Top

Published in:

01-02-2017

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

Authors: Albert M. Anderson, Jeffrey L. Lennox, Mark M. Mulligan, David W. Loring, Henrik Zetterberg, Kaj Blennow, Cari Kessing, Rajeth Koneru, Kirk Easley, William R. Tyor

Published in: Journal of NeuroVirology | Issue 1/2017

Abstract

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/μl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = −0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.

Abbott RJ, Bolderson I, Gruer PJ (1987) Assessment of an immunoassay for interferon-alpha in cerebrospinal fluid as a diagnostic aid in infections of the central nervous system. J Infect 15:153–160CrossRefPubMed

Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799CrossRefPubMedPubMedCentral

Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK, Hnrc Group (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26:307–319

Cysique LA, Hewitt T, Croitoru-Lamoury J, Taddei K, Martins RN, Chew CS, Davies NN, Price P, Brew BJ (2015) APOE epsilon4 moderates abnormal CSF-abeta-42 levels, while neurocognitive impairment is associated with abnormal CSF tau levels in HIV+ individuals - a cross-sectional observational study. BMC Neurol 15:51CrossRefPubMedPubMedCentral

Fritz-French C, Tyor W (2012) Interferon-alpha (IFNalpha) neurotoxicity. Cytokine Growth Factor Rev 23:7–14CrossRefPubMed

Fritz-French C, Shawahna R, Ward JE, Maroun LE, Tyor WR (2014) The recombinant vaccinia virus gene product, B18R, neutralizes interferon alpha and alleviates histopathological complications in an HIV encephalitis mouse model. J Interf Cytokine Res 34:510–517CrossRef

Hagberg L, Cinque P, Gisslen M, Brew BJ, Spudich S, Bestetti A, Price RW, Fuchs D (2010) Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res Ther 7:15CrossRefPubMedPubMedCentral

Hardy GA, Sieg S, Rodriguez B, Anthony D, Asaad R, Jiang W, Mudd J, Schacker T, Funderburg NT, Pilch-Cooper HA, Debernardo R, Rabin RL, Lederman MM, Harding CV (2013) Interferon-alpha is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers. PLoS One 8:e56527CrossRefPubMedPubMedCentral

Heaton RK, Miller SW, Taylor MJ, Grant I (2004) Revised Comprehensive norms for an expanded Halstead- Reitan Battery: Demographically adjusted neuropsycho-logical norms for African American and Caucasian adults scoring program.

Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, RJ E, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, OR V, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, CHARTER group (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–2096

Kakumu S, Fuji A, Yoshioka K, Tahara H (1989) Serum levels of alpha-interferon and gamma-interferon in patients with acute and chronic viral hepatitis. Hepato-Gastroenterology 36:97–102PubMed

Kessing CF, Tyor WR (2015) Interferon-alpha induces neurotoxicity through activation of the type I receptor and the GluN2A subunit of the NMDA receptor. J Interf Cytokine Res 35:317–324CrossRef

Marcotte TD, Deutsch R, Michael BD, Franklin D, Cookson DR, Bharti AR, Grant I, Letendre SL, for the CHARTER group (2013). A concise panel of biomarkers identifies neurocognitive functioning changes in HIV-infected individuals. J Neuroimmune Pharmacol.

Peterson J, Gisslen M, Zetterberg H, Fuchs D, Shacklett BL, Hagberg L, Yiannoutsos CT, Spudich SS, Price RW (2014) Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection. PLoS One 9:e116081CrossRefPubMedPubMedCentral

Potter MC, Figuera-Losada M, Rojas C, Slusher BS (2013) Targeting the glutamatergic system for the treatment of HIV-associated neurocognitive disorders. J NeuroImmune Pharmacol 8:594–607CrossRefPubMedPubMedCentral

Quarantini LC, Miranda-Scippa A, Schinoni MI, Sampaio AS, Santos-Jesus R, Bressan RA, Tatsch F, de Oliveira I, Parana R (2006) Effect of amantadine on depressive symptoms in chronic hepatitis C patients treated with pegylated interferon: a randomized, controlled pilot study. Clin Neuropharmacol 29:138–143PubMed

Rho MB, Wesselingh S, Glass JD, McArthur JC, Choi S, Griffin J, Tyor WR (1995) A potential role for interferon-alpha in the pathogenesis of HIV-associated dementia. Brain Behav Immun 9:366–377CrossRefPubMed

Robertson K, Yosief S (2014) Neurocognitive assessment in the diagnosis of HIV-associated neurocognitive disorders. Semin Neurol 34:21–26CrossRefPubMed

Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, McArthur JC, Collier AC, Evans SR, Ellis RJ (2007) The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 21:1915–1921CrossRefPubMed

Sacktor N, Miyahara S, Deng L, Evans S, Schifitto G, Cohen BA, Paul R, Robertson K, Jarocki B, Scarsi K, Coombs RW, Zink MC, Nath A, Smith E, Ellis RJ, Singer E, Weihe J, McCarthy S, Hosey L, Clifford DB, ACTG A5235 team (2011) Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial. Neurology 77:1135–1142

Sas AR, Bimonte-Nelson H, Smothers CT, Woodward J, Tyor WR (2009) Interferon-alpha causes neuronal dysfunction in encephalitis. J Neurosci 29:3948–3955CrossRefPubMedPubMedCentral

Skillback T, Farahmand B, Bartlett JW, Rosen C, Mattsson N, Nagga K, Kilander L, Religa D, Wimo A, Winblad B, Rosengren L, Schott JM, Blennow K, Eriksdotter M, Zetterberg H (2014) CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology 83:1945–1953CrossRefPubMed

Tozzi V, Balestra P, Galgani S, Murri R, Bellagamba R, Narciso P, Antinori A, Giulianelli M, Tosi G, Costa M, Sampaolesi A, Fantoni M, Noto P, Ippolito G, Wu AW (2003) Neurocognitive performance and quality of life in patients with HIV infection. AIDS Res Hum Retrovir 19:643–652CrossRefPubMed

Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ, Power C (2010) Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology 75:1150–1158CrossRefPubMedPubMedCentral

Zetterberg H, Skillback T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, Weiner MW, Blennow K, Alzheimer's Disease Neuroimaging I (2016) Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression. JAMA Neurol 73:60–67

Title: Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals
Authors: Albert M. Anderson
Jeffrey L. Lennox
Mark M. Mulligan
David W. Loring
Henrik Zetterberg
Kaj Blennow
Cari Kessing
Rajeth Koneru
Kirk Easley
William R. Tyor
Publication date: 01-02-2017
Publisher: Springer International Publishing
Published in: Journal of NeuroVirology / Issue 1/2017
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-016-0466-z

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2017

Human cytomegalovirus downregulates SLITRK6 expression through IE2

Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia

JC virus granule cell neuronopathy in the setting of chronic lymphopenia treated with recombinant interleukin-7

HIV and decreased risk of multiple sclerosis: role of low CD4+ lymphocyte count and male prevalence

Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1

Long-term follow-up of HTLV-1 proviral load in asymptomatic carriers and in incident cases of HAM/TSP: what is its relevance as a prognostic marker for neurologic disease?