Novel Insights Into Cerebral Ischemic Pathophysiology In Humans

通过我们的卒中自然史研究（Clinicaltrials.gov No.NCT00009243），我们研究了2,700多名参与者，以了解更多关于卒中的信息，并获得可能作为未来研究基础的信息。该方案使我们能够：1）建立脑血管疾病（卒中）患者的注册表; 2）描述急性卒中和短暂性脑缺血发作（TIA）的自然史（短暂性脑缺血发作是一种导致短时间内卒中症状的脑血流中断）; 3）评估数据以产生未来研究的想法。 MRI通过提供高度敏感和特异的疾病标志物，提高了我们对急性卒中患者的诊断和分层能力。基于成像的中风表型增加了客观性;然而，它们仍然是对中风引起的复杂生物系统的过度简化。下一代测序在通量和速度上有了前所未有的提高，为探索使用急性MRI分层的患者对卒中的复杂生物学反应提供了机会。基于导致成像异常的生物学将反映在外周血中的差异基因表达和微小RNA中的前提，下一代测序将用于鉴定和表征与成像表型相关的生物系统。将开发一种系统生物学方法来更好地描述中风，并希望更好地区分那些我们可以预期对干预有良好反应的患者，以及那些有进一步恶化风险的患者。 基于成像的卒中预后和治疗反应的预测因子对于成像生物标志物在药物开发中的效用和验证是必要的。有用的模型是那些可以区分患者的良好结果与不良结果，那些谁收到有效的治疗，那些谁没有，和治疗反应者从无反应者。我们正在研究几种预测模型。这些预测模型可用于急性治疗的开发、选择和使用。我们发现，从治疗前弥散加权成像到治疗后FLAIR的病变体积变化可以区分患者在接受有效的急性卒中治疗时的良好和不良结局，即，静脉注射tPA。因此，病变体积变化可能是卒中治疗发展中临床反应的有用标志物。 作为卒中分支的一部分，对血管性认知障碍和白色疾病非常感兴趣，最初由神经血管脑成像单位（NVBI）发起。研究人员继续访问数据和图像，以研究白色疾病和血脑屏障破坏。为此启动了一项新方案（PI Clinton Wright），但大流行导致所有研究相关活动暂停。通过作为该项目的一部分收集的数据，继续研究中风对白色疾病和认知障碍的影响。 在上一个财政年度，我们的工作主要集中在以下方面： 轻微斯托克（次）： 患者通常以非常轻微和潜在的非致残性或波动性症状出现在急诊科。这些可能导致延迟诊断和/或停止治疗。我们正在前瞻性地研究使用MRI来识别那些最有可能从干预中受益的患者。招生工作仍在继续，今年出版了第一份《时代》手稿。 机械栓子切除术后的继发性损伤（GUARDS）： 在大血管闭塞（最严重的卒中类型之一）患者中，已证明通过机械方法清除凝块是有效的。然而，许多患者尽管成功进行了机械干预，但结果仍不佳。我们正在使用MRI来研究和分类大血管再通后发生的损伤类型。在过去的一年里，我们通过合作发表了一项关于血管损伤后水肿发生的开创性研究。在我们的前瞻性观察性研究中已经取得了重大进展，以确定血脑屏障破坏，反常增加血流量，水肿和出血的标志物。我们已经设计了一个治疗水肿的试验，并正在积极采购干预所需的生物制剂 早期破坏血脑屏障（HARM）： 这是一个长期的项目，在该计划与许多出版物。结合我们对创伤性脑损伤的研究，我们发现了造影剂泄漏到脑膜附近血管周围充满液体的空间的证据。增强后可立即发现强化。手稿正在审查中，第二次高分辨率成像回顾性研究正在进行中。我们正在设计一项前瞻性研究，以比较急性卒中患者和对照人群，并测量清除率作为脑功能受损的标志物

Through our Natural History of Stroke study (Clinicaltrials.gov No. NCT00009243) we have studied over 2,700 participants in order to learn more about stroke and obtain information that may serve as the basis for future investigations. This protocol has allowed us to 1) establish a registry of patients with cerebrovascular disease (stroke); 2) characterize the natural history of acute stroke and transient ischemic attacks (TIA) an interruption of blood flow to the brain that causes stroke symptoms for a short period of time); and 3) evaluate the data to generate ideas for future studies. MRI has improved our ability to diagnose and stratify patients with acute stroke by providing highly sensitive and specific markers of the disease. Imaging based phenotypes of stroke increase objectivity; however, they remain a gross oversimplification of the complex biological system set in motion by a stroke. Next generation sequencing, with unprecedented improvement in throughput and speed, provides an opportunity to probe the complex biological response to stroke in patients stratified using acute MRI. Based on the premise that the biology responsible for the imaging abnormalities will be reflected in differential gene expression and micro RNA in peripheral blood, next generation sequencing will be used to identify and characterize the biological systems relevant to the imaging phenotype. A systems biology approach will be developed to better describe stroke, and hopefully, better differentiate those patients in whom we can expect a favorable response to an intervention, from those at risk of further deterioration. Imaging based predictors of stroke outcome and response to therapy are necessary for the utility and validation of imaging biomarkers in drug development. Useful models are those that can distinguish patients destined for good outcomes versus poor outcomes, those who received effective therapy from those who did not, and treatment responders from non-responders. We are investigating several predictive models. These prediction models may be useful for the development, selection and use of acute therapies. We found that change in lesion volume from pre-treatment diffusion-weighted imaging to post-treatment FLAIR can discriminate between patients destined for good and poor outcomes when treated with effective acute stroke therapy, i.e., intravenous tPA. Thus, lesion volume change may be a useful marker of clinical response in the stroke therapy development. As part of the Stroke Branch, there is significant interested in vascular cognitive impairment and white matter disease, originally initiated by the Neuro Vascular Brain Imaging Unit (NVBI). Investigators continue to access data and images to study white matter disease and BBB disruption. A new protocol was initiated for this purpose (PI Clinton Wright), but the pandemic caused a pause in all study related activity. Work continues to study the impact of stroke on white matter disease and cognitive impairment through data collected as part of this project. During this past fiscal year, our efforts have largely been focused as follows: Minor stoke (TIMES): Patients often present to the emergency department with very mild and potentially non-disabling or fluctuating symptoms. These may lead to delayed diagnosis and/or withholding of treatment. We are prospectively studying the use of MRI in identifying those patients who would most likely benefit from intervention. Enrollment is continuing and the first TIMES manuscript was published this year. Secondary damage post mechanical embolectomy (GUARDS): In patients with large vessel occlusion, one of the most severe categories of stroke, removal of the clot by mechanical means has proven to be efficacious. However, many patients go on to poor outcome despite successful mechanical intervention. We are using MRI to study and classify the kind of injury that occurs following recanalization of the large vessel. This past year, we have published, through collaboration, a seminal study on the genesis of edema following vascular injury. Significant progress has been made in our prospective observational study to identify markers of blood-brain barrier disruption, paradoxical increased blood flow, edema, and hemorrhage. We have designed a trial to treat edema and are actively working on procuring the biologic needed for the intervention Early disruption of the blood brain barrier (HARM): This has been a long-standing project within the program with numerous publications. In conjunction with our research in traumatic brain injury, we have found evidence of leakage of contrast agent into fluid filled spaces surrounding vessels near the meninges. We can detect the enhancement immediately after contrast administration. A manuscript is under review, a second retrospective study of high-resolution imaging is under way. We are designing a prospective study to compare acute stroke patients to a control population, and measure the rate of clearance as a marker of impaired cerebral lymphatics