Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment

Abstract

Background: Several positron emission tomography (PET) studies have explored the relationship between amyloid-␤ (A␤), glucose metabolism, and the APOE 4 genotype. It has been reported that APOE 4, and not aggregated A␤, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer's disease (AD) pathology. Objective: We hypothesize that typical measurements of A␤ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of A␤ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI). Methods: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the crosscorrelation structure between glucose metabolism, as measured by [ 18 F]2-fluoro-2-deoxyglucose (FDG) PET, and A␤, as measured by [ 18 F]florbetapir PET, from the Alzheimer's Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of A␤. Results: From an older population of CN and MCI subjects, we found that the SVD-based A␤ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding A␤ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of A␤ deposition. Conclusions: Our approach uncovered hidden patterns of the glucose metabolism-A␤ relationship. We showed that the SVD-based A␤ score produces a stronger relationship with decreasing glucose metabolism than either APOE 4 genotype or global measures of A␤ burden.

Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

“…This finding is largely consistent with existing literature, where this relationship is more often found in asymptomatic rather than symptomatic individuals. 30,31,46 Previous studies that have observed this relationship in clinical cohorts did not include tau-PET and either included amyloid-negative individuals or a distinction between APOE ε4 heterozygotes and homozygotes. 47,48 Additionally, the APOE ε4-associated decrease in glucose metabolism in Alzheimer’s disease-associated regions observed in clinically normal cohorts is small compared to metabolic decreases due to clinical neurodegeneration.…”

“…18,23,24 Tau-PET patterns consistently overlap with decreased FDG-PET in preclinical and clinical populations. 4,22,[25][26][27] Some studies have demonstrated a local correlation between amyloid-PET and FDG-PET as well, [28][29][30] but others have found no such association. 5,[31][32][33][34][35] Second, regional hypometabolism can be related to abnormalities occurring in distant regions.…”

“…[42][43][44][45][46] In symptomatic stages of Alzheimer's disease, findings are more conflicting with some studies suggesting that APOE ε4 is associated with a greater decrease in metabolism in Alzheimer's disease regions, 47,48 while others find no such association. 30,31,49 Previous findings about determinants of Alzheimer's disease-related hypometabolism may be discrepant due to small samples, the inclusion of amyloid-positive and amyloid-negative patients, or the inclusion of both impaired and unimpaired participants. The present study investigates these potential determinants in two independent samples of amyloid-positive, clinically impaired patients (total N = 232) to understand their relative contributions to hypometabolism in Alzheimer's disease.…”

“…42–46 In symptomatic stages of Alzheimer’s disease, findings are more conflicting with some studies suggesting that APOE ε4 is associated with a greater decrease in metabolism in Alzheimer’s disease regions, 47,48 while others find no such association. 30,31,49…”

Integrated Transcriptomic and Neuroimaging Brain Model Decodes Biological Mechanisms in Aging and Alzheimer’s Disease

“…For each group (i.e. HC or AD), SVD identified a few pairs of “principal components” that maximize the cross-correlation between the two sets of variables (Carbonell et al, 2020; Worsley et al, 2005). Then it mapped the gene-imaging parameters onto the obtained principal components (PC).…”