Imaging the brain’s immune response to alcohol with [11C]PBR28 TSPO Positron Emission Tomography

Molecular Psychiatry (2023)Cite this article

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In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [11C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Participants (n = 12; 5 F; 25–45 years) who reported consuming binge levels of alcohol (>3 drinks for females; >4 drinks for males) 1–3 months before scan day were enrolled. Imaging featured a baseline [11C]PBR28 scan followed by an oral laboratory alcohol challenge over 90 min. An hour later, a second [11C]PBR28 scan was acquired. Dynamic PET data were acquired for at least 90 min with arterial blood sampling to measure the metabolite-corrected input function. [11C]PBR28 volume of distributions (VT) was estimated in the brain using multilinear analysis 1. Subjective effects, blood alcohol levels (BAL), and plasma cytokines were measured during the paradigm. Full completion of the alcohol challenge and data acquisition occurred for n = 8 (2 F) participants. Mean peak BAL was 101 ± 15 mg/dL. Alcohol significantly increased brain [11C]PBR28 VT (n = 8; F(1,49) = 34.72, p > 0.0001; Cohen’s d’=0.8–1.7) throughout brain by 9–16%. Alcohol significantly altered plasma cytokines TNF-α (F(2,22) = 17.49, p < 0.0001), IL-6 (F(2,22) = 18.00, p > 0.0001), and MCP-1 (F(2,22) = 7.02, p = 0.004). Exploratory analyses identified a negative association between the subjective degree of alcohol intoxication and changes in [11C]PBR28 VT. These findings provide, to our knowledge, the first in vivo human evidence for an acute brain immune response to alcohol.

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Erickson EK, Grantham EK, Warden AS, Harris RA. Neuroimmune signaling in alcohol use disorder. Pharm Biochem Behav. 2019;177:34–60.

Article CAS Google Scholar

Montesinos J, Alfonso-Loeches S, Guerri C. Impact of the innate immune response in the actions of ethanol on the central nervous system. Alcohol Clin Exp Res. 2016;40:2260–70.

Article CAS PubMed Google Scholar

Molina PE, Happel KI, Zhang P, Kolls JK, Nelson S. Focus on: Alcohol and the immune system. Alcohol Res Health. 2010;33:97–108.

PubMed PubMed Central Google Scholar

Orio L, Antón M, Rodríguez-Rojo IC, Correas Á, García-Bueno B, Corral M, et al. Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women. Addict Biol. 2018;23:1130–44.

Article CAS PubMed Google Scholar

Pascual M, Montesinos J, Marcos M, Torres J-L, Costa-Alba P, García-García F, et al. Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence. Addict Biol. 2017;22:1829–41.

Article CAS PubMed Google Scholar

Leclercq S, De Saeger C, Delzenne N, de Timary P, Stärkel P. Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry. 2014;76:725–33.

Article CAS PubMed Google Scholar

Hillmer AT, Holden D, Fowles K, Nabulsi N, West BL, Carson RE, et al. Microglial depletion and activation: A [11 C]PBR28 PET study in nonhuman primates. EJNMMI Res. 2017;7:59.

Article PubMed PubMed Central Google Scholar

Szabo G, Saha B. Alcohol’s effect on host defense. Alcohol Res. 2015;37:159–70.

PubMed PubMed Central Google Scholar

Marshall SA, McClain JA, Kelso ML, Hopkins DM, Pauly JR, Nixon K. Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiol Dis. 2013;54:239–51.

Article CAS PubMed PubMed Central Google Scholar

Henriques JF, Portugal CC, Canedo T, Relvas JB, Summavielle T, Socodato R. Microglia and alcohol meet at the crossroads: Microglia as critical modulators of alcohol neurotoxicity. Toxicol Lett. 2018;283:21–31.

Article CAS PubMed Google Scholar

Walker CD, Risher WC, Risher M-L. Regulation of synaptic development by astrocyte signaling factors and their emerging roles in substance abuse. Cells. 2020;9:297.

