GENETICS OF EARLY NEUROLOGICAL INSTABILITY AFTER ISCHEMIC STROKE (GENISIS)

缺血性中风后早期神经系统不稳定的遗传学（GENISIS）

• 批准号: 10395870
• 负责人: Laura Heitsch
• 金额: $ 9.22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395870
• 关键词: Acute; Adult; Age; Alteplase; Award; Blood Pressure; Brain; Brain Injuries; Brain Ischemia; Caring; Cause of Death; Cerebrovascular Disorders; Clinical; Code; Complex; Data Set; Deterioration; Development; Diagnostic; Emergency Department Physician; Emergency Medicine; Familiarity; Fellowship; Frequencies; Genes; Genetic; Genetic Variation; Genomics; Goals; Hemorrhage; Hour; Human; International; Ischemic Stroke; Link; Measures; Mentors; Molecular; Neurologic; Neurologic Deficit; Neurological emergencies; Neurological outcome; Neurology; Outcome; Outcome Measure; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Play; Recovery; Research; Research Methodology; Research Personnel; Research Proposals; Role; Sampling; Severities; Stroke; Structure; Training; United States National Institutes of Health; Variant; acute stroke; artery occlusion; base; career development; cohort; disability; endophenotype; experience; genetic analysis; genetic variant; genome wide association study; improved; improved outcome; injury recovery; multidisciplinary; neurovascular injury; novel; patient oriented research; post stroke; programs; stroke outcome; stroke patient; therapeutic target

Stroke is the 2nd leading cause of death throughout the world, and the leading cause of long-term disability. Ischemic stroke, the most common subtype, is caused by occlusion of an artery in the brain, resulting in the abrupt development of neurological deficits. In the first hours after stroke onset, neurological deficits can be highly unstable, with many patients improving while others deteriorate. These early changes have a major impact on long-term outcome. In fact, changes in neurologic deficits during the first 24 hours account for 40% of the variance of the 90-day modified Rankin Scale (the most widely accepted stroke outcome measure) in patients treated with tissue plasminogen activator (tPA). In my preliminary analyses, it was discovered that baseline clinical factors account for very little of the variation seen in neurologic deficits during the first 24 hours while genetic factors appear to account for over 50%. Given the finding that genetics influence the variance of early neurologic changes, it is my central hypothesis that genetics play a significant role in determining the early outcomes experienced by patients suffering from acute ischemic stroke (AIS). As a fellowship-trained emergency physician subspecializing in neurologic emergencies, my long term goal is to develop an independent research program to investigate genetic influences on acute neurological emergencies to improve patient outcomes. In order to achieve this goal, I have developed two short term goals that will be achieved during the award period: 1) to become technically proficient in genetic/genomic analysis and research methodology and 2) to develop greater familiarity with cellular and molecular mechanisms involved with brain and neurovascular injury following AIS. In order to achieve these goals, I have crafted a multidisciplinary team of mentors, advisors and collaborators. Over the past several years, I have been working closely with my primary mentor, Dr. Jin-Moo Lee (Director of the Cerebrovascular Disease and Neurointensive Care Sections in Neurology) and my secondary mentor Dr. Carlos Cruchaga (a human geneticist with expertise in complex genetic analyses), to examine possible genetic influences on the early neurologic outcomes after acute ischemic stroke. They both have a strong track record of mentoring junior investigators and bring complimentary backgrounds and expertise to my mentoring and career development. Under the guidance of Drs. Jin-Moo Lee and Carlos Cruchaga, I will engage in structured coursework, advanced training and independent study to become proficient in patient-oriented research, genetic analysis, and research methodology. To capture early neurological change following AIS, we have developed a novel quantitative endophenotype, termed ΔNIHSS24h, which is a measure of the change in NIH stroke scale (NIHSS) score between baseline (<6 hours after onset) and 24 hours. Using a cohort of AIS patients treated with IV tPA that will consist of 3,000 phenotyped subjects drawn from an international multicenter consortium and representing the largest such dataset of early stroke outcomes linked to genetics in the world, I will explore the following: Aim 1: To perform genome-wide association studies (GWAS), examining early neurological change (ΔNIHSS24h) after AIS. Using the first 3,000 tPA-treated AIS patients (Discovery cohort, estimated accrual September, 2016), GWAS of common & rare coding variants will be performed to discover single variants, genes, and pathways associated with ΔNIHSS24h. An additional 3,000 tPA-treated patients (Replication Cohort) will be accrued by September 2019, and used to replicate findings from the initial Discovery cohort. Aim 2: To use extreme phenotype sampling with low frequency functional variants of large effect size for early neurological deterioration (Aim 2a) or improvement (Aim 2b) after AIS. We will select patients with the most extremes of ΔNIHSS24h, representing those with greatest deterioration or improvement, and compare to matched controls with little change in ΔNIHSS24h. Replication of the top hits in each extreme will be performed in the overall cohort with gene-based sequencing and analysis. Of those patients who deteriorate, we will determine which genetic variants associate with hemorrhagic transformation and which do not. This research plan reflects my multidisciplinary training and career development in emergency medicine, neurologic emergencies, and genetics. It is a long-term objective that the unbiased approach presented in this research proposal will reveal important variants, genes and pathways involved in acute brain ischemia, possibly leading to both diagnostic and therapeutic targets to improve outcomes following stroke.

