β-Amyloid Deposition Is Associated with Decreased Right Prefrontal Activation during Task Switching among Cognitively Normal Elderly

Abstract

The accumulation of β-amyloid (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD), has been associated with functional alterations, often in an episodic memory system with a particular emphasis on medial temporal lobe function. The topography of Aβ deposition, however, largely overlaps with frontoparietal control (FPC) regions implicated in cognitive control that has been shown to be impaired in early mild AD. To understand the neural mechanism underlying early changes in cognitive control with AD, we examined the impact of Aβ deposition on task-evoked FPC activation using functional magnetic resonance imaging (fMRI) in humans. Forty-three young and 62 cognitively normal older adults underwent an fMRI session during an executive contextual task in which task difficulty varied: single (either letter case or vowel/consonant judgment task) vs dual (switching between letter case and vowel/consonant decisions) task. Older subjects additionally completed (18)F-florbetaben positron emission tomography scans and were classified as either amyloid positive (Aβ+) or negative (Aβ-). Consistent with previous reports, age-related increases in brain activity were found in FPC regions commonly identified across groups. For both task conditions, Aβ-related increases in brain activity were found compared with baseline activity. For higher cognitive control load, however, Aβ+ elderly showed reduced task-switching activation in the right inferior frontal cortex. Our findings suggest that with Aβ deposition, brain activation in the cognitive control region reaches a maximum with lower control demand and decreases with higher control demand, which may underlie early impairment in cognitive control with AD progression.

Significance statement: The accumulation of β-amyloid (Aβ) peptides, a pathological hallmark of Alzheimer's disease, spatially overlaps with frontoparietal control (FPC) regions implicated in cognitive control, but the impact of Aβ deposition on FPC regions is largely unknown. Using functional magnetic resonance imaging with a task-switching task, we found Aβ-related increases in FPC regions compared with baseline activity. For higher cognitive control load, however, Aβ-related hypoactivity was found in the right inferior frontal cortex, a region highly implicated in cognitive control. The findings suggest that with Aβ deposition, task-related brain activity may reach a plateau early and undergo downstream pathways of neural dysfunction, which may relate to the early impairment of cognitive control seen in the progression of Aβ pathology.

Keywords: amyloid PET; cognitive control; cognitively normal older adults; fMRI; frontoparietal cortex; β-amyloid.

Figure 1.

fMRI task design and behavioral performance. A, A schematic diagram of single-task and dual-task conditions. The single-task condition was either a vowel/consonant judgment or a lower-case or upper-case judgment task, while the dual-task condition involved task switching between the two tasks. A green letter was associated with the vowel/consonant task (left press for vowel, right press for consonant); a red letter signaled lower/upper-case judgment (left press for lower case, right press for upper case); with white letters, no action was required. Each block started with instruction (4.7 s), and the time interval between the onsets of each letter trial was fixed at 2.4 s. For simplicity, the interstimulus interval blank screen and rest block were not shown in the figure. B, Behavioral data of RT and accuracy rate.

Figure 2.

Single-task and task-switching fMRI results by group. A, Brain activation during the single-task condition compared with baseline shows an age-related increase in task-positive regions, independent of Aβ deposition. Plots display mean contrast values of significant clusters showing task-related activation (i.e., warm-colored regions in the left panel) and deactivation (i.e., cool-colored regions in the left panel) for each group. B, Brain activation during the dual task compared with baseline shows an age-related increase in task-positive regions, independent of Aβ deposition. Plots display mean contrast values of significant clusters showing task-related activation (i.e., warm-colored regions in the left panel) and deactivation (i.e., cool-colored regions in the left panel) for each group. Brain activation maps are thresholded at p < 0.05, cluster corrected for multiple comparisons. Scales represent T values. L, Left hemisphere; R, right hemisphere. Error bars in the bar charts represent SEM. *p < 0.05; **p < 0.01.

Figure 3.

Aβ deposition is associated with increased brain activity in subregions that deactivate commonly across all subjects during the executive contextual task conditions. A, Aβ-related increases in brain activity for the single task compared with baseline. B, Aβ-related increases in brain activity for the dual task compared with baseline. These regions mostly overlap with task-related deactivation regions common across all subjects as shown in Figure 2A,B. The whole-brain voxelwise contrast maps between Aβ+ and Aβ− groups are thresholded at p < 0.05, cluster corrected for multiple comparisons. Scales represent T values. L, Left hemisphere; R, right hemisphere. Plots display mean contrast values of significant clusters showing Aβ-related increases in brain activation for each group. Contrast values of young subjects from the suprathreshold clusters are displayed for comparison purposes. Error bars in the bar charts represent SEM. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 4.

Age is associated with increased brain activity with higher cognitive control load compared with lower cognitive control load conditions. A, Brain regions demonstrating activation and deactivation in relation to higher cognitive control load commonly across all subject groups. Brain activation maps are thresholded at p < 0.05, cluster corrected for multiple comparisons. Scales represent T values. L, Left hemisphere; R, right hemisphere. B, Age is associated with greater increases with a higher cognitive control load in task-positive activation in the cognitive control regions common across all subjects. Plots display mean contrast values of significant clusters showing parametric increases with cognitive control load (i.e., yellow/red-colored regions in A; task-positive regions) and parametric decreases with cognitive control load (i.e., green/blue-colored regions in A; task-negative regions) for each group. Error bars represent SEM. *p < 0.05. C, Line charts represent mean contrast weights compared with baseline within cognitive control load-related task-positive and task-negative regions by cognitive control load condition and group. Red line: Dual-task, task-positive regions; orange line: single-task, task-positive regions; green line: dual-task, task-negative regions; blue line: single-task, task-negative regions.

Figure 5.

Aβ deposition is associated with decreased brain activity in the right prefrontal and insular cortices with higher cognitive control load compared with lower cognitive control load. A, Aβ-related decreases in brain activity for the dual-task compared with single-task conditions. These regions mostly overlap with task-related activation regions common across all subjects as shown in Figure 4A. The whole-brain voxelwise contrast maps between Aβ+ and Aβ− groups are thresholded at p < 0.05, cluster corrected for multiple comparisons. B, Plots display mean contrast values of significant clusters showing Aβ-related decreases in brain activation for each group. Contrast values of young subjects from the suprathreshold clusters are displayed for comparison purposes. Error bars in the bar charts represent SEM. **p < 0.01. C, Line charts represent mean contrast weights compared with baseline within regions showing Aβ-related decreases in brain activation by cognitive control load condition and group. Red line: Dual-task, task-positive regions; orange line: single-task, task-positive regions.