Skip to main content

Advertisement

SpringerLink
Log in

Neurocognitive impairment and gray matter volume reduction in HIV-infected patients

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Although neuropsychological studies of human immunodeficiency virus (HIV)-infected patients have demonstrated heterogeneity in neurocognitive impairment and neuroimaging studies have reported diverse brain regions affected by HIV, it remains unclear whether individual differences in neurocognitive impairment are underpinned by their neural bases. Here, we investigated spatial distribution patterns of correlation between neurocognitive function and regional gray matter (GM) volume across patients with HIV. Thirty-one combination antiretroviral therapy-treated HIV-infected Japanese male patients and 33 age- and sex-matched healthy controls were included in the analysis after strict exclusion criteria, especially for substance use. Fifteen neurocognitive tests were used, and volumetric magnetic resonance imaging was performed. We used voxel-based morphometry to compare GM volume between groups and identify regional GM volumes that correlated with neurocognitive tests across patients. Using the Frascati criteria, 10 patients were diagnosed with asymptomatic neurocognitive impairment, while the others were not diagnosed with HIV-associated neurocognitive disorders. Patients showed a significantly lower performance in five neurocognitive tests as well as significantly reduced GM volume relative to controls, with volume-reduced regions spread diffusely across the whole brain. Different aspects of neurocognitive impairment (i.e., figural copy, finger tapping, and Pegboard) were associated with different GM regions. Our findings suggest a biological background constituting heterogeneity of neurocognitive impairment in HIV infection and support the clinical importance of considering individual differences for tailor-made medicine for people living with HIV.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Amaral DG (2013) The functional organization of perception and movement. In: Kandel E, Schwartz JH, Jessell T (eds) Principles of neural science, 5th edn. McGraw-Hill Education, New York, pp 356–369

    Google Scholar 

  • Amiez C, Petrides M (2014) Neuroimaging evidence of the anatomo-functional organization of the human cingulate motor areas. Cereb Cortex 24:563–578

    Article  PubMed  Google Scholar 

  • 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 69:1789–1799

    Article  CAS  PubMed  Google Scholar 

  • Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38:95–113

    Article  PubMed  Google Scholar 

  • Becker JT, Maruca V, Kingsley LA, Sanders JM, Alger JR, Barker PB, Goodkin K, Martin E, Miller EN, Ragin A, Sacktor N, Selnes O, Multicenter ACS (2012) Factors affecting brain structure in men with HIV disease in the post-HAART era. Neuroradiology 54:113–121

    Article  PubMed  Google Scholar 

  • Bell RP, Foxe JJ, Nierenberg J, Hoptman MJ, Garavan H (2011) Assessing white matter integrity as a function of abstinence duration in former cocaine-dependent individuals. Drug Alcohol Depend 114:159–168

    PubMed  Google Scholar 

  • Biesbroek JM, van Zandvoort MJ, Kuijf HJ, Weaver NA, Kappelle LJ, Vos PC, Velthuis BK, Biessels GJ, Postma A, Utrecht VCISG (2014) The anatomy of visuospatial construction revealed by lesion-symptom mapping. Neuropsychologia 62:68–76

    Article  PubMed  Google Scholar 

  • Bush G, Luu P, Posner MI (2000) Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 4:215–222

    Article  CAS  PubMed  Google Scholar 

  • Butters N, Grant I, Haxby J, Judd LL, Martin A, McClelland J, Pequegnat W, Schacter D, Stover E (1990) Assessment of AIDS-related cognitive changes: recommendations of the NIMH workshop on neuropsychological assessment approaches. J Clin Exp Neuropsychol 12:963–978

    Article  CAS  PubMed  Google Scholar 

  • Chelune GJ, Heaton RK, Lehman RA (1986) Neuropsychological and personality correlates of patients’ complaints of disability. In: Goldstein G (ed) Advances in clinical neuropsychology. Springer, Berlin, pp 95–126

    Chapter  Google Scholar 

  • Chiang M-C, Dutton RA, Hayashi KM, Lopez OL, Aizenstein HJ, Toga AW, Becker JT, Thompson PM (2007) 3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry. Neuroimage 34:44–60

    Article  PubMed  Google Scholar 

  • 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:e0120488

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dahiya S, Irish BP, Nonnemacher MR, Wigdahl B (2013) Genetic variation and HIV-associated neurologic disease. Adv Virus Res 87:183–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dawes S, Suarez P, Casey CY, Cherner M, Marcotte TD, Letendre S, Grant I, Heaton RK, Group H (2008) Variable patterns of neuropsychological performance in HIV-1 infection. J Clin Exp Neuropsychol 30:613–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devlin KN, Giovannetti T (2017) Heterogeneity of neuropsychological impairment in HIV infection: contributions from mild cognitive impairment. Neuropsychol Rev 27:101–123

