Does glucose metabolism dissociate from tau deposition in Alzheimer’s disease?

Abstract

AbstractBackgroundAlzheimer’s disease progression is characterised by accumulation of tau and reductions in cerebral glucose metabolism. However, the spread of tau could be influenced by the presence of amyloid, while changes in cerebral glucose metabolism could be influenced by microglial activation, atrophy, synaptic dysfunction, along with oxidative stress and inflammation. Hence, the association between these biomarkers at a global cortical level remains unclear. Here we sought the establish the global cortical relationship in a novel single subject design.Method380 subjects were recruited from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu) (Table 1). Amyloid status (Aβ+/Aβ‐ ve) and T1‐weghted MRI scans were obtained for all participants. Dynamic PET scans were processed with SPM12 and standard uptake value ratio (SUVR) images were created. Cerebellum grey matter and pons were selected as reference region for [18F]AV1451 and [18F]FDG respectively. Each cognitively impaired SUVR image was compared against the healthy control group using Statistical Parametric Mapping software. We extracted the total number of voxels with increases of [18F]AV1451 and decreases of [18F]FDG compared to the controls; termed ‘global cortical tau load’ and ‘global hypometabolism’ for subsequent analysis.ResultIn this sample of 240 cognitively impaired subjects, in Aβ+ve AD subjects, there was no correlation between global cortical tau load and global hypometabolism. Interestingly, there was minimal correlation in Aβ+ve MCI subjects between global cortical tau and global hypometabolism (r=0.209, p=0.042). There were no significant correlations between global cortical tau load and global hypometabolism in Aβ‐ve cognitively impaired subjects.ConclusionGlucose hypometabolism and tau deposition dissociate at a global level in AD subjects; while in early stages there may be minimal association between these two processes. The dissociation between glucose metabolism and tau deposition in the later stages of AD trajectory suggests that other pathological features including microglial activation, inflammation, and oxidative stress all influence the metabolic decline in AD, perhaps explaining our apparent lack of association later in disease progression. As such, we argue changes in glucose metabolism and tau deposition have distinct trajectories in the context of Alzheimer’s disease and future clinical trials should consider separate evaluation.