Skip to main content

Advertisement

Log in

Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [11C]DPA-713, we conducted a positron emission tomography (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [11C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher volume-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-associated dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test–retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

HAND:

HIV-associated neurocognitive disorder

HAD:

HIV-associated dementia

cART:

Combination antiretroviral therapy

TSPO:

Translocator protein

PET:

Positron emission tomography

References

  • Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799

    Article  CAS  PubMed  Google Scholar 

  • Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH, Imaizumi M, Hong J, Pike VW, Innis RB (2007) Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J NuclMed: Off Publ, Soc Nucl Med 48:2072–2079

    CAS  Google Scholar 

  • Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B (2008) Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imag 35:2304–2319

    Article  Google Scholar 

  • 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: Off Publ, Soc Nucl Med 50:468–476

    Article  CAS  Google Scholar 

  • Chen Y, An H, Zhu H, Stone T, Smith JK, Hall C, Bullitt E, Shen D, Lin W (2009) White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV + patients. NeuroImage 47:1154–1162

    Article  PubMed  Google Scholar 

  • Chiang MC, Dutton RA, Hayashi KM, Lopez OL, Aizenstein HJ, Toga AW, Becker JT, Thompson PM (2007) 3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry. NeuroImage 34:44–60

    Article  PubMed Central  PubMed  Google Scholar 

  • Churchill M, Nath A (2013) Where does HIV hide? A focus on the central nervous system. Curr Opin HIV and AIDS 8:165–169

    Article  CAS  Google Scholar 

  • Cysique LA, Moffat K, Moore DM, Lane TA, Davies NW, Carr A, Brew BJ, Rae C (2013) HIV, vascular and aging injuries in the brain of clinically stable HIV-infected adults: a (1)H MRS study. PloS one 8:e61738

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC (2009) Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med: Off Publ, Soc Nucl Med 50:1801–1807

    Article  Google Scholar 

  • Drugan RC (1996) Peripheral benzodiazepine receptors: molecular pharmacology to possible physiological significance in stress-induced hypertension. Clin Neuropharmacol 19:475–496

    Article  CAS  PubMed  Google Scholar 

  • Endres CJ, Coughlin JM, Gage KL, Watkins CC, Kassiou M, Pomper MG (2012) Radiation dosimetry and biodistribution of the TSPO ligand 11C-DPA-713 in humans. J Nucl Med: Off Publ, Soc Nucl Med 53:330–335

    Article  CAS  Google Scholar 

  • Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC, Reynolds A, Hilton J, Dannals RF, Kassiou M (2009) Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med: Off Publ, Soc Nucl Med 50:1276–1282

    Article  CAS  Google Scholar 

  • Garvey LJ, Pavese N, Politis M, Ramlackhansingh A, Brooks DJ, Taylor-Robinson SD, Winston A (2013) Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART; An 11C–PK11195 PET study. Aids

  • Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (1999) Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 51:629–650

    CAS  PubMed  Google Scholar 

  • Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, McArthur JC, Pomper MG (2005) Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J Neurovirol 11:346–355

    Article  CAS  PubMed  Google Scholar 

  • Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C, Group H (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17:3–16

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jucaite A, Cselenyi Z, Arvidsson A, Ahlberg G, Julin P, Varnas K, Stenkrona P, Andersson J, Halldin C, Farde L (2012) Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain—a PET study in control subjects. EJNMMI Res 2:15

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994

    Article  CAS  PubMed  Google Scholar 

  • Kreisl WC, Jenko KJ, Hines CS, Hyoung Lyoo C, Corona W, Morse CL, Zoghbi SS, Hyde T, Kleinman JE, Pike VW, McMahon FJ, Innis RB, Biomarkers Consortium PETRPT (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. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 33:53–58

    Article  CAS  Google Scholar 

  • Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, Corona W, Morse CL, Zoghbi SS, Pike VW, McMahon FJ, Turner RS, Innis RB, Biomarkers Consortium PETRPT (2013b) In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease. Brain: J Neurol 136:2228–2238

    Article  Google Scholar 

  • Kuper M, Rabe K, Esser S, Gizewski ER, Husstedt IW, Maschke M, Obermann M (2011) Structural gray and white matter changes in patients with HIV. J Neurol 258:1066–1075

    Article  PubMed  Google Scholar 

  • Lopez-Villegas D, Lenkinski RE, Frank I (1997) Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy. Proc Natl Acad Sci U S A 94:9854–9859

