Discovery of Plasma Biomarkers of Delayed Cerebral Ischemia after Subarachnoid Hemorrhage

蛛网膜下腔出血后迟发性脑缺血血浆生物标志物的发现

• 批准号: 10358411
• 负责人: Huimahn Alex Choi
• 金额: $ 65.58万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358411
• 关键词: Address; Affect; Area; Binding Proteins; Biological Assay; Biological Markers; Biological Process; Blinded; Blood; Blood Tests; Brain; Brain Aneurysms; Brain hemorrhage; Caring; Cerebral Aneurysm; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Characteristics; Clinical; Clinical Research; Clinical Trials Design; Complex; Complication; Data; Detection; Development; Exposure to; Focal Neurologic Deficits; Functional disorder; GDF8 gene; Glycoproteins; Goals; Health; Hospitals; Hour; Individual; Intensive Care Units; Interferon Type II; Intervention; Intervention Studies; Investigation; Lead; Leucine; Logistic Regressions; Measures; Morbidity - disease rate; Neurologic Deficit; Patients; Pattern; Performance; Phase; Plasma; Plasma Proteins; Population; Preparation; Process; Prospective cohort; Proteins; Proteomics; Public Health; Randomized Clinical Trials; Reproducibility; Research; Resource Allocation; Resources; Risk; Rupture; Sampling; Sensitivity and Specificity; Series; Subarachnoid Hemorrhage; Subarachnoid Space; Technology; Testing; Treatment Side Effects; United States National Institutes of Health; base; biomarker signature; biomarker validation; candidate marker; cohort; detection assay; detection method; effective therapy; guanylate; high risk; improved; individualized medicine; innovation; machine learning model; member; minimally invasive; neurexophilin; novel; patient stratification; prevent; prognostic; prognostic assays; prognostic performance; prognostic value; prognostication; prospective; protein biomarkers; public health relevance; response; risk stratification; scavenger receptor; screening; statistical and machine learning; validation studies

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.

亚蛛网膜下腔出血（SAH）是一种令人衰弱的类型的出血性中风类型，每年影响约50,000 美国。它是由脑动脉​​瘤的破裂引起的，并出血到蛛网膜下腔周围的空间 大脑。在那些在初次出血的人中，约有30％的患者出现严重的次要并发症 称为延迟的脑缺血（DCI）。 DCI通常发生在SAH后4-21天，并以局灶性为特征 神经缺陷。尽管DCI是SAH之后的潜在可预防发病率的贡献者，但介入 针对DCI的研究失败了。 SAH研究中的一个主要障碍是我们无法预测哪个SAH 患者将发展DCI。这导致所有SAH患者在密集型中长时间观察到 护理单元导致院内并发症发生率更高，治疗的潜在延迟和挪用 资源。此外，由于无法将SAH患者施加风险，随机临床试验需要 大量人群，昂贵，未能识别有效的治疗方法。包括 开发DCI的可能性较小，导致他们暴露于治疗中的不良副作用，没有 潜在的好处。鉴定会开发DCI的患者是未满足的临床需求。目前，有 没有具有足够敏感性和特异性的生物标志物作为临床有用的筛查测试。这个建议 因此，解决了主要的未满足临床需求：缺乏可以预测DCI的生物标志物。通过一个 一系列以前的临床研究，我们已经证明了SAH导致全身性增加 病理生理反应。我们表明，早期升高的病理生理反应，通过 测量血浆蛋白生物标志物与DCI的发展有关。我们已经扩展了这个 研究线和通过靶向蛋白质组学分析中的试点。首先，我们确定了6个血浆蛋白 SAH 48小时内DCI的预后。其次，使用多元统计和机器学习 方法是，我们确定了改善DCI预后的生物标志物特征（蛋白质的组合）。 在这项研究中，我们建议识别和确认其他候选生物标志物，开发和内部验证 蛋白质检测技术并在前瞻性队列中验证概念证明。性能特征 候选标记和签名将被确定并验证以供临床使用。发展 DCI预后的有效，微创生物标志物将导致SAH的显着改善 管理。 公共/健康/相关性：SAH对个人健康和整个经济产生不利影响。拟议的研究与公共卫生有关，因为它将改善DCI的预后（SAH后可避免的并发症）。这将导致发现预测DCI的蛋白质，改善我们对DCI的病理生理学的理解，并改善针对DCI的临床试验设计。