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Biomarker Evidence of Axonal Injury in Neuroasymptomatic HIV-1 Patients

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Jessen Krut, Jan, Mellberg, Tomas, Price, Richard W., Hagberg, Lars, Fuchs, Dietmar, Rosengren, Lars, Nilsson, Staffan, Zetterberg, Henrik +1 more·2014·PLoS ONE
DOI 10.1371/journal.pone.0088591PMC PMC3921217
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Abstract

BACKGROUND: Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL) in CSF with a novel, sensitive method. METHODS: With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL) (marker of neuronal injury), neopterin (intrathecal immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity) were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n = 204). 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation. RESULTS: While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups. CONCLUSIONS: Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

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  • Many HIV-1-positive individuals today still develop HIV-1-associated dementia despite improved prognosis with anti-retroviral therapy.

    “Human immunodeficiency virus (HIV)-1 prognosis greatly improved with the era of anti-retroviral therapy; however, many HIV-1-positive individuals today still develop HIV1-associated dementia (HAD) (292, 511).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [292]

    The Introduction says antiretroviral therapy has markedly reduced the incidence of HIV-associated dementia (HAD) in developed countries. It reports a 20–30% HAD risk without treatment, but the persistent problems it describes in treated patients are largely milder neurocognitive disorders, not evidence that many people today still develop HAD. (LLM, conf=0.87)

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Authors
Jessen Krut, J., Mellberg, T., Price, R. W., Hagberg, L., Fuchs, D., Rosengren, L., Nilsson, S., Zetterberg, H., & Gisslén, M.
Affiliations
  • University of Gothenburg (SE)
  • University of California, San Francisco (US)
  • Innsbruck Medical University (AT)
  • Chalmers University of Technology (SE)
  • National Hospital for Neurology and Neurosurgery (GB)
Corresponding author
Mellberg, Tomas
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-02-11
Volume
9
Issue
2
Pages
e88591
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0088591
PMC
PMC3921217
OpenAlex
W2128275881
Cited by
167
References
2
Citations by year
2026: 6 · 2025: 13 · 2024: 14 · 2023: 10 · 2022: 15 · 2021: 12 · 2020: 9 · 2019: 21 · 2018: 18 · 2017: 14 · 2016: 18 · 2015: 12 · 2014: 5
FWCI
7.29
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Chalmers Publication Library (Chalmers University of Technology) (submittedVersion)
  • Chalmers Research (Chalmers University of Technology) (submittedVersion)
Funders
  • Vetenskapsrådet (K2011‐61X‐20401‐05‐6, K2010-63P-21562-01-4, 21562)
  • Göteborgs Universitet
  • National Institutes of Health (RR024131)
  • University of California, San Francisco (UL1RR024131)
  • Sahlgrenska Akademin
  • National Institute of Mental Health (R01 MH62701, R01MH062701, R21MH096619, P01MH094177)
  • National Institute of Allergy and Infectious Diseases (P30AI027763)
  • National Center for Research Resources (UL1RR024131)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
HIV-associated neurocognitive disorders, axonal injury, neurofilament light chain, cerebrospinal fluid biomarkers, neopterin, blood-brain barrier integrity, neuroinflammation, antiretroviral therapy, HIV-associated dementia, CD4 count
MeSH terms
Adult, Axons, Cognition Disorders, Cross-Sectional Studies, Humans, Longitudinal Studies, Middle Aged, Neurons, Biomarkers, CD4-Positive T-Lymphocytes, HIV-1, AIDS Dementia Complex, HIV Infections, Case-Control Studies, Neurofilament Proteins, Neopterin

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