Loss of 'small-world' networks in Alzheimer's disease: graph analysis of FMRI resting-state functional connectivity

Abstract

Background: Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.

Methodology/principal findings: 18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.

Conclusions/significance: We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

Figure 1. Synchronization matrix of AD group.

Intensities of SL values between any given pair of brain regions are color-coded (blue, SL = 0; red, SL = 1). Labels and guidelines represent groups of AAL brain ROIs. Upper left corner represents the synchronization level between brain regions in the right hemisphere; lower right corner is the synchronization within the left hemisphere; upper right corner (diagonal line) corresponds to the synchronization between hemispheres. On this region, main synchronization clusters are indicated: A) frontal cortex; A’) frontal cortex with pre and post-central gyri and parietal cortex; B) parietal and occipital cortices and precuneus; C) temporal lobe; C’) temporal lobe with parietal and occipital lobes. The overall synchronization pattern reveals a relative increase of connectivity in the frontal cortices in AD (A); compared to the control group (Figure 2), decreases of connectivity in AD are spread throughout temporal cortices (C and C’) and particularly the parietal and occipital region (B). Note that the synchronization matrices are symmetrical – lower half of the matrices are grayed out for convenience.

Figure 2. Synchronization matrix of control group.

See legend of Figure 1.

Figure 3. Cluster coefficient and path length.

Subplots (a) and (b): Mean cluster coefficient and path length calculated for a range of synchronization threshold values (0.05

Figure 4. Synchronization differences.

(a) Matrix of significant differences of synchronization between AD and controls (2-tail t-test, p<0.05 uncorrected). The white and black dots represent brain areas pairs with increased and decreased synchronization in AD respectively. (b-d) A subset of connectional differences corresponding to the matrix (a) are plotted at 3 superior-to-inferior levels through the AAL brain template: (b) = z53; (c) = z73; (d) = z111. Lines depict synchronization between pairs of regions: solid lines  =  enhanced synchronization; dashed lines  =  reduced synchronization. Note the pattern of generalized posterior (parietal and occipital) synchronization reductions and increased frontal synchronization.

Figure 5. Pattern of long-distance functional connections.

Connectivity pattern of AD and healthy groups (left and right panels respectively). Color-coded vertices correspond to individual AAL ROIs included in the orbital (yellow), medial (red) and dorsolateral frontal regions (light green), parietal (deep green) and occipital lobes (gray), the cuneus and lingual cortices (black). Upper 2-dimensional graphs (orientation front-down and left-right) represent the changes in functional connections: solid lines (left) correspond to increases and dashed lines decreases in connectivity in AD (right). Lower figures (orientation front-left) represent the projections of AD (right) and healthy networks (left) embedded in a 3-dimensional AAL brain template. The graphs demonstrate a net loss of long-distance fronto-parietal and fronto-occipital functional connections (for both groups, T = 0.05; K = 10).

Figure 6. Effect of increased functional connectivity in secondary atrophy sites.

Theoretical interpretation of simultaneous longer atrophy and shorter functional path length in AD. Initial correlated atrophy between vertices (1) is decoupled due to compensatory functional connectivity involving secondary atrophy vertices (2). The appearance of new functional edges (3 - shorter functional L) results in preserved functionality of secondary atrophy vertices (4) and the disappearance of cortical thickness edges linking to the primary atrophy vertex (5 - longer structural L). The rerouted functional flow could still gain partial access to the primary atrophy site and the rest of the network (6).