中风是全世界第二大死因，也是导致长期残疾的主要原因。 缺血性中风是最常见的亚型，是由大脑动脉闭塞引起的，导致 神经功能缺损的突然发展。在中风发作后的最初几个小时内，神经功能缺损可能会 高度不稳定，许多患者病情好转，而另一些患者病情恶化。这些早期的变化有一个 对长期结果产生重大影响。事实上，前 24 小时内神经功能缺陷的变化是造成 90 天改良兰金量表（最广泛接受的中风结果测量）方差的 40% 接受组织纤溶酶原激活剂（tPA）治疗的患者。经过我的初步分析，我发现 基线临床因素对前 24 年间神经功能缺损的变化影响很小 而遗传因素似乎占了50%以上。鉴于遗传学影响的发现 早期神经系统变化的差异，我的中心假设是遗传学在其中发挥着重要作用 确定急性缺血性中风（AIS）患者的早期结果。 作为一名接受过专科培训的神经科急诊急诊医师，我的长期目标是 目标是制定一个独立的研究计划来调查遗传对急性发作的影响 神经系统紧急情况，以改善患者的治疗效果。为了实现这个目标，我开发了 奖励期间将实现的两个短期目标： 1) 精通技术 遗传/基因组分析和研究方法，2) 更加熟悉细胞 以及 AIS 后脑和神经血管损伤涉及的分子机制。为了 为了实现这些目标，我组建了一支由导师、顾问和合作者组成的多学科团队。超过 在过去的几年里，我一直与我的主要导师 Jin-Moo Lee 博士（该中心主任）密切合作。 神经病学脑血管疾病和神经重症监护科）和我的第二导师 Dr. 卡洛斯·克鲁查加（Carlos Cruchaga）（一位具有复杂遗传分析专业知识的人类遗传学家），检查可能的遗传 急性缺血性卒中后早期神经系统结局的影响。他们都有着良好的记录 指导初级研究人员，并为我的指导和研究带来互补的背景和专业知识 职业发展。 在博士的指导下。 Jin-Moo Lee 和 Carlos Cruchaga，我将参加结构化课程， 高级培训和独立学习，精通以患者为导向的研究、基因分析、 和研究方法。为了捕捉 AIS 后的早期神经变化，我们开发了一种新颖的方法 定量内表型，称为 ΔNIHSS24h，它是 NIH 卒中量表变化的衡量标准 (NIHSS) 基线（发病后 6 小时内）和 24 小时之间的评分。使用接受治疗的 AIS 患者队列 IV tPA 将由来自国际多中心联盟的 3,000 名表型受试者组成 并代表了世界上与遗传学相关的最大的早期中风结果数据集，我将探索 下列： 目标 1：进行全基因组关联研究 (GWAS)，检查早期神经系统变化 AIS 之后 (ΔNIHSS24h)。使用首批 3,000 名接受 tPA 治疗的 AIS 患者（发现队列，估计应计 2016 年 9 月），将进行常见和罕见编码变体的 GWAS 来发现单一变体， 与 ΔNIHSS24h 相关的基因和途径。另外 3,000 名接受 tPA 治疗的患者（复制 Cohort）将于 2019 年 9 月累积，并用于复制最初的 Discovery 队列的研究结果。 目标 2：使用具有大效应量的低频功能变异的极端表型采样 用于 AIS 后早期神经功能恶化（目标 2a）或改善（目标 2b）。我们会选择患者 ΔNIHSS24h 的最极端，代表恶化或改善最大的那些，以及 与匹配对照相比，ΔNIHSS24h 变化很小。每个极端的热门点击的复制将是 在整个队列中进行基于基因的测序和分析。在那些病情恶化的患者中， 我们将确定哪些遗传变异与出血性转化相关，哪些则不然。 该研究计划反映了我在紧急情况下的多学科培训和职业发展 医学、神经急症和遗传学。公正的方法是一个长期目标 本研究提案中提出的内容将揭示急性脑中涉及的重要变异、基因和途径 缺血，可能导致诊断和治疗目标改善中风后的结果。

