Advertisement

Aging, comorbidities, and the importance of finding biomarkers for HIV-associated neurocognitive disorders

  • Jacqueline Rosenthal
  • William TyorEmail author
Article

Abstract

HIV-associated neurocognitive disorders (HAND) continue to affect a large proportion of persons living with HIV despite effective viral suppression with combined antiretroviral therapy (cART). Importantly, milder versions of HAND have become more prevalent. The pathogenesis of HAND in the era of cART appears to be multifactorial with contributions from central nervous system (CNS) damage that occur prior to starting cART, chronic immune activation, cART neurotoxicity, and various age-related comorbidities (i.e., cardiovascular and cerebrovascular disease, diabetes, hyperlipidemia). Individuals with HIV may experience premature aging, which could also contribute to cognitive impairment. Likewise, degenerative disorders aside from HAND increase with age and there is evidence of shared pathology between HAND and other neurodegenerative diseases, such as Alzheimer’s disease, which can occur with or without co-existing HAND. Given the aforementioned complex interactions associated with HIV, cognitive impairment, and aging, it is important to consider an age-appropriate differential diagnosis for HAND as the HIV-positive population continues to grow older. These factors make the accuracy and reliability of the diagnosis of mild forms of HAND in an aging population of HIV-infected individuals challenging. The complexity of current diagnosis of mild HAND also highlights the need to develop reliable biomarkers. Ultimately, the identification of a set of specific biomarkers will be required to achieve early and accurate diagnosis, which will be necessary assuming specific treatments for HAND are developed.

Keywords

HAND cognitive impairment HIV biomarkers aging 

Notes

References

  1. Abdulle S, Hagberg L, Svennerholm B, Fuchs D, Gisslén M (2002) Continuing intrathecal immunoactivation despite two years of effective antiretroviral therapy against HIV-1 infection. AIDS 16(16):2145–2149CrossRefPubMedGoogle Scholar
  2. Abdulle S, Mellgren Å, 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(8):1026–1032CrossRefPubMedGoogle Scholar
  3. Achim CL et al (2009) Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J NeuroImmune Pharmacol 4(2):190–199CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A, Zaman T, Stone D, Mefford M, Morgello S, Singer EJ, Wolinsky SM, Gabuzda D (2008) Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 3(6):e2516CrossRefPubMedPubMedCentralGoogle Scholar
  5. Anderson AM et al (2017) Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-infected individuals. J Neuro-Oncol 23(1):106–112Google Scholar
  6. Anglade P, Vyas S, Hirsch EC, Agid Y (1997) Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol Histopathol 12(3):603–610PubMedGoogle Scholar
  7. Ann HW, Jun S, Shin NY, Han S, Ahn JY, Ahn MY, Jeon YD, Jung IY, Kim MH, Jeong WY, Ku NS, Kim JM, Smith DM, Choi JY (2016) Characteristics of resting-state functional connectivity in HIV-associated neurocognitive disorder. PLoS One 11(4):e0153493CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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(18):1789–1799CrossRefPubMedPubMedCentralGoogle Scholar
  9. Asahchop EL, Akinwumi SM, Branton WG, Fujiwara E, Gill MJ, Power C (2016) Plasma microRNA profiling predicts HIV-associated neurocognitive disorder. AIDS 30(13):2021–2031CrossRefPubMedGoogle Scholar
  10. Baldewicz TT, Leserman J, Silva SG, Petitto JM, Golden RN, Perkins DO, Barroso J, Evans DL (2004) Changes in neuropsychological functioning with progression of HIV-1 infection: results of an 8-year longitudinal investigation. AIDS Behav 8(3):345–355CrossRefPubMedGoogle Scholar
  11. Becker JT et al (2004) Prevalence of cognitive disorders differs as a function of age in HIV virus infection. AIDS 18(Suppl 1):S11–S18CrossRefPubMedGoogle Scholar
  12. Bhaskaran K, Mussini C, Antinori A, Walker AS, Dorrucci M, Sabin C, Phillips A, Porter K, CASCADE Collaboration (2008) Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol 63(2):213–221CrossRefPubMedGoogle Scholar
