[¹⁸F]FDG Revisited: A New Perspective on the Temporal Dynamics of Brain Glucose Metabolism

[¹⁸F]FDG positron emission tomography (PET) is extensively utilized to assess brain glucose metabolism, typically through static images reflecting radiotracer accumulation of up to one hour. In comparison, functional PET (fPET) enables investigation of [¹⁸F]FDG dynamics occurring within seconds. However, the physiological mechanisms supporting these rapid changes in metabolism necessitate further attention to allow accurate interpretation of brain function and their clinical implications. 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, both 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 (K₁ and k₂ in a two-tissue compartment model), with subsequent increases in hexokinase activity (k₃). 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, as examined using molecular connectivity, reflect temporally synchronized supply in response to metabolic demand, mediated jointly by blood flow and BBB transport.We emphasize that, particularly during neuronal activation, the strong 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 changes of energy demands and moment-to-moment fluctuations of molecular connectivity represent a promising opportunity to investigate the underlying pathophysiological processes.