Histological correlation of diffusional kurtosis and white matter modeling metrics in cuprizone-induced corpus callosum demyelination

Abstract

The cuprizone mouse model is well established for studying the processes of both demyelination and remyelination in the corpus callosum, and it has been utilized together with diffusion tensor imaging (DTI) to investigate myelin and axonal pathology. Although some underlying morphological mechanisms contributing to the changes in diffusion tensor (DT) metrics have been identified, the understanding of specific associations between histology and diffusion measures remains limited. Diffusional kurtosis imaging (DKI) is an extension of DTI that provides metrics of diffusional non-Gaussianity, for which an associated white matter modeling (WMM) method has been developed. The main goal of the present study was to quantitatively assess the relationships between diffusion measures and histological measures in the mouse model of cuprizone-induced corpus callosum demyelination. The diffusional kurtosis (DK) and WMM metrics were found to provide additional information that enhances the sensitivity to detect the morphological heterogeneity in the chronic phase of the disease process in the rostral segment of the corpus callosum. Specifically, in the rostral segment, axonal water fraction (d = 2.6; p < 0.0001), radial kurtosis (d = 2.0; p = 0.001) and mean kurtosis (d = 1.5; p = 0.005) showed the most sensitivity between groups with respect to yielding statistically significant p values and high Cohen's d values. These results demonstrate the ability of DK and WMM metrics to detect white mater changes and inflammatory processes associated with cuprizone-induced demyelination. They also validate, in part, the application of these new WMM metrics for studying neurological diseases, as well as helping to elucidate their biophysical meaning.

Keywords: DKI; MRI; corpus callosum; cuprizone; demyelination; diffusion; mouse.

Figure 1

First Row: Coronal diagram of the mouse brain with slices (Paxinos’ mouse Brain Atlas) centered at anatomical positions corresponding to the bregma location for corpus callosum (CC) rostral (aCC), middle (bCC) and caudal (pCC) levels; Second Row: Representative fraction anisotropy (FA) maps (NC mice) with CC ROIs at each level. Third Row: Representative of the Solochrome stain (NC mice) with CC ROIs at each level.

Figure 2

Histological examples (4×) of the solochrome (A) and amino cupric silver (B) stains, and GFAP (C) and Iba1 (D) immunohistochemistry with detailed insert (100×) at the body from of the CC. Control group (NC) and cuprizone group (CPZ). Scale bar = 100 μm.

Figure 3

Morphological heterogeneity of the demyelination process in the cuprizone group; the figure illustrates histological sections from 3 cuprizone mice, showing the different degree of demyelination in the aCC (177.15±4.50) and similar, complete demyelination at the bCC (183.50±2.14) and pCC(179.89±3.83) for all three mice. Note the higher SD at the level of the aCC when compared is bCC and pCC, reflecting the morphological demyelination heterogeneity in the aCC. Intensity values as mean ± SD (arbitrary units).