  13. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12(12):1365–1371CrossRefPubMedGoogle Scholar
  14. Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L (2005) CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology 65(9):1490–1492CrossRefPubMedGoogle Scholar
  15. Brooks JT, Buchacz K, Gebo KA, Mermin J (2012) HIV infection and older Americans: the public health perspective. Am J Public Health 102(8):1516–1526CrossRefPubMedPubMedCentralGoogle Scholar
  16. Brouillette MJ, Yuen T, Fellows LK, Cysique LA, Heaton RK, Mayo NE (2016) Identifying neurocognitive decline at 36 months among HIV-positive participants in the CHARTER cohort using group-based trajectory analysis. PLoS One 11(5):e0155766CrossRefPubMedPubMedCentralGoogle Scholar
  17. Brown A et al (2011) Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals. J Neuro-Oncol 17(4):382–392Google Scholar
  18. Burdo TH, Ellis RJ, Fox HS (2008) Osteopontin is increased in HIV-associated dementia. J Infect Dis 198(5):715–722CrossRefPubMedPubMedCentralGoogle Scholar
  19. Burdo TH, Weiffenbach A, Woods SP, Letendre S, Ellis RJ, Williams KC (2013) Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS 27(9):1387–1395CrossRefPubMedGoogle Scholar
  20. Cai Y, Yang L, Callen S, Buch S (2016) Multiple faceted roles of cocaine in potentiation of HAND. Curr HIV Res 14(5):412–416CrossRefPubMedGoogle Scholar
  21. Calcagno A et al (2016) Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients. J Neuro-Oncol 22(1):88–92Google Scholar
  22. Carroll A, Brew B (2017) HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment. F1000Res 6:312CrossRefPubMedPubMedCentralGoogle Scholar
  23. Cassol E, Misra V, Morgello S, Gabuzda D (2013) Applications and limitations of inflammatory biomarkers for studies on neurocognitive impairment in HIV infection. J NeuroImmune Pharmacol 8(5):1087–1097CrossRefPubMedPubMedCentralGoogle Scholar
  24. Chaganti JR, Heinecke A, Gates TM, Moffat KJ, Brew BJ (2017) Functional connectivity in virally suppressed patients with HIV-associated neurocognitive disorder: a resting-state analysis. AJNR Am J Neuroradiol 38(8):1623–1629CrossRefPubMedGoogle Scholar
  25. Chang L, Lee PL, Yiannoutsos CT, Ernst T, Marra CM, Richards T, Kolson D, Schifitto G, Jarvik JG, Miller EN, Lenkinski R, Gonzalez G, Navia BA, HIV MRS Consortium (2004) A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age. Neuroimage 23(4):1336–1347CrossRefPubMedGoogle Scholar
  26. Chang L, Jiang C, Cunningham E, Buchthal S, Douet V, Andres M, Ernst T (2014) Effects of APOE epsilon4, age, and HIV on glial metabolites and cognitive deficits. Neurology 82(24):2213–2222CrossRefPubMedPubMedCentralGoogle Scholar
  27. Chiao S, Rosen HJ, Nicolas K, Wendelken LA, Alcantar O, Rankin KP, Miller B, Valcour V (2013) Deficits in self-awareness impact the diagnosis of asymptomatic neurocognitive impairment in HIV. AIDS Res Hum Retrovir 29(6):949–956CrossRefPubMedGoogle Scholar
  28. Ciavatta VT, Bichler EK, Speigel IA, Elder CC, Teng SL, Tyor WR, García PS (2017) In vitro and ex vivo neurotoxic effects of efavirenz are greater than those of other common antiretrovirals. Neurochem Res 42(11):3220–3232CrossRefPubMedGoogle Scholar
  29. Ciccarelli N, Fabbiani M, Baldonero E, Fanti I, Cauda R, Giambenedetto SD, Silveri MC (2012) Effect of aging and human immunodeficiency virus infection on cognitive abilities. J Am Geriatr Soc 60(11):2048–2055CrossRefPubMedGoogle Scholar
  30. Ciccarelli N, Fabbiani M, Grima P, Falasca K, Tana M, Baldonero E, Colafigli M, Silveri MC, Vecchiet J, Cauda R, di Giambenedetto S (2013) Comparison of cognitive performance in HIV or HCV mono-infected and HIV-HCV co-infected patients. Infection 41(6):1103–1109CrossRefPubMedGoogle Scholar
  31. Clifford DB, Fagan AM, Holtzman DM, Morris JC, Teshome M, Shah AR, Kauwe JSK (2009) CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology 73(23):1982–1987CrossRefPubMedPubMedCentralGoogle Scholar
  32. Cohen RA, Seider TR, Navia B (2015) HIV effects on age-associated neurocognitive dysfunction: premature cognitive aging or neurodegenerative disease? Alzheimers Res Ther 7(1):37CrossRefPubMedPubMedCentralGoogle Scholar
