个组件的回顾 核心A：行政和数据管理核心；Douglas Rosene博士(CL) 描述(申请人提供)：行政核心负责本计划项目的总体科学指导和财务行政管理。为此，核心将处理所有订单，并为所有核心和项目保持适当的财务记录。它还将向编写手稿和年度进展报告的核心和项目提供行政和文书支助。CORE还将组织计划项目工作人员(所有项目和核心领导及其协查人员)每两周举行一次的会议，会上将讨论科学方向和进展，并就优先事项或新方向作出决定，还将在计划的第二年和第四年组织外部咨询委员会的会议(被选来提供我们正在调查的领域的专门知识的外部科学家)。这将是一天的校外会议，项目工作人员将在上午向顾问介绍他们的工作总结，然后下午将专门与顾问进行圆桌讨论。这次小组会议将使我们能够获得他们对该计划的总体科学方向的意见。最后，核心还将为所有核心和项目提供统计支助，并维护方案项目数据档案方案数据库。

DESCRIPTION (provided by applicant): The rhesus monkey is a model of normal human aging that enables cognitive testing to be followed by optimal preservation of brain tissue for multidisciplinary studies. The proposed studies will test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning in early middle age with inflammation and damage in white matter that leads to functional changes in axons and progresses to functional and structural changes in neurons. We will study three cohorts of monkeys to test various aspects of this hypothesis. The first cohort of 36 monkeys will be used in a cross-sectional study and consist of subjects covering the adult life span from 5 to 30 years old. After behavioral testing, MRI scans will be followed by in vivo neurophysiology and a new two stage perfusion fixation to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys will be treated like cohort 1 except they will be perfusion fixed with mixed aldehydes for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes that are the first changes to appear in middle age in association with cognitive decline. A third cohort of 12 early middle aged monkeys (ages 13-15) will be followed longitudinally for 4+ years with repeated behavioral testing, MRI scans of the brain, and samples of blood and CSF. As the prevalence of cognitive impairment is low at 13-15 but high by 20, behavioral data will identify the cognitive profile and rate of decline of individual monkeys. Longitudinal MRIs will reveal concurrent changes in the in vivo brain structure, and CSF and blood samples will allow biomarkers to be followed. For cohorts 1 and 3, perfusion fixation will be preceded by in vivo neurophysiological assessment of compound action potentials. Then the two stage perfusion will follow to allow immediate collection of unfixed samples from one hemisphere before the remainder of the brain is fixed. Fresh tissue will be used for in vitro neurophysiology of synaptic currents and action potentials, for single cell PCR, and for biochemical and molecular studies of underlying mechanisms. Fixed tissue will be used for anatomical studies, including stereological studies of neuron numbers and immunocytochemical studies of inflammation and other degenerative processes. REVIEW OF INDIVIDUAL COMPONENETS CORE A: ADMINISTRATIVE AND DATA MANAGEMENT CORE; Dr. Douglas Rosene (CL) DESCRIPTION (provided by applicant): The Administrative Core is responsible for the overall scientific direction and financial and administrative management of this Program Project. To accomplish this the core will handle all orders and maintain appropriate financial records for all of the Cores and Projects. It will also provide administrative and clerical support to the Cores and Projects in preparation of manuscripts and the annual progress reports. The core will also organize biweekly meetings of the Program Project staff (all project and core leaders and their coinvestigators) at which scientific direction and progress will be discussed and decisions about priorities or new directions made and will also organize meetings of the External Advisory Committee (outside scientists selected to provide expertise in the areas we are investigating) in years two and four of the Program. These will be one day, off campus meetings at which the Program Project staff will present summaries of the their work to the advisors in the morning and then the afternoon will be devoted to round table discussion with the advisors. This group meeting will allow us to get their input on the overall scientific direction of this Program. Finally, the core will also provide statistical support for all of the Cores and Projects and will maintain the Archival Program Database of Program Project Data.