The FMRI Study Of Neurovascular Decoupling Pattern In Type 2 Diabetes Mellitus Patients With MCI

The latest epidemiological survey found that the prevalence of diabetes among Chinese adults has reached 12.8%,and the prevalence of pre diabetes even reached 35.2%,of which type 2 diabetes(T2DM)accounts for about 95%.It is estimated that the number of diabetes patients in the world will increase to 700 million in 2045.T2 DM usually causes various complications.Nearly half of T2 DM patients suffer from mild cognitive impairment(MCI)and progress to dementia at an annual growth rate of 8.7%,which seriously affects the quality of life of patients.In order to prevent MCI in T2 DM patients,it is necessary to explore the neuropathological mechanism of T2 DM cognitive impairment and screen the imaging biomarkers for early intervention of T2 DM cognitive impairment.In recent years,researchers have proposed that nerve and blood vessel are mutually coupled functional complexes.Nerve activity rapidly increases local blood flow to meet the transient changes in regional brain energy and nutritional needs.This is called the relevant pathophysiological mechanism of neurovascular(NV)coupling.Basic and clinical trials have confirmed that nerve and vascular injury is related to MCI associated with T2 DM.Previous imaging studies also found that the neurovascular function of T2 DM patients did not match.In addition,our research group,based on previous literature,combined with functional magnetic resonance imaging(f MRI)and arterial spin labeling(ASL),confirmed that neurovascular decoupling occurred early in T2 DM patients and was related to cognitive function changes.Based on the above evidence,neurovascular decoupling may be an important mechanism of MCI caused by T2 DM.However,at present,neuroimaging research has problems of small sample size and low repeatability,and some research results are also controversial.Only a few studies have explored the NV decoupling of T2 DM.In addition,at present,there is still controversy about which of the nerve injury factors and vascular injury factors is more important for T2 DM cognitive impairment.The interaction between nerves and blood vessels is a dynamic process.Only from the perspective of resting f MRI,it cannot fully reflect the cognitive level of the brain to cope with different tasks,nor can it fully reflect the neurovascular decoupling mode of T2 DM patients.Therefore,this topic is divided into the following four parts to explore the changes in neurovascular decoupling patterns in T2 DM.ObjectiveIn order to explore the specific brain regions of T2 DM cognitive impairment,quantitatively explore whether NV decoupling is related to cognitive impairment in T2 DM patients,study the pathological contribution of nerve and vascular injuries in T2 DM related cognitive impairment,and deeply explore the NV decoupling mode in T2DM-MCI patients under motor imagery,this study utilized evidence-based medical evidence and independent verification methods,used a resting state combined with task state,and adopted f MRI combined with ASL methods,to screen the imaging features of early cognitive impairment in T2 DM.MethodsPart one: A systematic literature search in the MEDLINE(Void),Pub Med,Web of Science,and the Cochrane Library was performed for the direction of brain function studies of T2 DM published between January 2007 and November 2021.Since the indicators obtained using varied post-processing methods reflect different neurophysiological and pathological characteristics,we further conducted a coordinate-based meta-analysis of the two categories of neuroimaging literature,which were grouped according to similar data processing methods: one group included regional homogeneity(Re Ho),independent component analysis(ICA),and degree centrality(DC)studies,while the other group summarized the literature on amplitude of low-frequency fluctuation(ALFF)and cerebral blood flow(CBF).Part two: A systematic literature search in the MEDLINE(void),Pub Med,Web of Science,Cochrane Library,and Psyc INFO databases was performed for functional magnetic resonance imaging(f MRI)and arterial spin labeling(ASL)studies of T2 DM published between January 2007 and April 2022.The coordinate-based meta-analysis was conducted by AES-SDM.Meta analysis of f MRI and ASL were used to screen regions of abnormal brain functional activity and CBF respectively.The NV decoupling brain regions were finally obtained by point multiplying the two selected regions.Then,an independent validation was performed by using f MRI and ASL datasets from 30 T2 DM patients and 29 HC.The NV coupling coefficients were defined as the Pearson correlation between ALFF,DC,Re Ho and CBF.Part three: A total of 30 T2 DM patients and 29 HC matched with age,sex,BMI and education years were included in the study.The Montreal Cognitive Assessment(Mo CA)test,Mini-Mental State Examination(MMSE),California Verbal Learning Test,Wisconsin Card Sorting Test,and Stroop Color Word Test were employed to evaluate the cognitive status of the participants.Multimodal