Stroke and aPL: Community-Based Clinicopathological Study

描述（由申请人提供）：我们建议研究抗磷脂抗体（aPL）在病理证实的缺血性脑梗死发展中的作用和机制。我们的主要目的是确定aPL是否是缺血性脑梗死的独立危险因素/预测因子。由于目前存在关于哪种aPL检测或哪种aPL检测组合最能预测随后的缺血性脑血管疾病的争议，因此将进行一系列（组合）aPL检测。我们还将分析aPL在不同梗死部位和亚型（小血管、大血管、无动脉粥样硬化的血栓性）中的作用。我们还将确定短暂性与持久性aPL阳性随时间的重要性（抗磷脂抗体综合征的诊断实验室标准是aPL阳性的持久性）以及aPL阳性检测次数的频率和重要性（0到4）。其他目标包括确认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耐药性，抗膜联蛋白抗体和aPL结合22-糖蛋白I （22GPI）的结构域I（血栓形成结构域）。我们建议在同意在死后捐献大脑的老年人中进行一项基于社区的研究。我们的研究能够检测到病理证实的缺血性卒中主要终点的比值比（OR）为2或更大。我们有足够的能力来比较多个和单个aPL阳性，并在尸检中评估aPL相关脑血管疾病的机制。拟议的研究将利用两项正在进行的大型纵向临床病理队列研究的死前生物标本、临床和死后数据：宗教秩序研究（P30AG10161, R01AG15819）有1100多名参与者和约425例脑尸检，以及Rush记忆和衰老项目（R01AG17917）有1200多名参与者和约250例脑尸检。这将是首个针对经病理证实的缺血性脑血管病中aPL所带来的风险的大型、充分研究的社区老年人队列的系统研究。此外，将首次在社区为基础的充分研究的前瞻性队列中检测非aCL的aPL。我们的研究也将允许直接比较其他前瞻性群组研究(没有病理学)发现一个积极的基线aPL是一个独立的危险因素:(a)静脉血栓(深静脉血栓形成和肺栓塞)在男性(医师健康研究)(金斯伯格等人1992),(b)心肌梗死和中风在男性(火奴鲁鲁心脏研究)(2001年Brey等),和(c)中风和TIA女性而不是男性(弗雷明汉队列和后代研究)(Janardhan等2004)。公共卫生相关性：中风是老年人中非常常见的健康问题，与包括高死亡率和高发病率在内的严重后果相关，并且随着老年人中风患病率的上升，给社会造成巨大负担。由于更好地了解导致中风的机制比以往任何时候都更重要，我们将重点放在抗磷脂抗体（aPL）上，因为它越来越被认为是与中风相关的相对常见的血液蛋白。我们建议对临床特征明确且来尸检的老年人进行首次大型社区研究，研究所有四种临床使用的aPL与尸检证实的脑梗死之间的关系，以及机制研究，以进一步阐明aPL发生缺血性卒中的基础；这项研究的发现有可能对理解导致中风的生物学机制产生重大影响，并对我们治疗和预防这种疾病的能力产生重大影响。

DESCRIPTION (provided by applicant): 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 22-glycoprotein I (22GPI). 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). PUBLIC HEALTH RELEVANCE: Stroke is a very common health problem in older persons, is associated with serious consequences including a high rate of mortality and significant morbidity, and causes a tremendous burden to society with the prevalence of stroke in older persons on the rise. As a better understanding of mechanisms leading to stroke is more important than ever, we are focusing on antiphospholipid antibodies (aPL) as a increasingly recognized as relatively common blood proteins that are associated with stroke. We propose the first, large community-based study of older persons well-characterized clinically and who come to autopsy, of the association of all four clinically utilized aPL with autopsy-proven brain infarction, along with mechanistic studies, to further elucidate the basis for developing ischemic stroke with aPL; the findings from this study have the potential to have a large impact on the understanding of biologic mechanisms leading to stroke, and on our ability to treat, and one day, prevent this condition.