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

Background and Objectives Clinical 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. Methods Combining magnetic resonance (MR) spectroscopy and 11C-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) of 11C-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. Results We measured globally elevated VT of 11C-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 VT of 11C-ABP688. VT of 11C-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). Conclusion Our results suggest that patients with Parkinson’s disease and RBD exhibit altered glutamatergic signaling indicated by higher VT of 11C-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. ### Competing Interest Statement GRF serves as an editorial board member of Cortex, Neurological Research and Practice, NeuroImage: Clinical, Zeitschrift für Neuropsychologie, and DGNeurologie; receives royalties from the publication of the books Funktionelle MRT in Psychiatrie und Neurologie, Neurologische Differentialdiagnose, and SOP Neurologie; received honoraria for speaking engagements from Bayer, Desitin, Ergo DKV, Forum für medizinische Fortbildung FomF GmbH, GSK, Medica Academy Messe Duesseldorf, Medicbrain Healthcare, Novartis, Pfizer, and Sportaerztebund NRW. ### Funding Statement C. E. J. Doppler is supported by the Clinician Scientist Program (CCSP) / Faculty of Medicine / University of Cologne, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, FI 773/15-1). N. J. Shah received institutional fundings. G. R. Fink is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project-ID 431549029, SFB 1451). GRF serves as an editorial board member of Cortex, Neurological Research and Practice, NeuroImage: Clinical, Zeitschrift für Neuropsychologie, and DGNeurologie; receives royalties from the publication of the books Funktionelle MRT in Psychiatrie und Neurologie, Neurologische Differentialdiagnose, and SOP Neurologie; received honoraria for speaking engagements from Bayer, Desitin, Ergo DKV, Forum für medizinische Fortbildung FomF GmbH, GSK, Medica Academy Messe Duesseldorf, Medicbrain Healthcare, Novartis, Pfizer, and Sportaerztebund NRW. M. Sommerauer is funded by the Koeln Fortune Program / Faculty of Medicine, University of Cologne (grant number 453/2018), and the Else Kroener-Fresenius-Stiftung (grant number 2019_EKES.02). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the faculty of medicine of the university of cologne gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Anonymized data are available upon reasonable request.