Article CAS PubMed PubMed Central Google Scholar

Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013;77:10–18.

Article CAS PubMed Google Scholar

Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci. 2014;15:209–16.

Article CAS PubMed Google Scholar

Frick LR, Williams K, Pittenger C. Microglial dysregulation in psychiatric disease. Clin Dev Immunol. 2013;2013:608654.

Article PubMed PubMed Central Google Scholar

Melbourne JK, Thompson KR, Peng H, Nixon K. Its complicated: the relationship between alcohol and microglia in the search for novel pharmacotherapeutic targets for alcohol use disorders. Prog Mol Biol Transl Sci. 2019;167:179–221.

Article CAS PubMed Google Scholar

Marshall SA, Casachahua JD, Rinker JA, Blose AK, Lysle DT, Thiele TE. IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6 J mice. Brain Behav Immun. 2016;51:258–67.

Article CAS PubMed Google Scholar

Blednov YA, Ponomarev I, Geil C, Bergeson S, Koob GF, Harris RA. Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol. 2012;17:108–20.

Article CAS PubMed Google Scholar

Valenta JP, Gonzales RA. Chronic intracerebroventricular infusion of monocyte chemoattractant protein-1 leads to a persistent increase in sweetened ethanol consumption during operant self-administration but does not influence sucrose consumption in Long-Evans rats. Alcohol Clin Exp Res. 2016;40:187–95.

Article CAS PubMed Google Scholar

Riikonen J, Jaatinen P, Rintala J, Pörsti I, Karjala K, Hervonen A. Intermittent ethanol exposure increases the number of cerebellar microglia. Alcohol Alcohol. 2002;37:421–6.

Article CAS PubMed Google Scholar

Pascual M, Blanco AM, Cauli O, Miñarro J, Guerri C. Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci. 2007;25:541–50.

Article PubMed Google Scholar

Marshall SA, Geil CR, Nixon K. Prior binge ethanol exposure potentiates the microglial response in a model of alcohol-induced neurodegeneration. Brain Sci. 2016;6:16.

Article PubMed PubMed Central Google Scholar

Qin L, He J, Hanes RN, Pluzarev O, Hong J-S, Crews FT. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflammation. 2008;5:10.

Article PubMed PubMed Central Google Scholar

Lewohl JM, Nunez YO, Dodd PR, Tiwari GR, Harris RA, Mayfield RD. Up-regulation of microRNAs in brain of human alcoholics. Alcohol Clin Exp Res. 2011;35:1928–37.

Article CAS PubMed PubMed Central Google Scholar

Crews FT, Qin L, Sheedy D, Vetreno RP, Zou J. High mobility group box 1/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry. 2013;73:602–12.

Article CAS PubMed Google Scholar

Sandiego CM, Gallezot J-D, Pittman B, Nabulsi N, Lim K, Lin S-F, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA. 2015;112:12468–73.

Article CAS PubMed PubMed Central Google Scholar

Hillmer AT, Sandiego CM, Hannestad J, Angarita GA, Kumar A, McGovern EM, et al. In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence. Mol Psychiatry. 2017;22:1759–66.

Article CAS PubMed PubMed Central Google Scholar

Kalk NJ, Guo Q, Owen D, Cherian R, Erritzoe D, Gilmour A, et al. Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [11 C]PBR28 PET study. Transl Psychiatry. 2017;7:e996.

Article CAS PubMed PubMed Central Google Scholar

Kim SW, Wiers CE, Tyler R, Shokri-Kojori E, Jang YJ, Zehra A, et al. Influence of alcoholism and cholesterol on TSPO binding in brain: PET [11 C]PBR28 studies in humans and rodents. Neuropsychopharmacology. 2018;43:1832–9.

Article CAS PubMed PubMed Central Google Scholar

Block ML, Hong J-S. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76:77–98.

