White matter hyperintensity-associated astrocytopathy in Alzheimers disease and vascular cognitive impairment A targeted histopathologic study using postmortem 7T MRI

项目总结 除年龄外，血管疾病是痴呆症最大的可识别风险因素，也是唯一的风险因素 可能是可以预防的。阿尔茨海默病(AD)的病理随着年龄的增长而成比例地减少 临床痴呆症，暗示非阿尔茨海默病机制是老年痴呆的重要决定因素。这些 机制本质上可能是血管的，因为在老年人中，“混合血管/AD”比单独的AD更常见 个人。血管认知障碍(VCI)的标志是皮质下白质疾病，可视化 磁共振成像(MRI)表现为白质高信号(WMH)。WMH无处不在， 年龄，增加痴呆症、中风和死亡的风险，并在AD中增加。我们的研究表明，WM 损害范围超出WMHs，在紧邻周围的正常外观白质(NAWM)内。 最近的研究表明，WM星形细胞功能障碍(“星形细胞病变”)在VCI中起着重要作用。我们的 初步数据支持这种联系，并已确定星形胶质细胞表型的变化和增加 WMHs覆盖的皮质灰质(GM)与NAWM覆盖的GM的tau病理比较， 提示WMH相关性星形细胞病变对VCI和AD患者的WM和GM功能障碍均有贡献。 我们假设局部慢性脑缺血导致GM和WM内的星形细胞改变， 仅此一项以及与AD相关的病理共同加重中枢神经系统功能障碍和随后的 老年人的认知障碍和痴呆，WMHs可能是这些疾病的生物标志物 改变。我们已经开发了一种7T尸检MR方案，它允许识别和靶向 WMH和周围正常外观组织的抽样进行组织病理学检查，包括 使用俄勒冈州一个特征良好的队列的脑组织对星形细胞变化进行详细评估 阿尔茨海默病中心来验尸的受试者。在目标1中，我们将确定工作流管理的特征 与WMH相关的星形细胞病变和转变为WMH的区域。在目标2中，我们将确定 GM中的这些变化与AD特有的病理变化相关，并决定它们的空间分布 与地区性WMH的关系。在目标3中，我们将确定哪些区域WM和GM星形胶质细胞异常 在AIMS 1和2中发现的与痴呆症状态和全球认知有关，以标准控制 与神经退行性疾病有关的病理学，如阿尔茨海默病。我们预计这些研究 将对VCI和AD之间的关系产生新的见解，并提示特定的 星形胶质细胞在调节这些联系中的功能和功能丧失。我们预计这种治疗方法 旨在保护星形胶质细胞和从缺氧损伤中恢复可能提出了一种新的可能性 用于预防阿尔茨海默病和相关痴呆的治疗靶点。

PROJECT SUMMARY Vascular disease is the largest single identifiable risk factor for dementia apart from age and the only one potentially preventable. Alzheimer's Disease (AD) pathology proportionately decreases with age in those with clinical dementia, implicating non-AD mechanisms as important determinants of older-onset dementia. These mechanisms are likely vascular in nature, as “mixed vascular/AD” is more common than AD alone in older individuals. The hallmark of vascular cognitive impairment (VCI) is subcortical white matter disease, visualized on magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs). WMHs are ubiquitous with age, increase the risk of dementia, stroke, and death, and are increased in AD. Our research shows WM damage extends beyond WMHs, within the immediately surrounding normal appearing white matter (NAWM). Recent studies suggest an important role of WM astrocytic dysfunction (“astrocytopathy”) in VCI. Our preliminary data support this association, and has identified changes in astrocyte phenotypes and increased tau pathology in the grey matter (GM) of cortex overlying WMHs compared with GM overlying NAWM, suggesting WMH-associated astrocytopathy contributes to both WM and GM dysfunction in both VCI and AD. We hypothesize that regional chronic cerebral ischemia results in astrocytic changes within the GM and WM, that alone and in combination with AD-associated pathologies potentiate CNS dysfunction and subsequent cognitive impairment and dementia in the elderly, and that WMHs may serve as a biomarker for these changes. We have developed a 7T postmortem MR protocol that allows for the identification and targeted sampling of WMHs and surrounding normal appearing tissue for histopathological examination that includes a detailed assessment of astrocytic changes, using brain tissue from a well-characterized cohort of Oregon Alzheimer's Disease Center subjects who come to autopsy. In Aim 1, we will identify the features of WM astrocytopathy associated with WMHs and areas in transition to becoming WMHs. In Aim 2, we will identify these changes in GM, associate these with AD-specific pathologic changes, and determine their spatial relationship to regional WMHs. In Aim 3, we will determine which regional WM and GM astrocyte abnormalities found in Aims 1 and 2 are associated with dementia status and global cognition, controlling for standard pathologies associated with neurodegenerative diseases, such as those of AD. We anticipate that the studies in human tissue will produce new insights into the relationship between VCI and AD, and suggest specific functions and functional losses of astrocytes in mediating these associations. We anticipate that treatments aimed at astrocytic protection and recovery from hypoxic injury could suggest a new spectrum of possibilities for therapeutic targets designed to prevent AD and related dementias.