Rest State Brain Functional Network Research In Subjects At Amnestic Mild Cognitive Impairment

BackgroundWith the coming of aging society in china,dementia in elderly is associated with a close attention because it is becoming a public health problem.Alzheimer’s disease(AD)is the most common type of dementia in elderly.Currently,the AD etiology and pathogenesis is still not fully understood,and none of the treatments are available for AD.currently.Recently,thecontinually revised AD diagnosis criteria indicate that the AD diagnosis should be established onthe integration of episodic memory impairment with abnormal AD biomarkers.This indication notonly advances the time window of AD diagnosis,but also identifies AD as a continuum spectrumincluding preclinical,mild cognitive impairment and dementia stages.However,current criteria remain limited in elucidating AD pathogenesis at predementia stage.especially at asymptomaticstage.In addition,the clinical applications of AD biomarkers are confronted with variousdifficulties.Therefore,it iS still imperative tO investigate AD insidious pathogenesis and update ADbiomarkers.The brain is a complex neural networks interconnected by a large number of neurons,Growing evidence from neuroimaging studies suggests that this complex and vast network is brain information processing and physiological basis of cognitive expression.aMCI is caused by the disorder of brain function network,is currently based on brain function in the resting state fMRI data network calculation method has been widely used in aMCI research,found that abnormal brain function in patients with aMCI local network efficiency,back to the default network such as the cingulate gyrus,parahippocampal gyrus,hippocampus,in areas such as the prefrontal area of the local efficiency increased.Further study found that patients with MCI reduced the function of the default network connectivity,executive function network connection.The apolipoprotein E(APOE)ε4 allele is the only well-established susceptibility gene for developing AD and lows the age at onset in a dose-dependent fashion.The ε4 allele is regarded as the strongest genetic risk factor for the progression of early AD,such as related to a higher risk for the developing AD,an earlier age at onset,increased amyloid-β deposition in the brain,increased numbers of neurofibrillary tangles,greater metabolism abnormalities,reduced GM volume,greater altered resting state functional connectivity,accelerating functional decline and an increased susceptibility of aMCI,and accelerating conversion of aMCI to AD.By contrast,theε2 allele is considered to possess protective effects,such as associated with a delayed emergence of AD,reduced risk of developing AD,fewer amyloid plaques,fewer senile plaques,fewer neurofibrillary tangles,incleased GM volume slower functional decline in aMCI and improvement of episodic memory over time.Growing evidence from neuroimaging studies suggest that the DMN consists of functionally differentiable subdivisions or subnetworks(e.g.anterior versus posterior or ventral versus dorsal).The repeated observation that the ventral medial prefrontal cortex(vmPFC)and posterior cingulate cortex(PCC)paradoxically exhibit high levels of activity during resting baseline and decreases in activity during externally-oriented cognitive tasks led to the characterization of these regions as belonging to a "DMN",where vmPFC and PCC have consistently considered to act independently across a wide array of cognitive tasks.The DMN has been associated with episodic memory and memory consolidationin some studies,and self-related or social processesin others.Furthermore,others studies have also demonstrated that the DMN has been linked to more general processes such as stimulus-independent or task-unrelated thought.Therefore,converging evidence from above-mentioned studies suggest that functionally differentiable subnetworks will arise explaining the network’s ability to support such a variety of functions.In addition,while several studies have indicated resting state functional connectivity changes within the DMN all across the spectrum from healthy aging,to aMCI to AD,these above-mentioned studies have mainly focused on one single DMN(when using an independent component analysis or a cross-correlation approach).It is note that previous studies have indicated that impairment and compensation coexist in DMN in aMCI.Most particularly,dividing the DMN into sub-networks,a recent follow-up study has indicated decreased connectivity at baseline in AD versus controls in the posterior DMN,and increased connectivity in the anterior and ventral DMN.These authors suggest that earlier in the disease,regions of the posterior DMN start to disengage whereas regions within the anterior and ventral networks enhance their connectivity.However,very little is known about resting state functional connectivity changes within sub-networks of the DMN,particularly in aMCI,the assumed pre-stage of AD.Therefore,this study recruited the cognitive normal elders,aMCI patients.For all participants,we assessed their cognitive function using multi-domain neurocognitive tests and constructed their whole-brain functional networks using the Rs-fMRI data.The prent study foucs on the aMCI patients to investigate the interaction of the APOE polymorphism with aMCI patients on sub-networks of DMN,and further evaluate the effect of the ε2 and s4 alleles on the relationships between the sub-networks of DMN and its anti-network in aMCI and healthy