    Article  PubMed  Google Scholar 

  • Dum RP, Strick PL (1993) Cingulate motor areas. In: Vogt BA, Gabriel M (eds) Neurobiology of cingulate cortex and limbic thalamus. Birkhäuser, Boston, pp 415–441

    Chapter  Google Scholar 

  • Fujita K, Maekawa H, Dairoku H, Yamanaka K (Japanese WAIS-III Publication Committee) (2006) Japanese version of the WAIS-III (Japanese). Nihon Bunka Kagakusha, Tokyo

    Google Scholar 

  • Goldberg ME, Wurtz RH (2013) Visual processing and action. In: Kandel E, Schwartz JH, Jessell T (eds) Principles of neural science, 5th edn. McGraw-Hill Education, New York, pp 638–653

    Google Scholar 

  • Hanlon CA, Dufault DL, Wesley MJ, Porrino LJ (2011) Elevated gray and white matter densities in cocaine abstainers compared to current users. Psychopharmacology 218:681–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Q, Huang X, Turel O, Schulte M, Huang D, Thames A, Bechara A, Hser Y-I (2018) Presumed structural and functional neural recovery after long-term abstinence from cocaine in male military veterans. Prog Neuro-Psychopharmacol Biol Psychiatry 84:18–29

    Article  CAS  Google Scholar 

  • Heaton RK, Kirson D, Verin R, Grant I, HNRC group (1994) The utility of clinical ratings for detecting early cognitive change in HIV infection. In: Grant I, Martin A (eds) Neuropsychology of HIV infection. Oxford University Press, Oxford, pp 188–206

    Google Scholar 

  • Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, McCutchan JA, Taylor MJ, Kelly MD, Ellis RJ (1995) The HNRC 500-neuropsychology of HIV infection at different disease stages. J Int Neuropsychol Soc 1:231–251

    Article  CAS  PubMed  Google Scholar 

  • Heaton RK, Clifford DB, Franklin DR Jr, 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, CHARTER group (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, CHARTER group, HNRC group (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17:3–16

  • Hightower GK, Wong JK, Letendre SL, Umlauf AA, Ellis RJ, Ignacio CC, Heaton RK, Collier AC, Marra CM, Clifford DB, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Grant I, Little SJ, Richman DD, Kosakovsky Pond SL, Smith DM (2012) Higher HIV-1 genetic diversity is associated with AIDS and neuropsychological impairment. Virology 433:498–505

    Article  CAS  PubMed  Google Scholar 

  • Klunder AD, Chiang M-C, Dutton RA, Lee SE, Toga AW, Lopez OL, Aizenstein HJ, Becker JT, Thompson PM (2008) Mapping cerebellar degeneration in HIV/AIDS. Neuroreport 19:1655–1659

    Article  PubMed  PubMed Central  Google Scholar 

  • Konishi M, Saito F, Terasawa Y, Umeda S, Fukunaga A, Tabuchi H, Mimura M, Kato M, Kashima H (2014) Normative data on tests for frontal lobe funcions: WCST (Keio version), verbal fluency, modified stroop task (conference proceedings) (Japanese). High Brain Funct Res 34:132–133

    Google Scholar 

  • Korponay C, Kosson DS, Decety J, Kiehl KA, Koenigs M (2017) Brain volume correlates with duration of abstinence from substance abuse in a region-specific and substance-specific manner. Biol Psychiatry Cogn Neurosci Neuroimaging 2:626–635

    PubMed  PubMed Central  Google Scholar 

  • Lafayette Instrument (2014) Grooved pegboard test user’s manual. Available at: http://www.limef.com/downloads/MAN-32025-forpdf-rev0.pdf

  • Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9:179–186

    Article  CAS  PubMed  Google Scholar 

  • Lench DH, DeVries W, Hanlon CA (2017) The effect of task difficulty on motor performance and frontal-striatal connectivity in cocaine users. Drug Alcohol Depend 173:178–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis-de Los Angeles CP, Williams PL, Huo Y, Wang SD, Uban KA, Herting MM, Malee K, Yogev R, Csernansky JG, Nichols S, Van Dyke RB, Sowell ER, Wang L, Pediatric HIVACS, the Pediatric Imaging N, Genetics S (2017) Lower total and regional grey matter brain volumes in youth with perinatally-acquired HIV infection: associations with HIV disease severity, substance use, and cognition. Brain Behav Immun 62:100–109

