NOVEL INSIGHTS INTO CEREBRAL ISCHEMIC PATHOPHYSIOLOGY IN HUMANS

对人类脑缺血病理生理学的新见解

• 批准号: 9358574
• 负责人: John Hallenbeck
• 金额: $ 60.48万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9358574
• 关键词: Acute; Aftercare; Alteplase; Big Data; Biological; Biology; Blood; Blood - brain barrier anatomy; Blood flow; Brain; Brain imaging; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Clinical Markers; Clinical Trials; Complex; Data; Data Set; Deterioration; Development; Diagnosis; Diagnostic Procedure; Disease Marker; Enrollment; Evolution; Functional disorder; Future; General Hospitals; Human; Image; Incidence; Interruption; Intervention; Intravenous; Investigation; Ischemia; Ischemic Stroke; Lead; Learning; Lesion; MRI Scans; Magnetic Resonance Imaging; Massachusetts; Measures; Methodology; Methods; MicroRNAs; Modeling; Motion; Multi-Institutional Clinical Trial; National Institute of Neurological Disorders and Stroke; Natural History; Outcome; Participant; Patients; Permeability; Phenotype; Process; Protocols documentation; Reperfusion Therapy; Research Personnel; Resources; Risk; Site; Speed; Statistical Data Interpretation; Stroke; Systems Biology; Testing; Thrombolytic Therapy; Time; Tissue-Specific Gene Expression; Transient Ischemic Attack; United States National Institutes of Health; Untranslated RNA; Validation; Weight; acute stroke; base; biological systems; clinical care; complex biological systems; drug development; effective therapy; imaging biomarker; improved; insight; neuroimaging; neurovascular; next generation sequencing; novel; patient registry; patient stratification; peripheral blood; phase 3 study; predictive modeling; programs; responders and non-responders; response; stroke symptom; stroke therapy; stroke treatment; therapy development; thrombolysis; transcriptome; treatment responders

Through our Natural History of Stroke study(Protocol No. 01-N-0007; Clinicaltrials.gov No. NCT00009243) we have collected data on more than 2,400 study 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 who we can expect a favorable response to an intervention, from those at risk of further deterioration. We have created a unique and comprehensive dataset of acute stroke MRIs (Lesion Evolution in Stroke and Ischemia On Neuroimaging LESION) analysis. This dataset of acute stroke MRI affords unprecedented opportunities for robust statistical analysis of the incidence of ischemia and reperfusion as related to time from stroke onset. 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 DWI 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, the Neuro Vascular Brain Imaging Unit (NVBI) heavily utilizes the data collected through the Natural History of Stroke protocol. The NVBI has taken on the big data challenge of co-registering and quantitatively processing the MRI scans acquired as part of the natural history study. In doing so the NVBI has created an interface, referred to as the pipeline, that leverages the massive amount of information contained in the natural history dataset to perform scientific hypothesis testing. The pipeline is available to the entire Stroke Branch as a research resource. NVBI has been using the natural history imaging pipeline to perform quantitative blood-brain permeability imaging. Using a novel post processing method, a measure of blood brain barrier integrity can be extracted from the existing dataset. This has lead to new insights into the pathophysiology of acute and chronic cerebrovascular disease that has the potential to influence clinical care. Future directions include expanding the natural history study to collect data at chronic time points as well as the introduction of new imaging methodologies such as pH-weighted imaging. In addition to the Natural History of Stroke protocol, we have recently completed a multi-center clinical trial - MR WITNESS: A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients (NIH Protocol No. 11-N-N019; Clinical Trials.gov No. NCT01282242). This clinical trial was jointly developed and was jointly led by investigators at Massachusetts General Hospital and our intramural stroke program at NINDS. The purpose of this study was to: 1) see if it is safe to give intravenous (IV) rt-PA to people with unwitnessed stroke but with MRI evidence of early ischemic stroke, 2) see if rt-PA is effective if given to people who are selected for treatment based on MRI evidence of an early stroke, and 3) get information about this new MRI diagnostic methods for guiding stroke treatment. Our intramural site enrolled 28 subjects into this study. The trial has completed enrollment and the data has been locked for analysis. Plans are underway to enter initiate a Phase III study based on the preliminary results.

