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In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence

Molecular Psychiatry volume 22, pages 1759–1766 (2017)Cite this article

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Abstract

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1–4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

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Acknowledgements

We thank the staff at the Yale PET center for their expertise and support of radiochemistry and imaging. We also thank Jon Mikael Anderson and the staff at the Clinical Neuroscience Research Unit at the Connecticut Mental Health Center for assistance with subject monitoring and evaluation. Dr Lesley Devine provided critical support for cytokine assay. We express our gratitude to Drs Betsy Bradshaw and Jean-Dominique Gallezot for insightful technical discussions. We gratefully acknowledge the funding support of the National Institute on Alcohol Abuse and Alcoholism (R21AA021866; K05AA014715), the National Institute on Drug Abuse (T32DA022975; K02DA031750) and the State of Connecticut Support for the Clinical Neuroscience Research Unit.

Author information

Author notes

  1. C M Sandiego

    Present address: 8Current address: Molecular NeuroImaging, LLC, New Haven, CT, USA.,

  2. J Hannestad

    Present address: 9Current address: Denali Therapeutics, South San Francisco, CA, USA.,

  3. E M McGovern

    Present address: 10Current address: Memorial Sloan Kettering Cancer Center, New York, NY, USA.,

Authors and Affiliations

  1. Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA

    A T Hillmer, Y Huang, R E Carson & K P Cosgrove

  2. Yale PET Center, Yale University School of Medicine, New Haven, CT, USA

    A T Hillmer, C M Sandiego, Y Huang, R E Carson & K P Cosgrove

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    C M Sandiego, G A Angarita, E M McGovern, S S O'Malley & K P Cosgrove

  4. UCB Pharma, Braine-l'Alleud, Belgium

    J Hannestad

  5. Connecticut Mental Health Center, New Haven, CT, USA

    G A Angarita

  6. Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

    A Kumar & K C O'Connor

  7. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    K P Cosgrove

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Correspondence to K P Cosgrove.

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Competing interests

JH was a full-time employee of UCB Pharma at the time this study was planned and conducted. KCO’C was speaking honoraria at Genentech, EMD Serono and a consultant at NeuroPhage Pharmaceuticals, Scitemex. Although not directly relevant to the reported work, SSO’M reports the following: donated study medications from AstraZeneca, Pfizer; consultant or advisory board member at Alkermes, Cerecor, Opiant; Scientific Review Group, Hazelden Betty Ford Foundation; member of the American Society of Clinical Pharmacology Alcohol Clinical Trials Initiative supported by Ethypharm, Lilly, Lundbeck, Otsuka, Pfizer, Arbor Pharmaceuticals, Indivior. The remaining authors declare no conflicts of interest.

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Hillmer, A., Sandiego, C., Hannestad, J. et al. In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence. Mol Psychiatry 22, 1759–1766 (2017). https://doi.org/10.1038/mp.2017.10

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