The Application Of Multi-modal Functional MRI Technolology In Mild Cognitive Impairment And Subjective Cognitive Decline Patients

BackgroundAlzheimer's disease(AD)is the most common type of dementia in the elderly,accompanied by progressive and irreversible cognitive decline.Extracellular?-amyloid(A?)and intercellular phosphorylated tau(p-tau)protein depositions are recognized as the characteristic pathological alterations in AD.No effective treatment currently exists and this morbidity,impacting the afflicted individuals and their families alike due to the accompanying financial and emotional stresses associated with caregiving.Therefore,the research has focused on improving our understanding of the pre-dementia stage,in the hopes of facilitating early intervention and inhibiting progression.Mild cognitive impairment(MCI)refers to the symptomatic pre-dementia phase of AD,characterized by mild decline in cognition involving memory,attention and languages.MCI is a heterogeneous group,and longitudinal studies have demonstrated that approximately 8.3 to 28%MCI patients will progress to AD per year,more than half of all MCI patients will not progress to dementia over a 10 year follow-up period.Therefore,according to their different clinical outcomes,the MCI patients could be further divided into progressive MCI(pMCI,who will progress to AD)and stable MCI(sMCI,who will keep stable cognition).Previous neuroimaging studies have reported that pMCI patients showed disruption of brain functional networks compared to sMCI patients.However,the underlying pathological mechanisms of network disruptions in pMCI and sMCI remain unclear.In addition,previous studies have reported that the cerebral perfusion changes could effectively predict the progression from MCI to AD using SPECT.Moreover,combining cerebral perfusion with neuropsychological tests and hippocampal volume could significantly improve predictive ability.However,the radiation toxicity and low resolution of SPECT may restrict its clinical application.Arterial spin-labeling magnetic resonance imaging(ASL-MRI)is a functional MRI technique that measures CBF with the advantages of noninvasiveness,avoidance of radiation exposure and short acquisition time.We hypothesized that cerebral perfusion in MCI patients as measured by ASL-MRI may serve as a suitable replacement of SPECT perfusion imaging for predicting conversion.Subjective cognitive decline(SCD),characterized by subjective cognitive worsening in the absence of objective cognitive impairment,is very common among elderly.Recent longitudinal studies have indicated that approximately 6.6%SCD patients will progress to MCI,and 2.3%SCD patients will further progress to AD.Importantly,SCD patients with high level of cerebral A?deposition in the brain are more likely to progress to MCI or AD compared to SCD patients with high level of deposition in the brain.Although the cerebral functional changes have been observed in SCD patients,the effect of A? deposition on functional changes in SCD patients remains unclear.Therefore,our study aimed to investigate the whole-brain functional network of pMCI and sMCI using fast eigenvector centrality mapping(fECM),and the correlation between functional network changes of pMCI and sMCI with cognition and CSF biomarkers(study 1);examine the perfusion changes via ASL-MRI for predicting AD conversion,and whether the ASL perfusion in combination with neuropsychological tests and hippocampal volume would improve the predictive power of conversion from MCI to AD(study 2);investigate the possible different whole-brain network organization of SCD+(SCD with high cerebral A(3 level)and SCD-(SCD with low cerebral A?level)using fECM method(study 3).MethodsStudy 1:This study included 21 pMCI,33 sMCI,29 normal controls(NC),and all the participants had neuropsychological tests,structural MRI,resting-state functional MRI data and CSF biomarkers(A?1-42,total-tau and p-tau)data.The fECM based on rsfMRI was used to investigate brain network organization differences among these groups.The EC values of regions that showed significant difference between pMCI and sMCI were extracted.Furthermore,Pearson correlation analysis was used to assess the correlation between EC values with cognition and CSF biomarkers.Study 2:This study included 19 pMCI and 30 sMCI patients,and all the patients had neuropsychological tests,structural MRI and ASL-MRI data.The ASL-MRI was preprocessed by ASL toolbox to obtain the cerebral blood flow(CBF)maps.The independent-samples t-test was used to investigate the CBF differences between pMCI and sMCI patients.The CBF values of regions that showed significant difference between two groups were extracted.Furthermore,we evaluated the predictive ability of ASL-perfusion,neuropsychological tests and hippocampal volume separately and the combination of three markers by logistic regression models(sensitivity,specificity and AUC).Study 3:This study included 25 SCD patients and 32 NC,and all the participants had neuropsychological tests,structural MRI,rsfMRI and amyloid-PET data.The cutoff value of mean SUVR from representative regions was set to 1.11,and the SCD patients and NC were further separately divided into SCD+ and SCD-groups,NC+ and NC-groups.In order to avoid the effect of high A?level in the NC+ group on our results,we only included the NC-group.Similarly,the fECM method was used to investigate the whole-brain network changes among the three groups.The EC values of regions that showed significant difference between SCD+ and SCD-/NC-were extracted.Furthermore,Pearson correlation analysis was used to assess the correlation between EC values with cognition and mean SUVR.ResultsStudy 1:The pMCI had decreased EC in left temporal pole and parahippocampal gyrus,and increased EC in left middle frontal gyrus compared to sMCI.In addition,compared to normal controls,patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus,and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule.Correlation analysis showed that EC value in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory(WMS-LM)delay score(r=0.467,p=0.044)and total-tau level in CSF(r=-0.509,p=0.026)in pMCI.Study 2:The pMCI showed hypoperfusion in left precuneus at baseline compared with sMCI.The regional CBF of left precuneus could predict conversion from MCI to AD with a sensitivity of 89.5%,a specificity of 66.7%,and an AUC of 0.809.The predictive ability of ASL-perfusion was significantly higher than neuropsychological test(63.2%,80%and 0.772)and hippocampal volume(68.4%,83.3%and 0.788).Moreover,adding ASL perfusion to neuropsychological test and hippocampal volume obtained the highest predictive power(94.7%,90%and 0.946).Study 3:The SCD+ group had lower EC value in bilateral lingual gyrus than the SCD-group,and lower EC values in bilateral LG,right inferior parietal lobule,and right inferior frontal gyrus than the NC-group.There was no statistically significant difference in EC between the SCD+ and NC-groups.Correlation analysis demonstrated that,in the SCD+ group,the EC value in bilateral LG was only significantly associated with mean SUVR(r=-0.649,p=0.042)?ConclusionsStudy 1:Our findings indicate that there is a different intrinsic network organization between pMCI and sMCI groups.Specially,the pMCI mainly showed the disruption of hippocampal network,while the sMCI primarily disrupted right frontal-parietal network.Importantly,the association between decreased EC of the left temporal pole and increased CSF total-tau level may provide improved understanding of the underlying pathophysiology of pMCI.Study 2:Our study suggests that regional cerebral hypoperfusion as detected by ASL-MRI could be a promising marker for predicting conversion from MCI to AD.Moreover,the predictive ability of ASL-perfusion is superior to neuropsychological test and hippocampal volume.The combination of ASL perfusion,neuropsychological tests and hippocampal volume achieved the highest predictive power for the conversion to AD.As ASL-perfusion and structural MRI can be acquired in a single MR imaging scan,it could represent a useful and practical method in future clinical application for MCI discrimination.Study 3:Our study indicated that different cerebral A?level could affect the brain functional networks of SCD.Specially,the SCD-group might only be a kind of subjective emotion and would not affect the cerebral functional changes.While with high level of cerebral Apaccumulation in SCD+ group,the brain networks damaged which involving in the memory,attention and execution functions.Moreover,the functional changes in the SCD+ group were similar to that in AD and MCI patients,confirming the role of the SCD+ group in the progression of AD.