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Open Access 01-08-2015

Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders

Authors: Jennifer L McGuire, Alexander J Gill, Steven D Douglas, Dennis L Kolson, CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group

Published in: Journal of NeuroVirology | Issue 4/2015

Abstract

HIV-associated neurocognitive disorders (HAND) affect up to 50 % of HIV-infected adults, independently predict HIV morbidity/mortality, and are associated with neuronal damage and monocyte activation. Cerebrospinal fluid (CSF) neurofilament subunits (NFL, pNFH) are sensitive surrogate markers of neuronal damage in several neurodegenerative diseases. In HIV, CSF NFL is elevated in individuals with and without cognitive impairment, suggesting early/persistent neuronal injury during HIV infection. Although individuals with severe cognitive impairment (HIV-associated dementia (HAD)) express higher CSF NFL levels than cognitively normal HIV-infected individuals, the relationships between severity of cognitive impairment, monocyte activation, neurofilament expression, and systemic infection are unclear. We performed a retrospective cross-sectional study of 48 HIV-infected adults with varying levels of cognitive impairment, not receiving antiretroviral therapy (ART), enrolled in the CNS Anti-Retroviral Therapy Effects Research (CHARTER) study. We quantified NFL, pNFH, and monocyte activation markers (sCD14/sCD163) in paired CSF/plasma samples. By examining subjects off ART, these correlations are not confounded by possible effects of ART on inflammation and neurodegeneration. We found that CSF NFL levels were elevated in individuals with HAD compared to cognitively normal or mildly impaired individuals with CD4+ T-lymphocyte nadirs ≤200. In addition, CSF NFL levels were significantly positively correlated to plasma HIV-1 RNA viral load and negatively correlated to plasma CD4+ T-lymphocyte count, suggesting a link between neuronal injury and systemic HIV infection. Finally, CSF NFL was significantly positively correlated with CSF pNFH, sCD163, and sCD14, demonstrating that monocyte activation within the CNS compartment is directly associated with neuronal injury at all stages of HAND.

Abdulle S, Mellgren A, Brew BJ, Cinque P, Hagberg L, Price RW, Rosengren L, Gisslén M (2007) CSF neurofilament protein (NFL)—a marker of active HIV-related neurodegeneration. J Neurol 254:1026–32PubMedCrossRef

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 69:1789–99PubMedCentralPubMedCrossRef

Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, Rosenberg ES, Ellis RJ, Williams KC (2011) Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis 204:154–63PubMedCentralPubMedCrossRef

Burdo TH, Weiffenbach A, Woods SP, Letendre S, Ellis RJ, Williams KC (2013) Elevated sCD163 is a marker of neurocognitive impairment in HIV infection. AIDS 27:1387–1395PubMedCrossRef

Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26:307–19PubMedCrossRef

Cherner M, Masliah E, Ellis RJ, Marcotte TD, Moore DJ, Grant I, Heaton RK (2002) Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis. Neurology 59:1563–7PubMedCrossRef

Clifford DB, Evans SR, Yang Y, Gulick RM (2005) The neuropsychological and neurological impact of hepatitis C virus co-infection in HIV-infected subjects. AIDS 19(Suppl 3):S64–71PubMedCrossRef

Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44PubMedCrossRef

Ellis RJ, Deutsch R, Heaton RK, Marcotte TD, McCutchan JA, Nelson JA, Abramson I, Thal LJ, Atkinson JH, Wallace MR, Grant I (1997) Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV neurobehavioral research center group. Arch Neurol 54:416–24PubMedCrossRef

Fischer-Smith T, Bell C, Croul S, Lewis M, Rappaport J (2008a) Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies. J Neurovirol 14:318–26PubMedCentralPubMedCrossRef

Fischer-Smith T, Tedaldi EM, Rappaport J (2008b) CD163/CD16 coexpression by circulating monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression. AIDS Res Hum Retrovir 24:417–21PubMedCentralPubMedCrossRef

Ganesalingam J, An J, Shaw CE, Shaw G, Lacomis D, Bowser R (2011) Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 117:528–37PubMedCentralPubMedCrossRef

Garvey LJ, Pavese N, Ramlackhansingh A, Thomson E, Allsop JM, Politis M, Kulasegaram R, Main J, Brooks DJ, Taylor-Robinson SD, Winston A (2012) Acute HCV/HIV coinfection is associated with cognitive dysfunction and cerebral metabolite disturbance, but not increased microglial cell activation. PLoS One 7:e38980PubMedCentralPubMedCrossRef

Gelman BB, Chen T, Lisinicchia JG, Soukup VM, Carmical JR, Starkey JM, Masliah E, Commins DL, Brandt D, Grant I, Singer EJ, Levine AJ, Miller J, Winkler JM, Fox HS, Luxon BA, Morgello S (2012) The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment. PLoS One 7:e46178PubMedCentralPubMedCrossRef

Gill AJ, Kolson DL (2014) Chronic inflammation and the role for cofactors (hepatitis C, drug abuse, antiretroviral drug toxicity, aging) in HAND persistence. Curr HIV/AIDS Rep 11:325–35PubMedCrossRef

Gisslen M, Hagberg L, Brew BJ, Cinque P, Price RW, Rosengren L (2007) Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 195:1774–8PubMedCrossRef

Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Collier AC, Marra CM, Clifford DB, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Smith DM, Heaton RK (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055–62PubMedCentralPubMedCrossRef

Gresle MM, Butzkueven H, Shaw G (2011) Neurofilament proteins as body fluid biomarkers of neurodegeneration in multiple sclerosis. Mult Scler Int 2011:315406PubMedCentralPubMed

