Discovery of Plasma Biomarkers of Delayed Cerebral Ischemia after Subarachnoid Hemorrhage

蛛网膜下腔出血(SAH)是一种使人衰弱的出血性中风，每年影响约50,000人 美国。它是由脑动脉瘤破裂和周围蛛网膜下腔出血引起的。 大脑。在那些在最初出血中幸存下来的患者中，约30%的患者会出现严重的继发性并发症。 称为迟发性脑缺血(DCI)。DCI通常发生在SAH后4-21天，以局灶性脑缺血为特征 神经缺陷。尽管DCI是SAH后发病率的潜在可预防因素，但干预性 针对DCI的研究已经失败。SAH研究的一个主要障碍是我们无法预测 病人会发展成DCI。这导致所有SAH患者在重症监护室接受长时间的观察 护理单元导致更高的住院并发症、潜在的治疗延误和挪用 资源。此外，由于无法对SAH患者进行风险分层，随机临床试验需要 人口众多，费用昂贵，而且未能找到有效的治疗方法。包括符合以下条件的科目 不太可能发生DCI，导致他们暴露在使用NO治疗的不良副作用中 潜在的好处。识别将发展为DCI的患者是一项尚未得到满足的临床需求。目前，有以下几种 没有足够的敏感性和特异性的生物标志物作为临床有用的筛查试验。这项建议 因此解决了一个主要的未得到满足的临床需求：缺乏可以预测DCI的生物标记物。通过一个 之前的一系列临床研究，我们已经证明SAH会导致系统性高血压的增加。 病理生理反应。我们表明，早期升高的病理生理反应，通过 血浆蛋白生物标志物的测定与DCI的发生有关。我们已经扩大了这一范围 通过在试点队列中进行有针对性的蛋白质组学分析。首先，我们鉴定了6种血浆蛋白 可预测SAH后48小时内DCI的预后。第二，使用多元统计和机器学习 方法，我们确定了一个改善DCI预后的生物标记物标志(蛋白质的组合)。 在这项研究中，我们建议识别和确认更多的候选生物标志物，开发和内部验证 蛋白质检测技术，并在预期队列中验证概念证明。性能特征 候选标记物和签名将被确定并验证用于临床。发展中的 用于DCI预测的有效、微创生物标志物将显著改善SAH 管理层。 公共/健康/相关性：SAH对个人健康和整个经济都有不利影响。这项拟议的研究与公共卫生相关，因为它将改善DCI(SAH后可避免的并发症)的预后。这将导致发现预测DCI的蛋白质，提高我们对DCI的病理生理学的理解，并导致针对DCI的临床试验设计的改进。

Subarachnoid Hemorrhage (SAH) is a debilitating type of hemorrhagic stroke that affects ~50,000 annually in the US. It is caused by a rupture of a cerebral aneurysm and hemorrhage into the subarachnoid space around the brain. In those who survive the initial bleed, ~30% of the patients develop a serious secondary complication called delayed cerebral ischemia (DCI). DCI typically occurs at 4-21 days after SAH and is characterized by focal neurological deficits. Though DCI is a potentially preventable contributor to morbidity after SAH, interventional studies targeting DCI have failed. A major hindrance in SAH research is our inability to prognosticate which SAH patient will develop DCI. This leads to all SAH patients being observed for prolonged periods in the intensive care unit leading to higher rates of in-hospital complications, potential delay in treatment and misappropriated resources. Furthermore, because of the inability to risk-stratify SAH patients, randomized clinical trials require large populations, are expensive and have failed to identify effective treatments. Inclusion of subjects who are less likely to develop DCI, have led to exposing them to unwanted side effects from the treatment with no potential benefits. Identification of patients who will develop DCI is an unmet clinical need. Currently, there are no biomarkers with sufficient sensitivity and specificity to serve as a clinically useful screening test. This proposal therefore addresses a major unmet clinical need: a lack of a biomarker that can prognosticate DCI. Through a series of previous clinical studies, we have demonstrated that SAH leads to increases in systemic pathophysiological responses. We showed that an early elevated pathophysiological response, quantified by measuring plasma protein biomarkers, was associated with the development of DCI. We have expanded this line of investigation and via targeted proteomic profiling in pilot cohorts. First, we identified 6 plasma proteins that are prognostic of DCI within 48 hours of SAH. Second, using multivariate statistical and machine learning approaches, we identified a biomarker signature (a combination of proteins) that improved DCI prognostication. In this study, we propose to identify and confirm additional candidate biomarkers, develop and internally validate protein detection technology and verify the proof of concept in a prospective cohort. Performance characteristics of the candidate markers and the signature will be determined and validated for clinical use. Development of effective, minimally invasive biomarkers for DCI prognostication will lead to significant improvements in SAH management. Public/Health/Relevance: SAH has detrimental effects on individual health and the economy as a whole. The proposed research is relevant to public health as it will improve prognostication of DCI (an avoidable complication after SAH). This would lead to discovery of proteins that prognosticate DCI, improve our understanding of the pathophysiology of DCI and lead to improvements in design of clinical trials targeting DCI.