Disruption of functional connectivity in clinically normal older adults harboring amyloid burden

Abstract

Amyloid deposition is present in 20-50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n = 38, aged 60-88 years) were characterized using (11)C-labeled Pittsburgh Compound B positron emission tomography imaging to estimate fibrillar amyloid burden and, separately, underwent functional magnetic resonance imaging (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimer's disease, revealed significant disruption in the default network including functional disconnection of the hippocampal formation.

Figure 1.

Amyloid deposition in clinically normal, MCI, and AD individuals. The DVR for PiB binding in an aggregate region (the FLR region) is plotted for each individual. The present sample of clinically normal older adults (CN) was compared with preexisting samples of MCI participants and AD patients. Means are indicated by black bars. Differences among all group comparisons were significant at p < 0.005.

Figure 2.

The default network is functionally disrupted in clinically normal older adults harboring amyloid burden. a, Default network correlations for clinically normal older adults with (PiB+) and without (PiB−) substantial amyloid burden. Each value represents the mean of the z-transformed correlation values between a priori regions of interest in the posterior cingulate, lateral parietal, and medial prefrontal cortices. Black bars indicate the group mean. **p < 0.001. b, Default network correlations plotted against amyloid retention in clinically normal older adults. Amyloid deposition (DVR in an aggregate region of interest—the FLR region) was treated as a continuous measure. A significant negative relationship was observed between amyloid burden and default network correlations (p < 0.02).

Figure 3.

Functional correlations between individual regions are reduced within the default network. Regions of interest in the PCC, LPC, and MPFC were defined a priori and examined for differences in z-transformed correlation values between clinically normal individuals with (PiB+) and without (PiB−) substantial amyloid burden. Comparisons involving the lateral parietal regions were averaged across the left and right regions. *p < 0.01.

Figure 4.

Exploratory whole-brain analyses confirm disruption of the default network including the hippocampal formation. Maps display regions that are significantly (cluster-corrected threshold of p < 0.05) correlated with a seed placed in the posterior cingulate cortex (shown in blue) for clinically normal participants with (PiB+) and without (PiB−) substantial amyloid burden. The third column displays regions with significantly greater functional correlations in the PiB− than in the PiB+ group. Regions displaying group differences included lateral parietal and medial prefrontal cortices, as well as bilateral regions within the hippocampal formation (family-wise error correction of p < 0.05 corresponding to p < 0.005 in conjunction with a cluster constraint k > 136).