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Hyperpolarized 13C metabolic imaging in an endovascular swine model of ischemic stroke

缺血性中风血管内猪模型的超极化 13C 代谢成像

基本信息

批准号：
10726555
负责人：
Miroslaw Janowski
金额：
$ 19.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726555
关键词：
Academia Affect Alteplase Animal Model Autopsy Bicarbonates Biological Models Blood flow Brain Brain Injuries Cerebral hemisphere hemorrhage Cerebrum Citric Acid Cycle Clinic Clinical Clinical Trials Complement Data Decarboxylation Detection Development Diffusion Diffusion Magnetic Resonance Imaging Drops Economic Burden Eligibility Determination Energy Metabolism Evolution Family suidae Functional disorder Future Glucose Glycolysis Goals Histology Image Imaging Techniques Impairment Industry Infarction Injections Injury Intervention Ischemia Ischemic Stroke Link Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant - descriptor Mammals Maps Measurement Measures Mechanics Metabolic Metabolic Pathway Metabolism Methods Microdialysis Noise Nuclear Oxygen Pathology Patients Perfusion Play Population Procedures Process Pyruvate Pyruvate Metabolism Pathway Reperfusion Injury Reperfusion Therapy Reporting Resolution Risk Role Scanning Selection for Treatments Signal Transduction Societies Stroke Surrogate Markers Therapeutic Thrombectomy Time Tissues Translating Urea acute stroke brain tissue clinical care clinically relevant disability imaging modality improved in vivo innovation insight ischemic injury metabolic imaging molecular imaging neuroimaging novel novel strategies pharmacologic porcine model post stroke pyruvate dehydrogenase real-time images response spectroscopic imaging stroke model stroke patient stroke therapy structural imaging therapeutic evaluation therapy outcome tool

项目摘要

Ischemic stroke (IS) is the most frequent cause of long-term severe disability, and places an enormous eco- nomic burden on society. One of the primary goals in clinical care of acute stroke is to salvage the so-called penumbra, i.e., tissue that is at risk of irreversible infarction, but is still viable. This can be achieved through various strategies that re-establish the perfusion of the affected tissue. However, there is a tight time window for intervention as well as a risk of cerebral hemorrhage during the establishment of reperfusion and it requires an accurate assessment of the extend of injury as benefits from reperfusion have to be weighed against potential complications arising from treatment. The most widely used tool in identifying the penumbra is magnetic resonance imaging (MRI) and exploiting the “mismatch” in abnormalities as measured with perfusion-weighted and diffusion-weighted MRI. However, multiple studies have found that these surrogate markers have mischaracterized irreversibly infarcted and salvageable tissue and the inaccuracy of these markers may have contributed to both inconclusive results from clinical trials and negative therapeutic outcomes. To this end, a more accurate identification of penumbra and ischemic core that could expand the patient pool that benefit from treatment is needed. The reduced delivery of oxygen and glucose following IS leads to impaired energy metabolism within the affected tissue, one of the hallmarks of the pathology. Therefore, new approaches for quantitative and spatially precise assessment of brain energy metabolism could lead to improved assessment of injury following IS. The recent development of hyperpolarized 13C magnetic resonance spectroscopy and spectroscopic imaging enables for the first time the real-time non-invasive measurement of critical dynamic metabolic processes in vivo. Given pyruvate’s central role in energy metabolism as the link between glycolysis and the Krebs cycle, we propose to use metabolic imaging of co-polarized pyruvate (Pyr) and urea for noninvasive assessment of brain energy metabolism and perfusion in a novel swine IS model. Specifically, we will use injections of co-polarized [1-13C]Pyr and [13C,15N2]urea to quantify cellular energy metabolism and brain perfusion at the time of IS completion in order to identify regions of ischemic core, penumbra, and healthy tissue using histology as the gold standard (Aim 1). Secondly, we will expand our study to include multiple time points during stroke evolution as well as after reperfusion. This will further characterize the temporal and spatial extent of metabolic changes in IS and allow the comparison with the time course of abnormalities as measured with diffusion-weighted MRI (Aim 2). The proposed combination of a novel endovascular swine model of IS and metabolic imaging of hyperpolarized substrates is a unique model system to study the pathophysiology of IS and develop new treatments prior to clinical trials. It also represents the first step in developing a novel neuroimaging approach for assessing ischemic injury in patients and improving treatment selection.

缺血性中风（IS）是长期严重残疾的最常见原因，并造成巨大的经济损失。社会的经济负担。急性卒中临床护理的主要目标之一是挽救所谓的半影，即，组织处于不可逆梗塞的风险中，但仍然是有活力的。这可以通过重建受影响组织的灌注的各种策略。然而，有一个紧迫的时间窗口，在建立再灌注过程中，干预以及脑出血的风险，由于再灌注的益处，损伤程度的准确评估必须与潜在的治疗引起的并发症。在识别半影时，最广泛使用的工具是磁磁共振成像（MRI）和利用“不匹配”的异常测量与灌注加权和弥散加权磁共振成像然而，多项研究发现，这些替代标记物具有不可逆梗死和可挽救组织的错误表征以及这些标志物的不准确性可能导致导致临床试验的不确定结果和负面的治疗结果。为此，一更准确地识别半暗带和缺血核心，可以扩大受益于需要治疗。 IS后氧气和葡萄糖的输送减少导致动脉内能量代谢受损。这是病理学的标志之一因此，新的方法，定量和空间对脑能量代谢的精确评估可以改善对IS后损伤的评估。的超极化13 C磁共振光谱和光谱成像的最新发展使得首次实现了对体内关键动态代谢过程的实时非侵入性测量。给定丙酮酸在能量代谢中的中心作用是糖酵解和克雷布斯循环之间的联系，我们建议使用共极化丙酮酸（Pyr）和尿素的代谢成像进行脑能量的非侵入性评估在新的猪IS模型中的代谢和灌注。具体来说，我们将使用共极化[1- 13 C]Pyr 和[13 C，15 N2]尿素来定量IS完成时的细胞能量代谢和脑灌注，以组织学为金标准，鉴定缺血核心区、半暗带和健康组织（目标1）。其次，我们将扩大我们的研究，包括中风演变过程中的多个时间点，以及之后，再灌注这将进一步表征IS中代谢变化的时间和空间范围，与弥散加权MRI测量的异常时间进程的比较（目的2）。一种新的血管内猪IS模型和代谢成像的组合，超极化底物是研究IS病理生理学和开发新的临床试验前的治疗。它也代表了开发新的神经成像方法的第一步用于评估患者的缺血性损伤和改善治疗选择。