Exploring The Neural Mechanism Of Alzheimer’s Disease Using Multimodal MRI

Background:Alzheimer’s disease（AD）is the most common form of dementia,characterized by progressive memory loss and other cognitive declines.As the population ages,AD has placed a huge social and economic burden around the world.However,there is no effective treatment for AD currently.The long disease course and complex pathogenesis maybe the key reasons for the failure of AD treatment research.Therefore,using accurate disease classification and combining different pathogenesis may help to explore the mechanism of AD,and provide evidence for the clinical diagnosis and treatment.On one hand,AD is clinically characterized by insidious onset and long disease course.According to the clinical symptoms,it can be divided into 3 stages:asymptomatic stage,lasting for about 20 years;cognitive decline stage,lasting for about10 years;and finally dementia.Today,the mainstream belief is:AD was resulted by the extracellular amyloid-βplaques and intracellular nerve fiber tangles.These AD neuropathological accumulation begins years before the onset of dementia and develops in a specific temporal-ordered manner,with extracellular amyloid-βplaques deposit appears the earliest and followed by intracellular phosphorylated tau deposition and downstream neurodegeneration events.Hence,combining the pathological stages with the symptomatic diagnosis can help to assess AD continuum more accurately.Thereinto,the neural damage in the preclinical AD stage is reversible and thus serves as the key stage for clinical early intervention.More attention should be paid to this stage.On the other hand,AD is a multifactorial neurodegenerative disease.In addition to the neuropathology（i.e.,β-amyloid and neurofibrillary tangles）,cerebral small vessel disease（CSVD）has also been recognized as crucial pathogenesis in AD.The vascular pathology is related to higher dementia risk and greater cognitive decline.Thus,it is very important to explore the role of CSVD in the pathogenesis of AD,which may provide a basis for clinical vascular factor intervention in AD.In summary,the neurological mechanism of AD is:multifactorial pathogenesis impair synaptic communication and fiber integrity,result in neuronal networks/structure disorganization,and finally lead to the cognitive decline.Multimodal MRI is an important and effective tool to explore the neural mechanism of AD,since its high sensitivity,specificity of capturing structural and functional abnormalities in the brain.However,most previous studies are lack of the accurate AD classification or ignored some non-neuropathological mechanism for AD,making the research conclusion unaccurate or sometimes one-sided.Accordingly,we aim to use multiple neuroimaging to explore neuronal mechanism of AD.Specifically,it contains（1）assessing the intrinsic connectivity network in SCD and its possible pathological mechanism;（2）exploring the progressive memory circuit impairments along with AD neuropathology spread;（3）exploring the evolution patterns of gray matter structural covariance networks（SCN）along AD continuum;（4）exploring the influence of CSVD on the brain functional connectivity in subjects along the AD continuum.Methods:Experiment 1:we included 44 SCD individuals and 40 healthy controls（HC）who underwent both resting-state functional MRI and positron emission tomography（PET）.Based on graph theory approaches,we detected local and global functional connectivity across the whole brain by using degree centrality（DC）and eigenvector centrality（EC）respectively.Additionally,we analyzed amyloid deposition and tauopathy via florbetapir-PET imaging and cerebrospinal fluid（CSF）data.The voxel-wise two-sample T-test analysis was used to examine between-group differences in the intrinsic functional network and cerebral amyloid deposition.Then,we correlated these network metrics with pathological results.Experiment 2:we included HC,mild cognitive impairment（MCI）and AD subjects,and further classified them using the AT（N）pathological classification system（Group 0:HC,A-T-;Group 1:HC,A+T-;Group 2:HC,A+T+;Group 3:MCI,A+T+;Group 4:AD,A+T+）.We investigated alterations of three core memory circuit structures:hippocampus（HP）subfields volume,cingulum-angular bundles（CAB）fiber integrity,and precuneus cortex volume.Finally,we performed correlation analysis between memory circuit impairments and neuropathology biomarkers as well as memory performance.Experiment 3:based on the AT（N）（i.e.,Amyloid/Tau/Neurodegeneration）pathological classification system,we classified subjects into four groups using cerebrospinal fluid amyloid-beta_1–42（A）and phosphorylated tau protein₁₈₁（T）.We identified 101 subjects with normal AD biomarkers（A-T-）,40 subjects with Alzheimer’s pathologic change（A+T-）,101 subjects with biological AD（A+T+）and91 biological AD with dementia（demented subjects with A+T+）.We used four regions of interest to anchor default mode network（DMN,medial temporal subsystem and midline core subsystem）,salience network（SN）and executive control network（ECN）.Finally,we used a multi-regression model-based linear-interaction analysis to assess the SCN changes.Experiment 4:we included 182 HC,27 individuals with SCD,27 with SCD+CSVD,104 with MCI,123 with MCI+CSVD,16 with AD,and 62 with AD+CSVD.We examined the static and dynamic functional network network（FNC）within the default mode network（DMN）,salience network（SN）,and executive control network（ECN）.We also assessed the association between atypical FNC patterns and cognitive impairments,as well as the pathologies.Results:Experiment 1:The SCD individuals showed higher DC in the bilateral HP and left fusiform gyrus and lower DC in the inferior parietal region than HC.Across all subjects,the DC of the bilateral HP and left fusiform gyrus was positively associated with total tau and phosphorylated tau₁₈₁.However,no significant between-group difference existed in EC and cerebral amyloid deposition.Experiment 2:Along with AD progression,HP subfields volume showed the trend of initially increased and then decreased（starting from Group 2）,while precuneus volume decreased in Group 3 and 4.The CAB integrity degenerated in Group 3 and 4and aggravated with higher disease stages.Further,memory circuit impairments were correlated with neuropathology biomarkers and memory performance.Experiment 3:Along with AD progression,DMN and SN showed increased structural association at the early stage while decreased structural association at the late stage.Moreover,ECN showed progressively increased structural association as AD neuropathological profiles progress.Experiment 4:Static FNC results showed progressively increased within-domain connectivity and decreased between-domain connectivity along AD continuum,especially in CSVD subjects.Dynamic FNC in CSVD subjects showed more occurrences in a highly-modularized state and fewer occurrences in the diffusely connected state.Further analysis showed that neuropathology and CSVD burden divergently affect the FNC changes.Conclusions:Our findings suggested that（1）SCD individuals showed impaired local,but not global,intrinsic connectivity networks.Given the relationships between DC value and tau level,we hypothesized that functional changes in SCD individuals might relate to pathological biomarkers;（2）memory circuit progressively impaired along with AD progression:starting from the HP,then propagating to the downstream projection fiber tract and cortex.These findings support the tau propagation theory to some extent;（3）SCN changes showed as a dynamic trajectory of changes along the AD continuum and support the network disconnection hypothesis underlying AD neuropathological progression.Further,SCN may potentially serve as an effective AD biomarker.（4）CSVD and non-CSVD individuals along the AD continuum demonstrate divergent abnormalities of FNC,which were divergently affected by neuropathology and CSVD burden.Specifically,those with CSVD show more static and dynamic FNC impairments,associated with cognitive decline.These findings may advance our understanding of the effect of CSVD on AD onset and progression,and provide potential hints for clinical treatment.