Heaton R, Franklin D, Woods S, Marra C, Clifford D, Gelman B, McArthur J, Morgello S, McCutchan A, Grant I (2012) Asymptomatic HIV-associated Neurocognitive Disorder (ANI) Increases Risk for Future Symptomatic Decline: A CHARTER Longitudinal Study. Abstract #77. In: 19th Conference on Retroviruses and Opportunistic Infections (CROI): Seattle, WA

Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, 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, Group C (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–96PubMedCentralPubMedCrossRef

Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, Nilsson S, Zetterberg H, Gisslen M (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One 9:e88591PubMedCentralPubMedCrossRef

Julien JP (1999) Neurofilament functions in health and disease. Curr Opin Neurobiol 9:554–60PubMedCrossRef

Letendre SL, Cherner M, Ellis RJ, Marquie-Beck J, Gragg B, Marcotte T, Heaton RK, McCutchan JA, Grant I (2005) The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance: biological correlates of disease. AIDS 19(Suppl 3):S72–8PubMedCrossRef

Lyons JL, Uno H, Ancuta P, Kamat A, Moore DJ, Singer EJ, Morgello S, Gabuzda D (2011) Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr 57:371–9PubMedCentralPubMedCrossRef

Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J (2003) Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 61:1720–1725PubMedCrossRef

Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I (1997) Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC group. The HIV neurobehavioral research center. Ann Neurol 42:963–72PubMedCrossRef

McArthur JC, Brew BJ (2010) HIV-associated neurocognitive disorders: is there a hidden epidemic? AIDS 24:1367–70PubMedCrossRef

McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67:699–714PubMed

Mellgren A, Price RW, Hagberg L, Rosengren L, Brew BJ, Gisslén M (2007) Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology 69:1536–41PubMedCrossRef

Møller HJ (2012) Soluble CD163. Scand J Clin Lab Invest 72:1–13PubMedCrossRef

Norgren N, Rosengren L, Stigbrand T (2003) Elevated neurofilament levels in neurological diseases. Brain Res 987:25–31PubMedCrossRef

Pasol J, Feuer W, Yang C, Shaw G, Kardon R, Guy J (2010) Phosphorylated neurofilament heavy chain correlations to visual function, optical coherence tomography, and treatment. Mult Scler Int 2010:542691PubMedCentralPubMed

Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, Young AC, Walter R, Fuchs D, Brew BJ, Cinque P, Robertson K, Hagberg L, Zetterberg H, Gisslen M, Spudich S (2013) Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis 207:1703–12PubMedCentralPubMedCrossRef

Peterson J, Zetterberg H, Hagberg L, Spudich S, Gisslen M, Price R (2013) Changing Cerebrospinal Fluid Concentrations of Neurofilament Light Chain Protein, Tau, and Amyloid Proteins Characterize Evolving Central Nervous System Injury in HIV-1 Infection. Abstract #441. In: 20th Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta, GA

Petzold A, Eikelenboom MJ, Keir G, Grant D, Lazeron RHC, Polman CH, Uitdehaag BMJ, Thompson EJ, Giovannoni G (2005) Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study. J Neurol Neurosurg Psychiatry 76:206–11PubMedCentralPubMedCrossRef

Roberts ES, Masliah E, Fox HS (2004) CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE). J Neuropathol Exp Neurol 63:1255–64PubMed

Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C (1996) Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 67:2013–8PubMedCrossRef

Ryan LA, Zheng J, Brester M, Bohac D, Hahn F, Anderson J, Ratanasuwan W, Gendelman HE, Swindells S (2001) Plasma levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection. J Infect Dis 184:699–706PubMedCrossRef

Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, Douek DC, Group ISS (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203:780–90PubMedCentralPubMedCrossRef

Sellner J, Patel A, Dassan P, Brown MM, Petzold A (2011) Hyperacute detection of neurofilament heavy chain in serum following stroke: a transient sign. Neurochem Res 36:2287–91PubMedCrossRef

Sherman KE, Thomas D, Chung RT (2014) Human immunodeficiency virus and liver disease forum 2012. Hepatology 59:307–17PubMedCrossRef

Szaro BG, Strong MJ (2010) Post-transcriptional control of neurofilaments: new roles in development, regeneration and neurodegenerative disease. Trends Neurosci 33:27–37PubMedCrossRef

Tan IL, McArthur JC (2012) HIV-associated neurological disorders: a guide to pharmacotherapy. CNS Drugs 26:123–34PubMedCrossRef

Valcour V, Paul R, Chiao S, Wendelken LA, Miller B (2011) Screening for cognitive impairment in human immunodeficiency virus. Clin Infect Dis 53:836–42PubMedCentralPubMedCrossRef

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 75:1150–8PubMedCentralPubMedCrossRef

Wilkinson J, Radkowski M, Eschbacher JM, Laskus T (2010) Activation of brain macrophages/microglia cells in hepatitis C infection. Gut 59:1394–400PubMedCrossRef

Wilkinson J, Radkowski M, Laskus T (2009) Hepatitis C virus neuroinvasion: identification of infected cells. J Virol 83:1312–9PubMedCentralPubMedCrossRef

Woods SP, Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM, Hinkin CH, Lazzaretto D, Cherner M, Marcotte TD, Gelman BB, Morgello S, Singer EJ, Grant I, Heaton RK (2004) Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 26:759–78PubMedCrossRef

Title: Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders
Authors: Jennifer L McGuire
Alexander J Gill
Steven D Douglas
Dennis L Kolson
CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group
Publication date: 01-08-2015
Publisher: Springer US
Published in: Journal of NeuroVirology / Issue 4/2015
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-015-0333-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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