Characterization of Intracranial Atherosclerotic Stenosis Using HR MRI

描述（由申请人提供）：候选人是一名经过奖学金培训的学术血管神经学家，其长期目标是成为一名独立的临床卒中研究人员，专注于了解影响颅内动脉粥样硬化发展和进展以及影响复发性卒中风险的因素。本申请提出了一个全面的培训计划，其中包括i.）临床研究方法学的教学培训，ii.）MRI成像和血管生物学方面的培训，以及iii.）通过参与NIH资助的临床试验中的监督领导角色并完成指导研究项目，获得临床研究的实践经验。本指导研究项目的目标是开发一种经验证的方法，使用HR MRI表征颅内动脉粥样硬化斑块成分，该方法将用作a.）用于风险分层的临床工具和疾病活动性的标志物，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脑卒中的主要原因，但对颅内动脉粥样硬化病变的组成以及颅内斑块形态与脑卒中风险的关系知之甚少。目前还没有确定的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、纤维帽和脂质核心），评分者之间的一致性很高，这些斑块成分是复发性卒中的预测因子。候选人的试点数据表明，动脉粥样硬化斑块的特征可以使用HR MRI在颅内动脉中可视化。本研究旨在通过在36例患者中以逐步方式系统性改变序列参数来完善HR MRI成像方案，以定义一种能够持续显示颅内动脉粥样硬化斑块成分的方案（本提案的第1部分）。随后将进行一项90例患者的前瞻性观察性研究，旨在证明HR MRI上识别颅内斑块成分的高评价者间一致性，确定这些成分在症状性与无症状性斑块中的频率，并估计高风险斑块成分区域的1年卒中发生率（本提案第2部分）。此外，将在因颅内狭窄而死于急性卒中的患者中比较HR MRI定义的斑块成分和死后血管组织学。在确定这些测量的可靠性和有效性后，候选人将提交R01资助申请，以使用K23中定义的HR MRI方案在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。这些研究将使人们对动脉粥样硬化性颅内狭窄患者脑缺血的病理生理机制有新的认识，改善风险分层，并可能为这种常见而严重的疾病提供新的治疗方法。

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.