7T MRS AND CEST IMAGING OF BRAIN TUMORS: BIOMARKERS OF THERAPEUTIC RESPONSE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 质子磁共振波谱(1H-MRS)为在体无创性测量人脑中的代谢物提供了有效的工具。由于标量耦合效应和大分子基线信号产生的光谱复杂性，标准的1H-MRS往往难以准确测量几种临床上重要的低丰度代谢物，即使在7T也是如此。这项研究的目的是开发MRS技术，为在7T和3T下检测甘氨酸、丝氨酸、N-乙酰天冬氨酸(NAAG)、谷氨酰胺、γ-氨基丁酸等提供改进的代谢物分辨能力。具体的临床目标是为涉及大脑的癌症开发更好的诊断工具。 患有脑肿瘤的患者，无论是胶质母细胞瘤(GBM)还是系统性癌症转移患者，尽管接受了积极的多模式治疗，但在一年多一点的时间里，他们面临着毁灭性的临床过程，包括进行性的身体和认知能力下降。在诊断、治疗和随访的所有阶段的管理决策依赖于基于对从一个时间点到另一个时间点的Gd增强和T2/FLAIR(液体衰减反转恢复)信号变化的解释的MR成像。然而，这充满了相互矛盾的解释，这可能会改变管理层，并可能对预后产生深远影响。不确定性最常见的集中在区分肿瘤进展和放疗后的治疗效果，这是GBM和转移患者的常见情况。经典的肿瘤进展与Gd增强肿块的大小增加和T2加权FLAIR的增加有关。然而，相同的影像特征被归因于经典的放射性坏死，在GBM中被称为“假进展”，因为现有的成像不可能与真实的肿瘤进展区分开来。因此，治疗神经肿瘤学团队依赖于基于临床背景的“最佳猜测”。由于预后和处理方式因肿瘤进展或治疗效果的不同而有很大不同，因此患者经常被带回手术室进行重复的开颅和活检以做出诊断。同样重要的是临床情况，T2/FLAIR信号的变化可能预示着肿瘤增强之前的早期进展性疾病，但与瘤周水肿或反应性胶质增生无法区分。因此，总的来说，迫切需要开发新的成像技术，以帮助在这些关键决策点进行非侵入性诊断。 基于MRI与其他技术的结合，如正电子发射断层扫描(MR-PET)、~(23)Na的MR成像和~(31)P或~(13)C的MR波谱，已经提出了许多方法来改善脑肿瘤的特征。虽然所有这些方法在研究疾病的基本生物学方面都很有吸引力，但它们在临床应用上受到限制，因为需要对额外设备进行大量投资。改进的诊断方法依赖于广泛可用的1H设备，如1H光谱和化学交换饱和转移(CEST)，为临床研究提供了相对简单的进展，这两种方法都固有地通过7T时增加的化学位移分散而得到改进，并可以在标准的1H成像系统中实施。在这项建议中，我们利用了在项目2中描述的用于GBM和MT的良好的人类原位小鼠模型，用于动物和人类的高场成像的可用性，以及7T脑瘤患者的开放式登记临床成像方案。首要目标是通过1H-MRS和CEST成像识别信号模式，以区分肿瘤进展和治疗效果，并检测超出标准T2/FLAIR和Gd边界的区域的早期进展。 目的：利用人原位小鼠肿瘤模型，研究放射治疗前后脑胶质瘤和四种最常见的脑转移瘤(黑色素瘤、肺癌、乳腺癌和肾癌)的7T磁共振氢谱和CEST图像特征。在AIM 2中将对患者进行验证。 目的：分析低度恶性脑胶质瘤患者7T的1HMR波谱和CEST图像特征，并找出与GBM的不同之处，以便在临床常用的MR指标或标准MR指标之前，产生一种可预示从低度恶性向GBM进展的信号模式。 目的：利用AIMS 1和AIMS 2中确定的标志性代谢物和7T CEST成像的特征模式，对低级别胶质瘤、胶质母细胞瘤和脑转移瘤患者进行脑成像，以识别胶质瘤中的浸润性肿瘤和转移性疾病的早期复发/进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Proton magnetic resonance spectroscopy (1H-MRS) provides an effective tool for measuring metabolites in the human brain noninvasively in vivo. Precise measurement of several clinically-important, low-abundance metabolites by standard 1H-MRS is often elusive even at 7T, due to the spectroscopic complexities arising from the scalar coupling effects and macromolecule baseline signals. The objectives of the research are to develop MRS techniques that provide improved inter-metabolite discrimination for detection of glycine, serine, N-acetylaspartyl-glutamate (NAAG), glutamine, gamma-aminobutyric acid, etc., at both 7T and 3T. The specific clinical goal is to develop better diagnostic tools for cancer involving the brain. Patients with brain tumors, either a glioblastoma (GBM) or a metastasis from systemic cancer, face a devastating clinical course consisting of progressive physical and cognitive decline over little more than a year, despite aggressive multimodality therapy. Management decisions in all phases of diagnosis, treatment and follow up rely on MR imaging based on interpretation of changes in gadolinium enhancement and T2/FLAIR (fluid attenuated inversion recovery) signal from one time point to another. However, this is fraught with conflicting interpretations which can alter management and can have profound impact on prognosis. The uncertainty is most commonly centered around differentiating tumor progression from treatment effect following radiation, a common scenario for both GBMs and metastases patients. Classic tumor progression is associated with increased size of a gadolinium enhancing