Enhanced Deuterium Metabolic Imaging (DMI) of Metabolic Reprogramming in Brain Tumors

摘要 氚代谢成像(DMI)是一种新兴的MRI技术，它可以使氚基底物和 他们的代谢产物是在体内成像的。一个主要的应用是研究能量代谢，一个 人体内几乎所有细胞的基本过程。特别是，葡萄糖(GLC)代谢起着至关重要的作用 在癌症中的作用，肿瘤代谢的两个关键指标是总葡萄糖消耗量和相对 糖酵解(GLY)组分与氧化磷酸化(OXPHOS)组分。与正常情况形成对比 在组织中，大多数癌症表现出GLY多于OXPHOS的优势。被称为华宝效应或更多 通常情况下，这些变化在胶质瘤和其他脑组织中尤为明显。 肿瘤。高级别脑肿瘤中Gly升高已被证明是肿瘤生长和 咄咄逼人。从治疗的角度来看，研究强烈支持这种Warburg表型是 对于癌症过程来说是必要的和充分的，这提供了一种非常新颖的治疗方法的框架 旨在影响这些代谢途径的策略。我们认为，临床翻译目前是 与其说是因为缺乏代理人，不如说是因为难以衡量这些基本的方面 肿瘤在体内的代谢。 在可用的成像技术中，18F-FDG-PET是公认的葡萄糖摄取成像技术，而 在体内对GLY和OXPHOS进行稳健的测量是相当具有挑战性的。三重15O-PET可以 用于评估氧气消耗(因此OXPHOS)，但由于2分钟的半小时- 150摄氏度的寿命以及协调多种吸入的放射性气体的挑战。超极化~(13)C的磁共振成像 标记丙酮酸已被证明能够评估肿瘤的GLY/OXPHOS比率；然而，这项技术是 非常昂贵，供应有限，而且面临着独特的挑战。最近，使用的可行性 用于测量GLY和OXPHOS的常规~2H氢化葡萄糖磁共振成像已成功 演示了。鉴于3T扫描仪的普遍存在，我们认为3T DMI将产生最大的临床影响， 在4T时报告的人脑初步结果，结合我们自己的3T DMI数据，表明有限 空间分辨率、低信噪比和相应较长的扫描时间是主要限制。这是技术上的 开发项目将通过合并多式联运增强DMI来应对这些挑战 信息。注意到1H MRI和FDG-PET共享重要的相互解剖和代谢信息 对于DMI，我们建议使用信号处理和机器学习来显著增强3T DMI 方法类似于使用MRI来提高FDG-PET分辨率和信噪比的技术。总体目标是 演示增强的DMI采集和图像处理管道，以实现最大的临床影响， 最初的应用是对脑瘤中的沃堡效应进行成像。

Abstract Deuterium metabolic imaging (DMI) is an emerging MRI technique whereby deuterated substrates and their metabolic products are imaged in vivo. A primary application is the study of energy metabolism, a fundamental process for virtually all cells in the body. In particular, glucose (Glc) metabolism plays a critical role in cancer, with two key metrics of tumor metabolism being total glucose consumption and the relative fraction of Glc undergoing glycolysis (GLY) versus oxidative phosphorylation (OXPHOS). In contrast to normal tissues, most cancers exhibit a preponderance of GLY over OXPHOS. Known as the Warburg effect or, more generally metabolic reprogramming, these alterations are particularly pronounced in glioma and other brain tumors. Elevated GLY in high-grade brain tumors has been shown to be a marker of tumor growth and aggressiveness. From a therapeutic perspective, studies strongly support that this Warburg phenotype is necessary and sufficient for the cancer process, which provides the framework of a highly novel therapeutic strategy targeted at affecting these metabolic pathways. We contend that clinical translation is presently impeded not so much by a lack of agents, but by the difficulty in measuring these fundamental aspects of tumor metabolism in vivo. Of the available imaging techniques, 18F-FDG-PET is well-established for imaging glucose uptake, whereas robust in vivo measurements of GLY and OXPHOS are considerably more challenging. Triple 15O-PET can be used to assess oxygen consumption (and hence OXPHOS) but is clinically problematic due to the 2-min half- life of 15O and the challenges of coordinating multiple inhaled radioactive gases. MRI of hyperpolarized 13C- labeled pyruvate has been shown capable of assessing tumor GLY/OXPHOS ratios; however, this technique is very expensive with limited availability and unique challenges. More recently, the feasibility of using conventional 2H MRSI of deuterated glucose to measure both GLY and OXPHOS has been successfully demonstrated. Given the ubiquity of 3T scanners, we contend that 3T DMI would have maximal clinical impact, and initial results for the human brain reported at 4T, in combination with our own 3T DMI data, indicate limited spatial resolution, low SNR, and correspondingly long scan times are the primary limitations. This technical development project will address these challenges by enhancing DMI via the incorporation of multimodal information. Noting that 1H MRI and FDG-PET share significant mutual anatomic and metabolic information with DMI, we propose to significantly enhance 3T DMI using signal processing and machine learning approaches analogous to techniques using MRI to enhance FDG-PET resolution and SNR. The overall goal is to demonstrate enhanced DMI acquisitions and image processing pipelines for maximal clinical impact, with the initial application being the imaging of the Warburg effect in brain tumors.