White matter damage in age-related cognitive decline

描述(申请人提供)：小(微)血管功能障碍(VBI)和阿尔茨海默病(AD)引起的脑血管损伤在老年人中非常普遍，通常是并存的，是导致老年人痴呆症的主要因素，超过85%的认知正常的75岁或以上的人存在，这些疾病可能导致与年龄相关的认知能力下降。令人费解的是，尽管人们投入了巨大的精力来了解神经退行性疾病中灰质损伤和神经元死亡的机制，但在人类和非人类灵长类动物中仔细执行的研究表明，神经元丧失并不是年龄增长的特征。相比之下，许多研究，主要是基于神经成像的，已经发现白质(WM)随着年龄的增加而变化；然而，这种WM损伤(WMI)随着年龄的增加而发生的分子和细胞基础仍然不清楚。在这次更新中，我们假设VBI和AD通过直接和间接的机制导致WMI，这些机制集中在阻碍髓鞘修复的有害反应上。事实上，我们从当前周期的观察表明，VBI和AD共同在成人大脑中产生WMI，并通过细胞和分子机制扰乱对WMI的反应和修复，这与我们和其他人之前在儿童WMI和成人脱髓鞘疾病中展示的非常相似。我们高度集成的多组分R01将继续追求以下具体目标：(1)从基于人群的脑老化和MCI事件研究中开发独特的、高度互补的脑组织资源。组织的准备是为了最大限度地研究白质。利用这一独特资源的组织，我们将继续我们的工作，确定脑白质损伤的磁共振成像(MRI)、组织学和免疫组织化学测量方法，(3)对髓鞘或轴突的自由基损伤，(4)特定的牙髓内胚前体细胞(OPC)亚群，以及(5)抑制老年脑中OPC适当成熟和功能的生化因素。这个项目不仅将继续为研究白质损伤的科学家社区开发一个独特的资源，而且还将利用这个资源来回答与老年人认知能力下降有关的WMI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人口结构，与年龄相关的认知能力下降和先兆痴呆症是最重要的公共卫生问题。虽然许多研究已经将白质变化与增龄联系在一起，但这种白质损伤的结构和细胞基础仍然是个谜。继续我们的研究项目不仅将继续为研究脑白质损伤的科学家社区开发独特的资源，还将利用这一资源回答与老年人认知能力下降相关的脑白质损伤的结构、细胞和生化基础的关键问题。

DESCRIPTION (provided by applicant): Vascular brain injury from small (micro) vessel dysfunction (¿VBI) and Alzheimer's disease (AD) are highly prevalent in older adults, are commonly co-morbid, are major contributors to the dementia syndrome in the elderly, and are present in over 85% of cognitively normal individuals 75 years of age or older where these diseases presumably contribute to age-related cognitive decline. Enigmatically, while tremendous effort has been invested in understanding mechanisms of gray matter damage and neuron death in 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 (WM) changes with advancing age; however, the molecular and cellular bases of this WM injury (WMI) with advancing age remain unclear. In this renewal, we hypothesize that ¿VBI and AD cause WMI through direct and indirect mechanisms that converge on deleterious responses that impede myelin repair. Indeed, our observations from the current cycle indicate that ¿VBI and AD conspire in the adult human brain to produce WMI and perturb response and repair of WMI through cellular and molecular mechanisms that are very similar to what we and others have demonstrated previously in pediatric WMI and adult demyelinating diseases. Our highly integrated multi-component R01 will continue to pursue the following Specific Aims: (1) Developing a unique and highly complementary resource of brain tissue from a human population-based study of brain aging and incident MCI. Tissue is prepared to maximize investigation of white matter. Using tissue from this unique resource, we will continue our work determining associations 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 suppress appropriate maturation and function of OPCs in aged brain. This project not only will continue to develop a unique resource for the community of scientists investigating white matter injury, but also employs this resource to answer key questions about the structural, cellular, and biochemical bases of WMI associated with cognitive decline in the elderly. PUBLIC HEALTH RELEVANCE: Age-related cognitive decline and prodromal dementia are of paramount public health import given the 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. Continuation of our research project not only will continue to 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.