Skip to main content

Advertisement

SpringerLink
Log in

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] dimentia complex [ADC] stage >1) via automated magnetic resonance imaging (MRI) segmentation. Magnetic resonance spectroscopy (MRS) was used to measure levels of cerebral metabolitesN-acetylaspartate (NAA),myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

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

Similar content being viewed by others

References

  • Akaike H (1974). A new look at the statistical model identification.IEEE Trans Autom Control 19: 716–723.

    Article  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 

  • Aylward EH, Brettschneider PD, McArthur JC, Harris GJ, Schlaepfer TE, Henderer JD, Barta PE, Tien AY, Pearlson GD (1995). Magnetic resonance imaging measurement of gray matter volume reductions in HIV dementia.Am J Psychiatry 152: 987–994.

    CAS  PubMed  Google Scholar 

  • Antuono PG, Jones JL, Wang Y, Li SJ (2001). Decreased glutamate + glutamine in Alzheimer’s disease detected in vivo with (1)H-MRS at 0.5 T.Neurology 56: 737–742.

    CAS  PubMed  Google Scholar 

  • Alemán-Gómez Y, Melie-García L, Valdés-Hernandez P (2006). IBASPM: toolbox for automatic parcellation of brain structures. Paper presented at Organization for Human Brain Mapping meeting; Florence, Italy; June 11–15, 2006.

  • Brew BJ (2004). Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex.AIDS 18(Suppl 1): S75-S78.

    CAS  PubMed  Google Scholar 

  • Burnham KP, Anderson DR (2002). Model selection and multimodel inference: a practical-theoretic approach, 2nd ed. New York: Springer.

    Google Scholar 

  • Broom KA, Anthony DC, Lowe JP, Griffin JL, Scott H, Blamire AM, Styles P, Perry VH, Sibson NR (2007). MRI and MRS alterations in the preclinical phase of murine prion disease: association with neuropathological and behavioural changes.Neurobiol Dis 26: 07–717.

    Article  Google Scholar 

  • Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G. (2009). Neurodegeneration and ageing in the HAART era.J Neuroimmune Pharmacol 4: 163–174.

    Article  PubMed  Google Scholar 

  • Binesh N, Huda A, Thomas MA, Wyckoff N, Bugbee M, Han S, Rasgon N, Davanzo P, Sayre J, Guze B, Martin P, Fawzy F (2006). Hepatic encephalopathy: a neurochemical, neuroanatomical, and neuropsychological study.J Appl Clin Med Phys 7: 86–96.

    Article  PubMed  Google Scholar 

  • Brew BJ, Rosenblum M, Cronin K, Price RW (1995). AIDS dementia complex and HIV-1 brain infection: clinicalvirological correlations.Ann Neurol 38: 563–570.

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E (1999). Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex.Neurology 52: 100–108.

    CAS  PubMed  Google Scholar 

  • Chang L, Ernst T, Tornatore C, Aronow H, Melchor R, Walot I, Singer E, Cornford M (1997). Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy.Neurology 48: 836–845.

    CAS  PubMed  Google Scholar 

  • Chang L, Ernst T, Witt MD, Ames N, Gaiefsky M (2002). Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naive HIV patients.NeuroImage 17: 1638–1648.

    Article  PubMed  Google Scholar 

  • Chang L, Ernst T, Witt MD, Ames N, Walot I, Jovicich J, DeSilva M, Trivedi N, Speck O, Miller EN (2003). Persistent brain abnormalities in antiretroviral-naive HIV patients 3 months after HAART.Antivir Ther 8: 17–26.

    CAS  PubMed  Google Scholar 

  • Cohen RA, Harezlak J, Schifitto G,et al. (2010). Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era.J NeuroVirol 16: 25–32.

    Article  CAS  PubMed  Google Scholar 

  • 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 (2004). A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age.NeuroImage 23: 1336–1347.

    Article  CAS  PubMed  Google Scholar 

  • Gropman AL, Batshaw ML (2004). Cognitive outcome in urea cycle disorders.Mol Genet Metab 81(Suppl 1): S58-S62.

    Article  CAS  PubMed  Google Scholar 

  • Gongvatana A, Schweinsburg BC, Taylor MJ, Theilmann RJ, Letendre SL, Alhassoon OM, Jacobus J, Woods SP, Jernigan TL, Ellis RJ, Frank LR, Grant I (2009). White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals.J NeuroVirol 15: 187–195.

    Article  PubMed  Google Scholar 

  • Heindel WC, Jernigan TL, Archibald SL, Achim CL, Masliah E, Wiley CA (1994). The relationship of quantitative brain magnetic resonance imaging measures to neuropathologic indexes of human immunodeficiency virus infection.Arch Neurol 51: 1129–1135.

