Stroke and aPL: Community-Based Clinicopathological Study

项目摘要 我们建议研究抗磷脂抗体(APL)在糖尿病发生发展中的作用和机制。 经病理证实为缺血性脑梗塞。我们的主要目标是确定APL是否是一种 缺血性脑梗塞的独立危险因素/预测因子。一组(组合)APL化验将是 进行，因为目前关于APL检测或APL检测的组合是最好的存在争议 预测后续的缺血性脑血管疾病。我们还将分析APL在各种情况下的作用 梗塞部位和亚型(小血管、大血管、血栓形成，无动脉粥样硬化)。 我们还将确定暂时性APL阳性与持久APL阳性随时间变化的意义(诊断 抗磷脂抗体综合征的实验室标准是APL阳性的持续性)和 APL阳性次数的频率和意义(0~4次)。其他目标包括 确认关于APL可能发挥作用的潜在重要机制的先前初步数据， 特别是通过改变膜联蛋白A5的抗性、抗膜联蛋白抗体和APL与结构域I( 2-糖蛋白I(2GPI)的血栓形成域)。 我们建议在同意捐献大脑的老年人中开展一项基于社区的研究 他们的死亡。我们的研究能力很强，能够检测出初选的优势比(OR)为2或更大 经病理证实的缺血性中风的终点。我们有足够的能力来比较多个和一个 APL阳性，并在尸检时评估APL相关性脑血管疾病的机制。 拟议的研究将利用死前生物样本、临床和死后数据。 来自两项正在进行的大型纵向临床-病理队列研究：宗教教团研究 (P30AG10161，R01AG15819)，迄今已有1100多名参与者和约425例脑部尸检，以及 快速记忆和衰老项目(R01AG17917)有1200多个粒子和大约250个大脑 到目前为止的尸检。这将是第一次对一个大型的、经过充分研究的以社区为基础的 APL在病理证实的缺血性脑血管疾病中的风险的老年个体。 此外，除ACL外，APL将首次在经过充分研究的社区预期队列中进行检测- 以主题为基础。 我们的研究还将允许与其他前瞻性队列研究(不含病理学)进行直接比较， 单一阳性基线APL是以下因素的独立危险因素：(A)静脉血栓(深静脉 血栓形成和肺栓塞)男性(医生健康研究)(Ginsburg等人，1992)，(B)MI和 男性中的中风(火奴鲁鲁心脏研究)(Brey等人，2001年)，以及(C)女性中的中风和短暂性脑缺血发作，但男性没有 (Framingham Cohort和后代研究)(Janardhan等人，2004年)。

Project Summary We propose to investigate the role and mechanisms of antiphospholipid antibodies (aPL) in the development of pathologically-proven ischemic brain infarction. Our primary objective is to determine whether aPL are an independent risk factor/predictor for ischemic brain infarction. A battery (portfolio) of aPL assays will be performed as there is currently controversy over which aPL assay or combination of aPL assays are best predictive of subsequent ischemic cerebrovascular disease. We will also analyze the role of aPL for various infarct locations and subtypes (small vessel, large vessel, thrombotic in the absence of atherosclerosis). We will also determine the significance of transient vs. persistent aPL positivity over time (a diagnostic laboratory criteria for the antiphospholipid antibody syndrome is persistence of aPL positivity) and the frequency and significance of the number of aPL positive assays (zero to 4). Additional objectives include confirming prior preliminary data on potentially important mechanisms by which aPL may play a role, specifically through altered annexin A5 resistance, anti-annexin antibodies, and aPL binding to domain I (the thrombogenic domain) of ¿2-glycoprotein I (¿2GPI). We propose a community-based study among older individuals who have agreed to donate their brains upon their death. Our study is well-powered to be able to detect an odds ratio (OR) of 2 or greater for the primary endpoint of pathologically-proven ischemic stroke. We have adequate power to compare multiple to single aPL positivity, and to assess mechanisms of aPL associated cerebrovascular disease at autopsy. The proposed study will take advantage of ante-mortem biologic specimens, clinical and post-mortem data from two ongoing large, longitudinal clinical-pathologic cohort studies: The Religious Orders Study (P30AG10161, R01AG15819) with more than 1,100 participants and about 425 brain autopsies to date, and the Rush Memory and Aging Project (R01AG17917) with more than 1,200 particpants and about 250 brain autopsies to date. This will be the first systematic study of a large, well-studied community-based cohort of older individuals for the risk conferred by aPL in pathologically-proven ischemic cerebrovascular disease. Also, for the first time, aPL other than aCL will be assayed in a well-studied prospective cohort of community- based subjects. Our study will also allow a direct comparison to other prospective cohort studies (without pathology) that found a single positive baseline aPL to be an independent risk factor for: (a) venous blood clots (deep venous thrombosis and pulmonary embolism) in men (Physicians Health Study) (Ginsburg et al 1992), (b) MI and stroke in men (Honolulu Heart Study) (Brey et al 2001), and (c) Stroke and TIA in women but not men (Framingham Cohort and Offspring Study)(Janardhan et al 2004).