Delayed cognitive impairment after stroke

中风后迟发性认知障碍

• 批准号: 8444364
• 负责人: MARION S BUCKWALTER
• 金额: $ 23.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444364
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Animal Model; Animals; Antibodies; Antigen Presentation; Appearance; Area; Autoantibodies; Autoimmune Process; B-Lymphocytes; Behavioral Symptoms; Brain; Cells; Cerebrovascular Disorders; Cholesterol; Cognition; Cognitive; Cognitive deficits; Complement Activation; Data; Dementia; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Distal; Drug Delivery Systems; Exploratory/Developmental Grant; Exposure to; FDA approved; Functional disorder; Funding; Future; Goals; Heavy-Chain Immunoglobulins; Hippocampus (Brain); Hour; Human; Hypertension; Hypoxia; Immunohistochemistry; Impaired cognition; Inbred BALB C Mice; Incidence; Infarction; Inflammation; Inflammatory Response; Ischemia; Knockout Mice; Lead; Learning; Lesion; Ligation; Link; MS4A1 gene; Measures; Mediating; Mediator of activation protein; Memory; Memory impairment; Mental Depression; Middle Cerebral Artery Occlusion; Modeling; Mouse Strains; Mus; Neurodegenerative Disorders; Outcome; Oxygen; Patients; Phenotype; Plasma; Process; Production; Quality of life; Risk; Risk Factors; Rodent; Short-Term Memory; Stroke; Structure; Survivors; Swimming; T-Cell Activation; Tail; Temperature; Testing; Time; Transgenic Mice; Vascular Dementia; Veins; Work; base; behavior test; chemokine; cohort; conditioned fear; cytokine; middle cerebral artery; morris water maze; mouse model; neuroinflammation; neurotoxic; neurotoxicity; novel; post stroke; prevent; research study; response; rituximab; sham surgery; stroke recovery

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.

描述（由申请人提供）：脑血管疾病是痴呆症的主要危险因素。全因痴呆（血管性痴呆、阿尔茨海默病和混合性疾病）在高达48%的中风幸存者中被诊断出，其中在中风后的第一年中约有20%的发病率。包括高血压、高胆固醇、糖尿病和年龄在内的几个中风风险因素也会独立增加痴呆症的风险。但多项研究表明，即使在控制了风险因素后，中风本身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延迟性认知功能障碍。在我们的模型中，小鼠由于大脑中动脉远端闭塞随后缺氧而经历DH中风。这是一个主要的皮质梗死。小鼠在中风后8天表现出正常的工作记忆，但在6-7周后，它们在工作和空间记忆方面出现缺陷，并伴有长期的炎症反应。这种炎症反应的一部分是B细胞出现在中风核心，在卵泡样结构。CNS中的这种结构最近与几种神经退行性疾病有关。我们建议在这里开发我们的模型，并测试是否B细胞在我们的模型中是致病的。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，并仔细表型中风的延迟炎症反应。我们假设神经炎症的致病特征先于认知障碍或与认知障碍同时发生。在目标2中，我们将使用B细胞耗竭抗体和B细胞敲除小鼠来研究认知功能障碍的发生是否需要B细胞。这项工作有很大的潜力产生重大影响，因为目前还没有公认的模型，而且对这种常见的衰弱性疾病的起源知之甚少。在这些实验结束时，我们将表征我们的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疗法的方法。 公共卫生相关性：中风是痴呆症的一个主要危险因素，但目前还没有建立动物模型来研究中风如何导致记忆障碍。在本申请中，我们建议开发这样的动物模型，并使用它来了解中风如何增加痴呆症的风险。我们希望发现机制，将导致治疗，可以预防痴呆症的中风幸存者。