    Article  PubMed  Google Scholar 

  • Li J, Gao L, Wen Z, Zhang J, Wang P, Tu N, Lei H, Lin F, Gui X, Wu G (2018) Structural covariance of gray matter volume in HIV vertically infected adolescents. Sci Rep 8:1182

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Loh KK, Hadj-Bouziane F, Petrides M, Procyk E, Amiez C (2018) Rostro-caudal organization of connectivity between cingulate motor areas and lateral frontal regions. Front Neurosci 11:753

    Article  PubMed  PubMed Central  Google Scholar 

  • Masters MC, Ances BM (2014) Role of neuroimaging in HIV-associated neurocognitive disorders. Semin Neurol 34:89–102

    Article  PubMed  PubMed Central  Google Scholar 

  • Matsuoka K, Kim Y (2006) Japanese adult reading test (JART) (Japanese). Shinkoh Igaku Shuppansha, Tokyo

    Google Scholar 

  • Matsuoka K, Uno M, Kasai K, Koyama K, Kim Y (2006) Estimation of premorbid IQ in individuals with Alzheimer's disease using Japanese ideographic script (kanji) compound words: Japanese version of National Adult Reading Test. Psychiatry Clin Neurosci 60:332–339

    Article  PubMed  Google Scholar 

  • Ministry of Health, Labour and Welfare, Japan (2017) Current drug abuse surveillance (Japanese). Available at: https://www.mhlw.go.jp/bunya/iyakuhin/yakubuturanyou/torikumi/

  • Ministry of Internal Affairs and Communications, Japan (2018) Population, population movement, households number (Japanese). Available at http://www.soumu.go.jp/main_content/000563135.pdf

  • National Institute of Infectious Diseases, Japan (2018) HIV/AIDS in Japan, 2017 (Japanese). Available at https://www.niid.go.jp/niid/en/index-e/865-iasr/8335-463te.html

  • Navia BA, Cho ES, Petito CK, Price RW (1986) The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525–535

    Article  CAS  PubMed  Google Scholar 

  • Olivier IS, Cacabelos R, Naidoo V (2018) Risk factors and pathogenesis of HIV-associated neurocognitive disorder: the role of host genetics. Int J Mol Sci 19:3594

    Article  PubMed Central  CAS  Google Scholar 

  • Osterrieth P (1944) Le test de copie d’une figure complexe; contribution a` l’e ́ tude de la perception et de la me ́ moire [test of copying a complex figure; contribution to the study of perception and memory]. Arch Psychol (Geneve) 30:206–356

    Google Scholar 

  • Picard N, Strick PL (2001) Imaging the premotor areas. Curr Opin Neurobiol 11:663–672

    Article  CAS  PubMed  Google Scholar 

  • Reger M, Welsh R, Razani J, Martin DJ, Boone KB (2002) A meta-analysis of the neuropsychological sequelae of HIV infection. J Int Neuropsychol Soc 8:410–424

    Article  PubMed  Google Scholar 

  • Ruff RM, Parker SB (1993) Gender- and age-specific changes in motor speed and eye-hand coordination in adults: normative values for the finger tapping and grooved pegboard tests. Percept Mot Skills 76:1219–1230

    Article  CAS  PubMed  Google Scholar 

  • Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ, McArthur JC (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248

    Article  PubMed  PubMed Central  Google Scholar 

  • Schouten J, Cinque P, Gisslen M, Reiss P, Portegies P (2011) HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 25:561–575

    Article  PubMed  Google Scholar 

  • Simioni S, Cavassini M, Annoni JM, Rimbault Abraham A, Bourquin I, Schiffer V, Calmy A, Chave JP, Giacobini E, Hirschel B, Du Pasquier RA (2010) Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 24:1243–1250

    Article  PubMed  Google Scholar 

  • Thompson PM, Jahanshad N (2015) Novel neuroimaging methods to understand how HIV affects the brain. Curr HIV/AIDS Rep 12:289–298

    Article  PubMed  PubMed Central  Google Scholar 

  • Towgood KJ, Pitkanen M, Kulasegaram R, Fradera A, Kumar A, Soni S, Sibtain NA, Reed L, Bradbeer C, Barker GJ, Kopelman MD (2012) Mapping the brain in younger and older asymptomatic HIV-1 men: frontal volume changes in the absence of other cortical or diffusion tensor abnormalities. Cortex 48:230–241

