Ali Khalidan Vibholm1, Anne Marlene Landau2, Aage Kristian Olsen Alstrup3, Jan Jacobsen4, Kim Vang5, Ole Lajord Munk6, Martin Jensen Dietz7, Dariusz Orlowski8, Jens Christian Hedemann Sørensen9, David James Brooks10. 1. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark. Electronic address: alikhalidan@dadlnet.dk. 2. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark; Translational Neuropsychiatry Unit, Institute of Clinical Medicine, Aarhus University, Denmark. Electronic address: alandau@clin.au.dk. 3. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark. Electronic address: aagealst@rm.dk. 4. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark. Electronic address: janjaobs@rm.dk. 5. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark. Electronic address: kimhasen@rm.dk. 6. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark. Electronic address: olelajmu@rm.dk. 7. Center of Functionally Integrative Neuroscience, Institute of Clinical Medicine, Aarhus University, Denmark. Electronic address: MARTIN@CFIN.AU.DK. 8. Department of Neurosurgery and CENSE, Aarhus University Hospital, Denmark. Electronic address: dariusz.orlowski@gmail.com. 9. Department of Neurosurgery and CENSE, Aarhus University Hospital, Denmark. Electronic address: jenssore@rm.dk. 10. Dept. of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University and University Hospital, Denmark; Translational and Clinical Research Institute, Newcastle University, UK. Electronic address: dbrooks@clin.au.dk.
Abstract
BACKGROUND: No PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [18F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels. OBJECTIVE: To show [18F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus. METHODS: Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline [18F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [18F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [15O]H2O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified. RESULTS: DBS induced a 47.75% global increase in brain [18F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [18F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block [18F]GE-179 uptake during stimulation. CONCLUSION: PET detected an increase in global brain [18F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [18F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation.
BACKGROUND: No PET radioligand has yet demonstrated the capacity to map glutamateN-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [18F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels. OBJECTIVE: To show [18F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus. METHODS: Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline [18F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [18F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [15O]H2O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified. RESULTS: DBS induced a 47.75% global increase in brain [18F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [18F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block [18F]GE-179 uptake during stimulation. CONCLUSION: PET detected an increase in global brain [18F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [18F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation.
Authors: Ali K Vibholm; Anne M Landau; Arne Møller; Jan Jacobsen; Kim Vang; Ole L Munk; Dariusz Orlowski; Jens Ch Sørensen; David J Brooks Journal: J Cereb Blood Flow Metab Date: 2020-09-22 Impact factor: 6.200
Authors: Matthew M Nour; Katherine Beck; Yunzhe Liu; Atheeshaan Arumuham; Mattia Veronese; Oliver D Howes; Raymond J Dolan Journal: Schizophr Bull Open Date: 2022-07-07