  33. Cole JH, Underwood J, Caan MW, de Francesco D, van Zoest R, Leech R, Wit FW, Portegies P, Geurtsen GJ, Schmand BA, Schim van der Loeff M, Franceschi C, Sabin CA, Majoie CB, Winston A, Reiss P, Sharp DJ, COBRA collaboration (2017) Increased brain-predicted aging in treated HIV disease. Neurology 88(14):1349–1357CrossRefPubMedPubMedCentralGoogle Scholar
  34. Cristiani SA, Pukay-Martin ND, Bornstein RA (2004) Marijuana use and cognitive function in HIV-infected people. J Neuropsychiatry Clin Neurosci 16(3):330–335CrossRefPubMedGoogle Scholar
  35. Cysique LA, Maruff P, Bain MP, Wright E, Brew BJ (2011) HIV and age do not substantially interact in HIV-associated neurocognitive impairment. J Neuropsychiatry Clin Neurosci 23(1):83–89CrossRefPubMedGoogle Scholar
  36. Cysique LA, Hey-Cunningham WJ, Dermody N, Chan P, Brew BJ, Koelsch KK (2015) Peripheral blood mononuclear cells HIV DNA levels impact intermittently on neurocognition. PLoS One 10(4):e0120488CrossRefPubMedPubMedCentralGoogle Scholar
  37. Cysique LA et al (2017) White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration. J Neuro-Oncol 23(4):539–547Google Scholar
  38. Dahl V, Peterson J, Fuchs D, Gisslen M, Palmer S, Price RW (2014) Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 28(15):2251–2258CrossRefPubMedPubMedCentralGoogle Scholar
  39. de Oliveira MF et al (2015) Circulating HIV DNA correlates with neurocognitive impairment in older HIV-infected adults on suppressive ART. Sci Rep 5:17094CrossRefPubMedPubMedCentralGoogle Scholar
  40. Deeks SG (2009) Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy. Top HIV Med 17(4):118–123PubMedGoogle Scholar
  41. Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M, Grant I, Masliah E (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80(15):1415–1423CrossRefPubMedPubMedCentralGoogle Scholar
  42. DeVaughn S, Müller-Oehring EM, Markey B, Brontë-Stewart HM, Schulte T (2015) Aging with HIV-1 infection: motor functions, cognition, and attention--a comparison with Parkinson’s disease. Neuropsychol Rev 25(4):424–438CrossRefPubMedPubMedCentralGoogle Scholar
  43. Dickens AM, Anthony DC, Deutsch R, Mielke MM, Claridge TD, Grant I, Franklin D, Rosario D, Marcotte T, Letendre S, McArthur J, Haughey NJ (2015) Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients. AIDS 29(5):559–569PubMedPubMedCentralGoogle Scholar
  44. du Plessis L et al (2017) Resting-state functional magnetic resonance imaging in clade C HIV: within-group association with neurocognitive function. J Neuro-Oncol 23(6):875–885Google Scholar
  45. Dumas JA, Newhouse PA (2011) The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation. Pharmacol Biochem Behav 99(2):254–261CrossRefPubMedPubMedCentralGoogle Scholar
  46. Eden A et al (2016) Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One 11(6):e0157160CrossRefPubMedPubMedCentralGoogle Scholar
  47. Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, Collier AC, Gelman B, McArthur J, Morgello S, McCutchan J, Grant I, CHARTER Group (2011) CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 25(14):1747–1751CrossRefPubMedGoogle Scholar
  48. Ernst T, Jiang CS, Nakama H, Buchthal S, Chang L (2010) Lower brain glutamate is associated with cognitive deficits in HIV patients: a new mechanism for HIV-associated neurocognitive disorder. J Magn Reson Imaging 32(5):1045–1053CrossRefPubMedPubMedCentralGoogle Scholar
  49. Fabbiani M, Ciccarelli N, Tana M, Farina S, Baldonero E, di Cristo V, Colafigli M, Tamburrini E, Cauda R, Silveri MC, Grima P, di Giambenedetto S (2013) Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients. HIV Med 14(3):136–144CrossRefPubMedGoogle Scholar
  50. Fois AF, Brew BJ (2015) The potential of the CNS as a reservoir for HIV-1 infection: implications for HIV eradication. Curr HIV/AIDS Rep 12(2):299–303CrossRefPubMedGoogle Scholar
  51. Gelman BB (2015) Neuropathology of HAND with suppressive antiretroviral therapy: encephalitis and neurodegeneration reconsidered. Curr HIV/AIDS Rep 12(2):272–279CrossRefPubMedPubMedCentralGoogle Scholar
