Abnormal Salience Network In Normal Aging And In Alzheimer’s Disease

Objective:To investigate the underlying mechanisms of normal aging and cognitive decline, we used a combined method of VBM and intra/inter-network functional connectivity (FC) to explore the alterations of structural and functional organization of the salience network (SN) and functional interactions between the SN and the central executive network (CEN)/default mode network (DMN) in Alzheimer’s disease (AD) and in normal aging.Methods:Seventy-four older subjects (34males and40females) were included in the study. After evaluating the degree of dementia and cognitive function of older subjects, we divided the subjects into three groups (21HOC,18aMCI, and35AD patients) for the following analyses. An additional75gender-matched HYC (age18-35years) were also included as normal controls in the study. Siemens3.0Tesla MR scanner was used to obtain high resolutions anatomic images and fMRI data in resting state. The rs-fMRI data were processed with the software of Matlab2009a, SPM8and DPARSFA, and we performed ICA using the group ICA (GICA) of the fMRI toolbox. VBM analysis was performed using SPM8software. One-way analysis of variance (ANOVA) was used to test the grey matter volume (GMV) and resting-state FC difference across four groups (HYC, HOC, aMCI and AD) within the SN mask with gender as a nuisance covariate. To determine the contributions of the structural and functional changes of the SN to cognitive decline, we performed voxel-based partial correlation analyses between the mini-mental state examination (MMSE) and GMV, and between MMSE and FCs within the SN in older people. Age, gender, and years of education were used as nuisance covariates. We further compared inter-network FC between the bilateral FICs and the CEN and DMN across the four groups using a voxel-wise one-way ANOVA method.Results:The SN components were identified by the SOI-GICA technique. They were bilateral fronto-insular cortices (FICs), the dorsal anterior cingulate cortex and dorsolateral prefrontal cortices. Most SN components showed significantly decreased GMV during normal aging (P<0.01, FDR corrected), even after correcting for whole brain GMV. In older people, only atrophy of the left FIC showed significantly decreased GMV between AD and aMCI, AD and HOC after correcting for whole brain GMV. In older people, almost all SN components showed significant correlations with MMSE. After atrophy correction, MMSE scores were only positively correlated with GMVs in the left FIC.Most SN components showed altered intra-network FC during normal aging (P<0.01, FDR corrected), even after atrophy correction. In older people, only the right FIC exhibited decreased intra-network FC during disease progression after atrophy correction and the reduced intra-network FC of the left FIC contributed to cognitive decline.We further compared inter-network FC between the bilateral FICs and the CEN and DMN across the four groups and found significantly weakened inter-network FC during normal aging (P<0.05, FWE corrected), parts of which were further weakened during disease progression; however, none of them differed between the two patient groups (P<0.05, corrected).Conclusions:1. Both the structural and functional organizations of the SN are impaired in AD/MCI and occur as early as in normal aging.2. The structural and functional deficits in the FICs are important contributors to cognitive decline in older people.3. The inter-network disconnection between the SN and the CEN and DMN occurs during normal aging and contributes to cognitive decline in elderly people.4. The inter-network disconnection between the SN and the CEN and DMN may be related to disease progression.