Multimodality Magnetic Resonance Imaging Study On The Neural Mechanism Of Cognitive Reserve In Alzheimer’s Disease

Background The reserve theory is established to interpret the apparent discrepancy between brain pathology and its clinical manifestations in different individuals.The theory supposes that certain life experiences enable some people to withstand the brain pathology more effectively compared with others through enhancing the adaption of neural networks.Cognitive reserve（CR）is present in both healthy individuals and those with brain damage.Most studies support the reserve hypothesis in neurodegenerative disorders.In Alzheimer’s disease（AD）,patients with higher CR can tolerate greater brain pathological damage at a particular degree of cognitive impairment than those with lower CR,such as coping with decreased cerebral 18F-fluorodeoxyglucose positron emission tomography（FDG-PET）metabolism,or cortical thickness;having more severe white matter damage;and greater amyloid-beta（Aβ）accumulation and increased tau deposition.ObjectiveTo explore the neural mechanisms of CR across the ageing–MCI–AD spectrum by using neuropsychological tests and multi-modal MRI techniques.（1）To examine the effect of education（CR proxy）on brain structure and function in AD and amnestic mild cognitive impairment（a MCI）patients and in cognitively healthy elderly（HC）individuals.（2）To investigate the alterations of resting-state cerebral blood flow（CBF）in different level of CR during AD progression and whether those alterations can moderate the relationship between education and cognition.（3）To investigate the pattern of neurovascular coupling in different level of CR during AD progression and whether these can moderate the relationship between education and cognition.Methods（1）Fifty-seven AD patients,57 a MCI patients and 48 HCs were included to investigate the relationships between education years and gray matter volume（GMV）,regional homogeneity（Re Ho）and resting-state functional connectivity（rs FC）.Taking the severity of dementia into account,we further assessed the relationships in AD stratified（mild,moderate,and severe AD）analyses.（2）According to education years（cut-off value: 9 years）,the participants were divided into high cognitive reserve（HCR）and low cognitive reserve（LCR）groups.Arterial spin labeling（ASL）magnetic resonance imaging data and cognitive scores were collected from 89 AD patients（67 LCR,22 HCR）,74 a MCI patients（44 LCR,30 HCR）,and 66 healthy controls（29 LCR,37 HCR）.A two-way analysis of variance was performed to investigate brain regions with significant interaction effect between groups（HC,a MCI,and AD）and education（LCR,HCR）,which were then chosen as regions of interest（ROI）to extract mean values.Mediation analyses were used to explore the relationship among education,CBF alteration,and cognitive score.Finally,stepwise multiple linear regression analyses were then performed to determine the possible predictors of cognitive performance in different CR group respectively.（3）According to education years（cut-off value: 9 years）,the participants were divided into HCR and LCR groups.Bold and ASL magnetic resonance imaging data and cognitive scores were collected from 89 AD patients（67 LCR,22 HCR）,74 a MCI patients（44 LCR,30 HCR）,and 66 healthy controls（29 LCR,37 HCR）.Two-way analyses of variance were performed to investigate brain regions with significant interaction effect in neurovascular coupling（CBF/ALFF and CBF/f ALFF）between groups（HC,a MCI,and AD）and education（LCR,HCR）,which were then chosen as ROI to extract mean values.Mediation analyses were used to explore the relationship among education,neurovascular coupling（CBF/ALFF and CBF/f ALFF）pattern,and cognitive score.Results（1）In AD group,the GMV of d ACC and the Re Ho of L＿ITC were inversely associated with education years,after adjustment for age,sex,Mini-Mental State Examination（MMSE）,and total intracranial volume（TIV）or head motion parameters.Seed-based rs FC analyses revealed that education years were negatively correlated with the rs FC between the left anterior ITC（L＿a ITC）and left mid frontal cortex as well as right superior frontal cortex and right angular gyrus.Stratifed analyses results indicated that this negative relation between education and GMV,Re Ho,rs FC was mainly present in mild AD,which was attenuated in moderate AD and a MCI groups.（2）Significant interactions between group（AD,a MCI,HC）and education（LCR,HCR）were observed in the CBF of right hippocampus,posterior cingulate cortex（PCC）,and right inferior parietal cortex（R＿IPC）.In addition,education regulated the episodic memory score through the mediation of CBF in the right hippocampus in HC＿HCR and a MCI＿HCR groups.Finally,we found CBF of R＿IPC may be a good predictor for the MMSE and Mo CA score just in LCR group（HC,a MCI and AD combined）.（3）Significant interaction between group（AD,a MCI,HC）and education（LCR,HCR）was observed in the CBF/ALFF of right posterior part of inferior temporal cortex（R＿p ITC）.Significant interactions between group（AD,a MCI,HC）and education（LCR,HCR）were observed in the CBF/f ALFF of right anterior part of inferior temporal cortex（R＿a ITC）,left postcentral gyrus（L＿post CG）,posterior cingulate cortex（PCC）,right precuneus and supplymentary motor area（SMA）.In addition,education regulated the working memory score through the mediation of CBF/ALFF of R＿p ITC and CBF/f ALFF of PCC in HC group（LCR and HCR combined）.Conclusions（1）Results from this study support the CR theory,and suggest that CR may be protective against AD related brain pathology in the early stage of clinical dementia.（2）Results from this study indicate that education may constitute a neurocognitive protective factor in AD progression,by modulating the CBF of right hippocampus and affecting the brain CBF connectivity patterns to maintain memory performance.（3）Our study reveals a neurovascular coupling and decoupling phenomenon in AD progression by using a combination of BOLD and ASL techniques.The neurovascular coupling pattern differed from individuals with HCR to individuals with LCR across the ageing–a MCI–AD spectrum.In healthy elderly,education improves the working memory by promoting neurovascular coupling in R＿p ITC and PCC.In summary,with the help of multi-modal MRI techniques and advanced analysis methods,we confirmed the existence of CR,and explored and revealed the discrepancy of CBF and neurovascular coupling pattern in different level of CR during AD progression,and provided underlying theoretical supports for education might influence cognitive trajectories.In addition,our results might provide the locus of CR-related functional brain mechanisms and a specifc time-window for therapeutic interventions to help AD patients to cope better with the brain pathological damage by increasing CR.