Synaptic density is associated with cognitive performance in early Alzheimer's disease: a PET imaging study with [11C]UCB-J

Introduction For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD; Terry, et al. 1991; DeKosky and Scheff. 1990). 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. Synaptic vesicle glycoprotein 2A (SV2A) is expressed in virtually all synapses and is located in synaptic vesicles at presynaptic terminals (Bajjalieh, et al. 1993). [11C]UCB-J was recently developed as a PET tracer for SV2A and advanced for human studies (Finnema, et al. 2016). In our recent study of [11C]UCB-J PET, we observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants (Mecca, et al. 2020). However, initial attempts using PET imaging to associate synaptic density with cognitive performance have been hindered by the use of limited cognitive measures. 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. Methods 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 was administered to assess performance in five cognitive domains: Verbal Memory (Logical Memory II, Rey Auditory Verbal Learning Test [RAVLT] total words recalled across trials 1-5, RAVLT delayed recall), Language (Boston Naming Test, Category Fluency), Executive Function (Stroop Color Word, Trails B, Letter Fluency), Processing Speed (Stroop Word, Trails A, WAIS-3 Digit Symbol Substitution), and Visuospatial Ability (Rey-Osterrieth Complex Figure, WAIS-3 Block Design, WAIS-3 Picture Completion). Neuropsychological test raw scores were converted to z-scores using the means and SDs from the pooled AD and CN sample), and cognitive domain scores were generated for each AD participant by averaging z-scores within the domain. Global cognitive scores were then generated for each participant by averaging the five domain scores. Results 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). Synaptic density was also a significant predictor of performance in all five cognitive domains: Verbal Memory (β=1.35, η2=0.11, P=0.022; Figure 1B), Language (β=3.82, η2=0.25, P=0.001; Figure 1C), Executive Function (β=3.28, η2=0.20, P=0.001; Figure 1D), Processing Speed (β=4.03, η2=0.23, P=0.001; Figure 1E), and Visuospatial Ability (β=3.58, η2=0.22, P=0.001; Figure 1F). The relatively weak association with verbal memory may have resulted from floor effects on the measures that comprised this domain. The observed associations between synaptic density and global cognition remained significant after correction for partial volume effects (β=2.16, η2=0.23, P=0.001), and synaptic density was a stronger predictor of cognitive performance than gray matter volume (β=0.01, η2=0.17, P=0.005). Conclusions These results confirm neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the mild and prodromal stages of AD. They further support the use of synaptic imaging as a potential surrogate biomarker outcome for therapeutic trials that is well-correlated with clinical measures. Longitudinal studies are needed to relate change in synaptic density as measured by [11C]UCB-J PET with change in cognitive performance. Funding R01-AG052560 [REC, CHvD], R01-AG062276 [CHvD], RF1-AG057553 [REC, CHvD], Dana Foundation [MKC]), P50-AG047270 [CHvD, MKC], P30-AG066508 [CHvD], K23-AG057784 [APM], R25-MH071584 (RSO), T32-MH019961 [RSO], and Thomas P. Detre Fellowship [RSO].