Date Published:
2019 May

Publication Type:
Journal Article

Authors:

A.R. Kallianpur
H. Gittleman
S. Letendre
R. Ellis
J.S. Barnholtz-Sloan
W.S. Bush
R. Heaton
D.C. Samuels
D.R. Franklin
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

Secondary:
Mol Neurobiol

Volume:
56

Pagination:
3808-3818

Issue:
5

PMID:
30209774

URL:
https://pubmed.ncbi.nlm.nih.gov/30209774

DOI:
10.1007/s12035-018-1329-9

Keywords:
Adult;Antiretroviral Therapy, Highly Active;Biomarkers;Ceruloplasmin;CHARTER;Comorbidity;Female;Haptoglobins;HIV Infections;Humans;Inflammation;Internal;Iron;Male;Multivariate Analysis;neurocognitive disorders;Regression Analysis;Vascular Endothelial Growth Factor A

Abstract:
<p>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.</p>