Development of kurtosis MRI to image acute stroke patients

描述（由申请人提供）：早期tPA溶栓对于缺血性卒中治疗至关重要，被称为“时间就是大脑”。然而，很少有患者在卒中发作后3小时内接受治疗，这是tPA的狭窄治疗窗。由于缺血性组织损伤是异质性的，成像在卒中患者管理中起着至关重要的作用。灌注和弥散（PWI和DWI）MRI已被证明在临床上可用作梗死前缺血组织（半暗带）的成像近似。其原理是PWI识别低灌注组织，而DWI定义严重受损的缺血核心。因此，PWI/DWI不匹配可识别缺血半暗带，并已在多项试验中用于选择接受tPA治疗的患者。此外，已选择基于DWI的变体范例，包括MR血管造影（MRA）/DWI和临床/DWI，以克服PWI的技术挑战，从而更实际地指导临床中的tPA治疗。然而，现在认识到，DWI病变作为缺血核心的近似值过于简单化。正如美国心脏协会在2009年和2013年对急性缺血性卒中成像的建议中所指出的，“DWI不是不可逆梗死的简单指标，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MRI作为增强标准DWI的一种手段的建议直接响应了这一呼吁。我们最近建立了峰度MRI成像急性中风。我们证明，峰度MRI检测到最严重的损伤缺血组织内的常规DWI病变。重要的是，使用短暂的细丝动物中风模型，我们表明，峰度MRI定义不可逆损伤的缺血核心，而DWI病变无峰度异常恢复后再灌注。在我们能够翻译新的峰度MRI并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是一个缺血核心特异性指标，它可以克服传统DWI成像急性卒中的局限性。具体来说，我们的建议将使用组织学来验证峰度MRI 定义更严重损伤的缺血组织（目标1），确定实验性卒中模型中tPA治疗的峰度病变反应（目标2），以及在急性卒中临床环境中翻译和评估峰度MRI（目标3）。我们的建议的成功将建立峰度MRI的生物学意义，并建立DKI在急性卒中临床设置为未来更大规模的临床研究。

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.