Delayed cognitive impairment after stroke

描述（申请人提供）：脑血管疾病是痴呆的主要危险因素。高达48%的中风幸存者被诊断为全因痴呆（血管性痴呆、阿尔茨海默病和混合性疾病），其中约20%的发病率发生在中风后的第一年。一些中风的危险因素，包括高血压、高胆固醇、糖尿病和年龄，也会独立增加痴呆的风险。但多项研究表明，即使控制了风险因素，中风本身仍会使新发痴呆的风险增加一倍。我们建议通过开发一种新的小鼠模型来模拟中风如何增加患痴呆症的风险，其中中风导致延迟性认知功能障碍。在我们的模型中，小鼠由于大脑中远端动脉闭塞后缺氧而发生DH卒中。这是一种主要的皮层梗死。小鼠在中风后8天表现出正常的工作记忆，但在6-7周后，它们的工作记忆和空间记忆出现缺陷，并伴有长时间的炎症反应。这种炎症反应的一部分是B细胞出现在脑卒中核心，在滤泡样结构中。中枢神经系统的这种结构最近与几种神经退行性疾病有关。我们建议在此建立我们的模型并测试B细胞在我们的模型中是否具有致病性。在Aim 1中，我们将在关键时间点使用一组认知测试来评估该模型中哪些认知区域受到影响，并仔细地对中风的延迟炎症反应进行表型分析。我们假设神经炎症的致病特征将先于或与认知障碍同时发生。在Aim 2中，我们将使用B细胞消耗抗体和B细胞敲除小鼠来询问B细胞是否需要发生认知功能障碍。这项工作有很大的潜力产生重大影响，因为目前还没有被广泛接受的模型，而且对这种常见的使人衰弱的疾病的起源知之甚少。在这些实验的结论中，我们将在我们的模型中描述认知缺陷和炎症反应，并将知道B细胞是否是致病的。这些信息将使我们能够对中风后痴呆的机制进行关键的未来研究，此外还将提供一种测试潜在治疗方法的方法。

DESCRIPTION (provided by applicant): Cerebrovascular disease is a major risk factor for dementia. All-cause dementia, (vascular dementia, Alzheimer's disease, and mixed disorders) is diagnosed in up to 48% of stroke survivors, with about 20% incidence in the first year after stroke. Several stroke risk factors, including hypertension, high cholesterol, diabetes, and age, also independently increase the risk of dementia. But multiple studies demonstrate that even after controlling for risk factors, stroke alone still doubles the risk of new onset dementia. We propose to model how stroke increases the risk of developing dementia by developing a new mouse model where stroke causes delayed cognitive dysfunction. In our model mice undergo DH stroke as a result of distal middle cerebral artery occlusion followed by hypoxia. This confers a primarily cortical infarct. Mice display normal working memory 8 days after stroke but by 6-7 weeks later they develop deficits in working and spatial memory, accompanied by a prolonged inflammatory response. A part of this inflammatory response is the appearance of B cells in the stroke core, in follicle-like structures. Such structures in the CNS have recently been linked to several neurodegenerative diseases. We propose here to develop our model and test whether B cells are pathogenic in our model. In Aim 1 we will use a panel of cognitive tests at key timepoints to assess which areas of cognition are affected in this model, and also carefully phenotype the delayed inflammatory response to stroke. We hypothesize that pathogenic features of neuroinflammation will precede or coincide with cognitive impairment. In Aim 2 we will use a B cell-depleting antibody and B cell knockout mice to ask whether B cells are required for cognitive dysfunction to occur. This work has high potential to produce significant impact because there are currently no well-accepted models and little is known about the genesis of this common and debilitating disorder. At the conclusion of these experiments we will have characterized the cognitive deficit and inflammatory responses in our model and will know whether B cells are causative. This information will allow us to pursue critical future studies on the mechanisms that underlie post-stroke dementia, and in addition will provide a way to test potential therapies. PUBLIC HEALTH RELEVANCE: Stroke is a major risk factor for dementia, but there are no established animal models to study how stroke causes memory impairment. In this application we propose to develop such an animal model, and use it to understand how stroke increases the risk of dementia. We hope to discover mechanisms that will lead to treatments that can prevent dementia in stroke survivors.