[18F]FDG functional PET revisited: A new perspective on the temporal dynamics of brain glucose metabolism.

[18F]FDG functional PET (fPET) enables investigation of dynamics in glucose metabolism occurring within seconds. However, the physiological mechanisms supporting rapid metabolic changes necessitate further attention to allow accurate interpretation. This work highlights candidate mechanisms driving [18F]FDG signal changes at high temporal resolution, offering complementary insights to existing interpretations. At rest, metabolic demands are closely matched by glucose supply across the blood-brain barrier (BBB), regulated by glucose transporter 1 (GLUT1). During neuronal activation, glucose transport and phosphorylation by hexokinase are elevated to meet increased energy requirements. Simulations indicate that rapid [18F]FDG signal increases are primarily driven by BBB transport, with subsequent increases in hexokinase activity. Mechanisms supporting increased BBB transport include elevated glucose concentration gradient towards the brain and changes in GLUT1 intrinsic properties, but only minor effects of blood flow. Conversely, moment-to-moment fluctuations in [18F]FDG used for metabolic connectivity, reflect temporally synchronized supply, mediated jointly by blood flow and BBB transport. We emphasize that the coupling between BBB transport and metabolism underpin the [18F]FDG fPET signal. Considering alterations of GLUT1 and subsequent metabolism in numerous brain disorders, stimulation-induced energy demands and metabolic connectivity represent a promising opportunity to investigate the underlying pathophysiological processes.