mass with associated increased T2-weighted FLAIR. However, the identical imaging characteristic are ascribed to classic radionecrosis and in GBM is called "pseudoprogression" because it is impossible to differentiate from true tumor progression by available imaging. Thus the treating neuro-oncology team relies on "best guess" based on the clinical context. Since the prognosis and management is vastly different depending on whether it is tumor progression or treatment effect, patients are often taken back to the operating room for a repeat craniotomy and biopsy to make the diagnosis. Of similar importance is the clinical scenario in which changes in T2/FLAIR signal may herald early progressive disease prior to the development of tumor enhancement but is indistinguishable from peritumoral edema or reactive gliosis. Thus, overall, there is an urgent need for the development of novel imaging techniques that would aid in non-invasive diagnosis at these critical decision points. Numerous methods to improve the characterization of brain tumors have been proposed based on the integration of MRI with other techniques such as positron emission tomography (MR-PET), MR imaging of 23Na, and MR spectroscopy of 31P or 13C. While all of these methods are attractive for studying the basic biology of the disease, they are limited in clinical application because of the substantial investment in additional equipment needed. Improved diagnostic methods that rely on widely-available 1H equipment such as 1H spectroscopy and chemical exchange saturation transfer (CEST) offer a relatively simple progression to clinical research and both methods are inherently improved by the increased chemical shifts dispersion at 7T and can be implemented in a standard 1H imaging system. In this proposal we take advantage of the well characterized human orthotopic mouse models for GBM and MT, described in Project 2, the availability of high field imaging for animals and humans, and the open enrolling clinical imaging protocol for brain tumor patients at 7T. The overarching goal is to identify signature patterns by 1H-MRS and CEST imaging that can differentiate tumor progression from treatment effect and detect early progression in regions beyond the borders delineated by standard T2/FLAIR and gadolinium. Aim 1: To characterize the 1H MR spectra and CEST images at 7T in GBM and each of the four most common tumors that metastasize to the brain (melanoma, lung, breast and renal cell cancer) using human orthotopic mouse models, before and after radiation therapy. Validation in patients will be performed in Aim 2. Aim 2: To characterize the 1H MR spectra and CEST images at 7T in patients with low grade gliomas and identify differences with GBM that could be used to generate a signature pattern that would herald progression from low grade to GBM prior to the commonly used clinical or standard MR indicators. Aim 3: To map the brain in patients with low grade glioma, glioblastoma and brain metastases using the signature metabolites identified in Aims 1 and 2 and the characteristic patterns on CEST imaging at 7T to identify infiltrating tumor in gliomas and early recurrence/progression in metastatic disease.