Impact of framing scheme optimization and smoking status on binding potential analysis in dynamic PET with [(11)C]ABP688

BACKGROUND: For positron emission tomography (PET) ligands, such as [(11)C]ABP688, to be able to provide more evidence about the glutamatergic hypothesis in schizophrenia (SZ), quantification bias during dynamic PET studies and its propagation into the estimated values of non-displaceable binding potential (BP(ND)) must be addressed. This would enable more accurate quantification during bolus + infusion (BI) neuroreceptor studies and further our understanding of neurological diseases. Previous studies have shown BP(ND)-related biases can often occur due to overestimated cerebellum activity (reference region). This work investigates whether an alternative framing scheme can minimize quantification biases propagated into BP(ND), whether confounders, such as smoking status, need to be controlled for during the study, and what the consequences for the data interpretation following analysis are. A group of healthy controls (HC) and a group of SZ patients (balanced and unbalanced number of smokers) were investigated with [(11)C]ABP688 and a BI protocol. Possible differences in BP(ND) quantification as a function of smoking status were tested with constant 5 min (‘Const 5 min’) and constant true counts (‘Const Trues’) framing schemes. In order to find biomarkers for SZ, the differences in smoking effects were compared between groups. The normalized BP(ND) and the balanced number of smokers and non-smokers for both framing schemes were evaluated. RESULTS: When applying F-tests to the ‘Const 5 min’ framing scheme, effect sizes (η(2)p) and brain regions which showed significant effects fluctuated considerably with F = 50.106 ± 54.948 (9.389 to 112.607), P-values 0.005 to < 0.001 and η(2)p = 0.514 ± 0.282 (0.238 to 0.801). Conversely, when the ‘Const Trues’ framing scheme was applied, the results showed much smaller fluctuations with F = 78.038 ± 8.975 (86.450 to 68.590), P < 0.001 for all conditions and η(2)p = 0.730 ± 0.017 (0.742 to 0.710), and regions with significant effects were more robustly reproduced. Further, differences, which would indicate false positive identifications between HC and SZ groups in five brain regions when using the ‘Const 5 min’ framing scheme, were not observed with the ‘Const Trues’ framing. CONCLUSIONS: Based on an [(11)C]ABP688 PET study in SZ patients, the results show that non-consistent BP(ND) outcomes can be propagated by the framing scheme and that potential bias can be minimized using ‘Const Trues’ framing.