Development and application of quantitative MRI methods for assessing white matter integrity in the mouse brain

Abstract

Healthy white matter in the brain and spinal cord is composed primarily of myelinated axons and glial cells. Myelinated axons transfer information between the peripheral nervous system and the central nervous system (CNS) as well as between centres within the CNS. Demyelination, a hallmark of neurodegenerative autoimmune diseases such as multiple sclerosis (MS), can cause nerve damage and degrade signal propagation. Magnetic resonance imaging (MRI) methods thought to assess myelin integrity and the structural integrity of axons are improving both the diagnosis and understanding of white matter diseases such as MS. Current methods, however, are sensitive to many different pathologies, making the interpretation of individual MRI results difficult. For this dissertation, several quantitative MRI methods were developed and compared, including single component T1 and T2 relaxometry, multicomponent T2 relaxometry, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI). These methods were tested on agarose gels, fixed rat spinal cords, healthy control mice, and the cuprizone mouse model of demyelination. Quantitative MRI measurements were correlated to ultrastructural measurements of white matter to determine the influence myelin content and axonal structure have on different MRI methods. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: longitudinal relaxation rates (RA/T1) vs. the myelinated axon fraction ( r = 0.90/-0.90), the qMTI-derived bound pool fraction (f) vs. the myelin sheath fraction ( r = 0.93), and the DTI-derived axial diffusivity vs. the non-myelinated cell fraction (r = 0.92). Using Pearson’s correlation coefficient, f was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37f −0.25). Of the calculated MRI metrics, f was the strongest indicator of myelin content while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. Multiparametric MRI measurements of relaxation, diffusion, and magnetization transfer give a more complete picture of white matter integrity.