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Background Synaptic density PET is an emerging technology with potential as a biomarker for tracking disease progression and therapeutic efficacy in studies of Alzheimer's disease (AD). Simplified methods of image acquisition and quantification would facilitate the use of synaptic density imaging in multicenter longitudinal studies. Therefore, we validated a simplified tissue‐to‐reference ratio method using standardized uptake value ratios (SUVR) for estimating synaptic density using [11C]UCB‐J PET. Method [11C]UCB‐J binding was measured in 31 participants with early AD and 16 cognitively normal (CN) participants aged 55‐85 years. All participants underwent 90 minute dynamic PET scans on the HRRT after bolus injection of [11C]UCB‐J. Parametric images of binding potential (BPND ) were generated using SRTM2 (0‐60 minutes) with a centrum semiovale reference region and converted to distribution volume ratios (DVR) with a cerebellum reference region. Parametric images of SUVR were generated by summing frames from 30‐60 or 60‐90 minutes and normalizing to the cerebellum. Regional group differences were assessed using unpaired t tests and Cohen’s d, while associations between DVR and SUVR were assessed using Pearson’s correlation. Result Widespread reductions in cortical and subcortical synaptic density were observed in AD (vs. CN) participants using measures of DVR, SUVR30‐60min , and SUVR60‐90min . In the entire sample, stronger regional correlations between measures of DVR and SUVR60‐90min (r=0.97, p<0.00001) were observed compared to DVR and SUVR30‐60min (r=0.91, p<0.00001; Figure 1). The correlation between DVR and SUVR60‐90min was also stronger for within‐group correlations (DVR vs. SUVR60‐90min r CN =0.97, r AD =0.97; DVR vs. SUVR30‐60min r CN =0.90, r AD =0.91). The within‐region correlation between measures of DVR and SUVR60‐90min ranged from 0.77 to 0.97 (p<0.00001) in the entire sample. Effect sizes to determine group differences in SV2A binding across all regions were highly correlated between both DVR and SUVR60‐90min (r=0.93, p<0.00001) and DVR and SUVR30‐60min (r=0.93, p<0.00001; Figure 2). Conclusion A simplified method of quantifying synaptic density with SUVR using a shortened (60‐90 minute) scan window and cerebellum reference region is highly correlated with measures of DVR generated with SRTM2 kinetic modeling. This simplified tissue‐to‐reference ratio methodology may be of practical use for multicenter and longitudinal studies seeking to measure synaptic density in AD.

Previous data point to neutral outcomes (draws) being subjectively assigned negative rather than positive value. The combined observations of faster rather than slower reaction times, subsequent actions defined by shift rather than stay behaviour, reduced flexibility, and, larger rather than smaller deviations from optimal performance all align with consequences of explicitly negative outcomes such as losses. We further tested the negative interpretation of draws via a value manipulation by assigning draws in a zero-sum game to +1, 0 or -1. If draws are inherently negative then the difference in behavioural profile comparisons should be greater when draw values are changed to a positive (+1) rather than negative (-1) value. Despite the observations of post-draw speeding and bias towards draw-shift behaviour, the degree of shift behaviour was equivalent between draw values of 0 and +1 and approached an approximation of optimal mixed-strategy performance. This was in contrast to draw values of -1 significantly increasing the degree of shift behaviour. This modification of draw behaviour was weaker when the same value modifications were applied to win or lose trials. Rather than viewing draws as neutral and valence-free outcomes, the processing cascade generated by stalemate produces a complex behavioural profile containing elements found in response to both explicitly positive and explicitly negative results.

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