Delayed cognitive impairment after stroke

描述(申请人提供)：脑血管疾病是痴呆症的主要危险因素。高达48%的中风幸存者被诊断为全因痴呆症(血管性痴呆症、阿尔茨海默病和混合性疾病)，中风后第一年的发病率约为20%。几个中风风险因素，包括高血压、高胆固醇、糖尿病和年龄，也独立地增加了痴呆症的风险。但多项研究表明，即使在控制了风险因素后，单是中风仍然会使新发痴呆症的风险增加一倍。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，在这种模型中，中风会导致迟发性认知功能障碍。在我们的模型中，由于大脑中动脉远端闭塞和缺氧，小鼠发生了遗传性卒中。这是一种主要的皮质梗塞。小鼠在中风后8天表现出正常的工作记忆，但到了6-7周后，它们出现了工作记忆和空间记忆的缺陷，并伴随着长期的炎症反应。这种炎症反应的一部分是B细胞出现在卒中核心的滤泡状结构中。最近，中枢神经系统中的这种结构与几种神经退行性疾病有关。我们建议在这里发展我们的模型，并在我们的模型中测试B细胞是否致病。在目标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。我们假设神经炎的致病特征将先于或同时出现认知损害。在目标2中，我们将使用B细胞耗尽抗体和B细胞基因敲除小鼠来询问B细胞是否是认知功能障碍发生所必需的。这项工作具有产生重大影响的巨大潜力，因为目前还没有得到广泛接受的模型，而且对这种常见的、令人衰弱的疾病的起源知之甚少。在这些实验的结论中，我们将描述我们模型中的认知缺陷和炎症反应，并将知道B细胞是否是病因。这些信息将使我们能够在未来对中风后痴呆的机制进行关键的研究，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.