Delayed cognitive impairment after stroke

中风后迟发性认知障碍

基本信息

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
项目类别：
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&apos 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

项目摘要

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。高达 48% 的中风幸存者被诊断为全因痴呆（血管性痴呆、阿尔茨海默氏病和混合性疾病），其中约 20% 的发病率发生在中风后第一年。一些中风危险因素，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，即使在控制了危险因素之后，仅中风仍然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，其中中风会导致迟发性认知功能障碍。在我们的模型中，小鼠由于远端大脑中动脉闭塞和缺氧而发生 DH 中风。这导致主要是皮质梗塞。中风后 8 天，小鼠表现出正常的工作记忆，但 6-7 周后，它们的工作记忆和空间记忆出现缺陷，并伴有长期的炎症反应。这种炎症反应的一部分是在中风核心、滤泡样结构中出现 B 细胞。最近发现中枢神经系统中的此类结构与多种神经退行性疾病有关。我们在此建议开发我们的模型并测试 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，并仔细分析对中风的延迟炎症反应的表型。我们假设神经炎症的致病特征将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 细胞敲除小鼠来探究认知功能障碍的发生是否需要 B 细胞。这项工作很有可能产生重大影响，因为目前还没有公认的模型，而且人们对这种常见且令人衰弱的疾病的起源知之甚少。在这些实验结束时，我们将描述模型中的认知缺陷和炎症反应，并了解 B 细胞是否是致病原因。这些信息将使我们能够对中风后痴呆的机制进行重要的未来研究，此外还将提供一种测试潜在疗法的方法。公众健康相关性：中风是痴呆症的主要危险因素，但目前还没有建立的动物模型来研究中风如何导致记忆障碍。在此应用中，我们建议开发这样的动物模型，并用它来了解中风如何增加痴呆症的风险。我们希望找到能够预防中风幸存者痴呆症的治疗机制。