McNicoll, C. | bioRxiv Science

bioRxiv2024

Tau-related reduction of glucose metabolism in mild cognitive impairment occurs independently of APOE ε4 genotype and is gradually modulated by β amyloid

BackgroundPET imaging studies have shown that spatially distributed measurements of {beta}-amyloid are significantly correlated with glucose metabolism in Mild Cognitive Impairment (MCI) independently of the APOE {varepsilon}4 genotype. In contrast, the relationship between tau and glucose metabolism at different stages of Alzheimers Disease (AD) has not been fully understood. ObjectiveWe hypothesize that spatially distributed scores of tau PET are associated with an even stronger reduction of glucose metabolism, independent of the APOE {varepsilon}4 genotype and gradually modulated by {beta}-amyloid. MethodsWe applied a cross-sectional statistical analysis to concurrent [18F]flortaucipir PET, [18F]florbetapir PET, and 2-[18F]fluoro-2-deoxyglucose (FDG) PET images from the Alzheimers Disease Neuroimaging Initiative (ADNI) study. We employed a Singular Value Decomposition (SVD) approach to the cross-correlation matrix between tau and the FDG images, as well as between tau and {beta}-amyloid PET images. The resulting SVD-based tau scores are associated with cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of tau, accounting for the effect of spatially distributed {beta}-amyloid. ResultsFrom a population of MCI subjects, we found that the SVD-based tau scores had their maximal spatial representation within the entorhinal cortex and the lateral inferior temporal gyrus, and were significantly correlated with glucose metabolism in several cortical regions, independently from the confounding effect of the {beta}-amyloid scores and APOE {varepsilon}4. Moreover, {beta}-amyloid gradually modulated the association between tau and glucose metabolism. ConclusionsOur approach uncovered spatially distributed patterns of the tau-glucose metabolism relationship after accounting for the {beta}-amyloid effects. We showed that the SVD-based tau scores have a strong relationship with decreasing glucose metabolism. By highlighting the more significant role of tau, rather than {beta}-amyloid, on the reduction of glucose metabolism, our results could have important consequences in the therapeutic treatment of AD.

neuroscience↗

bioRxiv2023

Spatial association between distributed β-amyloid and tau varies with cognition

Several PET studies have explored the relationship between {beta}-amyloid load and tau uptake at the early stages of Alzheimers disease (AD) progression. Most of these studies have focused on the linear relationship between {beta}-amyloid and tau at the local level and their synergistic effect on different AD biomarkers. We hypothesize that patterns of spatial association between {beta}-amyloid and tau might be uncovered using alternative association metrics that account for linear as well as more complex, possible nonlinear dependencies. In the present study, we propose a new Canonical Distance Correlation Analysis (CDCA) to generate distinctive spatial patterns of the cross-correlation structure between tau, as measured by [18F]flortaucipir PET, and {beta}-amyloid, as measured by [18F]florbetapir PET, from the Alzheimers Disease Neuroimaging Initiative (ADNI) study. We found that the CDCA-based {beta}-amyloid scores were not only maximally distance-correlated to tau in cognitively normal (CN) controls and mild cognitive impairment (MCI), but also differentiated between low and high levels of {beta}-amyloid uptake. The most distinctive spatial association pattern was characterized by a spread of {beta}-amyloid covering large areas of the cortex and localized tau in the entorhinal cortex. More importantly, this spatial dependency varies according to cognition, which cannot be explained by the uptake differences in {beta}-amyloid or tau between CN and MCI subjects. Hence, the CDCA-based scores might be more accurate than the amyloid or tau SUVR for the enrollment in clinical trials of those individuals on the path of cognitive deterioration.

neuroscience↗