The Outer Mitochondria Embrane 40 Homolog Polymorphism Modulation On Brain Functional Networks For Amnestic Mild Cognitive Impairment

BackgroundsAlzheimer’s disease (AD) is the most common dementia in elderly. Early diagnosis and intervention remains the critical measure for delaying disease progression effectively, as the AD pathogenesis is unclear and disease-modifying treatment is unavailable currently. Episodic memory dysfunction is a central characteristic of amnestic mild cognitive impairment (aMCI) subjects, and has a high risk of converting to AD.The risk of AD was affected by lots of factors. Mitochondrial dysfunction hypothesis suggests that the incidence of brain energy metabolism is associated with AD. The mitochondrial outer membrane translocase 40 (TOMM40), located upstream of the apolipoprotein E (APOE) gene, may play a key role in the encoding of mitochondrial function, and associated with the increasing susceptibility of AD. The genotype of rs157581 has been confirmed to be the AD risk by GWAS studies and other cross-section studies. But the mechanism is still unknown.Emerging evidences demonstrate that the AD is a disconnection syndrome. Recently, the AD network dysfunction hypothesis further indicate that the aberrant network activity may casually contribute to cognitive deficits of AD. Imaging genetics, combining the genetics and functional neuroimaging technologies, is the awareness methods to explore the interaction of polymorphisms and brain networks, to assess the relationship between genetic variation and behavior in vivo. In this case-control study, all of the subjects were completed multi-dimensional neuropsychological tests, and underwent functional magnetic resonance imaging scans during a resting-state and an episodic memory retrieval task state. Thus, we proposed the network-based hypothesis that the changed functional connectivity of the brain network from resting-state to episodic memory retrieval task state was modulated by TOMM40 rs157581 C allele, which can predict the cognitive decline in aMCI subjects.Part Ⅰ TOMM40 polymorphism modulation on resting-state network Chapter 1 Analysis of regional homogeneityObjective:To investigate the TOMM40 rs157581 polymorphism modulation on resting-state network in aMCI and Control normal (CN) by analysis of regional homogeneity (ReHo).Methods:All of the subjects were completed multi-dimensional neuropsychological tests, genotyping of APOE rs7412, rs429358, TOMM40 rsl57581, rs2075650, rs157580, and underwent functional magnetic resonance imaging (fMRI) scans during resting-state. ReHo were used to analysis the regional spontaneous neu functional magnetic resonance imaging ronal activity of the resting-state network. Two way anova detected the main effects of TOMM40 polymorphism and aMCI(p<0.01).Results:Patients in aMCI performed significantly poorer than that of CN in most of neuropsychological battery scores (p< 0.05). The significant frequency of the TOMM40 rsl57581C (p=0.02, OR=1.79) and rs2075650G (p=0.01, OR=2.49) alleles was found in aMCI patients, independent from sex, age and APOEs4 status. According to the number of subjects in each subgroups more than standard five cases, the Imaging Genetics Analysis was ran in the TOMM40 rs157581C allele carriers and no carriers. The interaction of disease and gene showed that the ReHo value was low in right anterior cerebellar lobe, left cuneus and bilateral superior frontal gyrus.Conclusion:The deficits of neural activity in bilateral superior frontal gyrus, right anterior cerebella lobe and left cuneus may be modulated by TOMM40 rs157581 C allele in aMCI subjects.Chapter 2 Analysis of amplitude of low-frequency fluctuationsObjective:To investigate the TOMM40 rs157581 polymorphism modulation on resting-state network in aMCI and CN by analysis of amplitude of low-frequency fluctuations (ALFF).Methods:All of the subjects were completed multi-dimensional neuropsychological tests, and underwent fMRI scans during resting-state. ALFF were used to analysis the regional spontaneous neuronal activity of the resting-state network. Two way anova detected the main effects of TOMM40 polymorphism and aMCI(p< 0.01).Results:The interaction of disease and gene showed that the ALFF value was low in right gyrus lingualis and bilateral superior frontal gyrus/supplementary motor area (SMA), and high in right parahippocampal gyrus (PHG) and superior parietal lobule (SPL).Conclusion:The deficits of neural activity in bilateral superior frontal gyrus/SMA and right gyrus lingualis may modulated by TOMM40 rs157581 C allele in aMCI subjects. Meanwhile, the compensation was existed in right PHG and SPL. Part Ⅱ TOMM40 polymorphism modulation on the hippocampal-related episodic memory networkChapter 1 The left hippocampal-related episodic memory networkObjective:To investigate the TOMM40 rs157581 polymorphism modulation on left hippocampal-related episodic memory in aMCI and CN subjects between resting and task state.Methods:All of the subjects were completed multi-dimensional neuropsychological tests, and underwent fMRI scans during resting-state and episodic memory task state. Left hippocampal was identified