项目成果

Quantitative Serial CT Imaging-Derived Features Improve Prediction of Malignant Cerebral Edema after Ischemic Stroke.

• DOI: 10.1007/s12028-020-01056-5
• 发表时间: 2020-12
• 期刊: Neurocritical care
• 影响因子: 3.5
• 作者: Foroushani HM;Hamzehloo A;Kumar A;Chen Y;Heitsch L;Slowik A;Strbian D;Lee JM;Marcus DS;Dhar R
• 通讯作者: Dhar R

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

• DOI: 10.1177/17474930211007288
• 发表时间: 2022-03
• 期刊: International journal of stroke : official journal of the International Stroke Society
• 作者: Lindgren AG;Braun RG;Juhl Majersik J;Clatworthy P;Mainali S;Derdeyn CP;Maguire J;Jern C;Rosand J;Cole JW;Lee JM;Khatri P;Nyquist P;Debette S;Keat Wei L;Rundek T;Leifer D;Thijs V;Lemmens R;Heitsch L;Prasad K;Jimenez Conde J;Dichgans M;Rost NS;Cramer SC;Bernhardt J;Worrall BB;Fernandez-Cadenas I;International Stroke Genetics Consortium
• 通讯作者: International Stroke Genetics Consortium

CSF-Based Volumetric Imaging Biomarkers Highlight Incidence and Risk Factors for Cerebral Edema After Ischemic Stroke.

基于脑脊液的体积成像生物标志物突出了缺血性中风后脑水肿的发病率和危险因素。

• DOI: 10.1007/s12028-023-01742-0
• 发表时间: 2024
• 期刊: Neurocritical care
• 影响因子: 3.5
• 作者: Bui,Quoc;Kumar,Atul;Chen,Yasheng;Hamzehloo,Ali;Heitsch,Laura;Slowik,Agnieszka;Strbian,Daniel;Lee,Jin-Moo;Dhar,Rajat
• 通讯作者: Dhar,Rajat

Accelerating Prediction of Malignant Cerebral Edema After Ischemic Stroke with Automated Image Analysis and Explainable Neural Networks.

• DOI: 10.1007/s12028-021-01325-x
• 发表时间: 2022-04
• 期刊: Neurocritical care
• 影响因子: 3.5
• 作者: Foroushani HM;Hamzehloo A;Kumar A;Chen Y;Heitsch L;Slowik A;Strbian D;Lee JM;Marcus DS;Dhar R
• 通讯作者: Dhar R

Automated Measurement of Net Water Uptake From Baseline and Follow-Up CTs in Patients With Large Vessel Occlusion Stroke.

• DOI: 10.3389/fneur.2022.898728
• 发表时间: 2022
• 期刊: Frontiers in neurology
• 影响因子: 3.4