Optimizing Glutamate Imaging using CEST MRI at 3T Clinical Scanners

项目摘要 谷氨酸（Glu）是大脑中主要的兴奋性神经递质， 水平与各种主要的神经和精神疾病有关，这导致了重大的努力， 非侵入性地测量Glu。1H MRS已被用于测量Glu，但在实践中受到低浓度的限制。 灵敏度、低空间分辨率和部分体积效应。一种潜在的方法来成像具有高血糖的Glu， 灵敏度是利用水质子和质子之间的化学交换饱和转移（CEST）效应 从水中快速交换0.3ppm的Glu的胺质子。然而，尽管Glu的CEST成像， 名为GluCEST，6年前推出，并已成功应用于诊断许多 临床前神经疾病模型（例如tau蛋白病、多巴胺缺乏、亨廷顿病和 阿尔茨海默病等），它还没有在3 T MRI上转化为临床应用。这是由于两 原因：首先，Glu处于快速交换状态并与水聚结，特别是在3 T下， 显著影响GluCEST信号，导致出现假共振和非特异性。 虽然有许多CEST分析方法试图隔离交换效应，但它们的设计目的是 仅适用于缓慢和中间交换制度，不能解决这种聚结效应， 适当地定量GluCEST;第二，GluCEST的分子起源还没有被全面地 其具体性仍在讨论中。例如，尽管Glu具有可交换的胺质子， 在0.13ppm时，蛋白赖氨酸胺在快速交换状态下具有相似的化学位移和交换速率， 因此使用CEST可能不容易与Glu区分开。在先前的GluCEST验证中，仅 考虑了主要脑代谢物的贡献，但忽略了蛋白质的贡献。 这可能是由于在实践中难以精确地模拟各种各样的多肽的赖氨酸残基。 在组织中发现的蛋白质。本申请提出克服这些挑战， 开发一种实用的数据分析方法，以实现Glu的常规成像。在目标1中，我们将开发和 实施新度量，称为tAREX（正切θ归一化表观交换依赖弛豫）， 解决了快速交换限值中更好的量化需求。我们的初步分析和模拟 表明tAREX可以成功地消除聚结效应。在目标2中，我们将使用透析来去除Glu 和其他小分子的脑组织匀浆样品，以研究蛋白质的影响， 在GluCEST上。连同对含有主要代谢物的体素的测量， 匀浆可以提供GluCEST起源的全面研究。最终，该方法 将有助于未来将Glu的测量转化为临床扫描仪和应用。它也可以用于 快速交换体系中的其他CEST应用（例如PARACEST、糖基CEST、脂质体CEST）。

PROJECT SUMMARY Glutamate (Glu) is the primary excitatory neurotransmitter in the brain, and disruptions of normal glutamate levels are implicated in a variety of major neurological and psychiatric disorders, which has led to major efforts to measure Glu non-invasively. 1H MRS has been exploited to measure Glu but in practice is limited by low sensitivity, low spatial resolution, and partial volume effects. A potential approach to imaging Glu with high sensitivity is to exploit the chemical exchange saturation transfer (CEST) effect between water protons and the rapidly exchanging amine protons of Glu at  3 ppm from water. However, although CEST imaging of Glu, named GluCEST, was introduced over 6 years ago and has been successfully applied in diagnosing many preclinical neurological disease models (e.g. tauopathy, dopamine deficiency, Huntington’s disease, and Alzheimer’s disease etc.), it has not been translated to clinical applications at 3 T MRI. This is due to two reasons: First, Glu is in the fast exchange regime and coalesces with water especially at 3 T, which significantly influences GluCEST signals, causing the appearance of false resonances and non-specificities. Although there are many CEST analysis methods that attempt to isolate exchange effects, they are designed only for the slow and intermediate exchange regimes and cannot solve this coalescence effect and fail to quantify GluCEST properly; Second, the molecular origin of GluCEST has not been comprehensively evaluated and its specificity is still under debate. For instance, although Glu has exchangeable amine protons at  3 ppm, protein lysine amines have similar chemical shifts and exchange rates in the fast exchange regime, and thus may not be easily distinguished from Glu using CEST. In previous validation of GluCEST, only contributions from the major brain metabolites were considered, but contributions from proteins were ignored. This may be due to that it is difficult in practice to precisely mimic the lysine residues of the wide variety of proteins found in tissues using simple models. This application proposes to overcome those challenges and develop a practical data analysis method to allow routine imaging of Glu. In Aim 1, we will develop and implement a new metric, termed tAREX (tangent theta normalized apparent exchange-dependent relaxation) to address the need for better quantification in the fast exchange limit. Our preliminary analysis and simulations show that tAREX can successfully remove the coalescence effect. In Aim 2, we will use dialysis to remove Glu and other small molecules from samples of brain tissue homogenates to investigate the influence of proteins on GluCEST. Together with measurements on phantoms containing major metabolites, the dialysis of tissue homogenates can provide a comprehensive investigation of the origins of GluCEST. Ultimately, the approach will help future translation of measurements of Glu to clinical scanners and applications. It may be also used in other CEST applications in the fast exchange regime (e.g. PARACEST, Sugar-based CEST, Liposome CEST).