The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

Ellis Chika Onwordi; Thomas Whitehurst; Ayla Mansur; Ben Statton; Alaine Berry; Marina Quinlan; Declan P. O’Regan; Maria Rogdaki; Tiago Reis Marques; Eugenii A. Rabiner; Roger N. Gunn; Anthony C. Vernon; Sridhar Natesan; Oliver D. Howes

doi:10.1038/s41398-021-01515-3

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

Ellis Chika Onwordi^*, Thomas Whitehurst, Ayla Mansur, Ben Statton, Alaine Berry, Marina Quinlan, Declan P. O’Regan, Maria Rogdaki, Tiago Reis Marques, Eugenii A. Rabiner, Roger N. Gunn, Anthony C. Vernon, Sridhar Natesan, Oliver D. Howes

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

33 Citations (Scopus)

Abstract

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [¹¹C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (¹H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [¹¹C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [¹¹C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [¹¹C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [¹¹C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain ¹H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

Original language	English
Article number	393
Journal	Translational psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01515-3
Publication status	Published - Dec 2021

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Onwordi, E. C., Whitehurst, T., Mansur, A., Statton, B., Berry, A., Quinlan, M., O’Regan, D. P., Rogdaki, M., Marques, T. R., Rabiner, E. A., Gunn, R. N., Vernon, A. C., Natesan, S., & Howes, O. D. (2021). The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study. Translational psychiatry, 11(1), Article 393. https://doi.org/10.1038/s41398-021-01515-3

@article{59bece20448e43619230b26b9393d8d5,

title = "The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study",

abstract = "Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.",

author = "Onwordi, {Ellis Chika} and Thomas Whitehurst and Ayla Mansur and Ben Statton and Alaine Berry and Marina Quinlan and O{\textquoteright}Regan, {Declan P.} and Maria Rogdaki and Marques, {Tiago Reis} and Rabiner, {Eugenii A.} and Gunn, {Roger N.} and Vernon, {Anthony C.} and Sridhar Natesan and Howes, {Oliver D.}",

note = "Funding Information: The authors thank the patients and healthy volunteers who participated in this study, and Rohini Akosa, Ryan Janisch, Daniela Ribeiro, Jim Anscombe and Dr. Maja Ranger for their expert assistance. ODH acknowledges financial support for this study from the Medical Research Council (grant nos. MC-A656–5QD30 and MR/L022176/1), Wellcome Trust (no. 094849/Z/10/Z) 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. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s41398-021-01515-3",

language = "English",

volume = "11",

journal = "Translational psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Onwordi, EC, Whitehurst, T, Mansur, A, Statton, B, Berry, A, Quinlan, M, O’Regan, DP, Rogdaki, M, Marques, TR, Rabiner, EA, Gunn, RN, Vernon, AC , Natesan, S & Howes, OD 2021, 'The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study', Translational psychiatry, vol. 11, no. 1, 393. https://doi.org/10.1038/s41398-021-01515-3

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study. / Onwordi, Ellis Chika; Whitehurst, Thomas; Mansur, Ayla et al.
In: Translational psychiatry, Vol. 11, No. 1, 393, 12.2021.

Research output: Contribution to journal › Article › peer-review

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T1 - The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia

T2 - a multimodal PET and magnetic resonance spectroscopy brain imaging study

AU - Onwordi, Ellis Chika

AU - Whitehurst, Thomas

AU - Mansur, Ayla

AU - Statton, Ben

AU - Berry, Alaine

AU - Quinlan, Marina

AU - O’Regan, Declan P.

AU - Rogdaki, Maria

AU - Marques, Tiago Reis

AU - Rabiner, Eugenii A.

AU - Gunn, Roger N.

AU - Vernon, Anthony C.

AU - Natesan, Sridhar

AU - Howes, Oliver D.

N1 - Funding Information: The authors thank the patients and healthy volunteers who participated in this study, and Rohini Akosa, Ryan Janisch, Daniela Ribeiro, Jim Anscombe and Dr. Maja Ranger for their expert assistance. ODH acknowledges financial support for this study from the Medical Research Council (grant nos. MC-A656–5QD30 and MR/L022176/1), Wellcome Trust (no. 094849/Z/10/Z) and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

AB - Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

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SN - 2158-3188

VL - 11

JO - Translational psychiatry

JF - Translational psychiatry

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ER -

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

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