  52. Ginsberg SD, Alldred MJ, Gunnam SM, Schiroli C, Lee SH, Morgello S, Fischer T (2018) Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis. Ann Neurol 83(2):406–417CrossRefPubMedPubMedCentralGoogle Scholar
  53. Gisslen M et al (2016) Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study. EBioMedicine 3:135–140CrossRefPubMedGoogle Scholar
  54. Glass JD, Wesselingh SL, Selnes OA, McArthur JC (1993) Clinical-neuropathologic correlation in HIV-associated dementia. Neurology 43(11):2230–2237CrossRefPubMedGoogle Scholar
  55. Goodkin K, Miller EN, Cox C, Reynolds S, Becker JT, Martin E, Selnes OA, Ostrow DG, Sacktor NC, Multicenter AIDS Cohort Study (2017) Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study. Lancet HIV 4(9):e411–e422CrossRefPubMedPubMedCentralGoogle Scholar
  56. Grant I, Franklin DR, 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, For the CHARTER Group (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82(23):2055–2062CrossRefPubMedPubMedCentralGoogle Scholar
  57. Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005) Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS 19(4):407–411CrossRefPubMedGoogle Scholar
  58. Grunfeld C, Delaney JAC, Wanke C, Currier JS, Scherzer R, Biggs ML, Tien PC, Shlipak MG, Sidney S, Polak JF, OʼLeary D, Bacchetti P, Kronmal RA (2009) Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS 23(14):1841–1849CrossRefPubMedPubMedCentralGoogle Scholar
  59. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, Berti A, Rossi E, Roverato A, Palella F (2011) Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis 53(11):1120–1126CrossRefPubMedGoogle Scholar
  60. Guha A, Brier MR, Ortega M, Westerhaus E, Nelson B, Ances BM (2016) Topographies of cortical and subcortical volume loss in HIV and aging in the cART era. J Acquir Immune Defic Syndr 73(4):374–383CrossRefPubMedPubMedCentralGoogle Scholar
  61. 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 7:15CrossRefPubMedPubMedCentralGoogle Scholar
  62. Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Alger J, Singer E, Campbell T, Yiannoutsos C, Cohen R, Navia B, HIV Neuroimaging Consortium (2011) Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 25(5):625–633CrossRefPubMedPubMedCentralGoogle Scholar
  63. Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001) HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78(3):457–467CrossRefPubMedGoogle Scholar
  64. 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, For the CHARTER Group (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75(23):2087–2096CrossRefPubMedPubMedCentralGoogle Scholar
  65. Heaton RK et al (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neuro-Oncol 17(1):3–16Google Scholar
  66. Heaton RK, Franklin DR, Deutsch R, Letendre S, Ellis RJ, Casaletto K, Marquine MJ, Woods SP, Vaida F, Atkinson JH, Marcotte TD, McCutchan JA, Collier AC, Marra CM, Clifford DB, Gelman BB, Sacktor N, Morgello S, Simpson DM, Abramson I, Gamst AC, Fennema-Notestine C, Smith DM, Grant I, for the CHARTER Group, Grant I, McCutchan JA, Ellis RJ, Marcotte TD, Franklin D, Ellis RJ, McCutchan JA, Alexander T, Letendre S, Capparelli E, Heaton RK, Atkinson JH, Woods SP, Dawson M, Smith DM, Fennema-Notestine C, Taylor MJ, Theilmann R, Gamst AC, Cushman C, Abramson I, Vaida F, Marcotte TD, Marquie-Beck J, McArthur J, Rogalski V, Morgello S, Simpson D, Mintz L, McCutchan JA, Toperoff W, Collier A, Marra C, Jones T, Gelman B, Head E, Clifford D, al-Lozi M, Teshome M (2015) Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis 60(3):473–480CrossRefPubMedGoogle Scholar
  67. Holt JL, Kraft-Terry SD, Chang L (2012) Neuroimaging studies of the aging HIV-1-infected brain. J Neuro-Oncol 18(4):291–302Google Scholar
  68. Ipser JC, Brown GG, Bischoff-Grethe A, Connolly CG, Ellis RJ, Heaton RK, Grant I, Translational Methamphetamine AIDS Research Center (TMARC) Group (2015) HIV infection is associated with attenuated frontostriatal intrinsic connectivity: a preliminary study. J Int Neuropsychol Soc 21(3):203–213CrossRefPubMedPubMedCentralGoogle Scholar
