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Considerations on nosology for HIV-associated neurocognitive disorders: it is time to update?

  • Nicoletta CiccarelliEmail author



The prognosis and the clinical manifestations of HIV infection have changed with the introduction of the potent combination antiretroviral therapy (cART); however, up to 50% of patients meet research criteria for “HIV-associated neurocognitive disorders” (HAND) according with current nosology. The majority of patients affected by HAND, especially in cohorts with suppressed plasma viremia, showed an Asymptomatic Neurocognitive Impairment (ANI), without any functional impairment. After more than 10 years from the introduction of the current so-called “Frascati criteria”, this mini-review aimed to address the emerging limitations in current diagnosis procedures.


We discussed the most relevant literature on HAND prevalence, etiology, and diagnosis.


We addressed three main emerging issues: (1) the unclear clinical relevance of ANI entity; (2) the evidences that Frascati criteria could produce a significant overestimation of HAND; (3) the need to better identify patients with a higher risk to develop HAND requiring routine neuropsychological examinations.


Frascati criteria should be updated to better respond to the present characteristics of HIV + cohorts and to help clinicians in their cognitive and global management.


HIV HIV-associated neurocognitive disorders Nosology Risk factors 


Compliance with ethical standards

Conflict of interest

The author declares that they have no competing interests.


