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Molecular Imaging of Neuroinflammation in HIV

  • Anna Boerwinkle
  • Beau M. Ances
LETTER TO THE EDITOR
  • 59 Downloads

Abstract

The development of combined antiretroviral therapy (cART) has increased the lifespan of persons living with HIV (PLWH), with most PLWH having a normal life expectancy. While significant progress has occurred, PLWH continue to have multiple health complications, including HIV associated neurocognitive disorders (HAND). While the exact cause of HAND is not known, persistent neuroinflammation is hypothesized to be an important potential contributor. Molecular imaging using positron emission tomography (PET) can non-invasively evaluate neuroinflammation. PET radiotracers specific for increased expression of the translocator protein18kDa (TSPO) on activated microglia can detect the presence of neuroinflammation in PLWH. However, results from these studies have been inconsistent and inconclusive. Future studies are needed to address key limitations that continue to persist with these techniques before accurate conclusions can be drawn regarding the role of persistent neuroinflammation in PLWH.

Keywords

Human immunodeficiency virus (HIV) HIV-associated neurocognitive impairment (HAND) Neuroinflammation Positron emission tomography (PET) Translocator protein 18 kDa (TSPO) 

Notes

Author Contributions

A.B and B.M.A conceived the study; A.B. analyzed the data; and A.B and B.M.A wrote the paper.

Funding

The study was supported by grants from the National Institute for Nursing Research (R01NR014449 and R01NR015738), the National Institute of Mental Health (R01MH118031), the Paula O and Rodger Riney Research Fund, and the Daniel J Brennan MD Research Fund.

