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Molecular Neurobiology

, Volume 56, Issue 5, pp 3808–3818 | Cite as

Cerebrospinal Fluid Ceruloplasmin, Haptoglobin, and Vascular Endothelial Growth Factor Are Associated with Neurocognitive Impairment in Adults with HIV Infection

  • A. R. KallianpurEmail author
  • H. Gittleman
  • S. Letendre
  • R. Ellis
  • J. S. Barnholtz-Sloan
  • W. S. Bush
  • R. Heaton
  • D. C. Samuels
  • D. R. FranklinJr
  • D. Rosario-Cookson
  • D. B. Clifford
  • A. C. Collier
  • B. Gelman
  • C. M. Marra
  • J. C. McArthur
  • J. A. McCutchan
  • S. Morgello
  • I. Grant
  • D. Simpson
  • J. R. Connor
  • T. Hulgan
  • the CHARTER Study Group
Article

Abstract

Dysregulated iron transport and a compromised blood–brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis—ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)—as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p = 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p = 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p = 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p = 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p < 0.05), and higher ceruloplasmin predicted worse impairment (higher cGDS values, p < 0.01). In the subgroup with undetectable viral load and minimal comorbidity, CSF ceruloplasmin and haptoglobin were strongly associated with GDS impairment (ORs 5.57 and 2.96, respectively; both p < 0.01) and HAND (both p < 0.01). Concurrently measured CSF IL-6 and TNF-α were only weakly correlated to these three biomarkers. Higher CSF ceruloplasmin, haptoglobin, and VEGF are associated with a significantly greater likelihood of HAND, suggesting that interventions aimed at disordered iron transport and angiogenesis may be beneficial in this disorder.

Keywords

Ceruloplasmin Haptoglobin Vascular endothelial growth factor Biomarker HIV-associated neurocognitive disorder Cerebrospinal fluid (CSF) 

Abbreviations

HAND

HIV-associated neurocognitive disorder

NC

Neurocognitive

ART

Combination antiretroviral therapy

CSF

Cerebrospinal fluid

VEGF

Vascular endothelial growth factor

TNF-α

Tumor necrosis factor-alpha

IL-6

Interleukin 6

CXCL-10

C-X-C chemokine motif ligand 10

cGDS/GDS

(continuous) Global Deficit Score

BBB

Blood–brain barrier

CHARTER

CNS HIV antiretroviral therapy effects research (study)

HCV

Hepatitis C virus

PC

Principal components

OR

Odds ratio

IQR

Interquartile range

T (1–3)

Tertile (1–3)

WRAT

Wide-range achievement test

Notes

Acknowledgments

The authors are indebted to all CHARTER study participants. They also wish to acknowledge the following CHARTER study site PIs at participating institutions: Justin McArthur (Johns Hopkins University School of Medicine, Baltimore, MD), Susan Morgello and David Simpson (Icahn School of Mt. Sinai, New York, NY), J. Allen McCutchan (University of California–San Diego, San Diego, CA), Ann Collier and Christina Marra (University of Washington, Seattle, WA), David Clifford (Washington University, St. Louis, MO), and Benjamin Gelman (University of Texas Medical Branch, Galveston, TX).

Authors’ Contributions

AK and TH designed, coordinated, and funded this study, and AK wrote the manuscript. HRG performed the analysis under the direction of JBS and AK and assisted in writing the statistical methods. DRF and DRC coordinated the selection of CSF samples, and DRC and SLL oversaw the laboratory assays. TH helped edit the manuscript. RJE, TH, SM, and JRC provided helpful comments on the manuscript. All remaining co-authors are CHARTER study investigators and/or site PIs, who assisted in the enrollment of participants and collection of primary data. All authors read and approved the final manuscript.

Funding

Funding for this study was provided by National Institutes of Health (NIH) R01 MH095621 (to T. Hulgan and A. Kallianpur), NIH N01 MH22005, HHSN271201000036C, and HHSN271201000030C (PI, I. Grant), NIH R01 MH107345 (PIs, S. Letendre and R. Heaton), and K24 MH097673 (PI, S. Letendre).