    CAS  PubMed  Google Scholar 

  • Jernigan TL, Archibald S, Hesselink JR, Atkinson JH, Velin RA, McCutchan JA, Chandler J, Grant I (1993). Magnetic resonance imaging morphometric analysis of cerebral volume loss in human immunodeficiency virus infection. The HNRC Group.Arch Neurol 50: 250–255.

    CAS  PubMed  Google Scholar 

  • Jones RS, Waldman AD (2004). 1H-MRS evaluation of metabolism in Alzheimer’s disease and vascular dementia.Neurol Res 26: 488–495.

    Article  CAS  PubMed  Google Scholar 

  • Kreis R, Arcinue E, Ernst T, Shonk TK, Flores R, Ross BD (1996). Hypoxic encephalopathy after near-drowning studied by quantitative 1H-magnetic resonance spectroscopy.J Clin Invest 97: 1142–1154.

    Article  CAS  PubMed  Google Scholar 

  • Lentz MR, Kim WK, Lee V, Bazner S, Halpern EF, Venna N, Williams K, Rosenberg ES, Gonzalez RG (2009). Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection.Neurology 72: 1465–1472.

    Article  CAS  PubMed  Google Scholar 

  • Long LL, Li XR, Huang ZK, Jiang YM, Fu SX, Zheng W (2009). Relationship between changes in brain MRI and (1)H-MRS, severity of chronic liver damage, and recovery after liver transplantation.Exp Biol Med (Maywood)234: 1075–1085.

    Article  CAS  Google Scholar 

  • Lee PL, Yiannoutsos CT, Ernst T, Chang L, Marra CM, Jarvik JG, Richards TL, Kwok EW, Kolson DL, Simpson D, Tang CY, Schifitto G, Ketonen LM, Meyerhoff DJ, Lenkinski RE, Gonzalez RG, Navia BA (2003). A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis.J Magn Reson Imaging 17: 625–633.

    Article  PubMed  Google Scholar 

  • McArthur JC (2004). HIV dementia: an evolving disease.J Neuroimmunol 157: 3–10.

    Article  CAS  PubMed  Google Scholar 

  • Provencher SW (2001). Automatic quantitation of localized in vivo 1H spectra with LCModel.NMR Biomed 14: 260–264.

    Article  CAS  PubMed  Google Scholar 

  • Paul RH, Ernst T, Brickman AM, Yiannoutsos CT, Tate DF, Cohen RA, Navia BA (2008). Relative sensitivity of magnetic resonance spectroscopy and quantitative magnetic resonance imaging to cognitive function among nondemented individuals infected with HIV.J Int Neuropsychol Soc 14: 725–733.

    Article  PubMed  Google Scholar 

  • Patel SH, Inglese M, Glosser G, Kolson DL, Grossman RI, Gonen O (2003). Whole-brain N-acetylaspartate level and cognitive performance in HIV infection.AJNR Am J Neuroradiol 24: 1587–1591.

    PubMed  Google Scholar 

  • Paul RH, Yiannoutsos CT, Miller EN, Chang L, Marra CM, Schifitto G, Ernst T, Singer E, Richards T, Jarvik GJ, Price R, Meyerhoff DJ, Kolson D, Ellis RJ, Gonzalez G, Lenkinski RE, Cohen RA, Navia BA (2007). Proton MRS and neuropsychological correlates in AIDS dementia complex: evidence of subcortical specificity.J Neuropsychiatry Clin Neurosci 19: 283–292.

    PubMed  Google Scholar 

  • Ross B, Bluml S (2001). Magnetic resonance spectroscopy of the human brain.Anat Rec 265: 54–84.

    Article  CAS  PubMed  Google Scholar 

  • Ratai EM, Pilkenton SJ, Greco JB, Lentz MR, Bombardier JP, Turk KW, He J, Joo CG, Lee V, Westmoreland S, Halpern E, Lackner AA, Gonzalez RG (2009). In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain.BMC Neurosci 10: 63.

    Article  PubMed  Google Scholar 

  • Sijens PE, Alkefaji H, Lunsing RJ, van Spronsen FJ, Meiners LC, Oudkerk M, Verkade HJ (2008). Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure.Eur Radiol 18: 2601–2609.

    Article  PubMed  Google Scholar 

  • Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002). HIV-associated cognitive impairment before and after the advent of combination therapy.J NeuroVirol 8: 136–142.

    Article  PubMed  Google Scholar 

  • Sacktor N, Skolasky RL, Ernst T, Mao X, Selnes O, Pomper MG, Chang L, Zhong K, Shungu DC, Marder K, Shibata D, Schifitto G, Bobo L, Barker PB (2005). A multicenter study of two magnetic resonance spectroscopy techniques in individuals with HIV dementia.J Magn Reson Imaging 21: 325–333.

