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

急性脑卒中代谢损伤成像快速pH MRI的建立

• 批准号: 8560081
• 负责人: Phillip Zhe Sun
• 金额: $ 38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8560081
• 关键词: Acidic Region; Acidosis; Acute; Algorithms; Alteplase; Amides; Animal Model; Animals; Biological Markers; Characteristics; Chemicals; Clinic; Clinical; Complex; Diffusion; Edema; Emergency Situation; FDA approved; Fibrinolytic Agents; Future; Goals; Image; Imaging Techniques; Infarction; Injury; Intervention; Ischemic Penumbra; Ischemic Stroke; Least-Squares Analysis; Lesion; Magnetic Resonance Imaging; Maps; Measurement; Measures; Metabolic; Metabolic Diseases; Metabolism; Modeling; Monitor; National Institute of Neurological Disorders and Stroke; Nature; Noise; Outcome; Oxygen; Patients; Peptides; Perfusion; Process; Progress Review Group; Proteins; Protocols documentation; Protons; Relaxation; Reporting; Risk; Sensitivity and Specificity; Signal Transduction; Stratification; Stroke; Techniques; Testing; Therapeutic; Thrombolytic Therapy; Time; Tissue Survival; Tissues; Translating; Triage; United States National Institutes of Health; Variant; Weight; acute stroke; brain metabolism; glucose metabolism; hemodynamics; improved; in vivo; indexing; injured; innovation; interest; nervous system disorder; novel; public health relevance; research clinical testing; research study; socioeconomics; stroke therapy; thrombolysis; tool

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.

描述（由申请人提供）：中风是一种使人衰弱的神经系统疾病，与巨大的社会经济负担相关。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内接受治疗。人们仍然对制定策略以将溶栓治疗扩展到可能受益于后期干预的亚人群抱有浓厚的兴趣。 MRI已成为急性缺血性脑卒中患者分诊和治疗的重要临床工具，但传统脑卒中MRI不足以充分表征异质缺血性组织损伤并有效指导晚期脑卒中患者的治疗。尽管最初热情高涨，但将弥散/灌注 MRI (DWI/PWI) 不匹配近似为缺血半暗带已被认为过于简单化。 PWI 病变包含没有梗塞风险的组织，而 DWI 病变如果及时再灌注可能会恢复。除了错误地将一些可挽救的组织描述为缺血核心之外，DWI 还可能无法识别已经遭受不可逆损伤的组织，因为最终的梗塞通常比急性 DWI 病变更大。正如 NIH/NINDS 卒中进展审查组 (SPRG) 2011 年报告中指出的那样，卒中成像的首要任务是了解血流动力学、侧支血流、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/葡萄糖代谢密切相关，并可能为定义缺血半暗带提供代谢生物标志物。然而，目前可用的体内 pH 测量技术有很大的局限性。我们的提案旨在开发内源酰胺质子化学交换饱和转移 (CEST) MRI，用于快速、非侵入性 pH 成像。我们将首先开发新颖的采集和后处理策略，以提高 CEST 成像的灵敏度（目标 1）。我们将开发定量分析，将 pH 加权 MRI 转化为实验性中风模型中的绝对组织 pH 映射，并在不同的血糖条件和中风发作时间下进行测试（目标 2）。然后，我们将评估 pH 成像（一种新型代谢成像标记物），以在模拟患者 tPA 溶栓的栓塞性卒中模型中指导 tPA 溶栓（目标 3）。总之，我们的建议在实验性中风模型中建立快速、定量的 pH 中风成像，一旦 pH MRI 在定义代谢半影中的敏感性和特异性得到证实，我们将把它转化为临床并评估其在晚期中风患者中的效用。