Optimizing Glutamate Imaging using CEST MRI at 3T Clinical Scanners

项目总结 谷氨酸(Glu)是大脑中主要的兴奋性神经递质，正常谷氨酸的破坏 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 无创测量谷氨酸。1H MRS已被用来测量血糖单位，但在实践中受到低的限制 敏感度、低空间分辨率和部分体积效应。一种潜在的高血糖的成像方法 敏感性是利用水-质子之间的化学交换饱和转移(CEST)效应。 从水中以3ppm的快速交换谷氨酸的胺质子。然而，虽然谷氨酸的CEST成像， GluCEST是6年多前推出的，已成功应用于多种疾病的诊断 临床前神经系统疾病模型(例如，牛磺酸、多巴胺缺乏症、亨廷顿病和 阿尔茨海默病等)，但在3T磁共振成像中尚未转化为临床应用。这要归功于两个 原因：首先，Glu处于快速交换状态，并与水结合，特别是在3T， 显著影响GluCEST信号，导致出现错误的共振和非特异性。 尽管有许多CEST分析方法试图隔离交换效应，但它们都是专门设计的 只针对慢交换和中间交换机制，不能解决这种合并效应，不能 GluCEST的定量；第二，GluCEST的分子起源尚未全面 对其进行了评估，其特殊性仍在争论中。例如，尽管谷氨酸具有可交换的胺质子 在为3ppm时，蛋白质赖氨酸胺在快速交换机制中具有类似的化学位移和交换率， 因此使用CEST可能不容易与Glu区分开来。在之前的GluCEST验证中，仅 主要大脑代谢物的贡献被考虑了，但蛋白质的贡献被忽略了。 这可能是因为在实践中很难精确地模仿各种不同的赖氨酸残基 使用简单模型在组织中发现的蛋白质。此应用程序旨在克服这些挑战，并 开发一种实用的数据分析方法，以便进行常规的Glu成像。在目标1中，我们将发展和 实施名为tAREX(切角归一化表观交易所依赖松弛)的新指标，以 解决在快速兑换限制中更好地量化的需求。我们的初步分析和模拟 结果表明，TAREX能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 和其他小分子从脑组织匀浆样本中研究蛋白质的影响 在GluCEST上。加上对含有主要代谢物的模体的测量，组织的透析 匀浆可以对GluCEST的来源进行全面的调查。归根结底，这种方法 将有助于未来将Glu的测量转换为临床扫描仪和应用程序。它也可以用在 快速交换机制中的其他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).