Region-specific hierarchy between atrophy, hypometabolism, and β-amyloid (Aβ) load in Alzheimer's disease dementia

Abstract

Gray matter atrophy, glucose hypometabolism, and β-amyloid Aβ deposition are well-described hallmarks of Alzheimer's disease, but their relationships are poorly understood. The present study aims to compare the local levels of these three alterations in humans with Alzheimer's disease. Structural magnetic resonance imaging, (18)F-fluorodeoxyglucose positron emission tomography (PET), and (18)F-florbetapir PET data from 34 amyloid-negative healthy controls and 20 demented patients with a high probability of Alzheimer's disease etiology (attested using neuroimaging biomarkers as recently recommended) were analyzed. For each patient and imaging modality, age-adjusted Z-score maps were computed, and direct between-modality voxelwise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism, and Aβ deposition were found in most brain areas, but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: (1) in the hippocampus, atrophy exceeded hypometabolism, whereas Aβ load was minimal; (2) in posterior association areas, Aβ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; and (3) in frontal regions, Aβ deposition was maximal, whereas structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex, whereas Aβ load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between Aβ load, hypometabolism, and atrophy. Altogether, these variations probably reflect the differential involvement of region-specific pathological or protective mechanisms, such as the presence of neurofibrillary tangles, disconnection, as well as compensation processes.

Figure 1.

Illustration of the different steps required to create W-score maps using the SPM software. This figure shows the procedure for the atrophy W-score map of a 65-year-old patient with Alzheimer's disease compared with six healthy controls (HC) for the sake of illustration. First, a simple linear regression was performed in the HC group to estimate age-related changes (1a), resulting in several files: the β1 map containing voxelwise age-related regression coefficients, the β2 map containing intercept values, and the individual maps of residuals. The SD of residuals was computed voxelwise (1b). A W-score map was then created using the corresponding formula and previously computed maps using the SPM “ImCalc” function (2a). Last, for MRI and FDG–PET data, W values were reversed so that positive numbers represent pathological features in all three imaging modalities (2b).

Figure 2.

Brain patterns of alteration in the 20 patients with Alzheimer's disease dementia. For each imaging modality, local degrees of alteration are expressed as mean W-score compared with the control group (n = 34) in each gray matter voxel. Note that, for all imaging modalities, a positive W-score indicates a pathological feature. Colors have been scaled to the range of each modality to fit to the regional distribution of each process. For clarity, only the left hemisphere is represented here, because results were mainly symmetrical.

Figure 3.

Voxelwise comparisons between the local degrees of atrophy, hypometabolism, and Aβ deposition in the 20 patients with Alzheimer's disease dementia. The t value of 5.2 used as a threshold in this figure corresponds to the p (FWE corrected) < 0.05 threshold described in Results.

Figure 4.

Voxelwise correlations between local degrees of atrophy and hypometabolism in the 20 patients with Alzheimer's disease dementia. The R value of 0.89 used as a threshold in this figure corresponds to the p (FWE corrected) < 0.05 threshold described in Results.

Figure 5.

Regions of interest analyses. Local degrees of atrophy (orange), hypometabolism (green), and Aβ deposition (blue) expressed as mean W-scores were compared using Friedman's ANOVA. When significant (p < 0.05), post hoc analyses were performed using Wilcoxon's test (*p < 0.05; **p < 0.005; ***p < 0.0001). Histograms represent median values, and error bars refer to the interquartile range. Regions presented here are ordered by increasing amyloid W-score. post. cingulate, Posterior cingulate cortex; PFC, prefrontal cortex.

Figure 6.

Classification of brain regions according to their degrees of atrophy, hypometabolism, and Aβ deposition. Left, Ward's hierarchical clustering analysis performed on the regions of interest distinguished four subsets of brain areas according to their three mean W-scores. Right, For each subset, degrees of atrophy (orange), hypometabolism (green), and Aβ load (blue) were averaged and compared using Friedman's ANOVA and Wilcoxon's test (*p < 0.05; **p < 0.005; ***p < 0.0001). Histograms represent median values, and error bars refer to the interquartile range. post. cingulate, Posterior cingulate cortex; PFC, prefrontal cortex.