通过我们中风研究的自然历史（第01-N-0007号协议； Clinicaltrials.gov No. NCT0000009243），我们收集了有关2400多名研究参与者的数据，以了解有关中风的更多信息，并获得可能作为未来研究的基础的信息。该方案使我们进入1）建立脑血管疾病患者（中风）的注册表； 2）表征急性中风和短暂性缺血发作（TIA）的自然历史（TIA）的血液流向大脑的血液中断，这会在短时间内引起中风症状）； 3）评估数据以生成未来研究的想法。 MRI通过提供高度敏感和特定的疾病标记来提高我们诊断和分层急性中风患者的能力。 基于成像的中风表型提高了客观性，但是它们仍然是对中风开始运动的复杂生物系统的过度简化。 下一代测序在吞吐量和速度方面具有前所未有的改善，为使用急性MRI分层的患者中卒中的复杂生物学反应提供了一个机会。 基于以下前提：负责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RNA中，下一代测序将用于识别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，以更好地描述中风，并希望更好地将那些可以预期对干预反应的患者与有进一步恶化的风险的患者区分开来。 我们创建了一个急性中风MRI的独特而全面的数据集（中风的病变进化和神经影像病变的缺血）分析。 该急性中风MRI的数据集为与中风发作时间有关的缺血和再灌注的强大统计分析提供了前所未有的机会。 基于成像的中风结局和对治疗反应的预测因素对于药物开发中生物标志物的实用性和验证是必要的。 有用的模型是那些可以区分有效结果与不良结局的患者，那些从未接受过的有效疗法的患者，以及与无反应者的治疗反应者。 我们正在研究几种预测模型。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，用有效的急性中风疗法（即静脉内TPA）治疗，病变体积从治疗前DWI变为治疗后才能可能会区分有目的和差的患者。 因此，病变体积变化可能是中风疗法发展中临床反应的有用标记。 作为中风分支的一部分，神经血管脑成像单元（NVBI）大量利用了通过中风协议的自然历史收集的数据。 NVBI采取了作为自然历史研究的一部分获得的共同注册和定量处理MRI扫描的大数据挑战。 为此，NVBI创建了一个界面，称为管道，该界面利用自然历史数据集中包含的大量信息来执行科学假设测试。 该管道可作为研究资源可用于整个中风分支。 NVBI一直在使用自然史成像管道来执行定量的血脑通透性成像。 使用新颖的后处理方法，可以从现有数据集中提取血液屏障完整性的度量。 这导致了对急性和慢性脑血管疾病的病理生理学的新见解，该病理可能会影响临床护理。 未来的方向包括扩展自然史研究以在慢性时间点收集数据，以及引入新成像方法（例如PH加权成像）。 除了中风方案的自然历史外，我们最近还完成了一项多中心临床试验 - MR证人：在MRI选择的患者中对静脉注射溶栓的研究（NIH方案编号11-N-N019；临床试验；临床试验。 该临床试验是共同开发的，并由马萨诸塞州综合医院的研究人员和我们在Ninds的壁内中风计划共同领导。 这项研究的目的是：1）查看是否可以安全地静脉内（iv）RT-PA给中风不明智的人，但有了MRI证据表明早期缺血性中风的证据，2）查看RT-PA是否有效，如果将基于MRI证据的人选择接受治疗的人是否有效，并获得此新的MRI诊断方法，以获取这种新的MRI诊断方法。 我们的壁内部位招募了28名受试者参加这项研究。 试验已经完成注册，数据已锁定以进行分析。 正在计划基于初步结果的III期研究。