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


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.


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



HIV-associated neurocognitive disorder




Combination antiretroviral therapy


Cerebrospinal fluid


Vascular endothelial growth factor


Tumor necrosis factor-alpha


Interleukin 6


C-X-C chemokine motif ligand 10


(continuous) Global Deficit Score


Blood–brain barrier


CNS HIV antiretroviral therapy effects research (study)


Hepatitis C virus


Principal components


Odds ratio


Interquartile range

T (1–3)

Tertile (1–3)


Wide-range achievement test



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 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)


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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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