Amyloid deposition is associated with impaired default network function in older persons without dementia

Abstract

Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Figure 1

A. Distribution volume ratio (DVR) maps of 11-C PiB activity in representative subjects from the study. Color scale from blue = low (1.0 DVR) to red = very high (3.0 DVR) levels of PiB retention. Shown on the Left is a 76 year old cognitively normal woman (CDR rating of 0) showing no evidence of specific cortical PiB retention (PiB-); Middle is a 75 year old woman, also cognitively normal (CDR 0) demonstrating elevated PiB retention in several regions of heteromodal cortices, especially precuneus/posterior cingulate (PPC) regions; Right is a 77 year old man, diagnosed with mild AD (CDR 1) demonstrating high levels of PiB retention in multiple cortical areas. B. Scatterplot of the anatomically defined PPC DVR values for the CDR 0 (n=22) and CDR 0.5 (n=13) groups compared to a group of AD patients (all CDR 1.0) imaged in a previous study (Johnson et al., 2007). Dots shown in red represent the CDR 0 and CDR 0.5 subjects who were classified as PiB+, based on a cut-off of PPC DVR >1.6, the lower end of PPC DVR values in the AD patients.

Figure 2

A. Anatomic distribution of PiB retention for the group-wise comparison of PiB+ (n=13) > PiB- (n=22) older subjects thresholded at p<0.001 FWE corrected for multiple comparisons. B-D. SPM2 one-sample t-test of young subjects (B), PiB- older subjects (C), and PiB+ older subjects (D) demonstrating significant task-related decreases in fMRI activity (deactivation shown in blue) during successful encoding of face-name pairs (Fixation > high confidence correct “hit” (HCH) responses based on subsequent memory testing).

Figure 3

Whole brain map demonstrating the intersection between the PiB+ > PiB- maps for PiB DVR (shown in red); the PiB+ > PiB- fMRI default activity (shown in blue) and overlap (shown in yellow) with peak region in the PPC (MNI coordinates -6, -57, 36).

Figure 4

A. Regression plot demonstrating significant correlation between PiB DVR values and fMRI activity extracted from the precuneus/posterior cingulate ROI (R= .46; p=0.006). B. Bar graph showing the fMRI response in ROI from divided by CDR and PiB status, demonstrating a main effect of PiB but not of CDR status. PiB+ CDR 0 subjects demonstrated significantly higher fMRI activity than PiB- CDR 0 subjects (p=0.003). C. Bar graph of fMRI response extracted from control region in the calcarine cortex did not reveal any relationship with PPC amyloid levels.

Figure 5

A. Bar graph of the NC vs. AD fMRI response in precuneus/posterior cingulate region (MNI coordinates 0, -75, 33). (Note that these are subjects from previously published studies: Celone 2006; Pihlajamaki 2008) B. fMRI activity extracted from same ROI comparing Young subjects (blue), PiB- Older Subjects (green) and PiB+ Older Subjects (red) from the current study, with PiB+ subjects demonstrating similar pattern of aberrant default activity to that seen in AD patients. C. MR Signal timecourse in PPC ROI demonstrating deactivation in young subjects, minimal deactivation in PiB- older subjects, and reversal of default activity (paradoxical activation) in PiB+ older subjects.

Figure 6

A. Whole brain exploratory analysis of PPC PiB DVR and fMRI activity across all 35 older subjects demonstrating significant positive correlations in multiple regions in the default network, as well as regions which activated during memory encoding. B. Regression of PiB and fMRI response from hippocampal ROI (circled region in 6A; R=.44; p<0.01) C. ANOVA of PiB and CDR groups demonstrated a significant effect on PiB on hippocampal activity only among the CDR 0.5 group (p<0.05).