| BackgroundAlzheimer’s Disease(AD)is a chronic progressive neurodegenerative disease with continuous pathological and clinical processes,which can be divided into subjective memory impairment(SMI),mild cognitive impairment(MCI)and Alzheimer’s Disease.MCI is a clinical stage between normal aging and dementia,in this stage,although the patient does not meet the diagnostic criteria for dementia,it has shown objective cognitive impairment.With the development of the disease,patients with cognitive impairment will have different degrees of pathophysiological changes in the brain,including β-amyloid deposition,neurofibrillary tangles(NFT)due to Tau protein deposition,Neuroinflammatory,which can cause atrophy of the cerebral cortex and changes in the brain function network.The head magnetic resonance imaging(MRI)technique not only provides a diagnostic basis for patients with Alzheimer’s Disease,but also reflects changes in the functional network of the brain by functional magnetic resonance imaging(f MRI).Hippocampal cortex atrophy is an important biomarker in patients with cognitive impairment.Recent studies have found that the hippocampus is composed of many interacting subarea that constitute a complex heterogeneous structure and display different changes in the course of AD.apolipoprotein E4(ApoE4)alleles are the only high-risk genes identified,which can lead to increased hippocampal volume atrophy,increased brain amyloid deposition,brain hypometabolism,and increased cognitive decline which plays an important role in the pathogenesis of AD.ObjectivesTo compare the changes of hippocampal subarea structure and functional connectivity in MCI patients and healthy control subjects,and to investigate the effect of ApoE gene on hippocampal subarea gray matter volume and functional connectivity using MRI.Provides the basis for early identification of MCI and early diagnosis combined with the structure and functional changes of each subarea of hippocampus in each group.Methods128 normal healthy control subjects(including 35 ApoE2 genotypes,44 ApoE3 genotypes,49 ApoE4 genotypes),85 mild cognitive impairment patients(including 10Apoe2 genotypes,45 ApoE3 genotypes,30 ApoE4 genotypes)were selected as subjects to evaluate their multi-dimensional cognitive function,s MRI and BOLD-MRI sequence were used to collect structural and functional images.SPSS20.0 software were used for ApoE2、ApoE3、ApoE4 intra-group cognitive function scale comparisons.Based on SPM12 and MATLAB R2014 a,REST software and Anatomy software were used to create the template of hippocampus and its sub areas(entorhinal cortex,hippocampal-amygdaloid transition region,dentate gyrus,inferior bracket,CA1 area,CA2 area,CA3 area)and resample with REST software.The standardized gray matter volume was calculated by VBM8 based on SPM8 software and MATLAB R2014 a platform,and the total volume of hippocampus and its sub regions were calculated by running code on MATLAB R2014 a.The differences of the volume of hippocampus and its sub regions in each group among Apoe2 genotypes,ApoE3 genotypes and ApoE4 genotypes were compared by using spss20.0 software.Using DPASF software based on MATLAB platform,the hippocampus and its sub regions were selected as seed to analyze the functional connection and extract the ROI value.Using AFNI software to do covariance analysis and post-hoc analysis with gender,age,sex and gray matter volume as covariate under Ubuntu 16.04 system,by3 DCluster Sim correction(P < 0.001,cluster size > 20 mm),the functional connection of the main gene effect,main disease effect,gene and disease interaction effect of each group of subjects were compared.At the same time,combined with the results of multi-dimensional cognitive assessment,using Origin Pro9.0 software for linear fitting to further analyze the correlation between the volume and functional connection of hippocampus sub area and multi-dimensional cognitive score.Results1.Results of cognitive function assessment in subjects.There was no significant difference in cognitive function among the subjects in HC group among ApoE2,ApoE3 and ApoE4 subgroup;in MCI group,the subjects in each subgroup had significant differences in general memory function,in which ApoE2>ApoE3>ApoE4.In terms of visual space function,ApoE4 carriers scored lower than the subjects in the ApoE2 group in the clock-drawing test,and the Rey-Osterrieth complex graphics test(imitation part)score was lower than the subjects in the ApoE3 group,and the difference was statistically significant.2.Gray matter volume comparison of hippocampus and its subarea.There was no significant difference in the total volume of hippocampus and the standardized gray matter volume of each subarea in HC group among ApoE2,ApoE3 and ApoE4subgroup;in MCI group,the volume of LHATA,LDG,LCA3 and RHATA in ApoE4 subgroup was reduced compared with the ApoE3 subgroup,The gray matter volume of ApoE4 subgroup was lower than that of ApoE2 subgroup in LCA,LCA3 and RHATA and the results were statistically different(P<0.05).3.Correlation analysis of hippocampal and its subarea volume and behavioral score in subjects.The bilateral tatol hippocampal volume and bilateral ERC,HATA,DG,Sub,CA1,CA2 and CA3 were significantly positively correlated with episodic memory(P<0.001).4.The results of whole brain functional connectivity analysis of gene main effect,disease main effect,gene and disease interaction effect were carried out when taking each subarea of bilatery hippocampus as seed point.The functional connectivity between the hippocampus and its subarea and different brain regions increased or decreased,especially the decrease functional connectivity between hippocampal subarea and frontal lobe and thalamus,and increase functional connectivity between hippocampal subarea and temporal lobe,occipital lobe and cuneus.5.Correlation analysis between hippocampal subarea and whole brain functional connectivity values and cognitive function assessment scale.The results showed that the functional connectivity between hippocampus and frontal lobe were positively correlated with episodic memory and visual spatial function,and negatively correlated with the function between occipital lobe and cuneus.ConclusionThe volume of gray matter in hippocampus and its subarea of ApoE4 gene carriers decreased significantly in MCI patients,accompanied by abnormal functional connectivity in the subarea of hippocampus and whole brain,especially the increase functional connectivity between hippocampus subarea and the frontal lobe and thalamus,and decrease functional connectivity between hippocampus subarea and temporal lobe,occipital lobe and cuneus.More importantly,the atrophy of gray matter in hippocampal subarea and its abnormal functional connectivity were significantly associated with cognitive function,suggesting that monitoring gray matter volume in hippocampal subarea and its functional network provide potential biomarkers for early recognition MCI patients with cognitive decline. |
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