Magnetic Resonance Imaging Of Genetic Mutation Carriers Of Leber’s Hereditary Optic Neuropathy

Objective:To investigate the early damage to the brain tissue of genetic mutation carriers of Leber’s hereditary optic neuropathy(LHON)using voxel-based morphometry(VBM)with multiple voxel analysis,diffusion tensor MRI(DTI)with tract-based spatial statistics(TBSS)and its relation with neuro-ophthalmologic changes.Methods:Fourteen genetic mutation carriers of LHON and fifteen gender and age-matched control subjects were assessed using VBM,DTI and neuro-ophthalmologic tools.High-resolution three-dimensional T1 weighted images were segmented into gray and white matter images,standardized to MNI space and modulated to get normalized volumes of the cerebral white and gray matter.DTI images were processed with correction of artifacts due to local current and head motions,extraction of brain tissue,calculation of eigenvalues,obtaining of FA,AD and RD images.The SPM extension“the decoding toolbox”was used to perform multiple-voxel analysis via searchlight method to obtain the discriminating accuracy images of cerebral gray and white matter regional volume.The accuracy images were z-score standardized and thresholded with 2,ROIs with more than 30 adjacent voxels when the smooth kernel is 3×3×3mm~3 or 260 adjacent voxels when the smooth kernel is 6×6×6mm~3 were used in the further analysis.Multiple testing was corrected by the false discovery rate(FDR)method.DTI images were normalized and group level white matter skeleton was calculated and white matter skeleton mask was produced to obtain individual skeletons of FA,AD,RD and MD images.And internal package,randomize,of FSL was used to perform randomization statistics and FWE correction was performed with TFCE.The John Hopkins white matter tract probability map was used to extract the DTI indexes of the fiber tracts with significant FA difference.Scatter plot images were created according to different LHON gene mutations with specific labeling of gender and minors.Robust test was performed with removal of outliers,regressing out age and gender,removal of minors and male subjects.Partial correlation analysis was performed to reveal the correlation between abnormal neuro-ophthalmologic measures and imaging metrics.Results:Of the neuro-ophthalmologic measures,only the thickness of the retinal nerve fibre layer(RFNL)of the right inferior quadrant showed weak increase in the LHON carriers(t=2.6117,p=0.0150,the corrected threshold of significance is p<0.0125)and no subgroup difference were found(Kruskal-Wallisχ2=0.072,p=0.9644).In the VBM analysis,gray matter volume reduction and white matter volume increase were found in multiple brain regions with significant correlation with RNFL thickness.For DTI analysis,there were widespread increase of FA and decrease of RD and MD.The abnormal areas of RD was the largest and that of FA is the smallest while that of MD lied in the middle.The FA reduction involved 9 of 20major WM fiber tracts.The RD within these fibers was increased.But the reduction of AD was not significant.No correlation between neuro-ophthalmologic measures and DTI indices was found.Conclusion:Non-symptomatic LHON carriers had gray matter volume reduction and white matter volume increase in multiple regions with significant correlation with RNFL thickness.DTI metric changes were widespread with reduction of FA and increase of MD and RD without significant correlation with RNFL thickness.White matter volume,grey matter volume and DTI indexes did not correlate with visual acuity and field measures,indicating the swelling of brain white matter of LHON mutant carriers was caused by injury of neurons and their axons not withstanding normal stimuli.Novelty:This is the first time to investigate the brain white matter changes in genetic mutant carriers of LHON with voxel based morphometry and diffusion tensor imaging.There are two novel findings in this study:the changes of regional brain volume and diffusion metrics,revealing the wide-spread white matter microstructure abnormality of LHON carriers.