  69. Iudicello JE, Woods SP, Deutsch R, Grant I, The HIV Neurobehavioral Research Pr (2012) Combined effects of aging and HIV infection on semantic verbal fluency: a view of the cortical hypothesis through the lens of clustering and switching. J Clin Exp Neuropsychol 34(5):476–488CrossRefPubMedPubMedCentralGoogle Scholar
  70. Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, Nilsson S, Zetterberg H, Gisslén M (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One 9(2):e88591CrossRefPubMedPubMedCentralGoogle Scholar
  71. Joska JA et al (2010) Association between apolipoprotein E4 genotype and human immunodeficiency virus-associated dementia in younger adults starting antiretroviral therapy in South Africa. J Neuro-Oncol 16(5):377–383Google Scholar
  72. Joska JA, Witten J, Thomas KG, Robertson C, Casson-Crook M, Roosa H, Creighton J, Lyons J, McArthur J, Sacktor NC (2016) A comparison of five brief screening tools for HIV-associated neurocognitive disorders in the USA and South Africa. AIDS Behav 20(8):1621–1631CrossRefPubMedPubMedCentralGoogle Scholar
  73. Kallianpur AR, et al. (2018) Cerebrospinal fluid ceruloplasmin, haptoglobin, and vascular endothelial growth factor are associated with neurocognitive impairment in adults with HIV infection. Mol Neurobiol.  https://doi.org/10.1007/s12035-018-1329-9 CrossRefPubMedGoogle Scholar
  74. Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, Gabuzda D (2012) Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr 60(3):234–243CrossRefPubMedPubMedCentralGoogle Scholar
  75. Kamkwalala A, Newhouse P (2017) Mechanisms of cognitive aging in the HIV-positive adult. Curr Behav Neurosci Rep 4(3):188–197CrossRefPubMedPubMedCentralGoogle Scholar
  76. Koneru R, Olive MF, Tyor WR (2014) Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model. J Neuro-Oncol 20(1):9–17Google Scholar
  77. Koneru R, Bimonte-Nelson H, Ciavatta V, Haile W, Elmore K, Ward J, Maroun L, Tyor WR (2018) Reversing interferon-alpha neurotoxicity in a HIV-associated neurocognitive disorder mouse model. AIDS 32(11):1403–1411CrossRefPubMedGoogle Scholar
  78. Kumar AM et al (2009) Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains. J Neuro-Oncol 15(3):257–274Google Scholar
  79. Kusao I, Shiramizu B, Liang CY, Grove J, Agsalda M, Troelstrup D, Velasco VN, Marshall A, Whitenack N, Shikuma C, Valcour V (2012) Cognitive performance related to HIV-1-infected monocytes. J Neuropsychiatry Clin Neurosci 24(1):71–80CrossRefPubMedPubMedCentralGoogle Scholar
  80. Lagathu C, Cossarizza A, Béréziat V, Nasi M, Capeau J, Pinti M (2017) Basic science and pathogenesis of ageing with HIV: potential mechanisms and biomarkers. AIDS 31(Suppl 2):S105–S119CrossRefPubMedGoogle Scholar
  81. Levine AJ et al (2016) Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders. J Neuro-Oncol 22(3):366–375Google Scholar
  82. Lewczuk P, Ermann N, Andreasson U, Schultheis C, Podhorna J, Spitzer P, Maler JM, Kornhuber J, Blennow K, Zetterberg H (2018) Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease. Alzheimers Res Ther 10(1):71CrossRefPubMedPubMedCentralGoogle Scholar
  83. Lin K, Taylor MJ, Heaton R, Franklin D, Jernigan T, Fennema-Notestine C, McCutchan A, Atkinson JH, Ellis RJ, McArthur J, Morgello S, Simpson D, Collier AC, Marra C, Gelman B, Clifford D, Grant I, CHARTER group (2011) Effects of traumatic brain injury on cognitive functioning and cerebral metabolites in HIV-infected individuals. J Clin Exp Neuropsychol 33(3):326–334CrossRefPubMedPubMedCentralGoogle Scholar
  84. 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(5):371–379CrossRefPubMedPubMedCentralGoogle Scholar
  85. Malaspina L et al (2011) Successful cognitive aging in persons living with HIV infection. J Neuro-Oncol 17(1):110–119Google Scholar
  86. 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(12):1720–1725CrossRefPubMedGoogle Scholar
  87. Mattsson N, Andreasson U, Zetterberg H, Blennow K, for the Alzheimer’s Disease Neuroimaging Initiative (2017) Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 74(5):557–566CrossRefPubMedPubMedCentralGoogle Scholar
  88. McArthur JC et al (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67(6):699–714PubMedGoogle Scholar
  89. McGuire JL et al (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neuro-Oncol 21(4):439–448Google Scholar
