Association of synaptic density and glucose metabolism with cognitive performance in early Alzheimer's disease: a PET imaging study with [11C]UCB‐J and [18F]FDG

Abstract

AbstractBackgroundTraditionally, [18F]FDG PET has been used in Alzheimer’s disease (AD) as a surrogate marker of disease progression and is highly correlated with cognitive and functional decline. Synaptic loss is an early pathological event and a major structural correlate with cognitive impairment, although this is based on limited post‐mortem studies at more severe disease stages. Recently, we have confirmed these neuropathologic studies in vivo, using [11C]UBC‐J PET to demonstrate significant correlations between synaptic density and cognitive performance in early AD. In this study, we examined the relationship between synaptic density, glucose metabolism, and cognitive performance in early AD using [11C]UCB‐J PET, [18F]FDG PET, and an extensive neuropsychological battery.Method[11C]UCB‐J and [18F]FDG binding was measured in 46 amyloid+ participants with AD (18 aMCI and 28 mild dementia) and 17 amyloid‐ cognitively normal participants aged 50‐85 years. Synaptic density was calculated as DVR and glucose metabolism as SUVR in a composite of AD‐affected regions, using a whole cerebellum reference region for both tracers. A validated neuropsychological battery assessed performance across six cognitive domains. Domain scores were calculated for each participant by averaging z‐scores within that domain, and global cognition scores averaged the domain scores.ResultIn a multiple linear regression model controlling for age, sex, and education, glucose metabolism was a stronger predictor of global cognitive performance compared to synaptic density in participants with AD (beta=2.90,eta2=0.38,P=0.000005 vs. beta=2.48,eta2=0.22,P=0.001), as well as executive function, language, processing speed, visual memory, and visuospatial ability. Synaptic density was a stronger predictor of verbal memory compared to glucose metabolism (beta=1.68,eta2=0.22,P=0.001 vs. beta=1.02,eta2=0.10,P=0.03). Using William’s tests, exploratory analyses demonstrated stronger correlations between medial temporal synaptic density and performance across all cognitive domains. In neocortical ROIs, glucose metabolism was more strongly correlated with cognitive performance across all domains with the exception of verbal memory, which demonstrated stronger correlations with synaptic density across all analyzed ROIs.ConclusionConsistent with a hypothesis of divergent synaptic loss and hypometabolism in early AD, these results demonstrate synaptic density is more strongly correlated with cognitive decline in medial temporal regions, while cerebral hypometabolism is more strongly correlated with cognitive decline in neocortical regions.