    Article  PubMed  Google Scholar 

  • Tross S, Price RW, Navia B, Thaler HT, Gold J, Hirsch DA, Sidtis JJ (1988) Neuropsychological characterization of the AIDS dementia complex: a preliminary report. AIDS 2:81–88

    Article  CAS  PubMed  Google Scholar 

  • Ullen F, Forssberg H, Ehrsson HH (2003) Neural networks for the coordination of the hands in time. J Neurophysiol 89:1126–1135

    Article  PubMed  Google Scholar 

  • Underwood J, Cole JH, Caan M, De Francesco D, Leech R, van Zoest RA, Su T, Geurtsen GJ, Schmand BA, Portegies P, Prins M, Wit F, Sabin CA, Majoie C, Reiss P, Winston A, Sharp DJ, Comorbidity in Relation to AC (2017) Gray and White matter abnormalities in treated human immunodeficiency virus disease and their relationship to cognitive function. Clin Infect Dis 65:422–432

    Article  PubMed  PubMed Central  Google Scholar 

  • United Nations Office on Drugs and Crime (2017) Best estimate of annual prevalence of use of drugs, time series. Available at: https://dataunodc.un.org/drugs/prevalence_time_series-2017

  • Wang G-J, Volkow ND, Chang L, Miller E, Sedler M, Hitzemann R, Zhu W, Logan J, Ma Y, Fowler JS (2004) Partial recovery of brain metabolism in methamphetamine abusers after protracted abstinence. Am J Psychiatry 161:242–248

    Article  PubMed  Google Scholar 

  • Wang X, Foryt P, Ochs R, Chung J-H, Wu Y, Parrish T, Ragin AB (2011) Abnormalities in resting-state functional connectivity in early human immunodeficiency virus infection. Brain Connect 1:207–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Zou F, Zhai T, Lei Y, Tan S, Jin X, Ye E, Shao Y, Yang Y, Yang Z (2016) Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years. Addict Biol 21:646–656

    Article  CAS  PubMed  Google Scholar 

  • Watamori T, Hara H, Miyamori T, Eto F (2015) Japanese version of the Rivermead Behavioural Memory Test (Japanese). Chiba Test Center, Tokyo

    Google Scholar 

  • Woods SP, Moore DJ, Weber E, Grant I (2009) Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev 19:152–168

    Article  PubMed  PubMed Central  Google Scholar 

  • Wright EJ, Grund B, Cysique LA, Robertson KR, Brew BJ, Collins G, Shlay JC, Winston A, Read TR, Price RW, International Network for Strategic Initiatives in Global HIVTSSG (2015) Factors associated with neurocognitive test performance at baseline: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med 16:97–108

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, He L, Huang S, Fan L, Li Y, Li P, Zhang J, Liu J, Yang R (2018) Alteration of brain structure with long-term abstinence of methamphetamine by voxel-based morphometry. Front Psychiatry 9:722

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are deeply grateful to the Department of Neuropsychiatry, Keio University, School of Medicine for their consent to use data from their healthy subjects in this study.

Funding

This work was supported by Grants-in-Aid for AIDS research from the Ministry of Health, Labour and Welfare of Japan (H24-AIDS-shitei002, H27-AIDS-shitei004, H30-AIDS-ippan007).

Author information

Authors and Affiliations

  1. Department of Psychiatry, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan

    Tadatsugu Kato, Yujiro Yoshihara & Toshiya Murai

  2. AIDS Medical Center, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Dai Watanabe & Takuma Shirasaka

  3. Department of Radiology, National Cerebral and Cardiovascular Center, Osaka, Japan

    Masaji Fukumoto

  4. Department of Radiology, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Keiko Wada & Keiko Kuriyama

  5. Department of Psychology, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto, Japan

    Takahiro Nakakura

Authors
  1. Tadatsugu Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yujiro Yoshihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dai Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaji Fukumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiko Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takahiro Nakakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keiko Kuriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takuma Shirasaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Toshiya Murai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tadatsugu Kato.

Ethics declarations

Our study was approved by the Institutional Review Board of the National Hospital Organization Osaka National Hospital (approval number: 13042), and the Committee on Medical Ethics of Kyoto University (approval number: C1026).

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 1424 kb)

ESM 2

(PDF 54 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kato, T., Yoshihara, Y., Watanabe, D. et al. Neurocognitive impairment and gray matter volume reduction in HIV-infected patients. J. Neurovirol. 26, 590–601 (2020). https://doi.org/10.1007/s13365-020-00865-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-020-00865-w

Keywords

Search

Navigation