Characterization of Intracranial Atherosclerotic Stenosis Using HR MRI

应聘者描述(申请人提供)：应聘者是一名受过奖学金训练的学术血管神经学家，长期目标是成为一名独立的中风临床研究人员，专注于了解影响颅内动脉粥样硬化的发展和进展并影响中风复发风险的因素。本申请提出了一个全面的培训计划，其中包括i.)临床研究方法论教学培训，2.)核磁共振成像和血管生物学方面的培训，以及通过参与美国国立卫生研究院资助的临床试验的监督领导角色和完成指导研究项目，获得临床研究方面的实践经验。这个有指导的研究项目的目标是开发一种有效的方法，使用HR MRI来表征颅内动脉粥样硬化斑块的成分，这将作为一种。)风险分层的临床工具和疾病活动性的标志和b。)进一步研究动脉粥样硬化斑块发展和进展的研究工具。颅内动脉粥样硬化是卒中的主要原因，但对颅内动脉粥样硬化病变的组成以及颅内斑块形态与卒中风险的关系知之甚少。目前还没有确定颅内斑块成分的体内模型，但高分辨率磁共振成像(HR MRI)在颅外颈动脉粥样硬化患者中的应用表明，该技术可以识别组织学定义的斑块成分(即斑块内出血、纤维帽和脂核)，评价者之间具有很高的一致性，并且这些斑块成分是复发卒中的预测因子。候选人的飞行员数据表明，使用HR MRI可以在颅内动脉显示动脉粥样硬化斑块的特征。这项研究旨在通过在36名患者中系统地改变序列参数来完善HR MRI成像方案，以便定义一种一致地显示颅内动脉粥样硬化斑块成分的方案(该方案的第一部分)。随后将对90名患者进行前瞻性观察研究，旨在证明在HR MRI上识别颅内斑块成分方面的高评分者间的一致性，确定症状性斑块与无症状性斑块中这些成分的出现频率，并估计在高危斑块成分所在地区的1年中风发生率(本提案的第二部分)。此外，还将对因颅内狭窄而死于急性中风的患者进行HR MRI定义的斑块成分与死后血管组织学的比较。在确定这些措施的可靠性和有效性后，候选人将提交R01拨款申请，以在一项使用K23中定义的HR MRI方案的多中心研究中确定颅内动脉粥样硬化斑块成分的患病率和预后。这些研究将导致对动脉粥样硬化性颅内狭窄患者脑缺血的病理生理机制的新理解，改善危险分层，并有可能找到这种常见和严重疾病的新治疗方法。

DESCRIPTION (provided by applicant): The candidate is a fellowship-trained academic vascular neurologist with a long-term goal of becoming an independent clinical stroke researcher focused on understanding factors which influence the development and progression of intracranial atherosclerosis and influence the risk of recurrent stroke. This application proposes a comprehensive training plan which includes i.) didactic training in clinical research methodology, ii.) training in MRI imaging and vascular biology, and iii.) hands-on experience in clinical research by participating in a supervised leadership role in an NIH-funded clinical trial and completion of a mentored research project. The goal of this mentored research project is to develop a validated approach to characterize intracranial atherosclerotic plaque components using HR MRI which will be used as both a.) a clinical tool for risk stratification and a marker for disease activity and b.) a research tool to further study atherosclerotic plaque development and progression. Intracranial atherosclerosis is a leading cause of stroke, but little is known about the composition of the intracranial atherosclerotic lesion and how intracranial plaque morphology is related to the risk of stroke. There is no established in vivo model for characterizing intracranial plaque components, but the use of high resolution magnetic resonance imaging (HR MRI) in patients with extracranial carotid atherosclerosis has shown this technique can identify histologically-defined plaque components (i.e. intraplaque hemorrhage, fibrous cap, and lipid core) with high inter-rater agreement and that these plaque components are predictors of recurrent stroke. The candidate's pilot data has demonstrated that features of atherosclerotic plaque can be visualized in the intracranial arteries using HR MRI. This study aims to refine a HR MRI imaging protocol by systematically altering sequence parameters in a step-wise fashion in 36 patients in order to define a protocol that will consistently visualize intracranial atherosclerotic plaque components (Part 1 of this proposal). This will be followed by a prospective observational study of 90 patients, which aims to demonstrate high inter-rater agreement for identifying intracranial plaque components on HR MRI, determine the frequency of these components in symptomatic vs. asymptomatic plaques, and estimate the 1 year rate of stroke in the territory of high risk plaque components (Part 2 of this proposal). Additionally, a comparison of HR MRI-defined plaque components and post-mortem vascular histology will be performed in patients who die of acute stroke from intracranial stenosis. After establishing the reliability and validity of these measures, the candidate will submit an R01 grant application to determine the prevalence and prognosis of intracranial atherosclerotic plaque components in a multicenter study using the HR MRI protocol defined in the K23. These studies will lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis, improvements in risk stratification, and potentially to new treatments of this common and serious disease.