Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV

• Published in: Molecular neurobiology 2021-10, Vol.58 (10), p.4842-4855
• Main Authors: Kaur, Harpreet, Bush, William S., Letendre, Scott L., Ellis, Ronald J., Heaton, Robert K., Patton, Stephanie M., Connor, James R., Samuels, David C., Franklin, Donald R., Hulgan, Todd, Kallianpur, Asha R.
• Format: Article
• Language: English
• Subjects: Adult; AIDS Dementia Complex - cerebrospinal fluid; AIDS Dementia Complex - diagnosis; AIDS Dementia Complex - psychology; Alzheimer's disease; Antiretroviral drugs; Antiretroviral therapy; Bioavailability; Biomarkers - cerebrospinal fluid; Biomedical and Life Sciences; Biomedicine; Brain injury; Brain research; Cell Biology; Cerebrospinal fluid; Charters; Cognition; Comorbidity; Drug therapy; Female; Ferritin; Ferritins - cerebrospinal fluid; HIV; HIV Infections - cerebrospinal fluid; HIV Infections - diagnosis; HIV Infections - psychology; Homeostasis; Human immunodeficiency virus; Humans; Hypotheses; Infections; Inflammation; Interleukin 6; Iron; Longitudinal Studies; Male; Medicine; Mental Status and Dementia Tests; Metabolism; Middle Aged; Myelination; Neurobiology; Neurology; Neuroprotection; Neurosciences; Oxidoreductases - cerebrospinal fluid; Predictive Value of Tests; Prospective Studies; Proteins; Psychiatry; Substantia alba; Transferrin - cerebrospinal fluid; Transferrins; Tumor necrosis factor-α; Viremia
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02433-7

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30–42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH ( p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.