controls(HC).The study is expected to advance our current understanding of the neurobiological mechanism underlying the cognitive dysfunction in individuals at aMCI,and shed lights on exploring network-based aMCI transfer to AD biomarker in the further.Chapter 1 The altered patterns of resting-state networks Regional Homogeneity in aMCI patientsObjective:In order to detect aMCI earlier and provide the best time window for prevention and treatment,this studv used resting-state functional magnetic resonance imaging(rs-fMRI)to explore the neural network structure and functions in aMCI patients.Meanwhile,it also contributes to better understanding of cerebral activity.Method:the present study utilized rs-fMRI scans of the EF network and the EM network to investigate this relationship in 79 aMCI patients and 119 healthy controls(HC).All subjects underwent neuropsychological battery assessment and rs-fMRI scan.Comparison of resting-state rs-fMRI network between aMCI patients and controls used regional homogeneity.Result:Based on these ReHo findings,four regions with abnormal local connectivity were identified in the aMCI group:the right DLPFC,RSC,superior parietal lobule(SPL),and left parahippocampal gyrus.Conclusions:The difference of ReHo in the regions among aMCI patients in resting state indicates that there is an abnormality with their abnormal network.It provides foundations for selecting potential interestingregions of the brain to conduct functional connectivity studies.Chapter 2 Mediation of episodic memory performance by the executivefunction network in patients with amnestic mild cognitive impairmentBackground:Deficits in episodic memory(EM)are a hallmark clinical symptom of patients with amnestic mild cognitive impairment(aMCI).Impairments in executive function(EF)are widely considered to exacerbate memory deficits and to increase the risk of conversion from aMCI to Alzheimer’s disease(AD).However,the specific mechanisms underlying the interaction between executive dysfunction and memory deficits in aMCI patients remain unclear.Method:The present study utilized resting-state functional magnetic resonance imaging(fMRI)scans of the EF network and the EM network to investigate this relationship in 79 aMCI patients and 119 healthy controls(HC).The seeds were obtained from the results of a regional homogeneity(ReHo)analysis in theChapter 1.Functional connectivity(FC)within the EM network was determined using a seed in the right retrosplenial cortex(RSC),and FC within EF network was assessed using seeds in the right dorsolateral prefrontal cortex(DLPFC).Results:There was a significant negative correlation between EM scores and EF scores in both the aMCI and HC groups.Compared to the HC group,aMCI patients had reduced right RSC connectivity but enhanced right DLPFC connectivity.The overlapping brain regions between the EM and EF networks were associated with FC in the right inferior parietal lobule(IPL)in the right RSC network,and in the bilateral middle cingulate cortex(MCC)and left IPL in the right DLPFC network.A mediation analysis revealed that the EF network had an indirect positive effect on EM performance in the aMCI patients.Conclusions:The present findings provide new insights into the neural mechanisms underlying the interaction between impaired EF and memory deficits in aMCI patients and suggest that the EF network may mediate EM performance in this population.Chapter 3 Differential effects of APOE genotypes on the anterior and posterior subnetworks of default mode network in amnestic mild cognitive impairmentBackground:The apolipoprotein E(APOE)gene is considered as the major genetic susceptibility factor for the conversion from amnestic mild cognitive impairment(aMCI)to Alzheimer’s disease(AD).Recent studies have indicated that the default mode network(DMN),based in ventromedial prefrontal cortex(vmPFC)and posterior cingulate cortex(PCC),consists of functionally differentiable anterior and posterior subnetworks.The present study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in aMCI.Method:We used a seed correlation approach to perform functional connectivity(FC)analyses in DMN subnetworks in 74 aMCI(9 APOE s2s3,44 ε3ε3,and 21 ε3ε4)and 105 healthy controls(HC,32 APOE ε2ε3,39 ε3ε3,and 34 ε3ε0).The logistic regression analysis was performed to obtain a model for classifying aMCI and HC subjects.Results:Significant interactions of APOE genotype by aMCI on FCs were found in right cerebellum posterior lobe,left lingual gyrus and right middle cingulate cortex(MCC)in vmPFC subnetwork,and bilateral fusiform gyrus(FG),left inferior frontal gyrus,and left precuneus in PCC subnetwork.The impairment of episodic memory for s4-carriers in aMCI negatively correlated with the altered FC between vmPFC and right MCC while positively correlated with the altered FC between PCC and left FG.The logistic regression analyses demonstrated that a model composed of episodic memory,FC between vmPFC and right MCC,and FC between PCC and left FG,dexterity correctly classified 89.4%of the aMCI and HC subjects.Conclusions:These results provide a novel insight that APOE s4 and ε2 alleles differentially mediate the anterior and posterior DMN subnetworks,which ε2-carriers in aMCI play a protective role in contributing to a compensatory mechanism in anterior DMN subnetwork.Furthermore,the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory.It further suggests that there may be a dynamically balanced mechanism between anterior and posterior DMN subnetworks in aMCI.