Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum

Abstract

The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated β-amyloid, designated as "A+," and hippocampal volume and (18)fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration ("N+") at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1-6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway.

Keywords: Alzheimer's disease; FDG PET imaging; Longitudinal study; MR imaging; PIB PET imaging.

Figure 1. Baseline FDG SUVR and GM Volume

Group mean (SE) estimates at baseline for FDG SUVR (A) and GM volume (B) estimates with 95% confidence interval (CI) estimates (thin gray lines) and 83.5% CI estimates (thicker black lines) by biomarker group for primary ROIs: medial temporal, medial parietal, lateral temporal, and lateral parietal. The 83.5% CI allows for visual comparisons between groups where any amount of overlap indicates a lack of significance at the 0.05 level. Estimates are from a linear mixed model for a male participant age 80 years.

Figure 2. Annual Percent change in FDG SUVR and GM Volume

Group mean (SE) estimated annual percentage change for FDG SUVR (A) and GM volume (B) with 95% confidence interval (CI) (thin gray lines) and 83.5% CI (thicker black lines) by biomarker group for primary ROIs: medial temporal, medial parietal, lateral temporal and lateral parietal. The 83.5% CI allows for visual comparisons between groups where any amount of overlap indicates a lack of significance at the 0.05 level. Estimates are from a linear mixed model for a male participant age 80 years.

Figure 3. Trajectory over time, by group

Regression plots for the 4 primary ROIs showing trajectories of FDG SUVR (top panels) and grey matter (GM) (bottom panels) over time for biomarker defined groups for a hypothetical male 80 years of age. The x-axis is time from baseline. The time scale was limited to 2 years for illustrative purposes. See Figures 1 and 2 for confidence intervals of baseline values and slopes. Color coding: CN (orange), MCI (blue), AD Dementia (green); A+N+ (solid lines); A+N− (dashed lines).

Figure 4. Global PIB SUVR at Baseline and Annual Percent Change

Group mean (SE) estimates for global PIB PET estimates at baseline (left panel) and estimated annual percentage change (right panel) with 95% confidence interval (CI) estimates (thin gray lines) and 83.5% CI estimates (thicker black lines) by biomarker and clinical diagnostic group. The 83.5% CI allows for visual comparisons between groups where any amount of overlap indicates a lack of significance at the 0.05 level. Estimates are from a linear mixed model for a male participant age 80 years.