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

描述（由申请人提供）：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，但确实表现出与年龄相关的认知功能衰退，这种衰退始于13岁（人类~ 39岁），并在20岁（人类~ 60岁）后加速。通过检查认知老化的神经基础，我们发现皮层神经元并没有丢失，相反，在电子显微镜（EM）和磁共振成像中可以看到，主要的病理发生在白质的髓鞘纤维中。虽然MRI标记物与EM标记物的关系尚不清楚，但两者都是认知衰老的有力预测指标。重要的是髓磷脂损伤的原因尚不清楚。一种假设是，损伤是由与年龄相关的氧化应激引起的。一个新的推论假设是，这种损伤被与年龄相关的髓磷脂修复减少放大。我们将在两组行为测试的雄性和雌性猴子中探索这两种假设，这些猴子的范围从年轻的成年猴（~5）到老年猴（bbb20）。第一组由24只猴子组成，它们将接受行为测试，并为这项研究分析它们的大脑。第二组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只猴子的数据包括认知、核磁共振扫描、BrdU标记、脑脊液样本和血清样本。在Aim 1中，我们将使用免疫组织化学与受损髓磷脂（EP）抗体定量脑髓磷脂病理，并使用多级免疫荧光评估其与其他病理（如脂质过氧化）的关系。为了确定其他潜在的致病因素，脑脊液、血清和大脑样本将用细胞因子阵列进行生化分析。在Aim 2中，使用BrdU和成熟和未成熟少突胶质细胞标记物的多标记免疫荧光将评估维持和修复髓磷脂的能力。在Aim 3中，EP处理的切片将与MRI扫描共同注册，从而产生白质体积和髓磷脂病理（例如分数各向异性）的测量，以验证这些MRI测量如何很好地反映组织成分。最后，将对所有测量方法进行分析，以确定哪一种方法最能预测认知老化。这将使未来的研究能够针对髓磷脂损伤的特定过程进行实验治疗，并使用经过验证的MRI测量来跟踪其效果。

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.