AbstractBackgroundDegeneration of the nigrostriatal dopaminergic (DA) and the raphe‐thalamic serotonergic (SE) systems is among the earliest changes observed in Parkinson's disease (PD). The consequences of those changes on brain metabolism, especially regarding their impact on the cortex, are poorly understood.ObjectivesUsing multi‐tracer molecular imaging, we assessed in a cohort of drug‐naive PD patients the association between cortical metabolism and DA and SE system deafferentation of either striatum or thalamus, and we explored whether this association was mediated by either striatum or thalamus metabolism.MethodsWe recruited 96 drug‐naive PD patients (aged 71.9 ± 7.5 years) who underwent [¹²³I]ioflupane single‐photon emission computed tomography ([¹²³I]FP‐CIT‐SPECT) and brain [¹⁸F]fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG‐PET). We used a voxel‐wise analysis of [¹⁸F]FDG‐PET images to correlate regional metabolism with striatal DA and thalamic SE innervation as assessed using [¹²³I]FP‐CIT‐SPECT.ResultsWe found that [¹²³I]FP‐CIT specific to nondisplaceable binding ratio (SBR) and glucose metabolism positively correlated with one another in the deep gray matter (thalamus: P = 0.001, r = 0.541; caudate P = 0.001, r = 0.331; putamen P = 0.001, r = 0.423). We then observed a direct correlation between temporoparietal metabolism and caudate DA innervation, as well as a direct correlation between prefrontal metabolism and thalamus SE innervation. The effect of caudate [¹²³I]FP‐CIT SBR values on temporoparietal metabolism was mediated by caudate metabolic values (percentage mediated: 89%, P‐value = 0.008), and the effect of thalamus [¹²³I]FP‐CIT SBR values on prefrontal metabolism was fully mediated by thalamus metabolic values (P < 0.001).ConclusionsThese data suggest that the impact of deep gray matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in drug‐naive PD. © 2021 International Parkinson and Movement Disorder Society