Novel Insights Into Cerebral Ischemic Pathophysiology In Humans

通过我们的中风自然史研究(ClinicalTrials.gov No.NCT00009243)我们对2700多名参与者进行了研究，以便更多地了解中风，并获得可能作为未来研究基础的信息。这一方案使我们能够1)建立脑血管疾病(中风)患者的登记；2)表征急性中风和短暂性脑缺血发作(TIA)的自然病史(即脑血流中断，导致短时间内出现中风症状)；以及3)评估数据，为未来的研究产生想法。 核磁共振通过提供高度敏感和特异的疾病标志物，提高了我们诊断急性中风患者并对其进行分层的能力。基于成像的中风表型增加了客观性；然而，它们仍然是对中风所启动的复杂生物系统的严重过度简单化。下一代测序在吞吐量和速度方面都有了前所未有的改进，为探索使用急性MRI分层的中风患者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差异基因表达和微小RNA的前提下，下一代测序将被用于识别和表征与成像表型相关的生物系统。一种系统生物学方法将被开发出来，以更好地描述中风，并有望更好地区分那些我们可以预期对干预措施有良好反应的患者和那些有进一步恶化风险的患者。 基于成像的中风预后和治疗反应的预测指标对于成像生物标记物在药物开发中的实用性和有效性是必要的。有用的模型是那些可以区分注定要获得良好结果和糟糕结果的患者，那些接受了有效治疗的患者和没有接受治疗的患者，以及治疗应答者和无应答者。我们正在研究几个预测模型。这些预测模型可能对急性疗法的开发、选择和使用有用。我们发现，从治疗前弥散加权成像到治疗后FLAIR，病变体积的变化可以区分接受有效的急性卒中治疗(即静脉注射tPA)的患者的预后好坏。因此，病变体积的变化可能是卒中治疗进展中临床反应的一个有用的标志。 作为卒中分支的一部分，人们对血管认知障碍和白质疾病非常感兴趣，最初是由神经血管脑成像单位(NVBI)发起的。调查人员继续获取数据和图像，以研究白质疾病和血脑屏障中断。为此目的启动了一项新的议定书(Pi Clinton Wright)，但大流行导致所有与研究相关的活动暂停。作为该项目的一部分，工作继续通过收集的数据来研究中风对脑白质疾病和认知障碍的影响。 在过去的财政年度，我们的工作主要集中在以下几个方面： 次要中风(次数)： 患者到急诊科就诊时经常出现非常轻微的、潜在的非致残性或波动的症状。这可能会导致延迟诊断和/或停止治疗。我们正在前瞻性地研究MRI在识别最有可能从干预中受益的患者方面的应用。招生工作仍在继续，今年首次发表了手稿。 机械取栓术后的二次损伤(警卫)： 大血管闭塞是中风最严重的类别之一，在患者中，通过机械手段清除血栓已被证明是有效的。然而，许多患者尽管成功地进行了机械干预，结果仍然很差。我们正在使用核磁共振对大血管再通后发生的损伤类型进行研究和分类。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浮肿的开创性研究。我们的前瞻性观察性研究在确定血脑屏障破坏、反常的血流增加、水肿和出血的标志物方面取得了重大进展。我们已经设计了一项治疗浮肿的试验，并正在积极努力获取干预所需的生物 血脑屏障早期破坏(危害)： 这是该计划中的一个长期项目，有许多出版物。结合我们对创伤性脑损伤的研究，我们发现了造影剂渗入脑膜附近血管周围充满液体的空间的证据。我们可以在注射造影剂后立即检测到增强。一份手稿正在审查中，第二次高分辨率成像的回顾研究正在进行中。我们正在设计一项前瞻性研究，将急性中风患者与对照人群进行比较，并测量清除率作为脑淋巴管受损的标志。

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