Regional brain hypometabolism is unrelated to regional amyloid plaque burden

Abstract

In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism.

Keywords: Alzheimer’s disease; amyloid imaging; glucose metabolism; positron emission tomography.

See Sorg and Grothe (doi:10.1093/brain/awv302) for a scientific commentary on this article. Early studies reported inconsistencies between amyloid plaque location and regional dysfunction implied by clinical course. Recent PET studies, however, highlight the overlap between amyloid deposition and regions affected early in Alzheimer’s disease. Altmann et al. report that regional hypometabolism is in fact related to cortex-wide rather than regional plaque burden.

Figure 1

Regions of interest and effects of diagnosis on imaging modalities. The 404 regions of interest used in the analysis (A), regions of interest with reduced grey matter in MCIs are shown in cyan (B); regions of interest with hypometabolism in MCI are shown in blue (C); regions of interest with increased amyloid plaque deposition in MCI are shown in red and yellow (D). All slices are in neurological convention (left side of the image corresponds to the left side of the brain).

Figure 2

Regional hypometabolism correlates of global amyloid biomarkers. Regions of interest showing significant reduction in glucose metabolism with increases in cortex-wide amyloid burden (A) or with decreases in CSF amyloid-β (B).

Figure 3

Regional metabolism correlates of regional amyloid plaque deposition. Regions of interest with significant positive association are shown in yellow (increased metabolism with increased amyloid plaque deposition) and regions of interest with significant negative association are shown in blue (decreased metabolism with increased amyloid plaque deposition). The figure displays axial and coronal slices for three sets of results: regions of interest that exhibit a significant association between regional amyloid burden and glucose metabolism after correcting for diagnosis association (DX), sex, age, education and regional grey matter (A); the same as before but additionally corrected for global amyloid burden (B); results from (A) that survived the permutation test for local specificity (C).

Figure 4

Number of significant negative associations in relation to global amyloid level. Bottom: Median of the global amyloid level for all 58 groupings of 100 subjects and the resulting number of regions of interest with significant negative association between regional amyloid deposition and regional metabolism. A fitted spline with 4 df is shown in blue. The grey vertical line depicts the threshold for amyloid positive scans. The axial slices on top show the pattern of negative associated regions of interest for three groupings: low global amyloid (blue), half amyloid positive and half amyloid negative (red) and high global amyloid (yellow). The groupings are highlighted in the graph below with the same colour code. Overlaps between red and blue are shown in violet.