Comparisons of MR and EM inferred tissue microstructure properties using a human autopsy corpus callosum sample

Degeneration of white matter (WM) microstructure in the central nervous system is characteristic of many neurodegenerative conditions. Previous research indicates that axonal degeneration visible in ex vivo electron microscopy (EM) photomicrographs precede the onset of clinical symptoms. Measuring WM microstructural features, such as axon diameter and packing fraction, currently require these highly invasive methods of analysis and it is therefore of great importance to develop methods for in vivo measurements. Diffusion weighted Magnetic Resonance Imaging (MRI) is a non-invasive method which can be used in conjunction with temporal diffusion spectroscopy (TDS) and an oscillating gradient spin echo (OGSE) pulse sequence to probe micron-scale structures within neural tissue. The current experiment aims to compare axon diameter measurements, mean effective axon diameter ($\overline{\mathrm{AxD}}$), and packing fractions calculated from EM histopathological analysis and inferred values from MR images. Mathematical models of axon diameters used for analysis include the ActiveAx Frequency-Dependent Extra-Axonal Diffusion (AAD) model and the AxCaliber Frequency-Dependent Extra-Axonal Diffusion (ACD) model using ROI (Region of Interest) based analysis (RBA) and voxel-based analysis (VBA), respectively. Overall, it was observed that MRI inferred WM microstructural parameters overestimate those calculated from EM. This may be attributable to tissue shrinkage during EM dehydration, the sensitivity of MR pulse sequences to larger diameter axons, and/or inaccurate model assumptions. The results of the current study provide a means to characterize the precision and accuracy of RBA-ACD and VBA-AAD OGSE-TDS and highlight the need for further research investigating the relationship between ex vivo MRI and EM, with the goal of reaching in vivo MRI.