Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO VT, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), and tumor necrosis factor alpha (TNFα)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO VT were measured in 3 cohorts: prefrontal cortex TSPO VT of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO VT of 20 subjects with obsessive-compulsive disorder. Ln(PGE2/CRP) and ln(TNFα/CRP) consistently correlated with TSPO VT (R2 = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO VT, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R2 = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO VT. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.
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WHO. 169 (World Health Organization, Geneva, Switzerland, 2001).
Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, et al. Inflammation in the neurocircuitry of obsessive-compulsive disorder. JAMA Psychiatry. 2017;74:833–40.
Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miler L, et al. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry. 2018;5:339–47.
Richards EM, Zanotti-Fregonara P, Fujita M, Newman L, Farmer C, Ballard ED, et al. PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects. EJNMMI Res. 2018;8:57.
Li H, Sagar AP, Keri S. Translocator protein (18kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy. Prog neuro-Psychopharmacol Biol Psychiatry 2018;83:1–7.
Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci 2018;21:1359–69.
Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.
Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry 2018;83:61–9.
Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.
Betlazar C, Harrison-Brown M, Middleton RJ, Banati R, Liu GJ. Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain. Int J Mol Sci. 2018;19:pii: E2707.
Banati RB, Myers R, Kreutzberg GW. PK (‘peripheral benzodiazepine’)–binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol. 1997;26:77–82.
Martin A, Boisgard R, Theze B, Van Camp N, Kuhnast B, Damont A, et al. Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab. 2010;30:230–41.
Narayanaswami V, Dahl K, Bernard-Gauthier V, Josephson L, Cumming P, Vasdev N. Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: outlook beyond TSPO. Mol imaging 2018;17:1536012118792317.
Horti AG, Naik R, Foss CA, Minn I, Misheneva V, Du Y, et al. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proceedings of the National Academy of Sciences of the United States of America. 2019.
Galasko D, Montine TJ. Biomarkers of oxidative damage and inflammation in Alzheimer’s disease. Biomark Med. 2010;4:27–36.
Wang AK, Miller BJ. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophrenia Bull 2018;44:75–83.
Pulli B, Chen JW. Imaging neuroinflammation - from bench to bedside. J Clin Cell Immunol. 2014;5:pii: 226.
Minghetti L, Polazzi E, Nicolini A, Creminon C, Levi G. Up-regulation of cyclooxygenase-2 expression in cultured microglia by prostaglandin E2, cyclic AMP and non-steroidal anti-inflammatory drugs. Eur J Neurosci. 1997;9:934–40.
Akanuma S, Higuchi T, Higashi H, Ozeki G, Tachikawa M, Kubo Y, et al. Transporter-mediated prostaglandin E(2) elimination across the rat blood-brain barrier and its attenuation by the activation of N-methyl-D-aspartate receptors. Drug Metab pharmacokinetics. 2014;29:387–93.
Tachikawa M, Hosoya K, Terasaki T. Pharmacological significance of prostaglandin E2 and D2 transport at the brain barriers. Adv Pharm. 2014;71:337–60.
Banks WA. The blood-brain barrier in neuroimmunology: tales of separation and assimilation. Brain Behav Immun. 2015;44:1–8.
Hagen AA, Gerber JN, Sweeley CC, White RP, Robertson JT. Levels and disappearance of prostaglandin F2alpha in cerebral spinal fluid: a clinical and experimental study. Stroke 1977;8:672–5.
Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol 2012;188:21–8.
Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci 2007;10:1116–24.
Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213:93–118.
Williams LM. Precision psychiatry: a neural circuit taxonomy for depression and anxiety. Lancet Psychiatry. 2016;3:472–80.
Adams KH, Hansen ES, Pinborg LH, Hasselbalch SG, Svarer C, Holm S, et al. Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei. Int J Neuropsychopharmacol. 2005;8:391–401.
Wong DF, Brasic JR, Singer HS, Schretlen DJ, Kuwabara H, Zhou Y, et al. Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette syndrome: clues from an in vivo neurochemistry study with PET. Neuropsychopharmacology. 2008;33:1239–51.
Saxena S, Brody AL, Schwartz JM, Baxter LR. Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br. J. Psychiatry. 1998;35:26–37.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, et al. The yale-brown obsessive compulsive scale. II. Validity. Arch Gen Psychiatry. 1989;46:1012–6.
Rusjan P, Mamo D, Ginovart N, Hussey D, Vitcu I, Yasuno F, et al. An automated method for the extraction of regional data from PET images. Psychiatry Res. 2006;147:79–89.
Rusjan PM, Wilson AA, Bloomfield PM, Vitcu I, Meyer JH, Houle S, et al. Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab. 2011;31:1807–16.
Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399–402.
Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, et al. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008;5:15.
Coughlin JM, Wang Y, Ambinder EB, Ward RE, Minn I, Vranesic M, et al. In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma. Transl Psychiatry. 2016;6:e777.
Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA. 2015;112:12468–73.
Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I, et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [(1)(1)C]PBR28 PET study. Brain Behav Immun. 2013;33:131–8.
Saito O, Svensson CI, Buczynski MW, Wegner K, Hua XY, Codeluppi S, et al. Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br J Pharmacol. 2010;160:1754–64.
Dong Y, Benveniste EN. Immune function of astrocytes. Glia 2001;36:180–90.
AN, LN, and CC worked as study PET technicians. AK, NK, AS, and RM provided medical coverage for the PET scans. JP, AG, and Michael Harkness of Research Imaging Centre, served as PET chemistry staff. AR, GED, and HB, worked as study MRI technicians. All other contributors are paid employees of the Centre for Addiction and Mental Health.
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Attwells, S., Setiawan, E., Wilson, A.A. et al. Replicating predictive serum correlates of greater translocator protein distribution volume in brain. Neuropsychopharmacol. (2019) doi:10.1038/s41386-019-0561-y