MRI included(1)voxel-based morphometry(VBM)to analysis gray matter volume,(2)surface-based morphometry(SBM)to measure cortical morphological and microstructure,(3)CBF map to explore cerebral perfusion,and(4)white matter hyperintensity(WMH)to assess microvascular injury.Part four: A total of 28 T2DM-MCI patients,16 T2 DM patients without MCI and 11 HC patients were included in the study.Through graph theory analysis,three groups of network topology attributes were identified and the NV coupling coefficient among networks was calculated.The activation mode of brain function and the NV coupling mode under the task state of three groups of people were discussed through the motor imagery task.Results(1)The final meta-analysis included 23 eligible trials with 27 data sets.Compared with the healthy control group,when neuroimaging studies were combined with Re Ho,ICA,and DC measurements,the brain activity of the right Rolandic operculum,right supramarginal gyrus,and right superior temporal gyrus in T2 DM patients decreased significantly.When neuroimaging studies were combined with ALFF and CBF measurements,there was no clear evidence of differences in the brain function between T2 DM and HC.(2)The meta-analysis of f MRI indicators included 27 datasets and 553 T2 DM patients,and that of CBF included 7 datasets and 148 patients.NV decoupling in the left lingual gyrus,right superior temporal gyrus,bilateral cingulate gyrus and right insula were showed in T2 DM.In the independent validation,compared with the HC group,the NV coupling coefficients decreased in the left lingual gyrus and the right superior temporal gyrus of T2 DM patients.The coupling coefficient of z-transformed CBF(z CBF)-z ALFF in the left lingual gyrus was related to cognition in T2 DM patients.(3)SBM analysis showed that the fractal dimension of left posterior cingulate gyrus and left superior frontal gyrus in T2 DM patients decreased(p FWE = 0.01088,cluster = 5567voxels;p FWE = 0.01459,cluster = 1652;p FWE = 0.04909,cluster = 133 voxels).In T2 DM patients,the sulcus depth of left insula and left superior marginal gyrus were shallower(p FWE = 0.01366,cluster = 10219 voxels;p FWE = 0.04358,cluster = 786voxels).The cortical thickness and gyrification index were not significantly different from HC.Compared with HC,the gray matter volume of T2 DM decreased in the right orbital inferior frontal gyrus(MNI spatial coordinate: x = 36 y = 35 z =-8;p FWE < 0.05;cluster = 13 voxels)and the right parietal inferior lobule(MNI spatial coordinate: x = 41 y=-50 z = 44;p FWE < 0.05;cluster = 6 voxels).There was no statistical difference in CBF and WMH between T2 DM patients and HC.Correlation analysis showed that the sulcus depth in the lower part of the middle frontal gyrus was positively correlated with the California Verbal Learning Test scale subitem(r = 0.51,p FDR = 0.048).(4)Graph theory analysis found that there was no statistical difference in the network topology attributes of T2DM-MCI,T2 DM and HC.There was no statistical difference in the functional network coupling coefficient among the three groups.In the motor imagery state,the brain activation degree of the three groups of subjects in the imagination stage was not completely the same.Compared with HC,T2DM-MCI significantly enhanced the left lingual gyrus,left calcarine,left upper cerebellum and right precuneus at motor imagery stage,and the z CBF-z ALFF and z CBF-z Re Ho of T2DM-MCI in the left lingual gyrus were significantly decreased.There was no statistical difference in the coupling coefficient of left calcarine,left upper cerebellum and right precuneus.Conclusion(1)T2DM patients have a series of spontaneous abnormal brain activities,mainly involving brain regions related to learning,memory,and emotion,which provide early biomarkers for clarifying the mechanism of cognitive impairment and neuropsychiatric disorders in diabetes.(2)The study combined meta-analysis and independent validation model demonstrated the NV decoupling of T2 DM and contributed to a better understanding of the mechanism in T2 DM cognitive impairment.The NV coupling coefficient would be a promising neuroimaging biomarker for early detecting MCI of T2 DM.(3)In T2 DM patients,neural degeneration was mainly concentrated in the default pattern network(DMN).The long-term memory ability of T2 DM patients was positively correlated with the sulcus depth of the middle frontal gyrus,but not with CBF and WMH.Multi-modal MRI found that neurodegenerative diseases rather than cerebrovascular diseases contributed more to the pathology of cognitive decline in T2 DM patients.(4)The static network topology attribute and the coupling coefficient between networks may not effectively reflect the neural loop of T2DM-MCI cognitive impairment,and the coupling coefficient under the task state may help to better understand the NV decoupling mode of T2DM-MCI.Our study may help to find the abnormal patterns of brain regions in patients with T2DM-MCI when performing tasks,and provide a new insight into the neural circuit of T2 DM cognitive impairment.