NEURAL SUBSTRATES OF AGE-RELATED COGNTIVE DECLINE IN MONKEYS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。（来自波士顿大学的父母衰老PPG：仅在NEPRC进行的纵向研究）恒河猴是正常人类衰老的模型，它可以在认知测试之后最佳地保存脑组织，用于多学科研究。拟议的研究验证了一个假设，即与年龄相关的认知能力下降是由一连串轻微的退行性变化引起的，首先是白质的炎症，然后是神经元的功能和结构变化。我们将研究三组猴子。第一组36人将被用于横断面研究，并将包括从5岁到30岁的成年人。行为测试后，将进行MRI扫描，随后进行体内神经生理学和两阶段灌注，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。第二组6只中年猴子将像第一组一样进行，除了它们将被固定在电子显微镜下，以补充现有的样本，并允许识别在中年首先出现的与认知能力下降有关的超微结构变化。第三组12只中年早期猴子（13-15岁）将被纵向跟踪4年以上，反复进行行为测试、大脑MRI扫描、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，这些数据将使我们能够确定单个猴子的认知概况和下降速度。纵向核磁共振成像将揭示大脑形态的同步变化，脑脊液和血液样本将允许评估生物标志物。对于第1组和第3组，在大脑的其余部分固定之前，将立即从一个半球收集未固定的样本，对复合动作电位进行体内神经生理学评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (From parent Aging PPG at Boston University ¿ Longitudinal Study only conducted at NEPRC) 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 test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning with inflammation in white matter followed by functional and then structural changes in neurons. We will study three cohorts of monkeys. The first cohort of 36 will be used in a cross-sectional study and will 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 two stage perfusion to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys will proceed like cohort 1 except they will be fixed for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes that appear first in middle age in relation to 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, these data will allow us to identify the cognitive profile and rate of decline of individual monkeys. Longitudinal MRIs will reveal concurrent changes in brain morphology, and CSF and blood samples will allow biomarkers to be assessed. For cohorts 1 and 3, in vivo neurophysiological assessment of compound action potentials will be followed immediately by collection of unfixed samples from one hemisphere before the remainder of the brain is fixed.