Widespread disruption of functional brain organization in early-onset Alzheimer's disease

Abstract

Early-onset Alzheimer's disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 "young" (<65 years old) and 31 "old" (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed.

Figure 1. Resting state network maps.

Standard masks of the eight resting state networks (RSNs) as described in Beckmann et al. (2005) are freely available and were downloaded from http://www.fmrib.ox.ac.uk/analysis/royalsoc8/. Blue regions show brain regions included in the RSNs; the medial-visual system, the lateral-visual, auditory system, sensori-motor system, the default mode network, the executive control network, right dorsal visual system and left dorsal visual system.

Figure 2. Lowered functional connectivity in AD patients when compared to age-matched controls.

Upper panel shows lower functional connectivity in early-onset AD patients when compared to ‘young’ age-matched controls. Lower panel shows decreased functional connectivity in late-onset AD patients (EOAD) when compared to ‘old’ age-matched controls. Standard maps of the Resting State Networks (RSNs) are shown in transparent blue. Upper panel: Lower functional connectivity was found in early-onset AD patients when compared to aged-matched young controls within the medial-visual system, lateral-visual system, auditory system, sensory-motor system, default mode network, the executive control network and bilateral dorsal-visual stream. Lower panel: late-onset AD patients (LOAD) show lower functional connectivity when compared to old age-matched controls within the default mode network only. Results are displayed in radiological orientation on standard MNI space (MNI152 2 mm), after correction for multiple comparisons across space (p<0.05). Gender and voxel-wise gray matter maps were used as covariates. Brighter colors represent most significant results. Abbreviations: R = right. L = left.

Figure 3. Functional connectivity in early-onset AD patients compared to late-onset AD patients.

Standard maps of the Resting State Networks (RSNs) are shown in transparent blue. Lower functional connectivity was found in early-onset AD (EOAD) patients when compared to late-onset AD (LOAD) patients within the default mode network, the auditory system, the sensory-motor system, and bilateral dorsal visual system. Results are displayed in radiological orientation on standard MNI space (MNI152 2 mm), after correction for multiple comparisons (p<0.05). Gender and voxel-wise gray matter maps were used as covariates. Brighter colors represent most significant results. Abbreviations: R = right. L = left.

Figure 4. Gray matter loss.

Regions of decreased gray matter volume in early-onset AD (EOAD) patients when compared to age-matched young controls (A). Regions of decreased gray matter volume in late-onset AD (LOAD) patients when compared to age-matched old controls (B). Regions of decreased gray matter volume in early-onset AD patients when compared to late-onset AD (C). Regions of decreased gray matter volume in late-onset AD patients when compared to early-onset AD (D). Results are corrected for multiple comparisons (p<0.05) and are shown in radiological orientation on standard MNI space (MNI152 2 mm). Brighter colors represent most significant results. R = Right. L = Left.

Figure 5. Significant correlations of functional connectivity with cognition in AD patients.

Scatterplots of significant Spearman correlations across AD patients are shown; mean z-scores representing functional connectivity within the resting state network (RSNs) are displayed on the y-axis. Mean z-scores composing the cognitive domains are displayed on the x-axis. Functional connectivity of the right dorsal visual stream (A) was associated with attention. Functional connectivity of the default mode network (B) was associated with visuo-construction. Black squares represent early-onset (EOAD), white squares represent late-onset AD patients (LOAD). Spearman correlation coefficients (ρ) are reported, with corresponding p-value and number of subjects included in the correlation analysis.