Synaptic vesicle protein SV2A imaging with [11C]UCB‐J as a novel biomarker of neurodegeneration in Alzheimer's disease

Abstract

AbstractBackgroundSynaptic loss is a known feature of symptomatic Alzheimer’s disease (AD). Conversely, abundance of synapses may confer resilience to cognitive decline in the presence of AD pathology. Currently, the extent and distribution of synapse loss during the asymptomatic stages of AD is unknown. Synaptic vesicle glycoprotein 2A (SV2A) is found on synaptic vesicles and recent developments in PET imaging provide the capability of assessing SV2A in vivo. [C‐11]UCB‐J is a high‐affinity ligand for SV2A currently being tested as a biomarker of neurodegeneration in AD. In this project, we are testing the extent to which loss of synaptic density tracks with cognitive decline, as well as determining the temporal course of synaptic loss in relation to development of regional amyloid and tau pathology, particularly in the asymptomatic phase of AD.MethodApproximately 120 participants from the Wisconsin Alzheimer’s Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer’s Prevention study will be imaged in this study. Participants include cognitively unimpaired biomarker negative, unimpaired biomarker positive, mild cognitive impairment (MCI), and dementia due to AD. Amyloid (A) and tau (T) status are determined via [C‐11]PiB and [F‐18]MK6240 PET imaging, while synaptic density is determined with [C‐11]UCB‐J.ResultEarly results indicate lower synapse density in AD dementia and among A+T+ even in the asymptomatic phase of AD (Figure). However, participants with dementia show greater regional loss of synapses compared to cognitively unimpaired A+T+.ConclusionOngoing analyses will test the extent to which severity of amyloid and tau accumulation are associated with synapse loss, and whether synaptic abundance is a correlate of preserved cognition in the context of lesion burden. Imaging with [C‐11]UCB‐J may provide improved prognostic precision in the context of AD.