Compliance with Ethical Standards

Ethics Approval and Consent to Participate

The CHARTER study abides by the principles set forth in the Declaration of Helsinki. All study participants provided written informed consent, and only de-identified data was used in the present analysis. The Institutional Review Boards of all participating institutions approved the study.

Consent for Publication

All subjects provided written informed consent to participate in the study. No individual’s protected health information is included in this report.

Conflicts of Interest

The authors declare that they have no potential conflicts of interest.

Supplementary material

12035_2018_1329_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 14 kb)

References

  1. 1.
    Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A et al (2016) HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat Rev Neurol 12:309CrossRefGoogle Scholar
  2. 2.
    Fields JA, Dumaop W, Crews L, Adame A, Spencer B, Metcalf J, He J, Rockenstein E et al (2015) Mechanisms of HIV-1 tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders. Curr HIV Res 13:43–54CrossRefGoogle Scholar
  3. 3.
    Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, Letendre SL, Marcotte TD et al (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055–2062CrossRefGoogle Scholar
  4. 4.
    Avci G, Sheppard DP, Tierney SM, Kordovski VM, Sullivan KL, Woods SP (2017) A systematic review of prospective memory in HIV disease: from the laboratory to daily life. Clin Neuropsychol:1–33Google Scholar
  5. 5.
    Group MEW (2013) Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program. Clin Infect Dis 56:1004–1017CrossRefGoogle Scholar
  6. 6.
    Patton SM, Wang Q, Hulgan T, Connor JR, Jia P, Zhao Z, Letendre SL, Ellis RJ et al (2017) Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults. Fluids and barriers of the CNS 14:11CrossRefGoogle Scholar
  7. 7.
    Rozzi SJ, Avdoshina V, Fields JA, Trejo M, Ton HT, Ahern GP, Mocchetti I (2017) Human immunodeficiency virus promotes mitochondrial toxicity. Neurotox Res 32:723–733CrossRefGoogle Scholar
  8. 8.
    Cherayil BJ (2010) Iron and immunity: immunological consequences of iron deficiency and overload. Arch Immunol Ther Exp 58:407–415CrossRefGoogle Scholar
  9. 9.
    Saghiri MA, Asatourian A, Orangi J, Sorenson CM, Sheibani N (2015) Functional role of inorganic trace elements in angiogenesis—part I: N, Fe, Se, P, Au, and Ca. Crit Rev Oncol Hematol 96:129–142CrossRefGoogle Scholar
  10. 10.
    Bhatia NS, Chow FC (2016) Neurologic complications in treated HIV-1 infection. Curr Neurol Neurosci Rep 16:62CrossRefGoogle Scholar
  11. 11.
    Eden A, Marcotte TD, Heaton RK, Nilsson S, Zetterberg H, Fuchs D, Franklin D, Price RW et al (2016) Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One 11:e0157160CrossRefGoogle Scholar
  12. 12.
    Janelidze S, Hertze J, Nagga K, Nilsson K, Nilsson C, Swedish Bio FSG, Wennstrom M, van Westen D et al (2017) Increased blood–brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol Aging 51:104–112CrossRefGoogle Scholar
  13. 13.
    Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S, Solomon T (2014) Controversies in HIV-associated neurocognitive disorders. Lancet Neurol 13:1139–1151CrossRefGoogle Scholar
  14. 14.
    Burkhart A, Skjorringe T, Johnsen KB, Siupka P, Thomsen LB, Nielsen MS, Thomsen LL, Moos T (2015) Expression of iron-related proteins at the neurovascular unit supports reduction and reoxidation of iron for transport through the blood–brain barrier. Mol NeurobiolGoogle Scholar
  15. 15.