Article CAS PubMed Google Scholar

Marshall SA, McClain JA, Wooden JI, Nixon K. Microglia dystrophy following binge-like alcohol exposure in adolescent and adult male rats. Front Neuroanat. 2020;14:52.

Article CAS PubMed PubMed Central Google Scholar

Hu P, Wang D, Zhang Y, Cai Z, Ye T, Tong L, et al. Apoptosis-triggered decline in hippocampal microglia mediates adolescent intermittent alcohol exposure-induced depression-like behaviors in mice. Neuropharmacology. 2020;170:108054.

Article CAS PubMed Google Scholar

Barton EA, Baker C, Leasure JL. Investigation of sex differences in the microglial response to binge ethanol and exercise. Brain Sci. 2017;7:139.

Article PubMed PubMed Central Google Scholar

Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T, et al. Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res. 2007;1157:100–11.

Article CAS PubMed Google Scholar

Toyama H, Hatano K, Suzuki H, Ichise M, Momosaki S, Kudo G, et al. In vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand: [11 C]PK-11195 and animal PET following ethanol injury in rat striatum. Ann Nucl Med. 2008;22:417–24.

Article PubMed Google Scholar

Obernier JA, White AM, Swartzwelder HS, Crews FT. Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharm Biochem Behav. 2002;72:521–32.

Article CAS Google Scholar

Saba W, Goutal S, Auvity S, Kuhnast B, Coulon C, Kouyoumdjian V, et al. Imaging the neuroimmune response to alcohol exposure in adolescent baboons: a TSPO PET study using 18 F-DPA-714. Addict Biol. 2018;23:1000–9.

Article CAS PubMed Google Scholar

Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage. 2008;40:43–52.

Article PubMed Google Scholar

Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.

Article CAS PubMed Google Scholar

Watson PE, Watson ID, Batt RD. Prediction of blood alcohol concentrations in human subjects. Updating the Widmark Equation. J Stud Alcohol. 1981;42:547–56.

Article CAS PubMed Google Scholar

Curtin JJ, Fairchild BA. Alcohol and cognitive control: implications for regulation of behavior during response conflict. J Abnorm Psychol. 2003;112:424–36.

Article PubMed Google Scholar

Martin CS, Earleywine M, Musty RE, Perrine MW, Swift RM. Development and validation of the biphasic alcohol effects scale. Alcohol Clin Exp Res. 1993;17:140–6.

Article CAS PubMed Google Scholar

Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O’Malley SS. The drug effects questionnaire: psychometric support across three drug types. Psychopharmacology. 2013;227:177–92.

Article CAS PubMed Google Scholar

Hannestad J, DellaGioia N, Gallezot J-D, Lim K, Nabulsi N, Esterlis I, et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [¹¹C]PBR28 PET study. Brain Behav Immun. 2013;33:131–8.

Article CAS PubMed PubMed Central Google Scholar

Park E, Gallezot J-D, Delgadillo A, Liu S, Planeta B, Lin S-F, et al. (11)C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas. Eur J Nucl Med Mol Imaging. 2015;42:1081–92.

Article CAS PubMed Google Scholar

Jin X, Mulnix T, Gallezot JD, Carson RE. Evaluation of motion correction methods in human brain PET imaging—A simulation study based on human motion data. Med Phys. 2013;40:102503.

Article PubMed PubMed Central Google Scholar

Ichise M, Liow J-S, Lu J-Q, Takano A, Model K, Toyama H, et al. Linearized reference tissue parametric imaging methods: application to [11 C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab. 2003;23:1096–112.

Article PubMed Google Scholar

Neupane SP, Skulberg A, Skulberg KR, Aass HCD, Bramness JG. Cytokine changes following acute ethanol intoxication in healthy men: a crossover study. Mediators Inflamm. 2016;2016:3758590.

Article PubMed PubMed Central Google Scholar

Monnig MA, Lamb PS, Parra JM, Cioe PA, Martone CM, Monti PM, et al. Immune response to an acute moderate dose of alcohol in healthy young adults. Alcohol Alcohol. 2020;55:616–23.

