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

谷氨酸敏感性定量 MRI 在 MS 中的应用：在认知障碍中的应用

• 批准号: 9396736
• 负责人: Kristin Poole O'Grady
• 金额: $ 5.67万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396736
• 关键词: Affect; Amides; Amination; Amines; Biological Markers; Brain; Brain Pathology; Chemicals; Chronic; Clinical; Clinical Research; Development; Early Diagnosis; Epilepsy; Evaluation; Frequencies; Future; Glutamate Metabolism Pathway; Glutamates; Goals; Hippocampus (Brain); Human; Imaging Techniques; Immune; Impaired cognition; Inflammatory; Label; Lesion; Link; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Methods; Molecular; Multiple Sclerosis; Nerve Degeneration; Neurotransmitters; Pathogenesis; Pathology; Patients; Peptides; Physiologic pulse; Population; Process; Proteins; Protons; Quality of life; Regulation; Research; Resolution; Scanning; Spinal Cord; Symptoms; Techniques; Testing; Time; Work; central nervous system demyelinating disorder; excitotoxicity; experimental study; glutamatergic signaling; gray matter; healthy volunteer; image processing; imaging biomarker; imaging detection; imaging study; indexing; insight; magnetic field; multiple sclerosis patient; neuron loss; preclinical study; simulation; treatment response; white matter

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.

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症性脱髓鞘疾病，影响着全球超过 230 万人。多发性硬化症的特点是大脑和脊髓广泛病变，但病因仍不清楚，每个患者的症状也不同。尽管症状差异很大，但认知障碍 (CI) 影响高达 70% 的多发性硬化症患者，并且不利于整体生活质量。灰质 (GM) 损伤与 CI 之间的关系已得到临床和磁共振成像 (MRI) 研究的支持，但 GM 病理学很微妙，很难使用传统的 T1 和 T2 加权 MRI 检测到。磁共振波谱已将谷氨酸（大脑 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，但其分辨率较差且采集时间较长。因此，开发高分辨率、临床可用的 MRI 技术的需求尚未得到满足，该技术可以早期检测 GM 的分子变化、预测未来的 CI 以及评估 MS 的治疗反应。最近，对蛋白质/肽中发现的缓慢交换酰胺质子敏感的酰胺质子转移 (APT) 化学交换饱和转移 (CEST) MRI 已在 3 特斯拉 (3T) 下开发出来，并在 7T 下作为 MS 中白质病理学的生物标志物进行研究。谷氨酸敏感的 CEST MRI 仅在临床前研究、健康人脑/脊髓和癫痫中以超高场强进行探索，但尚未应用于研究 MS 或 CI。文献中已经描述了提高对更快速交换胺质子（例如谷氨酸质子）敏感性的新 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 MRI 检测的最新进展，该项目的目标是开发定量、谷氨酸敏感的 MRI 技术，该技术对驱动 MS 中 CI 的灰质细微变化敏感。拟议的研究由两部分组成：1) 比较和优化 MRI 采集和分析技术，用于在体模和健康志愿者中生成 7T 谷氨酸相关的对比度，2) 测试成像技术对多发性硬化症患者皮质 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。这项工作旨在通过在临床人群中应用谷氨酸敏感 MRI，为 MS 中皮质 GM 病理学和 CI 的分子变化提供新的见解。