Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease

Abstract Background It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD). Objective To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD. Methods This cohort study included 28 patients with polysomnography‐confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder ( denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F‐fluorodeoxyglucose (all participants) and 18 F‐N‐3‐fluoropropyl‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl)‐nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel‐wise whole‐brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole‐brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group. Results From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4‐year follow‐up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra‐ and inter‐regional metabolic connectivities in the parieto‐occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia‐frontal connection by advancing dopaminergic denervation. Conclusions Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.