References

  1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69(18):1789–1799.  https://doi.org/10.1212/01.WNL.0000287431.88658.8b CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bae K-R, Shim H-J, Balu D, Kim SR, Yu S-W (2014) Translocator protein 18 KDa negatively regulates inflammation in microglia. J NeuroImmune Pharmacol 9(3):424–437.  https://doi.org/10.1007/s11481-014-9540-6 CrossRefPubMedGoogle Scholar
  3. Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G et al (2000) The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Quantitative in vivo imaging of microglia as a measure of disease activity. Brain 123(11):2321–2337.  https://doi.org/10.1093/brain/123.11.2321 CrossRefPubMedGoogle Scholar
  4. Beaino W, Janssen B, Kooij G, van der Pol SMA, van Het Hof B, van Horssen J, Windhorst AD, de Vries HE (2017) Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. Journal of Neuroinflammation 14(1):1–16.  https://doi.org/10.1186/s12974-017-1034-z CrossRefGoogle Scholar
  5. Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A, Boutin H, James M, Kassiou M, Tavitian B (2009) Comparative evaluation of the translocator protein Radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute Neuroinflammation. J Nucl Med 50(3):468–476.  https://doi.org/10.2967/jnumed.108.058669 CrossRefPubMedGoogle Scholar
  6. Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15(6):991–998.  https://doi.org/10.1046/j.1460-9568.2002.01938.x CrossRefPubMedGoogle Scholar
  7. Clifford DB, Ances BM (2013) HIV-associated neurocognitive disorder. Lancet Infect Dis 13(11):976–986.  https://doi.org/10.1016/S1473-3099(13)70269-X CrossRefPubMedPubMedCentralGoogle Scholar
  8. Coughlin JM, Wang Y, Ma S, Yue C, Kim PK, Adams AV, Roosa HV et al (2014) Regional brain distribution of translocator protein using [ 11C]DPA-713 PET in individuals infected with HIV. Journal of NeuroVirology 20(3):219–232.  https://doi.org/10.1007/s13365-014-0239-5 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Garvey LJ, Pavese N, Politis M, Ramlackhansingh A, Brooks DJ, Taylor-Robinson SD, Winston A (2014) Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. Aids 28(1):67–72.  https://doi.org/10.1097/01.aids.0000432467.54003.f7 CrossRefPubMedGoogle Scholar
  10. González-Scarano F, Martín-García J (2005) The Neuropathogenesis of AIDS. Nat Rev Immunol 5(1):69–81.  https://doi.org/10.1038/nri1527 CrossRefPubMedGoogle Scholar
  11. Gulyás B, Makkai B, Kása P, Gulya K, Bakota L, Várszegi S, Beliczai Z et al (2009) A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two Radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) Syst. Neurochem Int 54(1):28–36.  https://doi.org/10.1016/j.neuint.2008.10.001 CrossRefPubMedGoogle Scholar
  12. Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, McArthur JC, Pomper MG (2005) Imaging glial cell activation with [ 11 C]- R -PK11195 in patients with AIDS. J Neurovirol 11(4):346–355.  https://doi.org/10.1080/13550280500187351 CrossRefPubMedGoogle Scholar
  13. Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: charter study. Neurology 75(23):2087–2096.  https://doi.org/10.1212/WNL.0b013e318200d727 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Janssen B, Vugts DJ, Windhorst AD, Mach RH (2018) PET imaging of microglial activation - beyond targeting TSPO. Molecules 23(3):1–14.  https://doi.org/10.3390/molecules23030607 CrossRefGoogle Scholar
  15. Joint United Nations Programme on HIV/AIDS (UNAIDS) (2017) Ending Aids Progress Towards the 90–90-90 Targets. Global Aids Update. https://doi.org/UNAIDS/JC2900E. Accessed 12 July 2018
  16. Knezevic D, Mizrahi R (2018) Molecular imaging of Neuroinflammation in Alzheimer’s disease and mild cognitive impairment. Prog Neuro-Psychopharmacol Biol Psychiatry 80(January 2017). Elsevier):123–131.  https://doi.org/10.1016/j.pnpbp.2017.05.007 CrossRefGoogle Scholar
  17. Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, Zoghbi SS et al (2013a) A genetic polymorphism for translocator protein 18 kda affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. Journal of Cerebral Blood Flow and Metabolism 33(1). Nature Publishing Group):53–58.  https://doi.org/10.1038/jcbfm.2012.131 CrossRefPubMedGoogle Scholar
  18. Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, Corona W et al (2013b) In vivo Radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 136(7):2228–2238.  https://doi.org/10.1093/brain/awt145 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kreisl, William C., Chul Hyoung Lyoo, Jeih San Liow, Monica Wei, Joseph Snow, Emily Page, Kimberly J. Jenko, et al. 2016. “11C-PBR28 binding to translocator protein increases with progression of Alzheimer’s Disease.” Neurobiol Aging 44. Elsevier Inc: 53–61.  https://doi.org/10.1016/j.neurobiolaging.2016.04.011 CrossRefGoogle Scholar
  20. Kreisl WC, Henter ID, Innis RB (2017) Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia. Advances in Pharmacology. 1st ed. Vol. 82. Elsevier Inc.  https://doi.org/10.1016/bs.apha.2017.08.004 Google Scholar
