MRI identification of the rostral‐caudal pattern of pathology within the corpus callosum in the cuprizone mouse model

Abstract

Purpose: To characterize and compare histological and MRI-based changes within the corpus callosum (CC) in the cuprizone mouse model of multiple sclerosis (MS). Materials and Methods:A total of 12 C57/BL6 mice were fed cuprizone from eight weeks of age for four weeks. One cohort of six cuprizone and two control mice were scanned with a T2-weighted (T2W) sequence. The other cohort of six cuprizone and four control mice were scanned using a dualecho sequence for T2-mapping and a diffusion-weighted sequence with two orthogonal diffusion encoding directions to calculate water diffusivities parallel and perpendicular to the CC fiber (apparent diffusion coefficients [ADC] and ADC Ќ ). After the mice were killed, the rostral-caudal pattern of CC demyelination and other pathologies were examined using Luxol Fast Blue, neurofilament staining, and immunohistochemistry for microglia and were correlated with MRI. Results:In contrast to control mice, T2W imaging (T2WI) hyperintensity, reduced ADC , and elevated ADC Ќ were detected in the CC of cuprizone-fed mice, particularly in the caudal segment. The T2 value was increased in the entire CC. Marked demyelination, as well as axonal injury, microglia accumulation, and cellular infiltration were found in the caudal section of the cuprizone mouse CC. The rostralcaudal pattern of abnormalities within the CC in MRI measurements correlated well with histopathological findings. Conclusion:Noninvasive MRI using quantitative T2 and ADC mapping accurately characterized the rostral-caudal pattern of CC demyelination and other pathologies in cuprizone challenged mice, and thus could provide an effective way to assess the structural response to experimental therapeutics being designed for the treatment of MS.

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

“…Our data indicate that up-regulation of the chemokine CXCL12 is essential for the differentiation of CXCR4-expressing OPCs into mature oligodendrocytes within the demyelinated CC in vivo. We show that the pattern of CXCL12 expression mirrors rostralcaudal patterns of pathology previously observed during CPZmediated demyelination (21,22). Thus, highest levels of CXCL12 were expressed by activated astrocytes within caudal sections, which exhibit the most extensive demyelination and glial cell activation.…”

“…Cessation of CPZ after 6 wk is followed by OPC differentiation and remyelination, whereas continued ingestion leads to OPC apoptosis and chronic demyelination. Prior studies have demonstrated that demyelination and glial injury occurs most prominently in the caudal region of the CC and that continued ingestion of CPZ leads to extension of injury to OPCs and decreased remyelination even after cessation of toxin (21,22). Thus, this model provides an opportunity to examine signals associated with both successful and failed remyelination.…”

Sex matters: repetitive mild traumatic brain injury in adolescent rats

“…Another potential limitation is the lack of histological evidence to corroborate our MRI findings. Although previous studies have validated MRI measures against histology,72, 73, 74 this study would have been strengthened by complementary histological studies. Lastly, while it is unlikely that the rats reached sexual maturity during the course of this study, future investigations may want to examine the effects of estrous cycle on postinjury recovery.…”

The effect of triiodothyronine on maturation and differentiation of oligodendrocyte progenitor cells during remyelination following induced demyelination in male albino rat

“…In the present study, the supra-hippocampal portion of the CC which at more caudal position was described, while in the study of Silvestroff et al (2012) the brain sections were analyzed at a more rostral level. In fact, it has been shown that cuprizone induced demyelination produces a dramatic rostrocaudal gradient of white matter demyelination, with the caudal CC more injured than rostral area (Wu et al, 2008;Xie et al, 2010).…”