Development of Quantitative Deuterium MRS Imaging for Human Brain Tumor Application at Ultrahigh Field

超高场定量氘 MRS 成像在人脑肿瘤应用中的发展

• 批准号: 10468203
• 负责人: Clark Chin-Chung Chen
• 金额: $ 53万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468203
• 关键词: 3-Dimensional; Adult; Animal Experimentation; Animals; Area; Basic Science; Biochemical; Biological; Biopsy Specimen; Brain; Brain Neoplasms; Caring; Cell Respiration; Cells; Cerebrum; Chemotherapy and/or radiation; Citric Acid Cycle; Clinic; Clinical; Clinical Treatment; Computer software; Data; Detection; Deuterium; Development; Diagnosis; Disease; Energy Metabolism; Engineering; Fatality rate; Functional disorder; Funding; Future; Glioblastoma; Glucose; Glutamates; Glutamine; Glycolysis; Goals; Human; Human body; Ice; Image; Imaging Techniques; Imaging technology; Immune; Intake; Interdisciplinary Study; Intravenous infusion procedures; Label; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Metabolic; Metabolic Marker; Methods; Minnesota; Mitochondria; Modality; Modeling; Monitor; Mutation; Neurosurgeon; Noise; Normal tissue morphology; Operative Surgical Procedures; Oral; Outcome; Pathologic; Pathology; Patients; Physiologic pulse; Pilot Projects; Positron-Emission Tomography; Production; Prognosis; Property; Pyruvate; RF coil; Radiation therapy; Research; Research Personnel; Resistance; Resolution; Sensitivity and Specificity; Signal Transduction; Site; Specificity; Specimen; Techniques; Technology; Testing; Time; Training; United States National Institutes of Health; Universities; Warburg Effect; Work; aerobic glycolysis; anticancer research; base; brain disorder diagnosis; brain morphology; brain tissue; cancer cell; clinical diagnosis; contrast imaging; cost effective; data analysis pipeline; expectation; fluorodeoxyglucose; glucose metabolism; glucose uptake; human imaging; image processing; imaging modality; imaging study; improved; in vivo; indexing; innovation; kinetic model; magnetic field; magnetic resonance spectroscopic imaging; metabolic imaging; metabolic rate; neuro-oncology; neurochemistry; neuroimaging; neuropathology; novel; novel imaging technique; novel therapeutics; oxidation; quantitative imaging; software development; spatiotemporal; spectroscopic imaging; success; therapeutic development; tool; treatment response; tumor; tumor heterogeneity; tumor progression

PROJECT SUMMARY Glioblastoma (GBM) is the most aggressive form of human cancers with very high fatality rate and short survival time, and the cancer cells aggressively infiltrate the brain and are intrinsically resistant to chemotherapy and radiation therapy. Intra-tumoral heterogeneity is a major challenge in therapeutic development for GBM patients because surgical acquisition of clinical specimens cannot be used to monitor the tumor progression and/or the underlying metabolic changes. Various neuroimaging methods have been used to study the morphology of the brain tumors. However, the need for noninvasively characterizing the brain tumors and their metabolic features has not been met, which should be critical for prognosis or for monitoring the tumor progression and response to treatment. It is well known that a common hallmark of the cancer cells is disrupted glucose metabolism, in which upregulated glycolysis is accompanied by inhibited mitochondrial oxidation, i.e., the “Warburg effect”. Imaging the “Warburg effect” and its spatial variability in brain tumors is a new attempt that can have a major impact on cancer research, particularly in the treatment of GBM, because therapies aimed at reversing the Warburg effect have shown promise in GBM ; however, great efforts are needed to develop novel metabolic imaging techniques to achieve the capabilities sought by clinicians. We have recently initiated a project aiming to develop a neuroimaging technique based on deuterium (2H) MRS (DMRS) detection of 2H-labeled brain metabolites following an administration of D-Glucose-6,6-d2 (d66). Our preliminary results indicate that the dynamic DMRS imaging can determine the cerebral metabolic rates of glucose (CMRGlc) and TCA cycle (VTCA), thus, the lactate production rate (CMRLac) in addition to the concentrations of deuterium-labeled glucose (Glc), mixed glutamate/glutamine (Glx) and lactate (Lac) in living brains. Furthermore, we demonstrated for the first time that the uncoupling between the glycolysis and oxidation in brain tumor can be quantitatively imaged via mapping the [Lac]/[Glx] ratio defined as an index of Warburg effect (IWE); and it has been shown that IWE is highly sensitive for distinguishing brain tumor from surrounding normal tissues. In this application, we are seeking NIH funding support to move forward with the DMRS imaging development through: i) integrated hardware and software development and the ultrahigh field MR technology to further boost signal-to-noise ratio (SNR), spectral resolution and spatiotemporal resolution; ii) testing the ultrahigh resolution DMRS imaging in healthy subject, and tumor patients and establishing a quantification model and imaging processing pipeline for future application; and iii) comparing the DMRS imaging results with the neuropathological and immunohistochemical findings of the biospecimens to understand the correlation between the DMRSI measurements and biological features of brain tumor. Our interdisciplinary research team with unique expertise is ready for a full-scale development of this highly innovative and cost-effective neuroimaging essential for basic research and clinic application in neuro-oncology.