  90. Megra B, Eugenin E, Roberts T, Morgello S, Berman JW (2013) Protease resistant protein cellular isoform (PrP(c)) as a biomarker: clues into the pathogenesis of HAND. J NeuroImmune Pharmacol 8(5):1159–1166CrossRefPubMedGoogle Scholar
  91. Melendez RI et al (2016) Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J Neuro-Oncol 22(3):358–365Google Scholar
  92. Milanini B, Valcour V (2017) Differentiating HIV-associated neurocognitive disorders from Alzheimer’s disease: an emerging issue in geriatric NeuroHIV. Curr HIV/AIDS Rep 14(4):123–132CrossRefPubMedPubMedCentralGoogle Scholar
  93. Milanini B et al (2016) Cognitive reserve and neuropsychological functioning in older HIV-infected people. J Neuro-Oncol 22(5):575–583Google Scholar
  94. Molinuevo JL, Blennow K, Dubois B, Engelborghs S, Lewczuk P, Perret-Liaudet A, Teunissen CE, Parnetti L (2014) The clinical use of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement 10(6):808–817CrossRefPubMedGoogle Scholar
  95. Morgan EE et al (2013) Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders. J Neuro-Oncol 19(2):150–156Google Scholar
  96. Ndhlovu LC et al (2014) Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND). J Neuro-Oncol 20(6):571–582Google Scholar
  97. Ndhlovu LC, D'Antoni ML, Ananworanich J, Byron MM, Chalermchai T, Sithinamsuwan P, Tipsuk S, Ho E, Slike BM, Schuetz A, Zhang G, Agsalda-Garcia M, Shiramizu B, Shikuma CM, Valcour V, SEARCH 011 study group (2015) Loss of CCR2 expressing non-classical monocytes are associated with cognitive impairment in antiretroviral therapy-naive HIV-infected Thais. J Neuroimmunol 288:25–33CrossRefPubMedPubMedCentralGoogle Scholar
  98. Nightingale S, Winston A (2017) Measuring and managing cognitive impairment in HIV. AIDS 31(Suppl 2):S165–S172CrossRefPubMedGoogle Scholar
  99. Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S, Solomon T (2014) Controversies in HIV-associated neurocognitive disorders. Lancet Neurol 13(11):1139–1151CrossRefPubMedPubMedCentralGoogle Scholar
  100. Nir TM, Jahanshad N, Busovaca E, Wendelken L, Nicolas K, Thompson PM, Valcour VG (2014) Mapping white matter integrity in elderly people with HIV. Hum Brain Mapp 35(3):975–992CrossRefPubMedGoogle Scholar
  101. Norgren N, Rosengren L, Stigbrand T (2003) Elevated neurofilament levels in neurological diseases. Brain Res 987(1):25–31CrossRefPubMedGoogle Scholar
  102. Ortega M, Ances BM (2014) Role of HIV in amyloid metabolism. J NeuroImmune Pharmacol 9(4):483–491CrossRefPubMedPubMedCentralGoogle Scholar
  103. Pathai S, Bajillan H, Landay AL, High KP (2014) Is HIV a model of accelerated or accentuated aging? J Gerontol A Biol Sci Med Sci 69(7):833–842CrossRefPubMedGoogle Scholar
  104. 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(11):1703–1712CrossRefPubMedPubMedCentralGoogle Scholar
  105. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3):183–194CrossRefPubMedGoogle Scholar
  106. Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L (2014) Mild cognitive impairment: a concept in evolution. J Intern Med 275(3):214–228CrossRefPubMedPubMedCentralGoogle Scholar
  107. Petersen RC et al (2018) Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 90(3):126–135CrossRefPubMedPubMedCentralGoogle Scholar
  108. 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(12):e116081CrossRefPubMedPubMedCentralGoogle Scholar
  109. Pfefferbaum A, Rogosa DA, Rosenbloom MJ, Chu W, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Zahr NM, Sullivan EV (2014) Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study. Neurobiol Aging 35(7):1755–1768CrossRefPubMedPubMedCentralGoogle Scholar
  110. Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, Galluzzi S, Marizzoni M, Frisoni GB (2016) Brain atrophy in Alzheimer’s disease and aging. Ageing Res Rev 30:25–48CrossRefPubMedGoogle Scholar
  111. Plessis SD, Vink M, Joska JA, Koutsilieri E, Stein DJ, Emsley R (2014) HIV infection and the fronto-striatal system: a systematic review and meta-analysis of fMRI studies. AIDS 28(6):803–811CrossRefPubMedGoogle Scholar
