Module-level Structural And Functional Alternations In Amnestic Mild Cognitive Impairment

Chapter 1 Module division based on normal brain functional connectivityBackground: Functional connectivity(FC)refers to the level of resting state blood oxygen in the left and right cortex of the human brain.In recent years,researchers have applied this method of FC to multiple brain functional systems,and proved that the correlation of BOLD signals between different brain regions in this resting state widely existed in different functional systems.Objective:The purpose of this part of the experiment was to divide the brain into functional modules based on the FC network of the normal control(NC)group for further research.Methods: During July 2016 to June 2017,a total of 110 subjects were recruited and 51 were excluded due to the exclusion criteria.The final sample size was 59,including 23 patients with amnesia mild cognitive impairment(a MCI),18 patients with non-amnesia mild cognitive impairment(na MCI)and 18 normal controls(NC).All subjects were from the memory clinic of Affiliated Drum Tower Hospital,Nanjing University.The ethics committee of Drum Tower Hospital approved all the research procedure(clinical trial government code: 2016-063-01).All patients signed a written informed consent form.The subjects underwent a standardized program for examination,including neuropsychological screening,MRI,and general medical examination.The diagnostic criteria of a MCI were as follows: subjective or objective memory impairment;objective memory performance documented by an Auditory-Verbal Learning Test delayed recall(AVLT-DR)score ?1.5 standard deviations of age-adjusted and education-adjusted norms;normal general cognitive function: mini mental state examination(MMSE)? 24;Clinical dementia rating scale(CDR)equaling 0.5;little or no daily life activity damage;not reaching the diagnosis dementia.Similar criteria were used for classifying na MCI,but with objective memory impairment as an exclusion criterion.The exclusion criteria were as follows: cerebrovascular disease;severe depression(17 items of Hamilton Depression scale(HAMD)? 24),previous brain injury or alcoholism history;white matter high signal(WMH,no less than grade 2).The subjects in the normal control group had no cognitive impairment and neurological or mental disorders.Other exclusion criteria for all participants included contraindications for MRI,such as pacemakers and claustrophobia.All the participants were right-handed.After the MRI data were preprocessed,in order to construct a weighted FC network,weighted edges were used to determine the absolute FC intensity between connected regions of interest.Then the correlation matrix is transformed by Fisher-Z transformation to improve the normality of the correlation coefficient.Then the complex network was divided into different modules through improved greedy optimization algorithm.Results: No statistically significant differences among subjects was found in age(p = 0.147),sex(p = 0.862),education(p=0.092),or the Digital Span test.Significant differences in the MMSE,Mo CA,VR subtest,AVLT,AVLT-DR,and BNT were found among the three groups(p<0.05).The a MCI group had lower MMSE,VRDR,VRR,AVLT,AVLT-DR,and BNT scores than both the na MCI and the NC group(p<0.05).The NC group had higher Mo CA scores than both MCI groups(p<0.01).According to the FC matrices of the NC group,the healthy functional brain network comprised four connected modules.According to their anatomical locations and findings from previous studies,we labelled them the temporaloccipital module(Module I),the default mode module(Module II),the attention module(Module III),and the sensorimotor module(Module IV).These four modules contained 26,28,16,and 20 anatomical regions,respectively.Conclusions: Based on multimodal neuroimaging technology,we identified four interconnected modules in the healthy functional brain network,namely,the temporooccipital lobe module(module I),the default mode module(module II),the attention module(module III)and the sensorimo tor module(module ?).Chapter 2 The predictive effects of functional connection,structural connection and their correlation on amnesia mild cognitive impairmentBackground: Mild cognitive impairment(MCI),regarded as the prodromal stage before the clinical phase of Alzheimer's disease(AD),has been considered for early differential diagnosis.Patients with amnestic mild cognitive impairment(a MCI),an important subtype of MCI,are more likely to progress to clinical Alzheimer disease(AD).Objective:The aim of this study was to examine the structural and functional connectome in both subtypes of MCI and found differences in structural connectivity(SC)-functional connectivity(FC)coupling.Methods: Fifty-nine individuals with aMCI,naMCI and healthy controls(NC)underwent resting-state functional magnetic resonance imaging(rs-f MRI)and diffusion tensor imaging(DTI).Brains were parcellated into functional modules according to the FC networks of NC,and individual FC and SC within modules as well as average FC,average SC and average SC-FC correlation values in each module among groups were analyzed,while logistic regression was used to find predictive factors.The effect of prediction was tested by ROC curve.Results: 1)No significant differences were found in the average FC of the four modules among the three groups.2)In module I,module II and module III,the FN value of NC group was lower than that of a MCI and na MCI group,while in module IV,the FN of NC group was lower than that of a MCI group;in module I,III and IV,the FA of NC group was higher than that of a MCI group na MCI group;in module II,FA showed a trend of a MCI < na MCI < NC,significant differences were found between every two groups among the three groups.3)In module I,the FN-FC correlation value of NC group was higher than that of a MCI group and na MCI group,while the FA-FC correlation value of NC group was lower than that of a MCI group and na MCI group;in module II and IV,the FA-FC correlation value of NC group was lower than that of a MCI group and na MCI group.4)There are inter-group differences of FN-FC and FA-FC correlation curves in module I.5)Logistic regression analysis showed that FA values in the four modules all had predictive significance for a MCI(per 1%increment,OR=0.539,p=0.003 in module II;OR=0.805,p=0.031 in module III;OR=0.551,p=0.004 in module IV).The FN value in the module IV had a certain predictive significance for a MCI(OR=1.163,p=0.012).In addition,in the module II,the FA-FC correlation value had a certain predictive significance for a MCI(OR=2.095,p=0.028),and the FN-FC correlation value also had a certain predictive significance for a MCI(OR=1.205,p=0.026).The ROC curve further validated the effect of different indicators on a MCI prediction.In module I,the area under the curve(AUC)of the ROC curve of FN value was 0.702.The AUC of FA was 0.700.In the module II,the AUC of FA value was 0.818;in the module III,the AUC of FA value was 0.732;in the module IV,the AUC of FA was 0.829.In addition,in module I,the AUC of FN-FC correlation value was 0.668;in the module II,the AUC of FA-FC correlation value was 0.713;in the module IV,the AUC of FA-FC correlation value was 0.688.Conclusions: Module-level structural connectivity may be compensated in the progress of AD or a MCI;module-level structural connection parameters and structure-function correlation parameters may be meaningful for the prediction of a MCI,which need to be further verified.