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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.

缺血性卒中(IS)是导致长期严重残疾的最常见原因，对人类健康造成巨大的生态危害。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区，即有不可逆性脑梗塞风险，但仍可存活的组织。这可以通过以下方式实现重建受影响组织的灌注的各种策略。然而，有一个紧凑的时间窗口用于在建立再灌流期间进行干预以及脑出血的风险，这需要准确评估损伤的程度，因为必须权衡再灌注的益处和潜在的损伤程度治疗过程中出现的并发症。最广泛使用的识别半影的工具是磁力磁共振成像(MRI)和利用灌注加权测量的异常中的“失配” 弥散加权磁共振成像。然而，多项研究发现，这些替代标记具有错误地描述了不可逆转的梗塞和可挽救的组织，并且这些标志物的不准确可能导致临床试验结果不确定和治疗结果为阴性。为此，一个更准确地识别半暗带和缺血核心，从而扩大受益于治疗是必要的。随后氧和葡萄糖的输送减少导致体内能量代谢受损。受累组织，这是病理的标志之一。因此，定量和空间分析的新方法对大脑能量代谢的准确评估可以改善对IS后损伤的评估。这个超极化~(13)C磁共振波谱和光谱成像的最新进展首次实现了对体内关键动态代谢过程的实时无创测量。vt.给出丙酮酸在能量代谢中的中心作用，作为糖酵解和Krebs循环之间的纽带，我们建议利用共极化丙酮酸(PYR)和尿素的代谢成像无创性评估脑能量一种新型猪的代谢和灌流模型。具体地说，我们将使用共极化的[1-13C]PYR注入和[~(13)C，~(15)N]尿素依次定量细胞能量代谢和脑血流灌注以组织学为金标准，确定缺血核心、半暗带和健康组织的区域(目标1)。其次，我们将扩大我们的研究范围，包括中风演变过程中和之后的多个时间点再灌流。这将进一步表征IS代谢变化的时间和空间范围，并允许与磁共振弥散加权成像(AIM 2)测量的异常时间进程进行比较。一种新的猪血管内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模型系统的独特模型系统。临床试验前的治疗。这也是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进治疗选择。