Demyelination And Remyelination Detected In The Cuprizone Mouse Model Of Multiple Sclerosis With 7.0T Multiparameter Magnetic Resonance Imaging

Objects:To investigate the mechanisms underlying demyelination and remyelination with 7.0T multiparameter magnetic resonance imaging（MRI）in an alternative cuprizone（CPZ）mouse model of multiple sclerosis（MS）.Methods:Sixty mice were divided into six groups（The H0w group,D3w group,D4w group,D6w group,D6w R4w group,and D6w R7w group;n=10,each）,then using sodium carboxymethyl cellulose（CMCNa）for intragastric administration and adaptation for 1 week.Then those mice in the D3w,D4w,and D6w groups were gavaged by CPZ-CMCNa suspension for 3 weeks,4 weeks and 6 weeks to induce demyelination,respectively;mice in the D6w R4w and D6w R7w groups were gavaged by CPZ-CMCNa suspension to induced demyelination for 6 weeks,then the withdrew the suspension for spontaneous remyelination for 4 and 7 weeks,respectively;mice in the H0w group were served as the control group without CPZ-CMCNa gavage.T₁-weighted imaging（T₁WI）,T₂-weighted imaging（T₂WI）,diffusion tensor imaging（DTI）,and susceptibility-weighted imaging（SWI）were employed to compare the metrics in the splenium of corpus callosum（SCC）which was selected as the region of interest（ROI）among the groups at the corresponding time point.After the scan was completed,mice brain samples were drawn immediately.Prussian Blue（PB）and Luxol Fast Blue（LFB）staining were performed to assess pathology in SCC.Moreover,the semi-quantitative score system was employed to evaluate the PB staining,and the mean grayscale value（MGSV）was employed to evaluate the LFB staining.One-way ANOVA was performed to compare the differences among the six groups in the above MRI and pathological metrics.The correlations of the pathology metrics and the MRI metrics were analyzed by Spearman correlation analysis to evaluate the multiparameter MRI results.Results:（1）Successfully established the modified CPZ demyelination and remyelination mouse model.There were typical white matter demyelination lesions of the corpus callosum on those MRI mappings of each group.There was a myelin loss in the LFB staining which reduced to varying degrees.But no obvious abnormal iron deposition was found in PB staining,and the semi-quantitative score of PB staining was 0 in each group.（2）One-way ANOVA showed there were significant differences in the normalized T₂-weighted（T₂-nor）value,signal intensity ratio（SIR）,fractional anisotropy（FA）,mean diffusivity（MD）,radial diffusivity（RD）and axial diffusivity（AD）values among those six groups（P<0.05）;There was no significant difference in the mean phase（Φ）values of SWI among the groups（P>0.05）;Moreover,there was a significant difference in the MGSV of LFB staining（P<0.05）.（3）The post-hoc comparison between groups showed that there were significant differences in the T₂-nor value of the D4w group,D6w group,D6w R4w,and D6w R7w group compared with the H0w group,respectively（P<0.05）;And there were significant differences in SIR value of the D4w group,and the D6w group when compared with the H0w group,respectively（P<0.05）;Moreover,there were significant differences in the FA and RD values of the D4w group,D6w group,and D6w R4w group when compared with the H0w group,respectively（P<0.05）;Besides,there were also significant differences in the MD value of the D6w group,and D6w R4w group when compared with the H0w group,respectively（P<0.05）;Even thought,there was a significant difference in AD value of the D6w R4w group and the H0w group（P<0.05）;While the other groups all have significant differences in MGSV compared with the H0w group（P<0.05）.（4）Spearman correlation analysis shows that there were significant differences in the correlation analysis between SIR,T₂-nor,FA,RD,MD and MGSV,respectively（P<0.05）.Although there was no significant difference in theΦvalue among the groups,there was also a weak correlation with MGSV（P<0.05）.However,there was no significant correlation between AD value and MGSV value（P>0.05）.Conclusions:In this study,a modified acute CPZ-induced MS mouse model was successfully established to undergo demyelination and remyelination changes.The use of ultrahigh-field multi-parameter MRI can sensitively detect the pathological changes of demyelination and remyelination at SCC.Among those metrics,SIR,T₂-nor,FA,RD and MD values could sensitively detect the pathological changes such as myelin loss,inflammatory edema,and microstructure damage in acute demyelination and remyelination,while AD may be not sensitively in dectect microstructure changes during those process.Moreover,Φvalue is not yet sensitive to detect acute demyelination without iron deposits.