Development of kurtosis MRI to image acute stroke patients

说明(申请人提供)：早期tPA溶栓是治疗缺血性中风的关键，被称为“时间就是大脑”。然而，很少有患者在卒中发作后3小时内出现接受治疗，tPA的治疗窗口很窄。由于缺血性组织损伤的异质性，影像在卒中患者的治疗中起着至关重要的作用。磁共振灌注成像(PWI)和弥散成像(DWI)在临床上已被证明是一种与脑梗塞(半影区)前的缺血组织近似的成像方法。其基本原理是PWI识别低灌注组织，而DWI则定义严重受损的缺血核心。因此，PWI/DWI不匹配识别缺血半暗带，并已被用于选择患者进行tPA治疗的多项试验。此外，各种基于弥散加权成像的方法，包括磁共振血管成像(MRA)/弥散加权成像和临床/弥散加权成像，已经被选择来克服PWI的技术挑战，以更实际地指导临床上的tPA治疗。然而，现在人们认识到，将弥散加权成像病变近似为缺血核心过于简单化。正如美国心脏协会在2009年和2013年发表的急性缺血性卒中影像诊断建议中所指出的，“弥散加权成像不是不可逆转的脑梗塞的简单指标，而是一个复杂的变量，需要更多的研究。”因此，我们提出的开发峰度磁共振成像作为增强标准DWI的一种手段，直接响应了这一呼吁。我们最近建立了用于急性卒中成像的峰度MRI。我们证明，峰度MRI可以检测到常规DWI病变中受损最严重的缺血组织。重要的是，利用短暂性微丝卒中动物模型，我们发现峰度MRI定义了不可逆的缺血核心损伤，而没有峰度异常的DWI损伤在再灌注后恢复。在我们翻译新的峰度MRI和指导急性卒中患者的tPA治疗之前，关键的一步是在更合理地模拟人类卒中的栓塞性卒中模型中对其进行评估。我们的中心假设是峰度MRI是一种缺血核心特异性指标，可以克服常规DWI对急性卒中成像的局限性。具体地说，我们的提案将使用组织学来验证峰度核磁共振 定义更严重损伤的缺血组织(AIM 1)，在实验性卒中模型中确定峰度损害对tPA治疗的反应(AIM 2)，并翻译和评估急性卒中临床环境中的峰度MRI(AIM 3)。我们的建议的成功将确立峰度MRI的生物学意义，并为未来更大规模的临床研究建立DKI在急性卒中的临床环境中。

DESCRIPTION (provided by applicant): Early tPA thrombolysis is critical for ischemic stroke treatment, known as "time is brain". However, very few patients present for treatment within 3 hours of the stroke onset, the narrow therapeutic window of tPA. Because ischemic tissue injury is heterogeneous, imaging plays a crucial role in stroke patient management. Perfusion and diffusion (PWI and DWI) MRI have proven clinically useful as an imaging approximation to the ischemic tissue prior to infarction (penumbra). The rationale is that PWI identifies hypoperfused tissue while DWI defines the severely damaged ischemic core. As such, the PWI/DWI mismatch identifies the ischemic penumbra, and has been adopted in multiple trials to select patients for tPA therapy. Additionally, variant DWI- based paradigms, including MR angiogram (MRA)/DWI and clinical/DWI have been chosen to overcome the technical challenges of PWI to more practically guide tPA therapy in clinic. However, it is now recognized that the approximation of the DWI lesion as ischemic core is oversimplified. As noted in the recommendation for imaging of acute ischemic stroke from American Heart Association in both 2009 and 2013, "DWI is not a simple indicator of irreversible infarction but a complex variable that requires more study." Our proposal to develop kurtosis MRI as a means to augment the standard DWI is thus directly responsive to this call. We have recently established kurtosis MRI for imaging acute stroke. We demonstrated that kurtosis MRI detects the most severely damaged ischemic tissue within the conventional DWI lesion. Importantly, using a transient filament animal stroke model, we showed that kurtosis MRI defines the irreversibly damaged ischemic core while the DWI lesion without kurtosis abnormality recovers upon reperfusion. A key step before we can translate the new kurtosis MRI and guide tPA therapy in acute stroke patients is to evaluate it in an embolic stroke model that more reasonably mimics human stroke. Our central hypothesis is that kurtosis MRI is an ischemic core-specific index, which can overcome the limitation of conventional DWI for imaging acute stroke. Specifically, our proposal will use histology to verify that kurtosis MRI defines more severely injured ischemic tissue (Aim 1), determine kurtosis lesion response to tPA therapy in experimental stroke models (Aim 2), and translate and evaluate kurtosis MRI in the acute stroke clinical setting (Aim 3). The success of our proposal will establish the biologica significance of kurtosis MRI, and establish DKI in the acute stroke clinical setting for future larger scale clinical studies.