PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects

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Abstract

Background

Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and ¹¹C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated ( n = 12) or medicated ( n = 16)) and 20 healthy controls (HC) underwent PET imaging using ¹¹C-PBR28. Total distribution volume ( V _T, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma ( fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression.

Results

TSPO binding was higher in MDD versus HC in the sgPFC (Cohen’s d = 0.64, p = .038, 95% CI 0.04–1.24) and ACC ( d = 0.60, p = .049, 95% CI 0.001–1.21), though these comparisons missed the corrected threshold for statistical significance ( α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers.

Conclusions

This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

Electronic supplementary material

The online version of this article (10.1186/s13550-018-0401-9) contains supplementary material, which is available to authorized users.

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Most cited references 28

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Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.

Elaine Setiawan, Alan Wilson, Romina Mizrahi … (2015)

The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation.

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Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Johann Steiner, Martin Walter, Tomasz Gos … (2011)

Background Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described. Methods Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects. Results Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD. Conclusions These results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategies.

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Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity.

Daniel Lindqvist, Shorena Janelidze, Peter Hagell … (2009)

Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. We measured interleukin-1beta, interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MADRS scores and CSF IL-6 levels in all patients. IL-6 and TNF-alpha correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.

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Author and article information

Contributors

Erica M. Richards: (001) 301-402-7976 , ericha25@jhmi.edu

Masahiro Fujita: mfujitamd1@hotmail.com

Laura Newman: lauranewmane@gmail.com

Cristan Farmer: cristan.farmer@nih.gov

Elizabeth D. Ballard: elizabeth.ballard@nih.gov

Rodrigo Machado-Vieira: machadovieirar@gmail.com

Peixiong Yuan: peixiong.yuan@nih.gov

Mark J. Niciu: mark-niciu@uiowa.edu

Chul Hyoung Lyoo: lyoochel@gmail.com

Ioline D. Henter: ioline.henter@nih.gov

Giacomo Salvadore: GSalvado@its.jnj.com

Wayne C. Drevets: wdrevets@its.jnj.com

Hartmuth Kolb: hkolb1@its.jnj.com

Robert B. Innis: innisr@mail.nih.gov

Carlos A. Zarate Jr: zaratec@mail.nih.gov

Journal

Journal ID (nlm-ta): EJNMMI Res

Journal ID (iso-abbrev): EJNMMI Res

Title: EJNMMI Research

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Electronic): 2191-219X

Publication date (Electronic): 3 July 2018

Publication date PMC-release: 3 July 2018

Publication date Collection: 2018

Volume: 8

Electronic Location Identifier: 57

Affiliations

[1 ]ISNI 0000 0004 0464 0574, GRID grid.416868.5, Intramural Research Program, , National Institute of Mental Health, National Institutes of Health, ; Building 10, CRC Room 6-5340, 10 Center Drive, Bethesda, MD 20892 USA

[2 ]ISNI 0000 0004 0445 0041, GRID grid.63368.38, Houston Methodist Research Institute, Weill Cornell Medicine, ; Houston, Texas USA

[3 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Department of Psychiatry and Behavioral Sciences, , University of Texas Health Science Center, ; Houston, TX USA

[4 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Neurology, Gangnam Severance Hospital, , Yonsei University College of Medicine, ; Seoul, South Korea

[5 ]GRID grid.417429.d, Janssen Research and Development, LLC, ; Titusville, NJ USA

Article

Publisher ID: 401

DOI: 10.1186/s13550-018-0401-9

PMC ID: 6029989

PubMed ID: 29971587

SO-VID: 55a193ac-d8b5-4c39-9f4e-2e223fcbcb76

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 5 March 2018

Date accepted : 30 May 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;

Award ID: NCT01851356

Award Recipient : Robert B. Innis

Funded by: FundRef http://dx.doi.org/10.13039/100008897, Janssen Pharmaceuticals;

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ScienceOpen disciplines: Radiology & Imaging

Keywords: inflammation,major depressive disorder,biomarkers,peripheral benzodiazepine receptor,positron emission tomography

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ScienceOpen disciplines: Radiology & Imaging

Keywords: inflammation, major depressive disorder, biomarkers, peripheral benzodiazepine receptor, positron emission tomography

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects

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Biomarkers for Inflammatory Lung Disease

Most cited references 28

Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity.

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