Prediction of cognitive and metabolic changes after acute antidopaminergic treatment measured by FDOPA PET

Abstract

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Objectives: In previous PET studies the net influx of 6-[18F]-fluorodopa (FDOPA) correlated with cognitive performance in normal subjects. Furthermore, acute D2-antagonistic treatment elevated the FDOPA net influx by autoreceptor regulation. Using now an improved method of graphical analysis, diffusion of FDOPA metabolites can be unmasked and the total distribution volume of FDOPA and its acidic metabolites (VD) can be measured reflecting the dopamine storage capacity (Kumakura et al. 2005). The present study tested whether metabolic changes under acute antipsychotic treatment could predict changes in cognition. Methods: Nine healthy drug-free volunteers were scanned using FDOPA-PET. They performed cognitive tasks directly before the PET scans (TMT-A/B, Stroop, WCST, ds-CPT). They performed two scans, before and after three days of haloperidol treatment (5mg/day). The net blood-brain clearance of FDOPA (K) in striatum, the rate of diffusion of acidic metabolites from brain (kloss) and VD were calculated in striatal and extrastriatal regions. Results: K values showed an increase after haloperidol treatment similar to those previously observed using the conventional method of Martin et al. (1989). VD and kloss showed no significant changes after haloperidol treatment. However, the CPT performance was significantly and negatively correlated with the baseline K in the putamen and amygdala (NC: r = -678; P = 0.045 / amygdala: -0.862; P = 0.003). Furthermore, the change in kloss and the change in VD significantly correlated in NC with baseline K (kloss: r=+0.881; P=0.002; VD: -0.905; P<0.001). Conclusions: Under short treatment with a D2-like receptor antagonist low baseline net blood-brain FDOPA uptake (K) predicts an increase of dopamine storage capacity (VD) whereas high initial K values in principle led to decreased storage capacities. This is mainly caused by reciprocal changes in kloss. Furthermore a high baseline K predicts an impairment of CPT performance whereas low K values interestingly predict an improvement in CPT performance. These results help to understand the dopaminergic control of cognition.