Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve

Abstract

Inverse correlations between amyloid-beta (Abeta) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [(18)F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local Abeta-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Abeta deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Abeta deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Abeta deposition or increasing the level of Abeta necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Abeta deposition has been present for longer periods of time does Abeta become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Figure 1.

Correlation matrices for controls, MCI, and AD. Positive correlations are shown in red and negative correlations are shown in blue. The scale shows the FDR corrected values or uncorrected p values associated with each color. The numbers (1–24) at the left and the bottom are enlargements of the numbers on the rows and columns of the matrices (odd/white numbers for left-sided ROIs and even/black numbers for right-sided ROIs. Additional details about the organization of the matrices are described in the methods and results sections.

Figure 2.

Voxel-based correlations in AD and MCI. A, T values associated with negative correlations (blue) and positive correlations (red) in AD, between PiB retention in the bilateral/combined precuneus ROI and voxel-based measures of metabolism throughout the brain. Data are thresholded with FDR control at q = 0.1. B, T values associated with negative correlations (blue) and positive correlations (red) in AD, between FDG metabolism in the bilateral/combined precuneus ROI and voxel-based measures of PiB retention throughout the brain. Data are thresholded at an uncorrected p < 0.05. C, T values associated with negative correlations (blue) and positive correlations (red) in MCI, between PiB retention in the bilateral/combined precuneus ROI and voxel-based measures of metabolism throughout the brain. Data are thresholded at an uncorrected p < 0.05. D, T values associated with negative correlations (blue) and positive correlations (red) in MCI, between FDG metabolism in the bilateral/combined precuneus ROI and voxel-based measures of PiB retention throughout the brain. Data are thresholded with FDR control at q = 0.1.

Figure 3.

Group comparisons of PiB retention and glucose metabolism. A–D, PiB retention in bilateral, middle precuneus cortex (A, PCM) or bilateral, subgenual anterior cingulate cortex (B, SAC) and glucose metabolism in PCM (C) or SAC (D) in amyloid-negative controls (open squares), amyloid-positive controls (filled squares), MCI (filled circles), and AD (filled triangles). Significant differences of the amyloid-positive groups compared to the amyloid-negative controls are noted.

Figure 4.

A, Model of the combined effects of metabolism and Aβ load on cognition. At higher levels of metabolism, more Aβ is required for conversion from normal (white circles) to MCI (black circles) or from MCI to AD (gray circles). Also in this model, Aβ deposition results in decreased metabolism and, at high levels of Aβ, the rate of metabolic inhibition accelerates. B, The hypothetical data from A predicts that correlations between metabolism and Aβ load would be weak in controls (open triangles), strongly positive in MCI (closed circles), and moderately negative in AD (open squares).