  21. Krueger KE, Papadopoulos V (1990) Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. J Biol Chem 265(25):15015–15022 http://www.jbc.org/content/265/25/15015. Accessed 5 Oct 2018PubMedGoogle Scholar
  22. Kuhlmann AC, Guilarte TR (2000) Cellular and subcellular localization of peripheral benzodiazepine receptors after Trimethyltin neurotoxicity. J Neurochem 74(4):1694–1704.  https://doi.org/10.1046/j.1471-4159.2000.0741694.x CrossRefPubMedGoogle Scholar
  23. Lyoo CH, Ikawa M, Liow J-S, Zoghbi SS, Morse CL, Pike VW, Fujita M, Innis RB, Kreisl WC (2015) Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect Neuroinflammation measured with PET Radioligand binding to translocator protein. J Nucl Med 56(5):701–706.  https://doi.org/10.2967/jnumed.114.146027 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Masters M, Ances B (2014) Role of neuroimaging in HIV-associated neurocognitive disorders. Semin Neurol 34(01):089–102.  https://doi.org/10.1055/s-0034-1372346 CrossRefGoogle Scholar
  25. McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders mind the gap. Ann Neurol 67(6):699–714.  https://doi.org/10.1002/ana.22053 CrossRefPubMedGoogle Scholar
  26. Notter T, Coughlin JM, Sawa A, Meyer U (2018) Reconceptualization of translocator protein as a biomarker of Neuroinflammation in psychiatry. Mol Psychiatry 23(1). Nature Publishing Group):36–47.  https://doi.org/10.1038/mp.2017.232 CrossRefPubMedGoogle Scholar
  27. Owen DR, Qi Guo NJ, Kalk AC, Kalogiannopoulou D, Dimber R, Lewis YL et al (2014) Determination of [11C]PBR28 binding potential in vivo: A first human TSPO blocking study. J Cereb Blood Flow Metab 34(6). Nature Publishing Group):989–994.  https://doi.org/10.1038/jcbfm.2014.46 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Owen DR, Narayan N, Wells L, Healy L, Smyth E, Rabiner EA, Galloway D et al (2017) Pro-inflammatory activation of primary microglia and macrophages increases 18 KDa translocator protein expression in rodents but not humans. J Cereb Blood Flow Metab 37(8):2679–2690.  https://doi.org/10.1177/0271678X17710182 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Rissanen E, Tuisku J, Rokka J, Paavilainen T, Parkkola R, Rinne JO, Airas L (2014) In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using PET imaging and the Radioligand 11C-PK11195. J Nucl Med 55(6):939–944.  https://doi.org/10.2967/jnumed.113.131698 CrossRefPubMedGoogle Scholar
  30. Rubin LH, Sacktor N, Creighton J, Du Y, Endres CJ, Pomper MG, Coughlin JM (2018) Microglial activation is inversely associated with cognition in individuals living with HIV on effective antiretroviral therapy. AIDS 32(12):1661–1667.  https://doi.org/10.1097/QAD.0000000000001858 CrossRefPubMedGoogle Scholar
  31. Sanford R, Ances BM, Meyerhoff DJ, Price RW, Fuchs D, Zetterberg H, Spudich S, Louis Collins D (2018) Longitudinal trajectories of brain volume and cortical thickness in treated and untreated primary human immunodeficiency virus infection. Clin Infect Dis, no. August 67:1–8.  https://doi.org/10.1093/cid/ciy362 CrossRefGoogle Scholar
  32. Spudich S, González-Scarano F (2012) HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb Perspect Med 2(6):1–17.  https://doi.org/10.1101/cshperspect.a007120 CrossRefGoogle Scholar
  33. Tu LN, Morohaku K, Manna PR, Pelton SH, Butler WR, Stocco DM, Selvaraj V (2014) Peripheral benzodiazepine receptor/translocator protein global Knock-out mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem 289(40):27444–27454.  https://doi.org/10.1074/jbc.M114.578286 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Valcour V, Sithinamsuwan P, Letendre S, Ances B (2011) Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep 8(1):54–61.  https://doi.org/10.1007/s11904-010-0070-4 CrossRefPubMedGoogle Scholar
  35. Veenman L, Gavish M (2012) The role of 18 KDa mitochondrial translocator protein (TSPO) in programmed cell death, and effects of steroids on TSPO expression. Curr Mol Med 12:398–412.  https://doi.org/10.2174/156652412800163343 CrossRefPubMedGoogle Scholar
  36. Vera JH, Qi G, Cole JH, Boasso A, Greathead L, Kelleher P, Rabiner EA et al (2016) Neuroinflammation in treated HIV-positive individuals. Neurology 86(15):1425–1432.  https://doi.org/10.1212/WNL.0000000000002485 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Wiley CA, Lopresti BJ, Becker JT, Boada F, Lopez OL, Mellors J, Meltzer CC, Wisniewski SR, Mathis CA (2006) Positron emission tomography imaging of peripheral benzodiazepine receptor binding in human immunodeficiency virus-infected subjects with and without cognitive impairment. J Neurovirol 12(4):262–271.  https://doi.org/10.1080/13550280600873868 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyWashington University in Saint LouisSt. LouisUSA
  2. 2.Hope Center for Neurological DisordersWashington University in St. LouisSt. LouisUSA

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