White matter damage in age-related cognitive decline

描述（由申请人提供）：小（微）血管功能障碍（VBI）和阿尔茨海默病（AD）引起的血管性脑损伤在老年人中非常普遍，通常是共病，是老年人痴呆综合征的主要原因，并且存在于超过85%的75岁或以上认知正常个体中，这些疾病可能导致与年龄相关的认知下降。令人费解的是，虽然人们投入了巨大的努力来理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，神经元损失不是年龄增长的特征。相反，许多研究，主要是基于神经影像学，与白色物质（WM）的变化与年龄的增长，然而，这种WM损伤（WM）与年龄的增长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引起神经损伤，这些机制聚集在阻碍髓鞘修复的有害反应上。事实上，我们对当前周期的观察表明，VBI和AD在成人大脑中合谋，通过细胞和分子机制产生干扰和干扰反应，并修复脊髓损伤，这与我们和其他人以前在儿科脊髓损伤和成人脱髓鞘疾病中所证明的非常相似。我们高度集成的多组分R01将继续追求以下特定目标：（1）从基于人群的脑老化和MCI事件研究中开发独特且高度互补的脑组织资源。准备组织以最大限度地研究白色物质。利用来自这一独特资源的组织，我们将继续我们的工作，以确定协会磁共振成像（MRI），组织学和免疫组化措施的白色物质损伤，（3）自由基损伤髓鞘或轴突，（4）特定亚群的少突胶质细胞前体细胞（OPCs），和（5）生化因素，抑制适当的成熟和功能的OPCs在老年大脑。该项目不仅将继续为研究白色物质损伤的科学家社区开发独特的资源，而且还将利用该资源来回答与老年人认知能力下降相关的结构，细胞和生物化学基础的关键问题。

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.