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

项目摘要 胶质母细胞瘤（GBM）是人类癌症中最具侵袭性的形式，具有非常高的病死率和短的发病时间。 存活时间，并且癌细胞侵袭性地浸润大脑，并且本质上抵抗癌症。 化疗和放疗。肿瘤内异质性是肿瘤治疗中的主要挑战。 GBM患者的发展，因为临床标本的手术采集不能用于监测 肿瘤进展和/或潜在的代谢变化。各种神经成像方法已经被 用来研究脑瘤的形态然而，非侵入性地描述大脑的需要 肿瘤及其代谢特征尚未得到满足，这对预后或监测至关重要 肿瘤进展和对治疗的反应。众所周知，癌细胞的一个共同特征是 是破坏葡萄糖代谢，其中上调糖酵解伴随着抑制线粒体 氧化，即，“瓦尔堡效应”。脑肿瘤中的“瓦尔堡效应”及其空间变异性成像是一种 这是一项新的尝试，可以对癌症研究产生重大影响，特别是在GBM的治疗方面，因为 旨在逆转瓦尔堡效应的疗法在GBM中显示出前景;然而， 需要开发新的代谢成像技术，以实现临床医生所寻求的能力。 我们最近启动了一个项目，旨在开发基于氘（2 H）的神经成像技术。 D-葡萄糖-6，6-d2（d 66）给药后2 H标记脑代谢物的MRS（DMRS）检测。 我们的初步结果表明，动态DMRS成像可以确定脑代谢率， 葡萄糖（CMRGlc）和TCA循环（VTCA），因此，除了乳酸产生速率（CMRLac）之外， 活体中氘标记葡萄糖（Glc）、混合谷氨酸/谷氨酰胺（Glx）和乳酸（Lac）的浓度 大脑此外，我们还首次证明了糖酵解和 脑肿瘤中的氧化可以通过绘制[Lac]/[Glx]比率来定量成像，该比率被定义为 瓦尔堡效应（IWE）;并且已经表明，IWE对于区分脑肿瘤与脑胶质瘤是高度敏感的。 周围的正常组织。在这项申请中，我们正在寻求NIH的资金支持，以推进 DMRS成像开发，通过： MR技术进一步提高信噪比（SNR）、频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100分辨率DMRS成像， 用于未来应用的量化模型和成像处理流水线;以及iii）比较DMRS 影像学结果与生物标本的神经病理学和免疫组化结果， 了解DMRSI测量值与脑肿瘤生物学特征之间的相关性。我们 具有独特专业知识的跨学科研究团队已准备好全面开发这一高度 是神经肿瘤学基础研究和临床应用中必不可少的创新性和低成本的神经影像学。

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.