  112. Premeaux TA, et al. (2018) Elevated cerebrospinal fluid Galectin-9 is associated with central nervous system immune activation and poor cognitive performance in older HIV-infected individuals J Neuro-Oncol.  https://doi.org/10.1007/s13365-018-0696-3 CrossRefGoogle Scholar
  113. Pulliam L, et al. (2019) Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer’s disease. J Neuro-Oncol.  https://doi.org/10.1007/s13365-018-0695-4 CrossRefGoogle Scholar
  114. Rempel HC, Pulliam L (2005) HIV-1 Tat inhibits neprilysin and elevates amyloid beta. AIDS 19(2):127–135CrossRefPubMedGoogle Scholar
  115. 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(4):366–377CrossRefPubMedGoogle Scholar
  116. Rippeth JD, Heaton RK, Carey CL, Marcotte TD, Moore DJ, Gonzalez R, Wolfson T, Grant I, HNRC Group (2004) Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons. J Int Neuropsychol Soc 10(1):1–14CrossRefPubMedGoogle Scholar
  117. Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest DJ, For the A5170 Study Team (2010) Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74(16):1260–1266CrossRefPubMedPubMedCentralGoogle Scholar
  118. Robertson K et al (2016) International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271. J Neuro-Oncol 22(4):472–478Google Scholar
  119. 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(5):2013–2018CrossRefPubMedGoogle Scholar
  120. Rumbaugh JA, Tyor W (2015) HIV-associated neurocognitive disorders: five new things. Neurol Clin Pract 5(3):224–231CrossRefPubMedPubMedCentralGoogle Scholar
  121. 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(6):699–706CrossRefPubMedGoogle Scholar
  122. Sacktor N, Skolasky RL, Seaberg E, Munro C, Becker JT, Martin E, Ragin A, Levine A, Miller E (2016) Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology 86(4):334–340CrossRefPubMedPubMedCentralGoogle Scholar
  123. Schouten J, Su T, Wit FW, Kootstra NA, Caan MW, Geurtsen GJ, Schmand BA, Stolte IG, Prins M, Majoie CB, Portegies P, Reiss P, AGEhIV Study Group (2016) Determinants of reduced cognitive performance in HIV-1-infected middle-aged men on combination antiretroviral therapy. AIDS 30(7):1027–1038CrossRefPubMedGoogle Scholar
  124. Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K (2004) Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 63(11):2084–2090CrossRefPubMedGoogle Scholar
  125. Sheppard DP et al (2015) Elevated rates of mild cognitive impairment in HIV disease. J Neuro-Oncol 21(5):576–584Google Scholar
  126. Smail RC, Brew BJ (2018) HIV-associated neurocognitive disorder. Handb Clin Neurol 152:75–97CrossRefPubMedGoogle Scholar
  127. Spector SA, Singh KK, Gupta S, Cystique LA, Jin H, Letendre S, Schrier R, Wu Z, Hong KX, Yu X, Shi C, Heaton RK, HNRC Group (2010) APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors. AIDS 24(10):1471–1479CrossRefPubMedPubMedCentralGoogle Scholar
  128. Stout, J.C., Ellis R.J., Jernigan T.L., Archibald S.L., Abramson I., Wolfson T., McCutchan J., Wallace M.R., Atkinson J.H., Grant I., Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group. Arch Neurol, 1998. 55(2): p. 161–168CrossRefPubMedGoogle Scholar
  129. Su T, Wit FW, Caan MW, Schouten J, Prins M, Geurtsen GJ, Cole JH, Sharp DJ, Richard E, Reneman L, Portegies P, Reiss P, Majoie CB, AGEhIV Cohort Study (2016) White matter hyperintensities in relation to cognition in HIV-infected men with sustained suppressed viral load on combination antiretroviral therapy. AIDS 30(15):2329–2339CrossRefPubMedGoogle Scholar
  130. Tavazzi E, Morrison D, Sullivan P, Morgello S, Fischer T (2014) Brain inflammation is a common feature of HIV-infected patients without HIV encephalitis or productive brain infection. Curr HIV Res 12(2):97–110CrossRefPubMedPubMedCentralGoogle Scholar
  131. Turner RS, Chadwick M, Horton WA, Simon GL, Jiang X, Esposito G (2016) An individual with human immunodeficiency virus, dementia, and central nervous system amyloid deposition. Alzheimers Dement (Amst) 4:1–5Google Scholar
  132. Tyor WR, Bimonte-Nelson H (2018) A mouse model of HIV-associated neurocognitive disorders: a brain-behavior approach to discover disease mechanisms and novel treatments. J Neuro-Oncol 24(2):180–184Google Scholar
