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Mol Neurobiol. 2018 Sep 12. doi: 10.1007/s12035-018-1329-9. [Epub ahead of print]

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

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Department of Genomic Medicine and Department of Medicine, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue/NE50, Cleveland, OH, USA.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Department of Medicine, University of California-San Diego, San Diego, CA, USA.
Department of Neurology, University of California-San Diego, San Diego, CA, USA.
Department of Psychiatry, University of California-San Diego, San Diego, CA, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neurosurgery, Pennsylvania State Hershey Medical Center, Hershey, PA, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.


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.


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


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