Sensitivity of quantitative MRI to demyelination and axonal loss: validation against myelinated and unmyelinated axons from histology

Motivation: Attaining microstructural specificity to myelinated/unmyelinated axons from macroscopic in vivo quantitative MRI. Goal(s): Quantifying changes of myelinated and unmyelinated axons using dMRI. Approach: We apply compartmental diffusion models of white matter, White Matter Tract Integrity (WMTI) and Standard Model Imaging (SMI) to the dMRI signal. We also measure Magnetic Transfer Resonance and R2. We develop automated techniques to segment 2d transmission electron microscopy (TEM) images of white matter into their constituent microstructure and apply volumetric analysis. Results: We measured axonal water fraction (AWF) using WMTI and SMI. AWF correlated strongly with our EM volumetric analysis of myelinated and unmyelinated axons. Impact: Demyelination and axonal loss occur in neurodegenerative pathologies. This validation study reveals specificity of R2 to myelin volume, while AWF from dMRI detects both unmyelinated and unmyelinated axons. Combining both modalities has the potential to differentiate demyelination from axonal loss.