  133. Underwood J, Winston A (2016) Guidelines for evaluation and management of cognitive disorders in HIV-positive individuals. Curr HIV/AIDS Rep 13(5):235–240CrossRefPubMedPubMedCentralGoogle Scholar
  134. Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, Selnes OA, Grove J, Liu Y, Abdul-Majid KB, Gartner S, Sacktor N (2004) Age, apolipoprotein E4, and the risk of HIV dementia: the Hawaii Aging with HIV Cohort. J Neuroimmunol 157(1–2):197–202CrossRefPubMedGoogle Scholar
  135. Valcour V et al (2008a) Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy. J Neuro-Oncol 14(5):362–367Google Scholar
  136. Valcour V, Shiramizu B, Shikuma C (2008b) Frequency of apolipoprotein E4 among older compared with younger HIV patients: support for detrimental effect of E4 on survival. Proc Natl Acad Sci U S A 105(41):E66 author reply E67–8CrossRefPubMedPubMedCentralGoogle Scholar
  137. Valcour VG, Shiramizu BT, Shikuma CM (2010) HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications. J Leukoc Biol 87(4):621–626CrossRefPubMedPubMedCentralGoogle Scholar
  138. Valcour V, Paul R, Neuhaus J, Shikuma C (2011) The effects of age and HIV on neuropsychological performance. J Int Neuropsychol Soc 17(1):190–195CrossRefPubMedGoogle Scholar
  139. Valcour VG, Ananworanich J, Agsalda M, Sailasuta N, Chalermchai T, Schuetz A, Shikuma C, Liang CY, Jirajariyavej S, Sithinamsuwan P, Tipsuk S, Clifford DB, Paul R, Fletcher JLK, Marovich MA, Slike BM, DeGruttola V, Shiramizu B, for the SEARCH 011 Protocol Team (2013) HIV DNA reservoir increases risk for cognitive disorders in cART-naive patients. PLoS One 8(7):e70164CrossRefPubMedPubMedCentralGoogle Scholar
  140. Vassallo M, Mercié P, Cottalorda J, Ticchioni M, Dellamonica P (2012) The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review. Virol J 9:174CrossRefPubMedPubMedCentralGoogle Scholar
  141. Vassallo M et al (2013) Relevance of lipopolysaccharide levels in HIV-associated neurocognitive impairment: the Neuradapt study. J Neuro-Oncol 19(4):376–382Google Scholar
  142. Ventura N, Douw L, Correa DG, Netto TM, Cabral RF, Lopes FCR, Gasparetto EL (2018) Increased posterior cingulate cortex efficiency may predict cognitive impairment in asymptomatic HIV patients. Neuroradiol J 31(4):372–378CrossRefPubMedGoogle Scholar
  143. Vera JH, Guo Q, Cole JH, Boasso A, Greathead L, Kelleher P, Rabiner EA, Kalk N, Bishop C, Gunn RN, Matthews PM, Winston A (2016) Neuroinflammation in treated HIV-positive individuals: a TSPO PET study. Neurology 86(15):1425–1432CrossRefPubMedPubMedCentralGoogle Scholar
  144. Wendelken LA, Valcour V (2012) Impact of HIV and aging on neuropsychological function. J Neuro-Oncol 18(4):256–263Google Scholar
  145. Wendelken LA, Jahanshad N, Rosen HJ, Busovaca E, Allen I, Coppola G, Adams C, Rankin KP, Milanini B, Clifford K, Wojta K, Nir TM, Gutman BA, Thompson PM, Valcour V (2016) ApoE epsilon4 is associated with cognition, brain integrity, and atrophy in HIV over age 60. J Acquir Immune Defic Syndr 73(4):426–432CrossRefPubMedPubMedCentralGoogle Scholar
  146. Woods SP, Moore DJ, Weber E, Grant I (2009) Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev 19(2):152–168CrossRefPubMedPubMedCentralGoogle Scholar
  147. Yuan L et al (2013) Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neuro-Oncol 19(2):144–149Google Scholar
  148. Zetterberg H, Skillbäck T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, Weiner MW, Blennow K, for the Alzheimer’s Disease Neuroimaging Initiative (2016) Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression. JAMA Neurol 73(1):60–67CrossRefPubMedPubMedCentralGoogle Scholar
  149. Zipursky AR, Gogolishvili D, Rueda S, Brunetta J, Carvalhal A, McCombe JA, Gill MJ, Rachlis A, Rosenes R, Arbess G, Marcotte T, Rourke SB (2013) Evaluation of brief screening tools for neurocognitive impairment in HIV/AIDS: a systematic review of the literature. AIDS 27(15):2385–2401CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2019

Authors and Affiliations

  1. 1.Atlanta VA Medical CenterDecaturUSA
  2. 2.Department of NeurologyEmory University School of MedicineAtlantaUSA

Personalised recommendations