    McCarthy RC, Kosman DJ (2014) Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. PLoS One 9:e89003CrossRefGoogle Scholar
  16. 16.
    Mehta SR, Perez-Santiago J, Hulgan T, Day TR, Barnholtz-Sloan J, Gittleman H, Letendre S, Ellis R et al (2017) Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment. J Neuroinflammation 14:72CrossRefGoogle Scholar
  17. 17.
    Buechler C, Eisinger K, Krautbauer S (2013) Diagnostic and prognostic potential of the macrophage specific receptor CD163 in inflammatory diseases. Inflamm Allergy Drug Targets 12:391–402CrossRefGoogle Scholar
  18. 18.
    Thomsen JH, Etzerodt A, Svendsen P, Moestrup SK (2013) The haptoglobin-CD163-heme oxygenase-1 pathway for hemoglobin scavenging. Oxidative Med Cell Longev 2013:523652CrossRefGoogle Scholar
  19. 19.
    Burdo TH, Weiffenbach A, Woods SP, Letendre S, Ellis RJ, Williams KC (2013) Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. Aids 27:1387–1395CrossRefGoogle Scholar
  20. 20.
    Lange C, Storkebaum E, de Almodovar CR, Dewerchin M, Carmeliet P (2016) Vascular endothelial growth factor: a neurovascular target in neurological diseases. Nat Rev Neurol 12:439–454CrossRefGoogle Scholar
  21. 21.
    Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096CrossRefGoogle Scholar
  22. 22.
    Samuels DC, Kallianpur AR, Ellis RJ, Bush WS, Letendre S, Franklin D, Grant I, Hulgan T (2016) European mitochondrial DNA haplogroups are associated with cerebrospinal fluid biomarkers of inflammation in HIV infection. Pathog Immun 1:330–351CrossRefGoogle Scholar
  23. 23.
    Hulgan T, Samuels DC, Bush W, Ellis RJ, Letendre SL, Heaton RK, Franklin DR, Straub P et al (2015) Mitochondrial DNA haplogroups and neurocognitive impairment during HIV infection. Clin Infect Dis 61:1476–1484CrossRefGoogle Scholar
  24. 24.
    Kallianpur AR, Wang Q, Jia P, Hulgan T, Zhao Z, Letendre SL, Ellis RJ, Heaton RK et al (2016) Anemia and red blood cell indices predict HIV-associated neurocognitive impairment in the highly active antiretroviral therapy era. J Infect Dis 213:1065–1073CrossRefGoogle Scholar
  25. 25.
    Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799CrossRefGoogle Scholar
  26. 26.
    Jia P, Zhao Z, Hulgan T, Bush WS, Samuels DC, Bloss CS, Heaton RK, Ellis RJ et al (2017) Genome-wide association study of HIV-associated neurocognitive disorder (HAND): a CHARTER group study. Am J Med Genet B Neuropsychiatr Genet 174:413–426CrossRefGoogle Scholar
  27. 27.
    Jiang R, Hua C, Wan Y, Jiang B, Hu H, Zheng J, Fuqua BK, Dunaief JL et al (2015) Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain. J Nutr 145:1003–1009CrossRefGoogle Scholar
  28. 28.
    Rozek W, Horning J, Anderson J, Ciborowski P (2008) Sera proteomic biomarker profiling in HIV-1 infected subjects with cognitive impairment. Proteomics Clin Appl 2:1498–1507CrossRefGoogle Scholar
  29. 29.
    McCarthy RC, Kosman DJ (2015) Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy. Cell Mol Life Sci 72:709–727CrossRefGoogle Scholar
  30. 30.
    Marques L, Auriac A, Willemetz A, Banha J, Silva B, Canonne-Hergaux F, Costa L (2012) Immune cells and hepatocytes express glycosylphosphatidylinositol-anchored ceruloplasmin at their cell surface. Blood Cells Mol Dis 48:110–120CrossRefGoogle Scholar
  31. 31.
    Burdo TH, Lackner A, Williams KC (2013) Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev 254:102–113CrossRefGoogle Scholar
  32. 32.
    Texel SJ, Camandola S, Ladenheim B, Rothman SM, Mughal MR, Unger EL, Cadet JL, Mattson MP (2012) Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J Neurochem 120:125–134CrossRefGoogle Scholar
  33. 33.
