Establishment of fast pH MRI for imaging metabolic injury during acute stroke

描述(申请人提供)：中风是一种衰弱的神经疾病，与巨大的社会经济负担有关。尽管FDA批准的组织纤溶酶原激活剂(TPA)是治疗急性缺血性中风的有效溶栓剂，但很少有患者在其治疗窗口内接受治疗。人们对制定策略将溶栓治疗扩展到可能从晚期干预中受益的亚群中仍然有很大的兴趣。MRI已成为急性缺血性卒中患者分型和治疗的重要临床工具，然而常规的卒中MRI不足以全面描述脑缺血组织的异质性损伤，并有效地指导晚期卒中患者的治疗。磁共振弥散/灌注成像(DWI/PWI)的不匹配近似为缺血半暗带，尽管最初很热情，但已被认为过于简单化。PWI病变包含无梗死风险的组织，而DWI病变如果及时再灌流可能会恢复。除了错误地将一些可挽救的组织定性为缺血核心外，DWI也可能无法识别已经遭受不可逆转损伤的组织，因为最终的梗塞往往比急性DWI病变更大。NIH/NINDS卒中进展回顾小组(SPRG)在2011年的报告中指出，卒中成像的首要任务是了解血流动力学、侧支循环、氧气和脑代谢对组织存活和功能的影响。组织酸中毒与组织氧/糖代谢密切相关，可能为确定缺血半暗带提供代谢生物标志物。然而，目前可用的在体pH测量技术有很大的局限性。我们的建议旨在开发内源性酰胺质子化学交换饱和转移(CEST)磁共振成像，用于快速和非侵入性的pH成像。我们将首先开发新的采集和后处理策略，以提高CEST成像(Aim1)的灵敏度。我们将在实验性卒中模型中开展定量分析，将pH加权MRI转换为绝对组织pH图，并在不同的血糖条件和卒中发病时间下进行测试(目标2)。然后，我们将评估pH成像，一种新的代谢成像标记物，以指导tPA在模拟患者tPA溶栓的栓塞性卒中模型中的溶栓(目标3)。综上所述，我们的建议在实验性卒中模型中建立了快速、定量的pH卒中成像，一旦确定了pH MRI在确定代谢半暗带方面的敏感性和特异性，我们将把它转化到临床上，并评估其在晚期卒中患者中的应用。

DESCRIPTION (provided by applicant): Stroke is a debilitating neurological disorder that is associated with tremendous socioeconomic burden. Whereas FDA-approved tissue plasminogen activator (tPA) is a potent thrombolytic agent for treating acute ischemic stroke, few patients present for treatment within its therapeutic window. There remains substantial interest in developing strategies to extend the thrombolytic therapy into subpopulations who may benefit from late intervention. MRI has become an essential clinical tool for the triage and management of acute ischemic stroke patients, yet the conventional stroke MRI is inadequate to fully characterize the heterogeneous ischemic tissue injury and effectively guide treatment in late presenting stroke patients. The approximation of diffusion/perfusion MRI (DWI/PWI) mismatch as ischemic penumbra, despite its initial enthusiasm, has been recognized to be oversimplified. PWI lesion contains tissue at no risk to infarction, while DWI lesion may recover if promptly reperfused. Besides falsely characterizing some salvageable tissue as ischemic core, DWI may also fail to identify tissue that has already suffered irreversible injury, as the eventual infarction is often larger than acute DWI lesion. As noted in the report of NIH/NINDS Stroke Progress Review Group (SPRG) in 2011, the number one priority for stroke imaging is to understand the impact of hemodynamics, collateral flow, oxygen and brain metabolism upon tissue survival and function. Tissue acidosis is closely associated with tissue oxygen/glucose metabolism, and may provide a metabolic biomarker for defining ischemic penumbra. However, currently available in vivo pH measurement techniques have significant limitations. Our proposal aims to develop endogenous amide proton chemical exchange saturation transfer (CEST) MRI for fast and non-invasive pH imaging. We will first develop novel acquisition and post-processing strategies to enhance the sensitivity of CEST imaging (Aim1). We will develop quantitative analysis that transform pH-weighted MRI to absolute tissue pH mapping in experimental stroke model, and test it under varied glycemic conditions and stroke onset time (Aim 2). We will then evaluate pH imaging, a novel metabolic imaging marker, to guide tPA thrombolysis in an embolic stroke model that mimics tPA thrombolysis in patients (Aim 3). In summary, our proposal establishes fast and quantitative pH stroke imaging in experimental stroke models, and once the sensitivity and specificity of pH MRI in defining metabolic penumbra are confirmed, we will translate it to clinic and evaluate its utility in late-presenting stroke patients.