Functional connectivity tracks clinical deterioration in Alzheimer's disease

Abstract

While resting state functional connectivity has been shown to decrease in patients with mild and/or moderate Alzheimer's disease, it is not yet known how functional connectivity changes in patients as the disease progresses. Furthermore, it has been noted that the default mode network is not as homogenous as previously assumed and several fractionations of the network have been proposed. Here, we separately investigated the modulation of 3 default mode subnetworks, as identified with group independent component analysis, by comparing Alzheimer's disease patients to healthy controls and by assessing connectivity changes over time. Our results showed decreased connectivity at baseline in patients versus controls in the posterior default mode network, and increased connectivity in the anterior and ventral default mode networks. At follow-up, functional connectivity decreased across all default mode systems in patients. Our results suggest that earlier in the disease, regions of the posterior default mode network start to disengage whereas regions within the anterior and ventral networks enhance their connectivity. However, as the disease progresses, connectivity within all systems eventually deteriorates.

Figure 1. Group ICA z-stat maps of the 3 default mode networks and the sensorimotor network

The group independent components selected for between-group statistics include three networks of interest: (A) anterior; (B) ventral; and (C) posterior default mode network; and (D) the sensorimotor network as a control. Shown here using a posterior probability threshold of p>0.5; MNI coordinates axial slices: z=−18; 12; 42.

Figure 2. Functional connectivity difference maps of Alzheimer’s patients versus healthy elderly controls at baseline

Functional connectivity differences between Alzheimer’s patients and healthy elderly controls in the A) anterior; (B) ventral; and (C) posterior default mode network. The different colors represent the results with and without grey matter correction and the overlap between the two. Functional connectivity in the anterior and ventral default mode networks (A & B) is increased in Alzheimer’s patients compared to controls (displayed in violet for results with grey matter correction; in cyan for results without correction; and in red for the overlap). Functional connectivity in the posterior default mode network (C) is decreased (displayed in blue for results with grey matter correction (only visible for a few voxels here); in yellow for results without correction; and in green for the overlap). The statistical maps, thresholded using TFCE and p<0.05 family wise error corrected, are overlaid on the MNI152 brain; MNI coordinates (in mm) of the slices are displayed.

Figure 3. Functional connectivity reductions in Alzheimer’s disease patients and healthy controls at follow-up compared to baseline

Functional connectivity decreases in both Alzheimer’s patients (left panel) and healthy elderly controls (right panel) at follow-up compared to baseline in the A) anterior; (B) ventral; and (C) posterior default mode network; and (D) the sensorimotor network. The different colors represent the results with and without grey matter correction and the overlap between the two. Displayed in blue are the results with grey matter correction; in yellow the results without correction; and in green the overlap. The statistical maps, thresholded using TFCE and p<0.01 uncorrected, are overlaid on the MNI152 brain; MNI coordinates (in mm) of the slices are displayed.

Figure 4. Differential functional connectivity changes between Alzheimer’s disease patients and healthy elderly controls over time

Regions in which the functional connectivity changes over time are significantly different in Alzheimer’s patients than in healthy elderly controls, for the A) anterior; (B) ventral; and (C) posterior default mode network; and (D) the sensorimotor network. The different colors represent the results with and without grey matter correction and the overlap between the two. Displayed in blue are the results with grey matter correction; in yellow the results without correction; and in green the overlap. The statistical maps, thresholded using TFCE and p<0.01 uncorrected, are overlaid on the MNI152 brain; MNI coordinates (in mm) of the slices are displayed. To show the directionality of the effects, bar graphs are included. For the anterior and ventral default mode networks they are displayed above the corresponding brain images; for the posterior default mode and sensorimotor network they are displayed below the corresponding brain images. Bar graphs display the mean raw t-statistic of selected regions in the specific network for the follow-up>baseline contrast in patients and controls separately.