White matter damage in age-related cognitive decline

描述（由申请人提供）：与年龄相关的认知衰退（ARCD）存在于一个连续体中，并伴有更严重的认知功能障碍，这通常是痴呆的前驱症状，可以被定义为轻度认知障碍（MCI），最终伴有痴呆。ARCD是残疾和自主性降低的主要原因，更不用说前驱痴呆和痴呆了，鉴于美国人口的预测统计数据，这对公共卫生至关重要。尽管在理解脑老化和神经退行性疾病中灰质损伤和神经元死亡的机制方面已经投入了巨大的努力，但在人类和非人类灵长类动物中进行的仔细研究表明，神经元损失并不是衰老的特征。相比之下，许多研究（主要是基于神经影像学的研究）将白质变化与年龄增长联系起来；然而，这种白质损伤的结构和细胞基础仍然是个谜。我们建议验证脑白质中存在特定的结构和细胞脆弱性的假设，这些脆弱性对ARCD和MCI有重要影响。在这里，我们建议通过高度集成的多组分R01来验证这一假设，该R01追求以下具体目标：(1)首先，我们建议从基于人群的脑衰老和事件MCI研究中开发一种独特且高度互补的脑组织资源。准备组织以最大限度地检查白质。利用这一独特资源的组织，我们将确定认知功能与以下因素之间的关系：(2)磁共振成像（MRI）、白质损伤的组织学和免疫组织化学测量；(3)髓鞘或轴突的自由基损伤；(4)胶质前体细胞（OPCs）的特定亚群；(5)老年大脑中阻碍OPCs适当成熟和功能的生化因素。该项目不仅将为研究白质损伤的科学家社区提供独特的资源，而且还将利用该资源回答与老年人认知能力下降相关的白质损伤的结构、细胞和生化基础的关键问题。公共卫生相关性：考虑到美国人口的预测统计数据，与年龄相关的认知能力下降和前驱痴呆对公共卫生至关重要。虽然许多研究已经将白质的变化与年龄的增长联系起来，但这种白质损伤的结构和细胞基础仍然是一个谜。我们提出的项目不仅将为研究白质损伤的科学家社区开发一个独特的资源，而且还将利用该资源回答有关老年人认知能力下降相关白质损伤的结构、细胞和生化基础的关键问题。

DESCRIPTION (provided by applicant): Age-related cognitive decline (ARCD) exists in a continuum with more severe cognitive dysfunction that that often is a dementia prodrome and can be operationally defined as Mild Cognitive Impairment (MCI), and ultimately with dementia. ARCD is a major source of disability and reduced autonomy, to say nothing of prodromal dementia and dementia, which are of paramount public health import given projected demographics of the US population. While tremendous effort has been invested in understanding mechanisms of gray matter damage and neuron death in brain aging and neurodegenerative diseases, carefully executed studies in humans and non-human primates have shown that neuron loss is not a feature of advancing age. In contrast, numerous studies, mostly neuroimaging-based, have associated white matter changes with advancing age; however, the structural and cellular bases of this white matter damage remain enigmatic. We propose to test the hypothesis that there are specific structural and cellular vulnerabilities within cerebral white matter that contribute significantly to ARCD and MCI. Here we propose to test this hypothesis via a highly integrated multi-component R01 that pursues the following Specific Aims: (1) First, we propose to develop a unique and highly complementary resource of brain tissue from a human population-based study of brain aging and incident MCI. Tissue will be prepared to maximize investigation of white matter. Using tissue from this unique resource, we will determine associations between cognitive function and (2) magnetic resonance imaging (MRI), histological, and immunohistochemical measures of white matter damage, (3) free radical damage to myelin or axons, (4) specific subpopulations of oliogodendrocyte precursor cells (OPCs), and (5) biochemical factors that retard appropriate maturation and function of OPCs in aged brain. This project not only will develop a unique resource for the community of scientists investigating white matter injury, but also will employ this resource to answer key questions about the structural, cellular, and biochemical bases of white matter damage associated with cognitive decline in the elderly. PUBLIC HEALTH RELEVANCE: Age-related cognitive decline and prodromal dementia of paramount public health import given projected demographics of the US population. While numerous studies have associated white matter changes with advancing age, the structural and cellular bases of this white matter damage remain enigmatic. Our proposed project not only will develop a unique resource for the community of scientists investigating white matter injury, but also will employ this resource to answer key questions about the structural, cellular, and biochemical bases of white matter damage associated with cognitive decline in the elderly.