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

项目总结 胶质母细胞瘤(Gbm)是人类最具侵袭性的一种癌症，具有很高的死亡率和较短的病死率。 存活时间，癌细胞侵袭大脑，本质上对 化疗和放射治疗。肿瘤内的异质性是治疗中的主要挑战。 GBM患者的发展，因为手术获取的临床标本不能用于监测 肿瘤进展和/或潜在的代谢变化。各种神经成像方法已经被 用于研究脑肿瘤的形态。然而，需要对大脑进行非侵入性的表征 肿瘤及其代谢特征尚未得到满足，这应该是预后或监测的关键 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 是糖代谢紊乱，糖酵解上调伴随着线粒体的抑制 氧化，即“华宝效应”。对脑肿瘤的“沃堡效应”及其空间变异性进行成像是一种 可以对癌症研究产生重大影响的新尝试，特别是在治疗基底膜方面，因为 旨在逆转Warburg效应的疗法在GBM中显示出了希望；然而，巨大的努力是 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，旨在开发一种基于氘(2H)的神经成像技术 给予D-葡萄糖-6，6-D2(D66)后，磁共振波谱(DMRS)检测2H标记的脑代谢产物。 我们的初步结果表明，动态DMRS成像可以确定脑代谢率 葡萄糖(CMRGlc)和TCA循环(VTCA)，因此，乳酸生成速率(CMRLac)除了 活体中氚标记葡萄糖(GLC)、谷氨酸/谷氨酰胺混合体(GLX)和乳酸(Lac)的浓度 大脑。此外，我们首次证明了糖酵解和糖酵解之间的解偶联 脑肿瘤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 Warburg效应(IWE)；已有研究表明，IWE对区分脑瘤和脑瘤具有高度的敏感性。 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成像发展通过：i)硬件和软件集成开发和超高场 MR技术，以进一步提高信噪比、光谱分辨率和时空分辨率；ii) 对健康受试者和肿瘤患者进行超高分辨率DMRS成像检测，并建立 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 与神经病理和免疫组织化学结果相结合的成像结果 了解DMRSI测量结果与脑肿瘤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全面发展这一高度 创新和经济高效的神经成像对于神经肿瘤学的基础研究和临床应用是必不可少的。

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.