Histopathology, Neuroimaging and Mechanism of Myelin Damage in Aging Monkey Brain

描述(申请人提供)：我们将使用恒河猴作为正常衰老的模型，因为它没有神经退行性疾病，但确实显示出与年龄相关的认知功能下降，从13岁开始(人类~39岁)，并在20岁后加速(人类&>60岁)。检查这种认知老化的神经基础，我们发现皮质神经元并没有丢失，而是在电子显微镜(EM)和磁共振成像中看到的白质有髓纤维中发生了主要的病理变化。虽然MRI标记物和EM标记物之间的关系尚不清楚，但两者都是认知老化的有力预测指标。重要的是，髓鞘损伤的原因尚不清楚。一种假设是，损伤是由年龄相关的氧化应激引起的。一个新的推论是，这种损伤会因年龄相关的髓鞘修复减少而放大。我们将在两组行为测试的雄性和雌性猴子身上探索这两种假设，这些猴子的范围从年轻人(~5只)到老年人(&gt；20只)。第一组由24只猴子组成，这些猴子将接受行为测试，并为这项研究分析它们的大脑。第二项研究包括先前研究中使用的31只猴子的存档组织样本和相关数据。这55只猴子的数据将包括认知、核磁共振扫描、BrdU标记、脑脊液样本和血清样本。在目标1中，我们将使用抗受损髓鞘(EP)抗体的免疫组织化学方法对脑内髓鞘病理进行定量，并使用多水平免疫荧光技术评估其与其他病理(如脂质过氧化)的关系。为了确定其他潜在的致病因素，将使用细胞因子阵列对脑脊液、血清和大脑样本进行生化分析。在目标2中，用BrdU和成熟和未成熟少突胶质细胞的标志物进行多标记免疫荧光将评估维持和修复髓鞘的能力。在AIM 3中，使用EP处理的切片将与MRI扫描共同注册，以产生白质体积和髓鞘病理(例如分数各向异性)的测量，以验证这些MRI测量反映组织成分的程度。最后，将分析所有指标，以确定哪种指标最能预测认知老化。这将使未来的研究能够针对髓鞘损伤的特定过程进行实验性治疗，并使用经过验证的MRI措施来跟踪它们的影响。

DESCRIPTION (provided by applicant): We will use the rhesus monkey as a model of normal aging as it is free from neurodegenerative disease but does show age-related cognitive declines in cognitive function that begin by 13 years of age (humans ~ 39) and accelerate after 20 (humans > 60). Examining the neural bases of this cognitive aging, we found that cortical neurons are not lost but instead, major pathology occurs in myelinated fibers of the white matter as seen in the electron microscope (EM) and in MR imaging. Though the relationship of MRI markers to EM markers is unknown, both are strong predictors of cognitive aging. Importantly the causes of myelin damage are unknown. One hypothesis is that damage is caused by age-related oxidative stress. A novel corollary hypothesis is that this damage is magnified by age-related reductions in myelin repair. We will explore both hypotheses in two cohorts of behaviorally tested male and female monkeys that range from young adults (~5) to the elderly (>20). The first cohort consists of 24 monkeys that will be behaviorally tested and their brains analyzed for this study. The second consists of archived tissue samples and associated data from 31 monkeys used in prior studies. Data on these 55 monkeys will include cognition, MRI scans, BrdU labeling, CSF samples and serum samples. In Aim 1, we will quantify myelin pathology in brain using immunohistochemistry with an antibody to damaged myelin (EP) and assess its relationship to other pathology (e.g. lipid peroxidation) using multilevel immunofluroescence. To identify other potentially causal factors, samples of CSF, serum and brain will be analyzed biochemically with cytokine arrays. In Aim 2, multi-label immunofluorescence with BrdU and markers of mature and immature oligodendroglia will assess the capacity to maintain and repair myelin. In Aim 3, sections processed with EP will be co-registered to MRI scans that yield measures of white matter volume and myelin pathology (e.g. fractional anisotropy) to validate how well these MRI measures reflect tissue constituents. Finally, all measures will be analyzed to determine which best predict cognitive aging. This will enable future studies to target experimental treatments at specific processes of myelin damage and use validated MRI measures to follow their effects.