Multimoding MRI Study On KIBRA Gene Variants And The Default-mode, Executive Control Networks

Objective:Genetic variation at the KIBRA rs17070145polymorphism has been linked to episodic memory, executive function, and Alzheimer’s disease (AD); however its neural substrates remain elusive. We combined voxel-based morphometry (VBM) analysis of structural MRI data and independent component analysis (ICA) analysis of resting-state fMRI data to investigate to investigate neural correlates of KIBRA gene and brain networks in a large sample of healthy young adults.Subjects and Methods:A total of288healthy, young, right-handed subjects were recruited in this study. Resting-state fMRI, high-resolution structural imaging, and diffusion tensor imaging were performed using a GE3.0T Signa HDX scanner. During the scanning, all subjects were explicitly instructed to keep their eyes closed, relax, as motionless as possible and think of nothing.1. Genotyping We extracted genomic DNA from3000μl of whole blood using the EZgeneTM Blood gDNA Miniprep Kit (Biomiga Inc, San Diego, CA, USA). Then, we genotyped the KIBRA rs17070145in each subject using the PCR and ligation detection reaction (LDR) method.2. All preprocessing steps were carried out using the statistical parametric mapping (SPM8, http://www.fil.ion.ucl.ac.uk/spm) based on Matlab.3. The preprocessing of high resolution structural images including segmentation of gray and white matter, spatial normalization and smooth with a4mm full width at half maximum; while the preprocessing of rs-fMRI data including slice timing, realignment, spatial normalization to the MNI, resampling to to2×2×2mm3cubic voxels, and smoothed with a4mm full width at half maximum.4. Group ICA was performed using the MICA software based on Matlab, five RSNs were chosen from the results of ICA; and the group sychroniztion differences were investigated between the two KIBRA genotypes with the age, gender and education years as covariates. 5. Voxel-based morphometry (VBM) analysis of structural MRI data was performed to investigate group differences of grey matter volume and white matter integrity6. Multiple comparisons were statistically corrected by Monte Carlo simulation. Finally, the corrected statistical parameter mapping was overlapped onto MNI standard template and the coordinate, size and peak t values of each significant cluster were recorded.Results:1. The genotype distribution of the SNP was in Hardy-Weinberg equilibrium [χ2(2)=0.36, p-0.55]. There were no significant group differences in age, gender, years of education, memory and WCST scores although the CC group showed a trend towards decreased memory and executive function.2. Five meaningful resting state networks were obtained from the MICA results: default mode network (anterior, posterior), executive control network, sensorimotor netwok, and visual network.3. KIBRA C-allele carriers showed significantly increased synchronization in the right MPFC of the aDMN and left PCC of the pDMN, the right AI, bilateral Cau, and bilateral dACC of ECN. No significant differences in synchronization were found in either the SMN or the VN between the two genotypes.4. KIBRA C-allele carriers showed significant decrease GMV in the right MPFC of the aDMN and the dACC of the ECN. No significant differences in white matter volume and white matter integrity were found between the two genotypes.Conclusion:1. The structure and function of the DMN and ECN may be selectively affected by KIBRA rs17070145polymorphism;2. The increased synchronization in the DMN and ECN is likely a reflection of compensation for the GMV deficit in these networks in young healthy subjects.3. The white matter volume and integrity might not be affected by KIBRA rs17070145polymorphism.