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Marder K, Albert SM, McDermott MP, McArthur JC, Schifitto G, Selnes OA, Sacktor N, Stern Y, Palumbo D, Kieburtz K, Cohen B, Orme C, Epstein LG (2003) Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment. Neurology 60:1467–1473

    Article  CAS  PubMed  Google Scholar 

  • Melrose RJ, Tinaz S, Castelo JM, Courtney MG, Stern CE (2008) Compromised fronto-striatal functioning in HIV: an fMRI investigation of semantic event sequencing. Behav Brain Res 188:337–347

    Article  PubMed  Google Scholar 

  • Mizrahi R, Rusjan PM, Kennedy J, Pollock B, Mulsant B, Suridjan I, De Luca V, Wilson AA, Houle S (2012) Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 32:968–972

    Article  CAS  Google Scholar 

  • Mohamed MA, Lentz MR, Lee V, Halpern EF, Sacktor N, Selnes O, Barker PB, Pomper MG (2010) Factor analysis of proton MR spectroscopic imaging data in HIV infection: metabolite-derived factors help identify infection and dementia. Radiology 254:577–586

    Article  PubMed Central  PubMed  Google Scholar 

  • Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, Innis RB, Pike VW, Reynolds R, Matthews PM, Parker CA (2011) Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med: Off Publ, Soc Nucl Med 52:24–32

    Article  CAS  Google Scholar 

  • Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 32:1–5

    Article  CAS  Google Scholar 

  • Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (2006) Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trend Pharmacol Sci 27:402–409

    Article  CAS  Google Scholar 

  • Rahmim A, Lenox M, Reader AJ, Michel C, Burbar Z, Ruth TJ, Sossi V (2004) Statistical list-mode image reconstruction for the high resolution research tomograph. Phys Med Biol 49:4239–4258

    Article  CAS  PubMed  Google Scholar 

  • Roberts ES, Chana G, Nguyen TB, Perera G, Landau S, Rabe-Hesketh S, Glass JD, McArthur J, Everall IP (2013) The spatial relationship between neurons and astrocytes in HIV-associated dementia. J Neurovirol 19:123–130

    Article  PubMed  Google Scholar 

  • Rusjan PM, Wilson AA, Bloomfield PM, Vitcu I, Meyer JH, Houle S, Mizrahi R (2011) Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 31:1807–1816

    Article  CAS  Google Scholar 

  • Spudich S (2013) HIV and Neurocognitive Dysfunction. Curr HIV/AIDS Report 10:235–243

    Article  Google Scholar 

  • Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, Gerhard A, Hinz R, Tai YF, Brooks DJ (2007) Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med: Off Publ, Soc Nucl Med 48:158–167

    Google Scholar 

  • Venneti S, Lopresti BJ, Wiley CA (2006) The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol 80:308–322

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang X, Foryt P, Ochs R, Chung JH, Wu Y, Parrish T, Ragin AB (2011) Abnormalities in resting-state functional connectivity in early human immunodeficiency virus infection. Brain Connect 1:207–217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 12:262–271

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Wang M, Li H, Zhang H, Shi Y, Wei F, Liu D, Liu K, Chen D (2012) Accumulation of nuclear and mitochondrial DNA damage in the frontal cortex cells of patients with HIV-associated neurocognitive disorders. Brain Res 1458:1–11

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge NIH 5R21MH082277, NIH 5R01MH092443, NIH R01EB012547, NIEHS ES007062, NIH 5T32EB006351, the Lupus Foundation for America and NFL Charities for financial support. We are also grateful to Alimamy Kargbo for performing PET metabolite analyses, to Dean Wong, M.D., Ph.D. for sharing his knowledge and ideas, and to the Johns Hopkins PET Center for provision of the radiotracer.

Disclosure/Conflict of Interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin G. Pomper.

Additional information

Support

NIH 5R21MH082277, NIH 5R01MH092443, NIH R01EB012547, NIH 5T32EB006351, NIEHS ES007062, Lupus Foundation of America, NFL Charities.

Coughlin and Wang equally contributed to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 69 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coughlin, J.M., Wang, Y., Ma, S. et al. Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV. J. Neurovirol. 20, 219–232 (2014). https://doi.org/10.1007/s13365-014-0239-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-014-0239-5

Keywords

Navigation