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

衰老猴脑髓磷脂损伤的组织病理学、神经影像学和机制

• 批准号: 8578366
• 负责人: Douglas L Rosene
• 金额: $ 59.44万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578366
• 关键词: 13 year old; 5 year old; Accounting; Address; Adult; Affect; Age; Age-associated memory impairment; Aging; Agreement; Alzheimer' s Disease; Anisotropy; Antibodies; Archives; Area; Axon; Brain; Brain Pathology; Bromodeoxyuridine; Clinical; Cognition; Cognitive aging; Complement; Controlled Study; Data; Development; Diffusion Magnetic Resonance Imaging; Elderly; Electron Microscope; Experimental Designs; Female; Fiber; Future; Histopathology; Human; Immunofluorescence Immunologic; Immunohistochemistry; Impaired cognition; Inflammation; Inflammatory; Injection of therapeutic agent; Intervention; Label; Laboratories; Lead; Learning; Lipid Peroxidation; MRI Scans; Macaca mulatta; Magnetic Resonance Imaging; Measures; Medial; Memory; Modeling; Monkeys; Myelin; Neural Conduction; Neurodegenerative Disorders; Neurons; Oligodendroglia; Oxidative Stress; Pathology; Process; Program Research Project Grants; Prosencephalon; Role; Sampling; Serum; Severities; Source; Specificity; System; Technology; Temporal Lobe; Testing; Time; Tissue Sample; Tissues; Up-Regulation; Validation; age related; aging brain; base; brain tissue; cell type; cognitive function; cohort; cytokine; design; gliogenesis; inflammatory marker; male; middle age; neuroimaging; normal aging; novel; precursor cell; public health relevance; relating to nervous system; repaired; research study; restoration; tool; treatment effect; white matter; young adult

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.

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，但确实显示出认知功能的年龄相关性认知下降，开始于13岁（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没有丢失，而是在电子显微镜（EM）和MR成像中看到的白色物质的有髓纤维中发生主要病理学变化。虽然MRI标记物与EM标记物的关系尚不清楚，但两者都是认知老化的强预测因子。重要的是髓鞘损伤的原因是未知的。一种假设是，损伤是由年龄相关的氧化应激引起的。一个新的推论假设是，这种损害是由年龄相关的髓鞘修复减少放大。我们将在两组经过行为测试的雄性和雌性猴子中探索这两种假设，这些猴子的年龄范围从年轻人（约5岁）到老年人（>20岁）。第一组由24只猴子组成，这些猴子将接受行为测试，并对它们的大脑进行分析。第二部分由先前研究中使用的31只猴子的存档组织样本和相关数据组成。这55只猴的数据将包括认知、MRI扫描、BrdU标记、CSF样本和血清样本。在目标1中，我们将使用免疫组织化学与受损髓鞘（EP）的抗体定量脑中的髓鞘病理，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，将使用细胞因子阵列对CSF、血清和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记物的多标记免疫荧光将评估维持和修复髓鞘的能力。在目标3中，将使用EP处理的切片与MRI扫描进行共配准，以获得白色物质体积和髓鞘病理学（例如分数各向异性）的测量结果，从而验证这些MRI测量结果如何反映组织成分。最后，所有的措施将进行分析，以确定最好的预测认知老化。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措施来跟踪其效果。