项目摘要 胶质母细胞瘤（GBM）是人类癌的最具侵略性的形式，死亡率很高，短暂 生存时间，癌细胞积极浸润大脑，并且本质上具有抗性 化学疗法和放射疗法。肿瘤内异质性是治疗的主要挑战 GBM患者的开发是因为无法使用临床标本的手术获取来监测 肿瘤进展和/或潜在的代谢变化。各种神经影像学方法已经 用于研究脑肿瘤的形态。但是，需要非侵入性地表征大脑 肿瘤及其代谢特征尚未满足，这对于发病症或监测至关重要 肿瘤的进展和对治疗的反应。众所周知，癌细胞的共同标志 被破坏的糖糖代谢，其中通过抑制线粒体完成更新的糖酵解 氧化，即“ Warburg效应”。成像“ Warburg效应”及其在脑肿瘤中的空间变异性是一个 可能会对癌症研究产生重大影响的新尝试，尤其是在治疗GBM方面，因为 旨在逆转Warburg效应的疗法在GBM中表现出了希望。但是，巨大的努力是 需要开发新型的代谢成像技术来实现临床医生寻求的能力。 我们最近发起了一个项目，旨在开发基于氘（2H）的神经影像学技术 施用D-葡萄糖-6,6-D2（D66）后，MRS（DMR）检测2H标记的脑代谢产物。 我们的初步结果表明，动态DMRS成像可以确定大脑代谢率 葡萄糖（CMRGLC）和TCA循环（VTCA），因此，乳酸产量（CMRLAC）以外 氘标记的葡萄糖（GLC），混合谷氨酸/谷氨酰胺（GLX）和裂解（LAC）的浓度 大脑。此外，我们首次证明了糖酵解与 可以通过映射[lac]/[GLX]比率定量成像脑肿瘤中的氧化 Warburg效应（IWE）；并且已经表明，IWE对于区分脑肿瘤和 周围正常组织。在此应用程序中，我们正在寻求NIH资金支持，以继续 DMRS成像开发：i）集成硬件和软件开发以及超高领域 MR技术以进一步提高信噪比（SNR），光谱分辨率和时空分辨率； ii） 在健康受试者和肿瘤患者中测试超高分辨率DMRS成像并建立 定量模型和成像处理管道，以供将来应用； iii）比较DMR 成像结果是生物学的神经病理学和免疫组织化学发现 了解脑肿瘤的DMRSI测量和生物学特征之间的相关性。我们的 具有独特专业知识的跨学科研究团队已准备好对这一高度发展的全面发展 创新且具有成本效益的神经影像学对于神经肿瘤学中的基础研究和诊所应用至关重要。