    Kallianpur AR, Levine AJ (2014) Host genetic factors predisposing to HIV-associated neurocognitive disorder. Current HIV/AIDS reports 11:336–352CrossRefGoogle Scholar
  34. 34.
    Kallianpur AR, C. J., Coe CC, Gelman BB (2014) Brain iron transport is associated with neurocognitive performance in HIV/AIDS. In 21st conference on retroviruses and opportunistic infections; March 5–8, Boston, MA, USA.Google Scholar
  35. 35.
    Harned J, Ferrell J, Nagar S, Goralska M, Fleisher LN, McGahan MC (2012) Ceruloplasmin alters intracellular iron regulated proteins and pathways: ferritin, transferrin receptor, glutamate and hypoxia-inducible factor-1alpha. Exp Eye Res 97:90–97CrossRefGoogle Scholar
  36. 36.
    Wang H, Li C, Wang H, Mei F, Liu Z, Shen HY, Xiao L (2013) Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit. Neurosci Bull 29:251–259CrossRefGoogle Scholar
  37. 37.
    Ayton S, Zhang M, Roberts BR, Lam LQ, Lind M, McLean C, Bush AI, Frugier T et al (2014) Ceruloplasmin and beta-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron. Free Radic Biol Med 69:331–337CrossRefGoogle Scholar
  38. 38.
    Granziera C, Daducci A, Simioni S, Cavassini M, Roche A, Meskaldji D, Kober T, Metral M et al (2013) Micro-structural brain alterations in aviremic HIV+ patients with minor neurocognitive disorders: a multi-contrast study at high field. PLoS One 8:e72547CrossRefGoogle Scholar
  39. 39.
    Lee KH, Yun SJ, Nam KN, Gho YS, Lee EH (2007) Activation of microglial cells by ceruloplasmin. Brain Res 1171:1–8CrossRefGoogle Scholar
  40. 40.
    Potter MC, Figuera-Losada M, Rojas C, Slusher BS (2013) Targeting the glutamatergic system for the treatment of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol 8:594–607CrossRefGoogle Scholar
  41. 41.
    Gill AJ, Kovacsics CE, Cross SA, Vance PJ, Kolson LL, Jordan-Sciutto KL, Gelman BB, Kolson DL (2014) Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. J Clin Invest 124:4459–4472CrossRefGoogle Scholar
  42. 42.
    Wobeto VPD, Zaccariotto TR, Sonati MDF (2008) Polymorphism of human haptoglobin and its clinical importance. Genet Mol Biol 31:602–620CrossRefGoogle Scholar
  43. 43.
    Awadallah SM, Nimer NA, Atoum MF, Saleh SA (2011) Association of haptoglobin phenotypes with ceruloplasmin ferroxidase activity in beta-thalassemia major. Clin Chimica Acta; Int J Clin Chem 412:975–979CrossRefGoogle Scholar
  44. 44.
    Moestrup SK, Moller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 36:347–354CrossRefGoogle Scholar
  45. 45.
    Spitsin S, Stevens KE, Douglas SD (2013) Expression of substance P, neurokinin-1 receptor and immune markers in the brains of individuals with HIV-associated neuropathology. J Neurol Sci 334:18–23CrossRefGoogle Scholar
  46. 46.
    Tuluc F, Meshki J, Spitsin S, Douglas SD (2014) HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J Leukoc Biol 96:143–150CrossRefGoogle Scholar
  47. 47.
    Tippett E, Cheng WJ, Westhorpe C, Cameron PU, Brew BJ, Lewin SR, Jaworowski A, Crowe SM (2011) Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals. PLoS One 6:e19968CrossRefGoogle Scholar
  48. 48.
    Vallon M, Chang J, Zhang H, Kuo CJ (2014) Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci 71:3489–3506CrossRefGoogle Scholar
  49. 49.
    Sporer B, Koedel U, Paul R, Eberle J, Arendt G, Pfister HW (2004) Vascular endothelial growth factor (VEGF) is increased in serum, but not in cerebrospinal fluid in HIV associated CNS diseases. J Neurol Neurosurg Psychiatry 75:298–300CrossRefGoogle Scholar
  50. 50.
    Rosenberg GA (2012) Neurological diseases in relation to the blood–brain barrier. J Cereb Blood Flow Metab 32:1139–1151CrossRefGoogle Scholar
  51. 51.
