N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

Katherine Beck; Atheeshaan Arumuham; Mattia Veronese; Barbara Santangelo; Colm J McGinnity; Joel Dunn; Robert A McCutcheon; Stephen J Kaar; Nisha Singh; Toby Pillinger; Faith Borgan; James Stone; Sameer Jauhar; Teresa Sementa; Federico Turkheimer; Alexander Hammers; Oliver D Howes

doi:10.1038/s41398-021-01540-2

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

Katherine Beck, Atheeshaan Arumuham, Mattia Veronese, Barbara Santangelo, Colm J McGinnity, Joel Dunn, Robert A McCutcheon, Stephen J Kaar, Nisha Singh, Toby Pillinger, Faith Borgan, James Stone, Sameer Jauhar, Teresa Sementa, Federico Turkheimer, Alexander Hammers, Oliver D Howes

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Abstract

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

Original language	English
Article number	425
Journal	Translational psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01540-2
Publication status	Published - 12 Aug 2021

Keywords

Brain/diagnostic imaging
Humans
Neuroimaging
Positron-Emission Tomography
Psychotic Disorders/diagnostic imaging
Receptors, N-Methyl-D-Aspartate
Schizophrenia

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10.1038/s41398-021-01540-2

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title = "N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study",

abstract = "N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.",

keywords = "Brain/diagnostic imaging, Humans, Neuroimaging, Positron-Emission Tomography, Psychotic Disorders/diagnostic imaging, Receptors, N-Methyl-D-Aspartate, Schizophrenia",

author = "Katherine Beck and Atheeshaan Arumuham and Mattia Veronese and Barbara Santangelo and McGinnity, {Colm J} and Joel Dunn and McCutcheon, {Robert A} and Kaar, {Stephen J} and Nisha Singh and Toby Pillinger and Faith Borgan and James Stone and Sameer Jauhar and Teresa Sementa and Federico Turkheimer and Alexander Hammers and Howes, {Oliver D}",

note = "Funding Information: KB has received funding from the Royal College of Psychiatrists, Rosetrees Trust and Stoneygate Trust. MV is funded by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King{\textquoteright}s College London, and by the Wellcome Trust Digital Award 215747/Z/19/Z. CJM was supported by the Medical Research Council MR/ N013042/1 and subsequently by the Wellcome Trust/Engineering and Physical Sciences Research Council (EPSRC) Centre for Medical Engineering WT 203148/Z/16/Z and the Engineering and Physical Sciences Research Council Centre for Doctoral Training in Medical Imaging EP/L015226/1. JD{\textquoteright}s work was supported by the Wellcome/EPSRC Centre for Medical Engineering WT 203148/Z/16/Z. RM received funding from NIHR. NS was funded by a grant from the Medical Research Council, MR/K022733/1 (awarded to FT). TP{\textquoteright}s work is supported by the NIHR and Maudsley Charity. TS{\textquoteright}s work was funded by departmental funding Wellcome-EPSRC, Grant/ Award Number: WT 203148/Z/16/Z. FT has received MRC funding MR/K022733/1. AH is funded by King{\textquoteright}s College London. ODH has received funding from the Medical Research Council-UK no. MC_U120097115, Maudsley Charity no. 66, Brain and Behavior Research Foundation, and Wellcome Trust no. 094849/Z/10/Z grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. This research was funded in whole, or in part, by the Wellcome Trust 094849/Z/10/Z. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the author(s) and not necessarily those of H Lundbeck A/s, the NHS/NIHR or the Department of Health. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41398-021-01540-2",

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AU - Beck, Katherine

AU - Arumuham, Atheeshaan

AU - Veronese, Mattia

AU - Santangelo, Barbara

AU - McGinnity, Colm J

AU - Dunn, Joel

AU - McCutcheon, Robert A

AU - Kaar, Stephen J

AU - Singh, Nisha

AU - Pillinger, Toby

AU - Borgan, Faith

AU - Stone, James

AU - Jauhar, Sameer

AU - Sementa, Teresa

AU - Turkheimer, Federico

AU - Hammers, Alexander

AU - Howes, Oliver D

N1 - Funding Information: KB has received funding from the Royal College of Psychiatrists, Rosetrees Trust and Stoneygate Trust. MV is funded by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London, and by the Wellcome Trust Digital Award 215747/Z/19/Z. CJM was supported by the Medical Research Council MR/ N013042/1 and subsequently by the Wellcome Trust/Engineering and Physical Sciences Research Council (EPSRC) Centre for Medical Engineering WT 203148/Z/16/Z and the Engineering and Physical Sciences Research Council Centre for Doctoral Training in Medical Imaging EP/L015226/1. JD’s work was supported by the Wellcome/EPSRC Centre for Medical Engineering WT 203148/Z/16/Z. RM received funding from NIHR. NS was funded by a grant from the Medical Research Council, MR/K022733/1 (awarded to FT). TP’s work is supported by the NIHR and Maudsley Charity. TS’s work was funded by departmental funding Wellcome-EPSRC, Grant/ Award Number: WT 203148/Z/16/Z. FT has received MRC funding MR/K022733/1. AH is funded by King’s College London. ODH has received funding from the Medical Research Council-UK no. MC_U120097115, Maudsley Charity no. 66, Brain and Behavior Research Foundation, and Wellcome Trust no. 094849/Z/10/Z grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. This research was funded in whole, or in part, by the Wellcome Trust 094849/Z/10/Z. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the author(s) and not necessarily those of H Lundbeck A/s, the NHS/NIHR or the Department of Health. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/8/12

Y1 - 2021/8/12

N2 - N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

AB - N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

KW - Brain/diagnostic imaging

KW - Humans

KW - Neuroimaging

KW - Positron-Emission Tomography

KW - Psychotic Disorders/diagnostic imaging

KW - Receptors, N-Methyl-D-Aspartate

KW - Schizophrenia

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JO - Translational psychiatry

JF - Translational psychiatry

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ER -

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

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Keywords

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