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

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Abstract

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.

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Data Availability

All data and datasets used for the analyses reported herein will be made available upon request.

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Acknowledgements

We are grateful to all of the individuals who participated in this study. We also acknowledge the efforts of other CHARTER Study Group members who assisted in recruitment at participating study sites:

Other CHARTER Study Group members

In addition to the authors, the CHARTER study is affiliated with the following six participating study sites: Johns Hopkins University; the Icahn School of Medicine at Mount Sinai; University of California, San Diego; University of Texas, Galveston; University of Washington, Seattle; and Washington University, St. Louis. CHARTER is headquartered at the University of California, San Diego and includes Director: Igor Grant, M.D.; Co-Directors: Scott L. Letendre, M.D., Ronald J. Ellis, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D.; Laboratory and Virology Component: Scott Letendre, M.D. (Co-P.I.), Davey M. Smith, M.D. (Co-P.I.).; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Matthew Dawson; Imaging Component: Christine Fennema-Notestine, Ph.D. (P.I.), Michael J Taylor, Ph.D., Rebecca Theilmann, Ph.D.; Data Management Component: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman; Statistics Component: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Johns Hopkins University Site: Ned Sacktor (P.I.), Vincent Rogalski; Icahn School of Medicine at Mount Sinai Site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P.; University of California, San Diego Site: J. Allen McCutchan, M.D. (P.I.); University of Washington, Seattle Site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Sher Storey, PA-C.; University of Texas, Galveston Site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N.; and Washington University, St. Louis Site: David Clifford, M.D. (P.I.), Muhammad Al-Lozi, M.D., Mengesha Teshome, M.D.

Code Availability

Not applicable.

Funding

This work was supported by National Institutes of Health grant 1R01 MH095621 (to AK and TH). The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study was also supported by National Institutes of Health awards NIH R01 MH107345 (to SL and RH).

Author information

Author notes

  1. Harpreet Kaur and Asha R. Kallianpur contributed equally to this work.

Authors and Affiliations

  1. Genomic Medicine Institute, Cleveland Clinic/Lerner Research Institute, 9500 Euclid Ave/Mail Code R4-008, Cleveland, OH, 44195, USA

    Harpreet Kaur & Asha R. Kallianpur

  2. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    William S. Bush & Asha R. Kallianpur

  3. Departments of Medicine and Psychiatry, University of California-San Diego, San Diego, CA, USA

    Scott L. Letendre

  4. Departments of Neurology and Psychiatry, University of California-San Diego, San Diego, CA, USA

    Ronald J. Ellis

  5. Department of Psychiatry, University of California-San Diego, San Diego, CA, USA

    Robert K. Heaton & Donald R. Franklin

  6. Department of Neurosurgery, Pennsylvania State/Hershey College of Medicine, Hershey, PA, USA

    Stephanie M. Patton & James R. Connor

  7. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA

    David C. Samuels

  8. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Todd Hulgan

  9. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    Asha R. Kallianpur

Authors
  1. Harpreet Kaur
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  2. William S. Bush
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  3. Scott L. Letendre
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  4. Ronald J. Ellis
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  5. Robert K. Heaton
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  6. Stephanie M. Patton
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  7. James R. Connor
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  8. David C. Samuels
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  9. Donald R. Franklin
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  10. Todd Hulgan
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  11. Asha R. Kallianpur
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Contributions

The first and last authors contributed equally to this work. All other authors reviewed the manuscript, provided helpful comments, and agreed to its submission for publication.

Corresponding author

Correspondence to Asha R. Kallianpur.

Ethics declarations

Ethics Approval

CHARTER is a multi-center study which has received continuous approval by the institutional review boards (IRBs) of all participating institutions/sites. IRB approval numbers can be provided upon request.

Consent to Participate

All CHARTER study participants provided written informed consent for the parent study that provided the de-identified CSF samples and data for this analysis.

Consent for Publication

All authors provided consent for publication.

Conflict of Interest

Authors Kaur, Bush, Letendre, Franklin, Ellis, Hulgan, Heaton, Samuels, and Kallianpur have no potential conflicts of interest to disclose. Author S. Patton is a paid consultant for SideroBiosciences, Inc., and J.R. Connor, a longstanding collaborator, is co-founder and Chairman of the Board of SideroBiosciences, which has a product in clinical trials for treating iron deficiency.

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Supplementary Information

Supplemental Fig 1:

Changes in neurocognitive performance in CHARTER study participants, as measured by the Global Deficit Score (GDS) over time, in all three tertiles at baseline of CSF Fth1 and transferrin (panels a and b, respectively; both p<0.05 for tertiles 3 (red) vs. 1 (blue) of Fth1 over at 30 and 42 months (adjusting for comorbidity and plasma HIV RNA), and all p<0.01 for tertiles 3 vs. 1 of CSF transferrin at 30, 36, and 42 months, adjusting for comorbidity, zidovudine use and plasma HIV RNA). (PNG 183 kb)

High resolution image (EPS 119 kb)

Supplemental Fig 2:

Changes in GDS over time, in all three tertiles at CSF Fth1 among individuals with no/minimal comorbidity (panel a, p<0.05 at 30, 36, and 42 months) adjusting for plasma HIV RNA and in individuals who were virally suppressed (panel b, p<0.001 at 30, 36, and 42 months of follow-up), adjusting for comorbidity. (PNG 181 kb)

High resolution image (EPS 118 kb)

Supplemental Fig 3:

Changes in GDS over time in tertiles 3 vs. 1 of CSF transferrin among virally suppressed individuals (p>0.05 at 30, 36, and 42 months) adjusting for comorbidity and zidovudine use. (PNG 88 kb)

High resolution image (EPS 96 kb)

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Kaur, H., Bush, W.S., Letendre, S.L. et al. Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV. Mol Neurobiol 58, 4842–4855 (2021). https://doi.org/10.1007/s12035-021-02433-7

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