Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains

Abstract

Advanced neuroimaging techniques provide the possibility to non-invasively understand and monitor white matter during development and disease. While data from quantitative MRI techniques, such as multiexponential T2 (MET2) and quantitative magnetization transfer (qMT), correlate with myelin content, neither provide an absolute measure of the myelin volume fraction (MVF). Additionally, in preclinical studies, despite time-intensity and small tissue samples, histology remains the gold standard for quantitatively assessing changes in myelin content and white matter microstructural properties, such as myelin thickness and the g-ratio (ratio of axon radius to myelinated fiber radius). Therefore, the work in this dissertation first established and validated methods for MVF imaging from MET2 and qMT against quantitative electron microscopy. We show strong agreement in adult, control mice along with three mouse models of white matter disease. Next, we applied MVF imaging in mice during normal development and observe good agreement between MET2 and qMT and with expected myelin development. To further investigate specific changes in myelin microstructure, recent methods proposed measuring the g-ratio from MRI (gMRI). We revised the model and displayed with quantitative histology that gMRI provides an axon-area-weighted g-ratio. Calculating gMRI requires an accurate measure of MVF; thus, we utilize our MVF imaging techniques to measure gMRI in mouse brain and detect changes in g-ratio with disease in agreement with quantitative histology. In short, we develop and validate measures of MVF and g-ratio from MRI which have the potential to non-invasively provide more specific and thorough assessment of white matter not obtainable with currently used methods.