Article CAS PubMed PubMed Central Google Scholar

Kane CJM, Phelan KD, Douglas JC, Wagoner G, Johnson JW, Xu J, et al. Effects of ethanol on immune response in the brain: region-specific changes in adolescent versus adult mice. Alcohol: Clin Exp Res. 2014;38:384–91.

Article CAS PubMed Google Scholar

Tajuddin N, Moon K-H, Marshall SA, Nixon K, Neafsey EJ, Kim H-Y, et al. Neuroinflammation and neurodegeneration in adult rat brain from binge ethanol exposure: abrogation by docosahexaenoic acid. PLoS One. 2014;9:e101223.

Article PubMed PubMed Central Google Scholar

Tournier BB, Tsartsalis S, Ceyzériat K, Medina Z, Fraser BH, Grégoire M-C, et al. Fluorescence-activated cell sorting to reveal the cell origin of radioligand binding. J Cereb Blood Flow Metab. 2020;40:1242–55.

Article CAS PubMed Google Scholar

Nutma E, Gebro E, Marzin MC, van der Valk P, Matthews PM, Owen DR, et al. Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain. Glia. 2021;69:2447–58.

Article CAS PubMed PubMed Central Google Scholar

Owen DR, Narayan N, Wells L, Healy L, Smyth E, Rabiner EA, et al. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans. J Cereb Blood Flow Metab. 2017;37:2679–90.

Article CAS PubMed PubMed Central Google Scholar

Tyler RE, Kim SW, Guo M, Jang YJ, Damadzic R, Stodden T, et al. Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: a comparison between in vivo and in vitro TSPO radioligand binding. Eur J Neurosci. 2019;50:1831–42.

PubMed Google Scholar

Leclercq S, Cani PD, Neyrinck AM, Stärkel P, Jamar F, Mikolajczak M, et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun. 2012;26:911–8.

Article CAS PubMed Google Scholar

Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Stärkel P, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA. 2014;111:E4485–4493.

Article CAS PubMed PubMed Central Google Scholar

Hillmer AT, Nadim H, Devine L, Jatlow P, O’Malley SS. Acute alcohol consumption alters the peripheral cytokines IL-8 and TNF-α. Alcohol. 2020;85:95–9.

Article CAS PubMed Google Scholar

Bromander S, Anckarsäter R, Kristiansson M, Blennow K, Zetterberg H, Anckarsäter H, et al. Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study. J Neuroinflammation. 2012;9:242.

Article CAS PubMed PubMed Central Google Scholar

Khan W, Corben LA, Bilal H, Vivash L, Delatycki MB, Egan GF, et al. Neuroinflammation in the cerebellum and brainstem in Friedreich Ataxia: an [18 F]-FEMPA PET study. Mov Disord. 2022;37:218–24.

Article CAS PubMed Google Scholar

Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev. 2018;98:477–504.

Article CAS PubMed Google Scholar

Woodcock EA, Schain M, Cosgrove KP, Hillmer AT. Quantification of [11 C]PBR28 data after systemic lipopolysaccharide challenge. EJNMMI Res. 2020;10:19.

Article CAS PubMed PubMed Central Google Scholar

Matheson GJ, Plavén-Sigray P, Forsberg A, Varrone A, Farde L, Cervenka S. Assessment of simplified ratio-based approaches for quantification of PET [11 C]PBR28 data. EJNMMI Res. 2017;7,:58.

Article PubMed Google Scholar

Wilhelm CJ, Fuller BE, Huckans M, Loftis JM. Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory. Drug Alcohol Depend. 2017;176:71–78.

Article PubMed PubMed Central Google Scholar

Maynard ME, Barton EA, Robinson CR, Wooden JI, Leasure JL. Sex differences in hippocampal damage, cognitive impairment, and trophic factor expression in an animal model of an alcohol use disorder. Brain Struct Funct. 2018;223:195–210.

