Aβ-related hyperactivation in frontoparietal control regions in cognitively normal elderly

Abstract

The accumulation of amyloid-beta (Aβ) peptides, a pathologic hallmark of Alzheimer's disease, has been associated with functional alterations in cognitively normal elderly, most often in the context of episodic memory with a particular emphasis on the medial temporal lobes. The topography of Aβ deposition, however, highly overlaps with frontoparietal control (FPC) regions implicated in cognitive control/working memory. To examine Aβ-related functional alternations in the FPC regions during a working memory task, we imaged 42 young and 57 cognitively normal elderly using functional magnetic resonance imaging during a letter Sternberg task with varying load. Based on (18)F-florbetaben-positron emission tomography scan, we determined older subjects' amyloid positivity (Aβ+) status. Within brain regions commonly recruited by all subject groups during the delay period, age and Aβ deposition were independently associated with load-dependent frontoparietal hyperactivation, whereas additional compensatory Aβ-related hyperactivity was found beyond the FPC regions. The present results suggest that Aβ-related hyperactivation is not specific to the episodic memory system but occurs in the PFC regions as well.

Keywords: Aging; Amyloid PET; Amyloid-beta deposition; Frontoparietal control regions; Working memory; fMRI.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Age and Aβ deposition are associated with greater parametric increases in delay-period activation in a verbal WM brain network common across all subjects. Brain regions demonstrating activation and deactivation in relation to WM load (1, 3, or 6 letters) during a stimulus presentation (A), delay (B), and probe (C) phase of the letter Sternberg task. Warm colors indicate load-dependent increases in activation and cool colors indicate load-dependent decreases in activation (i.e., deactivation). Results are thresholded at p < 0.05, cluster corrected for multiple comparisons. Scales represent T values. L: Left hemisphere; R: Right hemisphere. Within each task phase, upper plots display mean contrast values of significant clusters showing load-related increases in activation (i.e., warm-colored regions in lateral and medial views of semi-inflated brain surfaces) for each group. Lower plots display mean contrast values of significant clusters showing load-related increases in deactivation (i.e., cool-colored regions in lateral and medial views of semi-inflated brain surfaces) for each group. For the probe phase, significant parametric changes occurred only in deactivation. Error bars represent s.e.m. * p<0.05; ** p<0.01

Figure 2

Voxel-wise comparisons between young and Aβ− older subjects and between Aβ+ and Aβ− older subjects in load-dependent delay activity slope within the frontoparietal control regions. Brain regions showing greater load-dependent activity slope for Aβ−O compared to young subjects and Aβ+ compared to Aβ − older subjects (yellow; p > 0.05, cluster size corrected for multiple comparisons) are overlaid on regions showing a common load-dependent parametric increase in the delay period activity across all groups (orange), which are shown in Figure 1B (warm colors).

Figure 3. Parametric activity increases for WM load relates to Aβ deposition as a continuous measure

(A) Warm colors indicate regions showing a positive relationship between load-related linear increases of activity and global SUVR. These regions mostly do not overlap with regions common across all subjects. Results are thresholded at p<0.05, cluster corrected for multiple comparisons. Scales represent T values. L: Left hemisphere; R: Right hemisphere. (B) Scatterplots visualize that greater parametric increases are positively related to the amount of amyloid deposition as measure by global SUVR. Contrast values of young subjects are displayed on the left for comparison purposes.