Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

Background And Objectives: Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive.

Methods: Combining magnetic resonance (MR) spectroscopy and [C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (V) of [C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia.

Results: We measured globally elevated V of [C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants ((2,45) = 5.579, = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional V of [C]ABP688. V of [C]ABP688 correlated with the amount of REM sleep without atonia ((1,42) = 5.600, = 0.023) and with dopaminergic treatment response in patients with PD ((1,30) = 5.823, = 0.022).

Discussion: Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher V of [C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.