Association Of CNTN4 Polymorphism With Brain Structure And Function In Amyotrophic Lateral Sclerosis

Background:Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease that involves motor neurons in the cerebral cortex,anterior horn cells of the spinal cord,and brainstem motor nuclei.The main feature is the loss of selective upper and lower motor neurons,and progressively worsening muscle atrophy,muscle weakness,and pyramidal tract signs.In recent years,with the rapid development of molecular biology,it has been discovered that multiple genes are related to the pathogenesis of ALS,and the protein encoded by the contactin4(CNTN4)may play a role in the formation of axon connections in the development of the nervous system.Regulate the formation and plasticity of neuronal networks.The previous research of our research group found that the C allele(CC + CT)carried by the CNTN4 rs2619566 gene polymorphism in the Han population in China's mainland can increase the risk of ALS.With the development of resting state functional magnetic resonance imaging(rs-f MRI)and diffusion tensor imaging(DTI)and other magnetic resonance imaging technologies,many studies have analyzed the functional connectivity and structural connectivity of the motor network of ALS to explore the characteristics of endogenous functional connectivity and structural connectivity of the motor network of ALS.With the advancement of research technology,brain images of human brain structure and function can be used as phenotypes to analyze the influence of genes on the individual to be studied.This study mainly explores the impact of CNTN4rs2619566 polymorphism on brain structure and function of ALS,To provide preliminary evidence for genetic imaging studies of ALS.Purpose:To explore the influence mode of CNTN4 rs2619566 polymorphism on brain structure and function of ALS.Methods:The study grouped ALS and normal control subjects according to the genetic polymorphism of CNTN4 rs2619566,using voxel-based morphometry(VBM)technology,diffusion tensor imaging(DTI)technology based on body Voxel-based analysis(VBA),Tract-Based Spatial Statistics(TBSS)based on fiber bundle tracing,resting state functional magnetic resonance imaging(rs-f MRI)uses the amplitude of low frequency fluctuation(ALFF)algorithm and independent component analysis(ICA)technology,we explored the effects of the genetic polymorphism of CNTN4rs2619566 on gray matter volume,white matter fiber bundle integrity,spontaneous activity of brain functional network,and the structure and function of resting state network.Based on the above results,the neural mechanism of the influence of CNTN4 rs2619566 polymorphism on brain structure and functional network was elaborated.Results:(1)The clinical data of CNTN4 rs2619566 CC+CT genotype and TT genotype in the ALS group were statistically analyzed.There was no statistical difference in age of onset,course of disease,ALS functional rating scale(ALSFRSl)score,and location of onset(p>0.05).(2)In the ALS group,CNTN4 rs2619566 CC+CT genotype decreased the gray matter volume of the right side of the hippocampus and the outer nucleus of the bilateral upper longitudinal tract,and the decrease of the gray matter density of the outer nucleus of the bilateral upper longitudinal tract was positively correlated with the ALSFRS score.(3)Compared with the CNTN4 rs2619566 CC+CT genotype ALS group and the Health Control(HC)group,both VBA and TBSS methods showed that the fractional anisotropy(FA)decreased in the bilateral corticospinal tract and the bilateral upper longitudinal tract.The VBA method showed that the mean diffusivity(MD)of the bilateral corticospinal tract increased,and the TBSS method showed that the MD of the bilateral upper longitudinal tract increased;and both two methods CNTN4rs2619566 TT genotype ALS group did not find significant FA and MD change in the brain area compared with the HC group.Both analysis methods can find the FA value of the corpus callosum in the ALS group decreased and the MD value increased.(4)Compared ALS group with HC group,the increase in fractional amplitude of low frequency fluctuations(f ALFF)value is mainly concentrated in the left middle frontal gyrus,and the decrease is mainly concentrated in the bilateral lingual gyrus/tallar gyrus(i.e.bilateral primary visual cortex,secondary visual cortex and combined visual cortex).Compared with the CNTN4 rs2619566 CC+CT ALS group and the HC group,the f ALFF value decreased area was mainly concentrated in the right primary visual cortex.(5)The CNTN4 rs2619566 CC+CT genotype in the ALS group has decreased functional connectivity in the right central anterior gyrus,suggesting that this genotype may lead to a decrease in the motor primary cortical functional connectivity of sensorimotor network(SMN),while functional connectivity in the right lenticular nucleus and left middle frontal gyrus increased.The functional connection of the right legume nucleus is positively correlated with ALSFRS;Comparing the CNTN4rs2619566 CC+CT genotype ALS group with the HC group,it was found that the default mode network(DMN)functional connection did not change significantly.The CNTN4 gene and the disease interaction area bilateral cingulate gyrus posterior/precuneus functional connection increased,which may be the default compensatory increase in network activities;The bilateral executive network study found that the functional connection between the right anterior cingulate and the left middle frontal gyrus was enhanced in the ALS group compared with the HC,and the CNTN4 rs2619566 CC+CT genotype ALS group was compared with the HC group,and the right parietal lower lobule and left middle frontal gyrus functional connection was enhanced,And the functional connection of the left middle frontal gyrus is positively correlated with ALSFRS.Conclusion:(1)The gray matter volume of the right parahippocampal gyrus and the outer nucleus of the bilateral upper longitudinal tract in the CC+CT genotype of the ALS group decreased,which may affect the functions of the limbic system such as memory and orientation in patients with ALS,and may affect the upper longitudinal tract.Integrity in turn affects related functions such as motor regulation,working memory,and spatial attention.(2)ALS have bilateral corticospinal tracts,bilateral upper longitudinal tracts,and corpus callosum abnormalities.CNTN4 rs2619566 CC+CT genotype may be an important risk factor for this type of upper longitudinal tract and corpus callosum white matter fiber injury.It is also one of the possible mechanisms that cause extra-motor symptoms.(3)The CNTN4 rs2619566 CC+CT genotype of the ALS group was associated with decreased activity of neurons in the right visual cortex.Combining CNTN4 functions related to the visual pathway may explain the visual cortex function and structural damage associated with ALS.(4)The CNTN4 rs2619566 gene polymorphism of ALS showed significant changes in SMN,DMN,and ECN in the resting state network,while salience network(SN)and visual network(VN)did not change significantly.The CNTN4rs2619566 CC+CT genotype may be involved in motor executive function and can be an effective observation index,and it may play an important role in the compensation mechanism in the executive network.