    Scheidegger P, Weiglhofer W, Suarez S, Console S, Waltenberger J, Pepper MS, Jaussi R, Ballmer-Hofer K (2001) Signalling properties of an HIV-encoded angiogenic peptide mimicking vascular endothelial growth factor activity. Biochem J 353:569–578CrossRefGoogle Scholar
  52. 52.
    Khan NA, Di Cello F, Nath A, Kim KS (2003) Human immunodeficiency virus type 1 tat-mediated cytotoxicity of human brain microvascular endothelial cells. J Neurovirol 9:584–593CrossRefGoogle Scholar
  53. 53.
    Capo CR, Arciello M, Squitti R, Cassetta E, Rossini PM, Calabrese L, Rossi L (2008) Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer's disease patients. Biometals 21:367–372CrossRefGoogle Scholar
  54. 54.
    Rahimy E, Li FY, Hagberg L, Fuchs D, Robertson K, Meyerhoff DJ, Zetterberg H, Price RW et al (2017) Blood–brain barrier disruption is initiated during primary HIV infection and not rapidly altered by antiretroviral therapy. J Infect Dis 215:1132–1140CrossRefGoogle Scholar
  55. 55.
    Borda JT, Alvarez X, Mohan M, Hasegawa A, Bernardino A, Jean S, Aye P, Lackner AA (2008) CD163, a marker of perivascular macrophages, is up-regulated by microglia in simian immunodeficiency virus encephalitis after haptoglobin–hemoglobin complex stimulation and is suggestive of breakdown of the blood–brain barrier. Am J Pathol 172:725–737CrossRefGoogle Scholar
  56. 56.
    Zhao X, Song S, Sun G, Strong R, Zhang J, Grotta JC, Aronowski J (2009) Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 29:15819–15827CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • A. R. Kallianpur
    • 1
    • 2
    Email author
  • H. Gittleman
    • 3
  • S. Letendre
    • 4
  • R. Ellis
    • 5
  • J. S. Barnholtz-Sloan
    • 3
  • W. S. Bush
    • 3
  • R. Heaton
    • 6
  • D. C. Samuels
    • 7
  • D. R. FranklinJr
    • 6
  • D. Rosario-Cookson
    • 6
  • D. B. Clifford
    • 8
  • A. C. Collier
    • 9
  • B. Gelman
    • 10
  • C. M. Marra
    • 11
  • J. C. McArthur
    • 12
  • J. A. McCutchan
    • 4
  • S. Morgello
    • 13
    • 14
    • 15
  • I. Grant
    • 6
  • D. Simpson
    • 13
  • J. R. Connor
    • 16
  • T. Hulgan
    • 17
  • the CHARTER Study Group
  1. 1.Department of Genomic Medicine and Department of Medicine, Cleveland ClinicLerner Research InstituteClevelandUSA
  2. 2.Department of Molecular MedicineCleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityClevelandUSA
  3. 3.Department of Population and Quantitative Health SciencesCase Western Reserve University School of MedicineClevelandUSA
  4. 4.Department of MedicineUniversity of California–San DiegoSan DiegoUSA
  5. 5.Department of NeurologyUniversity of California–San DiegoSan DiegoUSA
  6. 6.Department of PsychiatryUniversity of California–San DiegoSan DiegoUSA
  7. 7.Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleUSA
  8. 8.Department of NeurologyWashington University School of MedicineSt. LouisUSA
  9. 9.Department of MedicineUniversity of Washington School of MedicineSeattleUSA
  10. 10.Department of PathologyUniversity of Texas Medical BranchGalvestonUSA
  11. 11.Department of NeurologyUniversity of Washington School of MedicineSeattleUSA
  12. 12.Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  13. 13.Department of NeurologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  14. 14.Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  15. 15.Department of PathologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  16. 16.Department of NeurosurgeryPennsylvania State Hershey Medical CenterHersheyUSA
  17. 17.Department of MedicineVanderbilt University Medical CenterNashvilleUSA

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