Glutamate-Sensitive, Quantitative MRI in MS: Application to Cognitive Impairment

多发性硬化症(MS)是一种不可预测的、免疫介导的炎症性中枢神经系统脱髓鞘疾病，全球有230多万人受到影响。多发性硬化症的特点是大脑和脊髓广泛受损，但病因尚不清楚，每个患者的症状也不同。尽管症状差异很大，但认知障碍(CI)影响了高达70%的MS患者，并损害了整体生活质量。灰质损伤与脑梗塞之间的关系已经得到临床和磁共振成像(MRI)研究的支持，然而GM的病理是微妙的，很难用常规的T1和T2加权MRI检测出来。磁共振波谱将大脑GM中主要的兴奋性神经递质谷氨酸的功能失调调节与CI联系在一起，但存在分辨率低和获取时间长的问题。因此，有一个尚未得到满足的高分辨率，临床可访问的MRI技术，允许早期检测GM的分子变化，预测未来的CI，并评估MS的治疗反应。最近，在3Tesla(3T)开发了酰胺质子转移(APT)化学交换饱和转移(CEST)MRI，对蛋白质/多肽中发现的缓慢交换的酰胺质子敏感，并作为7T时MS白质病理的生物标志物进行了研究。谷氨酸敏感的CEST MRI仅在临床前研究、健康人脑/脊髓和癫痫中在超高场强下被探索，但尚未被应用于MS或CI的研究。文献中已经描述了提高对更快速交换的胺质子，例如谷氨酸的敏感性的新的MRI策略(频率标记交换转移和可变延迟多脉冲CEST)，但尚未优化用于临床实施。利用MRI检测可交换质子的这些最新进展，该项目的目标是开发对灰质细微变化敏感的定量谷氨酸敏感MRI技术，这些灰质变化是导致MS CI的原因。建议的研究包括两部分：1)比较和优化MRI采集和分析技术，以产生与7T模体和健康志愿者的谷氨酸相关的对比；2)测试成像技术对MS患者皮质GM病理的敏感性，并检查MRI衍生指标与CI临床指标之间的相关性。这项工作旨在通过在临床人群中应用谷氨酸敏感的磁共振成像，为MS患者皮质GM病理和CI的分子变化提供新的见解。

Multiple sclerosis (MS) is an unpredictable, immune-mediated, inflammatory demyelinating disease of the central nervous system that affects more than 2.3 million people worldwide. MS is characterized by widespread lesions in the brain and spinal cord, but the cause remains unknown and symptoms differ in each patient. Although symptoms vary widely, cognitive impairment (CI) affects up to 70% of patients with MS and is detrimental to overall quality of life. A relation between gray matter (GM) damage and CI has been supported by clinical and magnetic resonance imaging (MRI) studies, yet GM pathology is subtle and difficult to detect using conventional T1- and T2-weighted MRI. Magnetic resonance spectroscopy has linked dysfunctional regulation of glutamate, the principle excitatory neurotransmitter in the brain GM to CI, yet suffers from poor resolution and long acquisition times. Thus, there is an unmet need to develop high-resolution, clinically-accessible MRI techniques that allow early detection of molecular changes in GM, prediction of future CI, and evaluation of treatment response in MS. Recently, amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI sensitive to slowly exchanging amide protons found in proteins/peptides has been developed at 3 Tesla (3T) and investigated as a biomarker of white matter pathology in MS at 7T. Glutamate-sensitive CEST MRI has only been explored at ultra-high field strengths in preclinical studies, in healthy human brain / spinal cord, and in epilepsy but has not been applied to study MS or CI. New MRI strategies for increasing sensitivity to more rapidly exchanging amine protons, such as those of glutamate, have been described in the literature (frequency-labeled exchange transfer and variable delay multi-pulse CEST) but have not yet been optimized for clinical implementation. Leveraging these recent advances in MRI detection of exchangeable protons, the goal of this project is to develop quantitative, glutamate-sensitive MRI techniques sensitive to subtle changes in gray matter that drive CI in MS. The proposed research consists of two parts: 1) Compare and optimize MRI acquisition and analysis techniques for generating contrast related to glutamate at 7T in phantoms and healthy volunteers, and 2) test the sensitivity of the imaging techniques to pathology in cortical GM of MS patients and examine correlations between MRI-derived indices and clinical measures of CI. This work aims to provide new insights into molecular changes underlying cortical GM pathology and CI in MS through the application of glutamate-sensitive MRI in a clinical population.