as the seed. Two way anova detected the main effects of TOMM40 polymorphism and aMCI(p<0.01). Three way anova detected the interaction of TOMM40 polymorphism, aMCI and task state(p<0.01). The peak Z value from rest to task state was extracted and be related to the behavior by Spearman analysis.Results:The deficits of functional connectivity between left hippocampal and bilateral cuneus was found for the interaction of polymorphism, disease and state. The changes of functional connectivity from rest to task state were associated with MMSE, AVMT-DR and DST scores in aMCI CC/CT subjects (p=0.02, r=-0.66; p=0.01, r=-0.68; p=0.00, r=0.81). While in aMCI TT subjects the changes were associated with CFT and TMT-A scores(p=0.01, r=--0.67; p=0.03, r=0.62).Conclusion:The changes of functional connectivity between left hippocampal and left cuneus from rest to task state were associated with cognitive impairment, while attention was stronger for compensation. Visuospatial function and execution maybe modulated by T allele, different from C allele.Chapter 2 The right hippocampal-related episodic memory networkObjective:To investigate the TOMM40 rs157581 polymorphism modulation on right hippocampal-related episodic memory in aMCI and CN subjects between resting and task state.Methods:All of the subjects were completed multi-dimensional neuropsychological tests, and underwent fMRI scans during resting-state and episodic memory task state. Right hippocampal was identified as the seed. Two way anova detected the main effects of TOMM40 polymorphism and aMCI(p< 0.01). Three way anova detected the interaction of TOMM40 polymorphism, aMCI and task state(p< 0.01).Results:The interaction of polymorphism and disease in resting-state showed that the functional connectivity was weaker from right hippocampal to right middle temporal lobe, left insula, right parietal lobe and frontal/postcentral gyrus (PCG). There is no region was shown for interaction between polymorphism, disease and task state.Conclusion:There is hemi-differences existed between left and right hippocampal. The left hippocampal-related episodic memory deficits maybe serious and occurred earlier than right hippocampal in aMCI patients, as a proper biomarker for diagnosis the AD.Chapter 3 The left posterior parahippocampal gyrus episodic memory networkObjective:To investigate modulation on the left posterior parahippocampal gyrus (LpPHG) episodic memory network in aMCI and CN subjects between resting and task state.Methods:All of the subjects were completed multi-dimensional neuropsychological tests, and underwent fMRI scans during resting-state and episodic memory task state. LpPHG was identified as the seed. Two way anova detected the main effects of disease and state (p< 0.005). The peak Z value from rest to task state was extracted and be related to the behavior by Spearman analysis.Results:The connectivity of the LpPHG connected to the left ventral medial p< 0.001 cortex (MPFC) and the right PCG was significantly decreased in aMCI subjects compared to CN subjects. Meanwhile, there was increased connectivity of the LpPHG to the right dorsal MPFC (RDMPFC), right PCG, left inferior parietal cortex, and bilateral SPL in all of the subjects that changed from a resting-state to a task-state (p< 0.005). Interestingly, the changed LpPHG-RDMPFC connectivity strength was significantly correlated with episodic memory scores and executive function in the aMCI subjects (F(1,25)=8.590,p=0.020,R2=0.205; F(1,25)=5.631, p=0.038,R2=0.168; F(1,25)=4.485,p=0.023, R2=0.196; F(1,25)=2.74, p=0.022, R2=0.201).Conclusion:The changed functional connectivity of LpPHG-RDMPFC may suggested that more cognitive resources are mobilized to meet the challenge of cognitive demand in the aMCI patients and task state. Part Ⅲ TOMM40 polymorphism modulation on the default mode networkObjective:To investigate the TOMM40 rs 157581 polymorphism modulation on the default mode network (DMN) in aMCI and CN subjects between resting and task state.Methods:All of the subjects were completed multi-dimensional neuropsychological tests, and underwent fMRI scans during resting-state and episodic memory task state. The posterior cingulated cortex (PCC) was identified as the seed. Two way anova detected the main effects of TOMM40 polymorphism and aMCI. Three way anova detected the interaction of TOMM40 polymorphism, aMCI and task state.Results:The brain regions of the DMN in task state showed weaker neural activities than that of resting-state, including temporal lobe (bilateral middle temporal gyrus, right inferior temporal gyrus, left PHG), frontal cortex (bilateral MPFC), occipital lobe (right middle occipital gyrus, angular gyrus) and cerebellum (right posterior cerebellum lobule). While the neural activities of the parietal lobe (left inferior parietal lobule, precuneus) were stronger in task state than that of resting state.Conclusion:The whole brain functional connectivity between the DMN was weaker than that of resting-state. The TOMM40 rs157581 polymorphism modulation on the DMN in aMCI maybe by the functional connectivity deficits of frontal cortex, while the compensation was shown on parietal cortex.