  1. 1.
    Gongvatana A, Schweinsburg BC, Taylor MJ, Theilmann RJ, Letendre SL, Alhassoon OM, et al. White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals. J Neurovirol. 2009;15:187–95.CrossRefGoogle Scholar
  2. 2.
    Klunder AD, Chiang MC, Dutton RA, Lee SE, Toga AW, Lopez OL, et al. Mapping cerebellar degeneration in HIV/AIDS. Neuroreport. 2008;19:1655–9.CrossRefGoogle Scholar
  3. 3.
    Janssen RS, Cornblath DR, Epstein LG, Foa RP, McArthur JC, Price RW, et al. Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type-1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41:778–85.CrossRefGoogle Scholar
  4. 4.
    Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol J. 1986;19:517–24.CrossRefGoogle Scholar
  5. 5.
    Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69:1789–99.CrossRefGoogle Scholar
  6. 6.
    Torti C, Focà E, Cesana BM, Lescure FX. Asymptomatic neurocognitive disorders in patients infected by HIV: fact or fiction? BMC Med. 2011;9:138.CrossRefGoogle Scholar
  7. 7.
    Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, et al. HIV-associated neurologic disease incidence changes: multicenter AIDS Cohort Study, 1990–1998. Neurology. 2001;56:257–60.CrossRefGoogle Scholar
  8. 8.
    Mc Arthur JC. HIV Dementia: an evolving disease. J Neuroimmunol. 2004;157:3–10.CrossRefGoogle Scholar
  9. 9.
    Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75:2087–96.CrossRefGoogle Scholar
  10. 10.
    Simioni S, Cavassini M, Annoni JM, Rimbault Abraham A, Bourquin I, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24:1243–50. Scholar
  11. 11.
    Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G. Neurodegeneration and aging in the HAART era. J Neuroimmune Pharmacol. 2009;4:163–74.CrossRefGoogle Scholar
  12. 12.
    Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:141–55. Scholar
  13. 13.
    Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, Selnes O, et al. Higher frequency of dementia in older HIV-1 individuals: the Hawaii aging with HIV-1 cohort. Neurology. 2004;63:822–7.CrossRefGoogle Scholar
  14. 14.
    Achim CL, Adame A, Dumaop W, Everall IP, Masliah E. Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J Neuroimmune Pharmacol. 2009;4:190–9.CrossRefGoogle Scholar
  15. 15.
    Ciccarelli N, Fabbiani M, Baldonero E, Fanti I, Cauda R, Di Giambenedetto S, et al. Effect of aging and human immunodeficiency virus infection on cognitive abilities. J Am Geriatr Soc. 2012;60:2048–55. Scholar
  16. 16.
    Ciccarelli N, Limiti S, Fabbiani M, Baldonero E, Milanini B, Lamonica S, et al. Verbal list learning and memory profiles in HIV-infected adults, Alzheimer’s disease, and Parkinson’s disease: an evaluation of the “cortical hypothesis” of NeuroAIDS. Appl Neuropsychol Adult. 2017;24:410–9. Scholar
  17. 17.
    Cysique LA, Maruff P, Bain MP, Wright E, Brew BJ. HIV and age do not substantially interact in HIVassociated neurocognitive impairment. J Neuropsychiatry. 2011;23:83–9. Scholar
  18. 18.
    Scott JC, Woods SP, Carey CL, Weber E, Bondi MW, Grant I. Neurocognitive consequences of HIV infection in older adults: an evaluation of the “cortical” hypothesis. AIDS Behav. 2011;6:1187–96. Scholar
  19. 19.
    Valcour V, Paul R, Neuhaus J, Shikuma C. The effects of age and HIV on neuropsychological performance. J Int Neuropsychol Soc. 2011;17:190–5. Scholar
  20. 20.
    Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc. 2002;8:448–60.CrossRefGoogle Scholar
  21. 21.
    Milanini B, Ciccarelli N, Fabbiani M, Limiti S, Grima P, Rossetti B, et al. Cognitive reserve and neuropsychological functioning in older HIV-infected people. J Neurovirol. 2016;22:575–83.CrossRefGoogle Scholar
  22. 22.
    Morgan EE, Woods SP, Smith C, Weber E, Scott JC, Grant I. Lower cognitive reserve among individuals with syndromic HIV-associated neurocognitive disorders (HAND). AIDS Behav. 2012;16:2279–85.CrossRefGoogle Scholar
  23. 23.
    Lovejoy T, Suhr JA. The relationship between neuropsychological functioning and HAART adherence in HIV-positive adults: a systematic review. J Behav Med. 2009;32:389–405. Scholar
  24. 24.
    Ciccarelli N, Fabbiani M, Di Giambenedetto S, Fanti I, Baldonero E, Bracciale L, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology. 2011;76:1403–9. Scholar
  25. 25.
    Underwood J, Robertson KR, Winston A. Could antiretroviral neurotoxicity play a role in the pathogenesis of cognitive impairment in treated HIV disease? AIDS. 2015;29:253–61.CrossRefGoogle Scholar
  26. 26.
    Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65–70.CrossRefGoogle Scholar
  27. 27.
    Letendre S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med. 2011;19:137.PubMedGoogle Scholar
  28. 28.
    Cysique LA, Waters EK, Brew BJ. Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol. 2011;11:148. Scholar
  29. 29.
    Ciccarelli N, Fabbiani M, Colafigli M, Trecarichi EM, Silveri MC, Cauda R, et al. Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected patients with controlled plasma viraemia. Antivir Ther. 2013;18:153–60. Scholar
  30. 30.
    Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin Infect Dis. 2014;58:1015–22. Scholar
  31. 31.
    Fabbiani M, Grima P, Milanini B, Mondi A, Baldonero E, Ciccarelli N, et al. Antiretroviral neuropenetration scores better correlate with cognitive performance of HIV-infected patients after accounting for drug susceptibility. Antivir Ther. 2015;20:441–7. Scholar
  32. 32.
    Canestri A, Lescure FX, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis. 2010;50:773–8.CrossRefGoogle Scholar
  33. 33.
    Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS. 2012;26:1765–74. Scholar
  34. 34.
    Edén A, Fuchs D, Hagberg L, Nilsson S, Spudich S, Svennerholm B, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. 2010;202:1819–25.CrossRefGoogle Scholar
  35. 35.
    Valero IP, Letendre S, Ellis R, Deutsch R, Franklin D, Clifford D, et al. Prevalence and risk factors for HIV CSF Viral Escape: results from the CHARTER and HNRP cohorts. J Int AIDS Soc. 2012;15:18189.Google Scholar
  36. 36.
    Brew BJ, Letendre SL. Biomarkers of HIV related central nervous system disease. Int Rev Psychiatry. 2008;20:73–88. (Review).CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S, et al. Controversies in HIV associated neurocognitive disorders. Lancet Neurol. 2014;13:1139–51.CrossRefGoogle Scholar
