QSI and DTI of Inherited White Matter Disorders in Rat Spinal Cord: Early Detection and Comparison with Quantitative Electron Microscopy Findings

<b>Background:</b> Inherited white matter (WM) disorders of the central nervous systems (CNS), or leukodystrophies, are devastating diseases that primarily affect children, many of whom die early in life or suffer from long-term disability. <b>Methods</b>: q-Space diffusion MR imaging (QSI) and diffusion tensor MR imaging (DTI) with the same resolution and timing parameters were used to study the spinal cords (SCs) of two myelin mutants that are experimental models of WM diseases of different severity, namely the 28-day-old <i>taiep</i> and Long-Evans Shaker <i>(les</i>) rats. The aim was to verify if and which of the diffusion methodologies used is more suitable for early detection of the milder <i>taiep</i> pathology and to characterize its early phase. We also aimed to compare the diffusion MRI results with quantitative electron microscopy (EM) findings. <b>Results</b>: We found that at this early age (28 days), both QSI and DTI were able to detect the severe <i>les</i> WM pathology, while the milder WM pathology in the SC of the <i>taiep</i> rats was detected only by QSI. An increase in the mean radial displacement (RaDis), representing the MRI axon diameter (AD), and a decrease in the probability for zero displacement (PZD) were observed in the dorsal column (ROI 1) of the <i>taiep</i> SCs. In other WM areas, the same trends were observed but the differences were not of statistical significance. In DTI, we found some lower fractional anisotropy (FA) values in the <i>taiep</i> SCs compared to the controls; however, these differences were not statistically significant. For the more severe <i>les</i> pathology, we observed a dramatic increase in the RaDis values and a large decrease in PZD values in all ROIs examined. There, even the FA values were lower than that of the control SCs in all ROIs, albeit with much smaller statistical significance. These MRI results, which show a higher detectability of WM pathology with heavier diffusion weighting, followed histological findings that showed significant myelin deficiency in the dorsal column in the <i>taiep</i> SCs and a practically complete myelin loss in all WM areas in the <i>les</i> SCs. This study also revealed that, under the experimental conditions used here, the apparent increase in RaDis agrees better with myelin thickness and not with average AD extracted form EM, probably reflecting the effect of water exchange. <b>Conclusions:</b> These results, corroborated by diffusion time-dependent QSI, also imply that while diffusion MRI in general and QSI in particular provide acceptable apparent axon diameter estimations in heathy and mature WM, this appears not to be the case in severely damaged WM where exchange appears to play a more important role.