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，能够在认知测试之后最佳保存脑组织用于多学科研究。拟议的研究将检验这一假设，即年龄相关的认知能力下降是由一系列轻度退行性变化引起的，这些变化始于中年早期，伴随白色物质的炎症和损伤，导致轴突的功能变化，并进展为神经元的功能和结构变化。我们将研究三组猴子，以测试这一假设的各个方面。第一个队列的36只猴将用于横断面研究，由涵盖5至30岁成年寿命的受试者组成。在行为测试后，MRI扫描将随后进行体内神经生理学和新的两阶段灌注固定，以提供新鲜和固定的组织，以识别认知下降背后的大脑变化。第二个队列的6只中年猴将按照队列1进行处理，不同之处在于它们将用混合醛进行灌注固定，用于电子显微镜检查，以补充现有样品，并允许鉴定超微结构变化，这些变化是中年出现的与认知下降相关的第一个变化。第三组12只中年早期猴（年龄13-15岁）将纵向随访4年以上，进行重复行为测试、脑部MRI扫描以及血液和CSF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，因此行为数据将确定个体猴子的认知特征和下降速度。纵向MRI将揭示体内脑结构的同时变化，并且CSF和血液样本将允许跟踪生物标志物。对于队列1和3，灌注固定之前将进行复合动作电位的体内神经生理学评估。然后进行两阶段灌注，以便在固定大脑的其余部分之前立即从一个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、单细胞PCR以及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和炎症及其他退行性过程的免疫细胞化学研究。 审查个别构成部分 核心A：行政和数据管理核心; Dr.道格拉斯罗克斯（CL） 描述（由申请人提供）：行政核心负责本计划项目的整体科学方向和财务及行政管理。为实现这一目标，核心将处理所有订单，并为所有核心和项目保留适当的财务记录。它还将为核心文件和项目提供行政和文书支助，以编写手稿和年度进展报告。核心还将组织两周一次的计划项目工作人员会议（所有项目和核心领导人及其共同研究者），讨论科学方向和进展，并决定优先事项或新方向，还将在计划的第二年和第四年组织外部咨询委员会会议（选定的外部科学家在我们正在研究的领域提供专业知识）。这将是一天，校外会议，在该计划项目的工作人员将提出他们的工作总结，以顾问在上午，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总体科学方向的投入。最后，核心还将为所有核心和项目提供统计支持，并将维护计划项目数据的档案计划数据库。

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.