The Application Of MRI Technology In Preclinical Alzheimer's Disease And Mild Cognitive Impairment

BackgroundAlzheimer's disease(AD)is the most prevalent form of dementia,characterized by progressive cognitive impairment,especially for the memory function.Currently,the cost of the AD has placed a heavy burden on Chinese society and families.Unfortunately,no effective clinical treatment of AD until now,this is because we always miss the best cure opportunity.Ten to fifteen years before the AD symptoms onset,many studies observed slight AD-related neuropathological changes,mainly extracellular amyloid plaques containing abnormal A? protein,intracellular neuronal fibrillary tangles(NFTs)composed of hyperphosphorylated tau protein.These neuropathologies would have toxic effects on neuron and its axon,further,lead to irreversible brain injury in AD patients.According to the latest research view,adopting early interventions at AD preclinical stage or mild cognitive impairment(MCI)could delay the disease progression,for the reason that individuals still preserve most cognitive ability.By definition,the preclinical AD and MCI represents a disease continuum,from the AD-related pathologies appear firstly until the diagnosis of AD dementia.Recent year,MRI gradually become the main technologies to explore the preclinical AD and MCI,with the non-invasive and non-radiative characters.The method principle is that AD-related pathologies induced downstream event would affect neuronal activity and injury fiber integrity,further,lead to one's brain function abnormalities.Exactly right,MRI could detect these signals with high sensitivity.However,previous studies were cross-sectional design,therefore they could not assess which neuroimaging features would predict the clinical prognosis well.On the other side,also evidence showed that vascular risk factor,such as cerebral small vascular disease(CSVD)would increase the risk of cognitive decline and AD risk.However,previous studies regarding the relationship between WMH and preclinical AD were still controversial.On the one side,most studies adopted visual rating to assess WMH burden.Compared with automatic quantitative WMH segmentation,these subjective approaches are time-consuming and easily affected by evaluator's experience.Moreover,subjective assessment of WMH is unsuitable for identifying WMH progression.To solve these problems,we aim to use multiple neuroimaging to explore neuronal mechanism in preclinical AD and MCI.Specifically,it contains(1)to explore the aMCI subtypes heterogeneity by assessing both brain activity alteration and CSVD;(2)to predict clinical prognosis of subjective cognitive decline by using multi-shell biological biomarkers;(3)to longitudinally assess the effect of APOE genotypes on CSVD in cognitively intact elderly;(4)explore brain connectivity in healthy elderly APOE ?4 carriers.MethodsExperiment 1:a total of 49 healthy controls and 32 single-domain amnestic MCI and 32 multi-domain amnestic MCI were included in the present study.Based on T1 structure and rsfMRI scan,we assessed the PWMH and DWMH burden,and the voxel-wise ReHo value.Besides,we analyzed the AD-related hallmarks including A?1-42,t-tau and p-tau181.We tested whether two aMCI subtypes had very different injury pattern,and correlated the differenced measures to cognition and AD-related pathologies.Experiment 2:we included 101 controls and 69 SCD subjects.On the basis of clinical prognosis,we further divided the SCD into 54 stable SCD(S-SCD)and 15 progressive SCD(P-SCD).We assessed the baseline beta-amyloid deposition reflected by PET-PiB,baseline and two year follow-up PWMH and DWMH burden and the changes of grey matter volume.Moreover,we constructed the path model to estimate the predictive value of beta-amyloid,WMH burden,grey matter volume,and neuropsychiatric score in SCD disease progression.Experiment 3:We included 74 APOE ?3 homozygotes as controls,41 APOE ?4 carriers and 20 APOE ?2 carriers,all of them were cognitively intact elderly.Both subjects underwent three time point image acquisitions,including the baseline,1-year and 2 years later.We assessed the most common CSVD index including WMH,PVRs,MBs and lacune.Moreover,based on the general linear model(GLM),our study aims to explore the relationships among APOE genotype,CSVD,and cognitive.Experiment 4:A total of 13 healthy APOE ?4 carriers and 22 APOE s3 homozygotes were included in the present study.The eigenvector centrality mapping(ECM)was used to identify brain network hub organization based on resting-state functional MRI(rsfMRI).Besides,we evaluated comprehensive cognitive ability and tested AD-related neuropathologeis from CSF.Comparisons of ECM between the two groups were conducted,followed by correlations analyses between EC values with significant group differences and cognitive ability/CSF biomarkers.ResultsExperiment 1:compared to controls,we found SD-aMCI patients had decreased ReHo value in medial temporal gyrus and increased ReHo value in lingual gyrus and superior temporal gyrus.However,no difference of WMH burden between controls and SD-aMCI.By contrast,MD-aMCI had widespread ReHo value decrease,involving precuneus,lingual gyrus and postcentral gyrus.Moreover,MD-aMCI had significant increased PWMH relative to controls.Correlation analyses showed that in all aMCI subjects,ReHo Value in different regions related to memory,language and executive function.In SD-aMCI patients,ReHo of STG was related to A?1-42 level(r=-0.48,p<0.005).Experiment 2:both the S-SCD and P-SCD group had increased amyloid deposition and relatively increased depression score(sub-clinical level),relative to controls.Meanwhile,Both SCD group had increased baseline PWMH burden and faster PWMH progression,but only P-SCD had increased baseline DWMH burden and faster DWMH progression compared to controls.Regarding grey matter volume,we found P-SCD had accelerated atrophy in MTG and precuneus during the follow-up than other two groups.Path model showed increased beta-amyloid would contribute to cognitive decline and disease progression mediated by PWMH.Moreover,individuals with increased depression score would face a higher AD risk.Experiment 3:compared to controls and protective group,we found APOE ?4 carriers had increased baseline frontal WMH burden and BG dPVS.After two-year follow-up,APOE e4 carriers had faster frontal WMH progression.Moreover,we found APOE s4 carriers had more amyloid deposition,and it correlated well with baseline and progression WMH.The GLM showed the interaction between baseline frontal WMH and APOE ?4 allele would contribute to cognitive decline.Besides,no significant protective effects of APOE ?2 on CSVD existed.Experiment 4:compared to controls,we found APOE ?4 carriers had decreased EC value in memory-related regions,including medial temporal region and lingual gyrus.However,APOE ?4 carriers had compensatory increased EC value in left middle frontal gyrus.In APOE ?4 carriers,EC in left LG related to AVLT(r=0.55,p<0.05),reflecting memory function;while EC in the left MFG related to TMT-B(r=-0.67,p<0.05).Besides,we found decreased EC of left LG correlated to increased t-tau level(r=-0.57,p<0.05).ConclusionsOur findings suggested that(1)aMCI is heterogeneous disease entity.MD-aMCI had more complex neuroimaging features abnormalities than SD-aMCI patients,including the more widespread intrinsic brain activity decrease and more severe WMH burden;(2)there was a link between CSVD and SCD individuals.SCD individuals with higher baseline amyloid deposition,depression score,and WMH burden are at greatest risk for disease progression(3)our findings suggested APOE ?4 allele was associated with increased amyloid deposition,which may lead to the formation and progression of WMH,especially in the frontal lobe.Besides,the interaction between the increased frontal WMH burden and ?4 allele can exert long-term detrimental effects on individual's trajectory of cognition;(4)The APOE ?4 allele contributes to disruption of brain connectedness in certain functional nodes,which may result from neuronal death caused by toxicity of neurofibrillary tangles.