Article CAS PubMed Google Scholar

Melbourne JK, Ryan Thompson K, Peng H, Nixon K. Its complicated: the relationship between alcohol and microglia in the search for novel pharmacotherapeutic targets for alcohol use disorders. Prog Mol Biol Transl Sci. 2019;167:179–221.

Article CAS PubMed Google Scholar

Lewis SA, Sureshchandra S, Doratt B, Jimenez VA, Stull C, Grant KA, et al. Transcriptional, epigenetic, and functional reprogramming of blood monocytes in non-human primates following chronic alcohol drinking. Front Immunol. 2021;12:724015.

Messaoudi I, Asquith M, Engelmann F, Park B, Brown M, Rau A, et al. Moderate alcohol consumption enhances vaccine-induced responses in rhesus macaques. Vaccine. 2013;32:54–61.

Article CAS PubMed PubMed Central Google Scholar

King AC, de Wit H, McNamara PJ, Cao D. Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking. Arch Gen Psychiatry. 2011;68:389–99.

Article PubMed PubMed Central Google Scholar

King AC, McNamara PJ, Hasin DS, Cao D. Alcohol challenge responses predict future alcohol use disorder symptoms: a 6-year prospective study. Biol Psychiatry. 2014;75:798–806.

Article PubMed Google Scholar

King A, Vena A, Hasin DS, deWit H, O’Connor SJ, Cao D. Subjective responses to alcohol in the development and maintenance of alcohol use disorder. Am J Psychiatry. 2021;178:560–71.

Article PubMed PubMed Central Google Scholar

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We thank the wonderful staff at the Yale PET center for their expertise and support of radiochemistry, metabolite analysis, and image acquisition. We also thank the staff at the Clinical Neuroscience Research Unit at the Connecticut Mental Health Center and the Hospital Research Unit at the Yale Clinical Center for Investigation for assistance with participant monitoring and evaluation. We thank Dr. Lesley Devine for support with cytokine assays.

We gratefully acknowledge the funding support from the National Institute on Alcohol Abuse and Alcoholism (K01AA024788; U54AA027989) and State of Connecticut Support for the Clinical Neuroscience Research Unit.

Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

Nakul R. Raval, David Matuskey, Rachel Miller, Lindsey R. Drake, Michael Kapinos, Nabeel Nabulsi, Yiyun Huang, Richard E. Carson, Kelly P. Cosgrove & Ansel T. Hillmer

Yale PET Center, Yale University, New Haven, CT, USA

Nakul R. Raval, Gustavo Angarita, David Matuskey, Lindsey R. Drake, Michael Kapinos, Nabeel Nabulsi, Yiyun Huang, Richard E. Carson, Kelly P. Cosgrove & Ansel T. Hillmer

Department of Psychiatry, Yale University, New Haven, CT, USA

Gustavo Angarita, David Matuskey, Stephanie S. O’Malley, Kelly P. Cosgrove & Ansel T. Hillmer

Department of Neurology, Yale University New Haven, New Haven, CT, USA

David Matuskey

Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, CT, USA

Richard E. Carson & Ansel T. Hillmer

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ATH, KPC, SSOM, REC: conceptualized study, oversaw data acquisition, NRR, LRD, and ATH: analyzed data, GA, DM: study physicians, RM, MK: key data acquisition and analysis contributions, NN and YH: senior radiochemists, NRR, SSOM, KPC, ATH: prepared initial manuscript draft and figures. All authors contributed edits and revisions to the final manuscript.

Correspondence to Ansel T. Hillmer.

The authors declare no competing interests.

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Raval, N.R., Angarita, G., Matuskey, D. et al. Imaging the brain’s immune response to alcohol with [11C]PBR28 TSPO Positron Emission Tomography. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02198-6

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Received: 06 February 2023

Revised: 18 July 2023

Accepted: 20 July 2023

Published: 02 August 2023

DOI: https://doi.org/10.1038/s41380-023-02198-6

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