Resting-state network dysfunction in Alzheimer's disease: A systematic review and meta-analysis

Abstract

Introduction: We performed a systematic review and meta-analysis of the Alzheimer's disease (AD) literature to examine consistency of functional connectivity alterations in AD dementia and mild cognitive impairment, using resting-state functional magnetic resonance imaging.

Methods: Studies were screened using a standardized procedure. Multiresolution statistics were performed to assess the spatial consistency of findings across studies.

Results: Thirty-four studies were included (1363 participants, average 40 per study). Consistent alterations in connectivity were found in the default mode, salience, and limbic networks in patients with AD dementia, mild cognitive impairment, or in both groups. We also identified a strong tendency in the literature toward specific examination of the default mode network.

Discussion: Convergent evidence across the literature supports the use of resting-state connectivity as a biomarker of AD. The locations of consistent alterations suggest that highly connected hub regions in the brain might be an early target of AD.

Keywords: Alzheimer's disease; Functional connectivity; Meta-analysis; Mild cognitive impairment; Resting-state fMRI.

Fig. 1

Flowchart of the study selection process. Selection process for AD and MCI studies included in the meta-analyses. Studies using rsfMRI methods dissimilar to seed-based and ICA methods, such as degree centrality or graph theory, amplitude of low-frequency fluctuations, and regional homogeneity were not included. Abbreviations: AD, Alzheimer's disease; EEG, electroencephalogram; ICA, independent component analysis; MCI, mild cognitive impairment; MEG, magnetoencephalography; rsfMRI, resting-state functional magnetic resonance imaging.

Fig. 2

Seed region network-level findings. (A) R7 atlas; (B) histograms showing the ratio of counts (or hits) across the seven networks for all seeds in ADMCI, MCI, and AD. Significant (^∗ denoting qFDR < 0.05) prevalence of seeds in the DMN was demonstrated across all three cohorts; (C) seed region hit maps (ratio of dysconnectivity coordinates in each network) at R7. Maps are superimposed onto the anatomic International Consortium for Brain Mapping (ICBM) 152 template. x, y, and z Montreal Neurological Institute (MNI) coordinates are given for sagittal, coronal, and axial slices. Abbreviations: AD, Alzheimer's disease; ADMCI, AD dementia and MCI; CER, cerebellar network; DMN, default mode network; FDR, false discovery rate; FPN, frontoparietal network; HC, healthy control; LIM, limbic network; MCI, mild cognitive impairment; MOT, motor network; SAL, salience network; VIS, visual network.

Fig. 3

Network-level findings using the R7 atlas. (A) Histograms showing per contrast the ratio of hits across the seven networks for all seeds, DMN seeds only, and non-DMN seeds. Networks with significant count (or hit) ratios are indicated by ^∗ denoting qFDR < 0.05, whereas ^† denotes P < .05 uncorrected. (B) Hit maps at R7 are shown for contrasts ADMCI < HC, ADMCI > HC, MCI < HC, MCI > HC, AD < HC, and AD > HC. Maps are superimposed onto the anatomic ICBM 152 template. x, y, and z MNI coordinates are given for sagittal, coronal, and axial slices. Abbreviations: AD, Alzheimer's disease dementia; ADMCI, AD dementia and MCI; CER, cerebellar network; DMN, default mode network; FDR, false discovery rate; FPN, frontoparietal network; HC, healthy control; LIM, limbic network; MCI, mild cognitive impairment; MOT, motor network; SAL, salience network; VIS, visual network.

Fig. 4

Network-level findings using the R36 atlas. (A) Functional template at R36 showing the breakdown of the DMN and LIM into subnetworks. These two networks were significant (qFDR < 0.05 for contrasts ADMCI < HC for DMN, ADMCI > HC for DMN, MCI > HC for DMN and LIM, AD < HC for DMN) or trended toward significance (P < .05 uncorrected for contrasts MCI < HC for DMN) for the “all-seeds” condition at R7. (B) Histograms showing per selected contrast (as described in A), the ratio of counts (or hits) across the subnetworks. Subnetworks with significant hit ratios are indicated by ^∗ denoting qFDR < 0.05, whereas ^† denotes a trend with P < .05 uncorrected. (C) Hit maps at R36 for brain regions that overlap with significant or trending toward significance networks (as described in A). Maps are superimposed onto the anatomic ICBM 152 template. x, y, and z MNI coordinates are given for sagittal, coronal, and axial slices. Abbreviations: AD, Alzheimer's disease dementia; ADMCI, AD dementia and MCI; CER, cerebellar network; DMN, default mode network; FDR, false discovery rate; FPN, frontoparietal network; HC, healthy control; LIM, limbic network; MCI, mild cognitive impairment; MOT, motor network; SAL, salience network; VIS, visual network.

Fig. 5

Location of significant convergence of the voxel-level findings. Regions exhibiting significant rsfMRI abnormalities for contrasts ADMCI < HC, AD < HC, and AD > HC. Activation likelihood estimation images were thresholded at P < .05 (cluster-level family wise error or FWE corrected for multiple comparisons; cluster-forming threshold P < .001 at the voxel level) and displayed as t scores, with hyperconnectivity in red-orange and hypoconnectivity in blue-green. Maps are superimposed onto the anatomic ICBM 152 template. x, y, and z MNI coordinates are given for sagittal, coronal, and axial slices. Abbreviations: AD, Alzheimer's disease dementia; ADMCI, AD dementia and mild cognitive impairment; HC, healthy control; rsfMRI, resting-state functional magnetic resonance imaging.