  38. 38.
    Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011;25:1747–51.CrossRefGoogle Scholar
  39. 39.
    Van Sighem AI, Gras LA, Reiss P, Brinkman K, De Wolf F. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS. 2010;24:1527–35.CrossRefGoogle Scholar
  40. 40.
    McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol. 2010;67:699–714.Google Scholar
  41. 41.
    Garvey LJ, Pavese N, Politis M, Ramlackhansingh A, Brooks DJ, Taylor-Robinson SD, et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS. 2014;28:67–72.CrossRefGoogle Scholar
  42. 42.
    Nakamoto BK, Shikuma CM, Ogata-Arakaki D, Umaki T, Neuwelt EA, Shiramizu BT, et al. Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder. J Neurovirol. 2013;19:601–5.CrossRefGoogle Scholar
  43. 43.
    Hellmuth J, Milanini B, Valcour V. Interactions between ageing and NeuroAIDS. Curr Opin HIVAIDS. 2014;9:527–32. Scholar
  44. 44.
    Peterson J, Gisslen M, Zetterberg H, Fuchs D, Shacklett BL, Hagberg L, et al. Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection. PLoS One. 2014;9:e116081.CrossRefGoogle Scholar
  45. 45.
    Krut JJ, Zetterberg H, Blennow K, Cinque P, Hagberg L, Price RW, et al. Cerebrospinal fluid Alzheimer’s biomarker profiles in CNS infections. J Neurol. 2013;260:620–6. Scholar
  46. 46.
    Gisslén M, Price RW, Andreasson U, Norgren N, Nilsson S, Hagberg L, et al. Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study. EBioMedicine. 2015;3:135–40. Scholar
  47. 47.
    Milanini B, Valcour V. Differentiating HIV-associated neurocognitive disorders from Alzheimer’s disease: an emerging issue in geriatric NeuroHIV. Curr HIV AIDS Rep. 2017;14:123–32. (Review).CrossRefGoogle Scholar
  48. 48.
    Hammond ER, Crum RM, Treisman GJ, Mehta SH, Marra CM, Clifford DB, et al. The cerebrospinal fluid HIV risk score for assessing central nervous system activity in persons with HIV. Am J Epidemiol. 2014;180:297–307. Scholar
  49. 49.
    May MT, Gompels M, Delpech V, et al. UK collaborative HIV cohort (UK CHIC)-study impact on life expectancy of HIV-1 positive individuals of CD4 + cell count and viral load response to antiretroviral therapy. AIDS. 2014;28:1193–202.CrossRefGoogle Scholar
  50. 50.
    Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials. 2011;12:333–8. Scholar
  51. 51.
    Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, et al. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014;82:2055–62. Scholar
  52. 52.
    Gisslén M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis. 2011;11:356.CrossRefGoogle Scholar
  53. 53.
    Ciccarelli N, Fabbiani M, Grima P, Falasca K, Tana M, Baldonero E, et al. Comparison of cognitive performance in HIV or HCV mono-infected and HIV-HCV co-infected patients. Infection. 2013;41:1103–9. Scholar
  54. 54.
    Vivithanaporn P, Nelles K, DeBlock L, Newman SC, Gill MJ. Power C Hepatitis C virus co-infection increases neurocognitive impairment severity and risk of death in treated HIV/AIDS. J Neurol Sci. 2012;312:45–51.CrossRefGoogle Scholar
  55. 55.
    Wright EJ, Grund B, Robertson K, Brew BJ, Roediger M, Bain MP, et al. Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology. 2010;75:864–73.CrossRefGoogle Scholar
  56. 56.
    Ammassari A, Antinori A, Aloisi MS, Trotta MP, Murri R, Bartoli L, et al. Depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy among HIV-infected persons. Psychosomatics. 2004;45:394–402.CrossRefGoogle Scholar
  57. 57.
    Fabbiani M, Ciccarelli N, Tana M, Farina S, Baldonero E, Di Cristo V, et al. Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients. HIV Med. 2013;14:136–44. Scholar
  58. 58.
    Akgün KM, Gordon K, Pisani M, Fried T, McGinnis KA, Tate JP, et al. Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV-infected Veterans. J Acquir Immune Def Syndr. 2013;62:52–9.CrossRefGoogle Scholar
  59. 59.
    Marquine MJ, Montoya JL, Umlauf A, Fazeli PL, Gouaux B, Heaton RK, et al. The veterans aging cohort study (VACS) index and neurocognitive change: a longitudinal study. Clin Infect Dis. 2016;63:694–702. Scholar
  60. 60.
    Sochocka M, Zwolińska K, Leszek J. The infectious etiology of Alzheimer’s disease. Curr Neuropharmacol. 2017;15:996–1009. (Review).CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Romeo MA, Faggioni A, Cirone M. Could autophagy dysregulation link neurotropic viruses to Alzheimer’s disease? Neural Regen Res. 2019;14:1503–6.CrossRefGoogle Scholar
  62. 62.
    Valle Del, Piña-Oviedo S. Human polyomavirus JCPyV and its role in progressive multifocal leukencephalopathy and oncogenesis. Front Oncol. 2019;9:711.CrossRefGoogle Scholar
  63. 63.
    Clay PG, Yuet WC, Moecklinghoff CH, Duchesne I, Tronczyński KL, Shah S, Shao D. A meta-analysis comparing 48-week treatment outcomes of single and multi-tablet antiretroviral regimens for the treatment of people living with HIV. AIDS Res Ther. 2018;15:17. Scholar
  64. 64.
    Portilla I, Reus S, León R, van-der Hofstadt C, Sánchez J, López N, et al. Neurocognitive impairment in well-controlled HIV-infected patients: a cross-sectional study. AIDS Res Hum Retrovir. 2019;35:634–41. Scholar
  65. 65.
    Robertson K, Liner J, Heaton R. Neuropsychological assessment of HIV-infected populations in international settings. Neuropsychol Rev. 2009;19:232–49. Scholar
  66. 66.
    Jongsiriyanyong & Limpawattana. Mild cognitive impairment in clinical practice: a review article. Am J Alzheimers Dis Other Demen. 2018;33:500–7. Scholar
  67. 67.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–8.CrossRefGoogle Scholar
  68. 68.
    Capitani E, Laiacona M. Composite neuropsychological batteries and demographic correction: standardization based on equivalent scores, with a review of published data: the Italian group for the neuropsychological study of ageing. J Clin Exp Neuropsychol. 1997;19:795–809.CrossRefGoogle Scholar
  69. 69.
    Blackstone K, Moore DJ, Franklin DR Jr, Clifford DB, Collier AC, Marra CM, For the CHARTER group, et al. Defining neurocognitive impairment in HIV: deficit scores versus clinical ratings. K. Clin Neuropsychol. 2012. Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychologyCatholic UniversityMilanItaly

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