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

项目摘要 血管疾病是除年龄外最大的单一可识别的痴呆症风险因素，也是唯一一个 可能是可以预防的阿尔茨海默病（AD）病理学比例随着年龄的增长而下降， 临床痴呆，暗示非AD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性的，因为在老年人中，“混合性血管/AD”比单独的AD更常见。 个体血管性认知障碍（VCI）的标志是皮质下白色病变， 磁共振成像（MRI）显示为白色高信号（WMH）。WMH无处不在， 年龄，增加痴呆，中风和死亡的风险，并增加AD。我们的研究表明WM 损害延伸到WMH之外，在直接周围的正常外观的白色物质（NAWM）内。 最近的研究表明WM星形细胞功能障碍（“星形细胞病”）在VCI中的重要作用。我们 初步数据支持这种关联，并已确定星形胶质细胞表型的变化， 与覆盖NAWM的GM相比，覆盖WMH的皮质的灰质（GM）中的tau病理学， 提示在VCI和AD中，WMH相关的星形细胞病有助于WM和GM功能障碍。 我们假设区域性慢性脑缺血导致GM和WM内的星形胶质细胞改变， 其单独或与AD相关的病理学组合增强CNS功能障碍和随后的 老年人的认知障碍和痴呆症，WMH可以作为这些疾病的生物标志物。 变化我们已经开发了一种7 T死后MR协议，允许识别和靶向 对WMH和周围正常外观组织进行组织病理学检查，包括 使用来自俄勒冈州一个特征明确的队列的脑组织，对星形胶质细胞变化进行详细评估 阿兹海默症中心的受试者前来验尸。在目标1中，我们将识别WM的特征 与WMH相关的星形细胞病和向WMH过渡的区域。在目标2中，我们将确定 GM中的这些变化，将这些与AD特异性病理变化相关联，并确定它们的空间分布。 与区域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， 在目标1和2中发现的与痴呆状态和整体认知相关，控制标准 与神经退行性疾病相关的病理学，例如AD的那些。我们预计这些研究 在人体组织中的研究将对VCI和AD之间的关系产生新的见解，并提出具体的 星形胶质细胞在介导这些关联中的功能和功能丧失。我们预计， 旨在保护星形胶质细胞并使其从缺氧损伤中恢复， 用于预防AD和相关痴呆症的治疗靶点。

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.