Amyloid burden and neural function in people at risk for Alzheimer's Disease

Abstract

To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimer's Disease (AD), we used multimodal imaging with [C-11]Pittsburgh compound B positron emission tomography, [F-18]fluorodeoxyglucose, positron emission tomography , and magnetic resonance imaging, together with cognitive measurement in 201 subjects (mean age, 60.1 years; range, 46-73 years) from the Wisconsin Registry for Alzheimer's Prevention. Using a qualitative rating, 18% of the samples were strongly positive Beta-amyloid (Aβ+), 41% indeterminate (Aβi), and 41% negative (Aβ-). Aβ+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aβ- group, Aβ+ and Aβi participants had increased glucose metabolism in the bilateral thalamus; Aβ+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aβ+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aβ- group, and no areas of significant atrophy. Cognitive performance and self report cognitive and affective symptoms did not differ between groups. Amyloid burden can be identified in adults at a mean age of 60 years and is accompanied by glucometabolic increases in specific areas, but not atrophy or cognitive loss. This asymptomatic stage may be an opportune window for intervention to prevent progression to symptomatic AD.

Keywords: AD risk; Alzheimer's disease; Amyloid imaging; Cognitive function; Glucose metabolism.

Fig. 1

Example Pittsburgh compound B (PiB) scans that were classified according to the rating system explained in the Methods. Shown are 6 participants who were classified as PiB Aβ-positive (A–B), indeterminate (C–D), and negative (EβF). All images are [C-11]PiB distribution volume ratio (DVR) maps and are displayed here using the ACTC color lookup table and scaled uniformly from 0.0 to 2.0 according to the inset color bar. The ages of these participants are 62, 54, 53, 67, 64, and 62 years, respectively, from top to bottom. Abbreviations: DVR, distribution volume ratio; PiB, Pittsburgh compound B.

Fig. 2

Spatial location of amyloid positivity in subjects rated as beta-amyloid intermediate (Aβi) and beta-amyloid positive (Aβ+) versus subjects rated as beta-amyloid negative (Aβ–). Top row: Left lateral and medial renderings with color overlay of the statistical map where the Aβi group has more amyloid load than the Aβ– group. Bottom row: Left lateral and medial views where the Aβ+ group exhibited significantly more amyloid load than the Aβ– group. Color bar represents the value of the t-statistic. The minimum t value in these maps is t = 5.0 which exceeds the voxel-level family wise error correction threshold. Abbreviations: Aβi, beta-amyloid intermediate; Aβ–, beta-amyloid negative; Aβ+, beta-amyloid positive.

Fig. 3

Scatter plot of age by amyloid burden in selected regions of interest including (A) the posterior cingulate (MNI coordinate –6, –54, 30) and (B) left lateral temporal cortex (–60, –60, 0). Transformed Pittsburgh compound B (PiB) region of interest (ROI) distributions were also computed and plotted in C and D on age together with the least squares regression line. Amyloid group classifications of Aβ– (red), Aβi (green) and Aβ+ (blue) are shown for reference. Abbreviations: PiB, Pittsburgh compound B; ROI, region of interest.

Fig. 4

Fluorodeoxyglucose (FDG) group differences: regions where the Aβ+ (red) and Aβi (green) groups exhibited significantly higher FDG uptake compared with the Aβ– group. Areas in yellow depict overlapping results. There were no regions where the Aβ+ and Aβi groups had significantly less uptake compared with the Aβ– group. The result maps are displayed on axial slices of a template image from inferior to superior at MNI z-coordinates: –7, –2, 3, 8, and 32. A mid-sagittal reference image is also shown depicting the elevations of the axial slices. Left is on left. Abbreviation: FDG, fluorodeoxyglucose.