Synaptic density is associated with cognitive performance in Alzheimer’s disease: A PET imaging study with [11C]UCB‐J.

Background: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer’s disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy in limited brain regions, largely at the moderate to severe stages of disease. With the recent advent of synaptic positron emission tomography (PET) imaging, we have begun to evaluate synaptic alterations in vivo. In this study we examined the relationship between synaptic density and cognitive performance in early AD using [11C]UCB‐J PET and an extensive neuropsychological test battery. Method: Using [11C]UCB‐J binding to SV2A, synaptic density was measured in 45 amyloid positive participants with AD (17 amnestic mild cognitive impairment and 28 mild dementia) and 20 amyloid negative cognitively normal (CN) participants aged 50‐85 years. Synaptic density was calculated as the distribution volume ratio (DVR) in a composite region of interest (ROI) of AD‐affected regions (prefrontal, lateral temporal, medial temporal, lateral parietal, anterior cingulate, posterior cingulate, precuneus, and lateral occipital) using cerebellum as reference region. A neuropsychological test battery assessed performance in five cognitive domains. Domain scores were generated for each AD participant by averaging z‐scores within the domain, and global cognitive scores averaged the domain scores. Result: In a multiple linear regression model controlling for age, sex, and education, synaptic density ([11C]UCB‐J DVR) was a significant predictor of global cognitive performance in participants with AD (β=3.21, η2=0.29, P=0.0001; Figure 1A), as well as Verbal Memory (P=0.022; Figure 1B), Language (P=0.001; Figure 1C), Executive Function (P=0.001; Figure 1D), Processing Speed (P=0.001; Figure 1E), and Visuospatial Ability (P=0.001; Figure 1F). The association between synaptic density and global cognition survived partial volume correction (PVC; β=2.16, η2=0.23, P=0.001), and synaptic density was a stronger predictor of cognitive performance than gray matter volume. Figure 2 shows correlation maps of global cognitive performance with regional synaptic density (DVR; without and with PVC) and gray matter volume. Conclusion: These results confirm neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD. [ABSTRACT FROM AUTHOR]