Characterization of Intracranial Atherosclerotic Stenosis Using HR MRI

描述（由申请人提供）：候选人是一位接受过专科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中风研究员，专注于了解影响颅内动脉粥样硬化发生和进展以及影响中风复发风险的因素。该申请提出了一个全面的培训计划，其中包括 i.) 临床研究方法的教学培训，ii.) MRI 成像和血管生物学培训，以及 iii.) 通过参与 NIH 资助的临床试验的监督领导角色和完成指导研究项目来获得临床研究的实践经验。该指导研究项目的目标是开发一种经过验证的方法，利用 HR MRI 来表征颅内动脉粥样硬化斑块的成分，该方法将用作 a.) 风险分层的临床工具和疾病活动的标记，b.) 进一步研究动脉粥样硬化斑块发生和进展的研究工具。 颅内动脉粥样硬化是中风的主要原因，但人们对颅内动脉粥样硬化病变的组成以及颅内斑块形态与中风风险的关系知之甚少。目前还没有建立表征颅内斑块成分的体内模型，但在颅外颈动脉粥样硬化患者中使用高分辨率磁共振成像（HR MRI）表明，该技术可以识别组织学上定义的斑块成分（即斑块内出血、纤维帽和脂质核心），并且具有较高的评估者间一致性，并且这些斑块成分是复发性中风的预测因子。候选人的试验数据表明，使用 HR MRI 可以在颅内动脉中显示动脉粥样硬化斑块的特征。本研究旨在通过系统地逐步改变 36 名患者的序列参数来完善 HR MRI 成像方案，以便定义一个能够一致地可视化颅内动脉粥样硬化斑块成分的方案（本提案的第 1 部分）。随后将进行一项针对 90 名患者的前瞻性观察性研究，旨在证明评估者在 HR MRI 上识别颅内斑块成分方面的高度一致性，确定这些成分在有症状斑块与无症状斑块中的频率，并估计高风险斑块成分区域的 1 年卒中发生率（本提案的第 2 部分）。此外，还将对死于颅内狭窄的急性中风的患者进行 HR MRI 定义的斑块成分和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，以确定在使用 K23 中定义的 HR MRI 协议的多中心研究中颅内动脉粥样硬化斑块成分的患病率和预后。这些研究将带来对动脉粥样硬化性颅内狭窄患者脑缺血病理生理机制的新认识，改善风险分层，并有可能为这种常见且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.