Cerebrospinal Fluid Ceruloplasmin, Haptoglobin, and Vascular Endothelial Growth Factor Are Associated with Neurocognitive Impairment in Adults with HIV Infection
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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.
KeywordsCeruloplasmin Haptoglobin Vascular endothelial growth factor Biomarker HIV-associated neurocognitive disorder Cerebrospinal fluid (CSF)
HIV-associated neurocognitive disorder
Combination antiretroviral therapy
Vascular endothelial growth factor
Tumor necrosis factor-alpha
C-X-C chemokine motif ligand 10
(continuous) Global Deficit Score
CNS HIV antiretroviral therapy effects research (study)
Hepatitis C virus
- T (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).
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.
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