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、免疫介导的中枢神经系统炎性脱髓鞘疾病，影响全球230多万人。MS的特征是大脑和脊髓的广泛病变，但原因仍然未知，每个患者的症状不同。虽然症状差异很大，但认知障碍（CI）影响高达70%的MS患者，并对整体生活质量有害。灰质（GM）损伤和CI之间的关系已经得到了临床和磁共振成像（MRI）研究的支持，但GM病理是微妙的，难以检测使用传统的T1和T2加权MRI。磁共振波谱已经将谷氨酸盐（脑GM中的主要兴奋性神经递质）的功能失调调节与CI联系起来，但其分辨率差且采集时间长。因此，存在开发高分辨率、临床上可获得的MRI技术的未满足的需求，所述MRI技术允许GM中的分子变化的早期检测、未来CI的预测和MS中的治疗反应的评估。酰胺质子转移（APT）化学交换饱和转移（CEST）MRI对蛋白质/肽中发现的缓慢交换酰胺质子敏感，已开发出3特斯拉（3 T）并在7 T下作为MS中白色物质病理学的生物标志物进行研究。谷氨酸敏感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进行了探索，但尚未应用于MS或CI研究。文献中描述了用于增加对更快速交换胺质子（如谷氨酸盐）的灵敏度的新MRI策略（频率标记交换转移和可变延迟多脉冲CEST），但尚未针对临床实施进行优化。利用可交换质子的MRI检测的这些最新进展，该项目的目标是开发定量，谷氨酸敏感的MRI技术，对驱动MS中CI的灰质的细微变化敏感。1）比较和优化MRI采集和分析技术，用于在幻影和健康志愿者中在7 T下生成与谷氨酸相关的对比度，和2）测试成像技术对MS患者皮质GM病理的敏感性，并检查MRI衍生指数与CI临床测量之间的相关性。这项工作的目的是通过在临床人群中应用谷氨酸敏感的MRI，为MS中皮质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.