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

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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.