Running head : SV 2-PET imaging in Alzheimer ’ s disease In vivo imaging of synaptic loss in Alzheimer ’ s disease with [ 18 F ] UCBH Positron Emission Tomography

Purpose: Loss of brain synapses is an early pathological feature of Alzheimer’s disease. The current study assessed synaptic loss in vivo with Positron Emission Tomography and an 18Flabelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. Methods: Twenty-four patients with Mild Cognitive Impairment or Alzheimer’s disease and positive [18F]Flutemetamol amyloid-PET were compared to nineteen healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an imagederived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. Results: A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients’ cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). Conclusions: The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer’s disease and to relate them to patients’ cognitive impairment.