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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，但确实显示出与年龄相关的认知功能下降，这种下降从 13 岁（人类 ~ 39 岁）开始，并且20 后加速（人类 > 60）。通过检查这种认知老化的神经基础，我们发现皮质神经元并未丢失，而是在电子显微镜 (EM) 和 MR 成像中看到，主要病理发生在白质的有髓鞘纤维中。尽管 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因子。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，这种损害会因年龄相关的髓磷脂修复减少而放大。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，这些猴子的范围从年轻的成年猴子 (~5) 到老年人 (>20)。第一个队列由 24 只猴子组成，将在本研究中对它们进行行为测试并分析它们的大脑。第二个包含先前研究中使用的 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、MRI 扫描、BrdU 标记、脑脊液样本和血清样本。在目标 1 中，我们将使用受损髓磷脂 (EP) 抗体进行免疫组织化学定量大脑中的髓磷脂病理学，并使用多级免疫荧光评估其与其他病理学（例如脂质过氧化）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，使用 BrdU 以及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。在目标 3 中，经 EP 处理的切片将与 MRI 扫描共同配准，产生白质体积和髓磷脂病理学（例如分数各向异性）的测量值，以验证这些 MRI 测量值反映组织成分的程度。最后，将对所有测量进行分析，以确定哪些最能预测认知衰老。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性治疗，并使用经过验证的 MRI 测量来跟踪其效果。