Altered glutamate signaling in Parkinson’s disease patients with REM sleep behavior disorder

Abstract

AbstractBackground and ObjectivesClinical heterogeneity of patients with Parkinson’s disease is well recognized. Parkinson’s disease with rapid eye movement (REM) sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher non-motor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning disbalances in neurotransmitter systems remain elusive.MethodsCombining magnetic resonance (MR) spectroscopy and11C-ABP688 positron emission tomography (PET) on PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with Parkinson’s disease. Thirty-three patients were grouped according to their RBD status in overnight video-polysomnography and compared to 15 age- and sex-matched healthy control (HC) subjects. Total volumes of distribution (VT) of11C-ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between minutes 45 to 60 of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single voxel STEAM MR spectroscopy of the left putamen.ResultsWe measured globally elevated VTof11C-ABP688 in patients with Parkinson’s disease and RBD compared to patients without RBD and HC subjects (F(2,45) = 5.579,p= 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VTof11C-ABP688. VTof11C-ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600,p= 0.023), and with dopaminergic treatment response in Parkinson’s disease patients (F(1,30) = 5.823,p= 0.022).ConclusionOur results suggest that patients with Parkinson’s disease and RBD exhibit altered glutamatergic signaling indicated by higher VTof11C-ABP688 despite unaffected glutamate metabolism. The disbalance of glutamate receptors and neurotransmitter might indicate a novel mechanism contributing to the heterogeneity of Parkinson’s disease and warrants further investigation of drugs targeting mGluR5.