    Article  PubMed  Google Scholar 

  • Schweinsburg BC, Taylor MJ, Alhassoon OM, Gonzalez R, Brown GG, Ellis RJ, Letendre S, Videen JS, McCutchan JA, Patterson TL, Grant I (2005). Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors.J NeuroVirol 11: 356–364.

    Article  CAS  PubMed  Google Scholar 

  • Schifitto G, Yiannoutsos CT, Ernst T, Navia BA, Nath A, Sacktor N, Anderson C, Marra CM, Clifford DB (2009a). Selegiline and oxidative stress in HIV-associated cognitive impairment.Neurology 73: 1975–1981.

    Article  CAS  PubMed  Google Scholar 

  • Schifitto G, Zhong J, Gill D, Peterson DR, Gaugh MD, Zhu T, Tivarus M, Cruttenden K, Maggirwar SB, Gendelman HE, Dewhurst S, Gelbard HA (2009b). Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment.J NeuroVirol 15: 176–186.

    Article  CAS  PubMed  Google Scholar 

  • Thompson PM, Dutton RA, Hayashi KM, Toga AW, Lopez OL, Aizenstein HJ, Becker JT (2005). Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline.Proc Natl Acad Sci U S A 102: 15647–15652.

    Article  CAS  PubMed  Google Scholar 

  • Tkac I, Dubinsky JM, Keene CD, Gruetter R, Low WC (2007). Neurochemical changes in Huntington R6/ 2 mouse striatum detected by in vivo 1H NMR spectroscopy.J Neurochem 100: 1397–1406.

    Article  CAS  PubMed  Google Scholar 

  • Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.NeuroImage 15: 273–289.

    Article  CAS  PubMed  Google Scholar 

  • Tate D, Harezlak J, Price J, Dewey J, Yiannoutsos C, Campbell T, Daar E, McMahon D, Schifitto G, Zhong J, Taylor M Singer E, Alger J, Brown M, Cohen R, Navia B (2010). Progressive brain atrophy in chronic HIV infection: longitudinal analysis of the HIVNC Cohort Study.Human Brain Mapping. Barcelona, Spain; June6–10, 2010.

    Google Scholar 

  • Tarasow E, Wiercinska-Drapalo A, Kubas B, Dzienis W, Orzechowska-Bobkiewicz A, Prokopowicz D, Walecki J (2003). Cerebral MR spectroscopy in neurologically asymptomatic HIV-infected patients.Acta Radiol 44: 206–212.

    Article  CAS  PubMed  Google Scholar 

  • Valcour V, Sacktor N (2002). HIV-associated dementia and aging.J Ment Health Aging 8: 295–306.

    Google Scholar 

  • Valcour V, Shikuma C, Waters M, Sacktor N (2004). Cognitive impairment in older HIV-1 seropositive individuals: prevalence and potential mechanisms.AIDS 18(Suppl 1): S79-S86.

    PubMed  Google Scholar 

  • Yiannoutsos CT, Ernst T, Chang L, Lee PL, Richards T, Marra CM, Meyerhoff DJ, Jarvik JG, Kolson D, Schifitto G, Ellis RJ, Swindells S, Simpson DM, Miller EN, Gonzalez RG, Navia BA (2004). Regional patterns of brain metabolites in AIDS dementia complex.NeuroImage 23: 928–935.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuropsychology, The Miriam Hospital, Alpert School of Medicine, Brown University, Coro Building, 3-Wes, One Hoppin Street, 02903, Providence, RI, USA

    Ronald A Cohen, Assawin Gongvatana & Uraina Clark

  2. Indiana University School of Medicine, Indianapolis, Indiana, USA

    Jaroslaw Harezlak & Constantin T Yiannoutsos

  3. University of Hawaii, Honolulu, Hawaii, USA

    Steven Buchthal

  4. University of Rochester School of Medicine, Rochester, New York, USA

    Giovanni Schifitto & Jianhui Zhong

  5. University of Missouri, St. Louis, Missouri, USA

    Robert Paul

  6. University of California, San Diego, California, USA

    Michael Taylor

  7. University of California, Los Angeles, California, USA

    Paul Thompson, Jeffery Alger, Elyse Singer & Eric Daar

  8. Brigham and Women’s Hospital, Boston, Massachusetts, USA

    David Tate

  9. University of Colorado, Denver, Aurora, Colorado, USA

    Mark Brown & Thomas Campbell

  10. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Deborah McMahon

  11. Stanford University School of Medicine, Palo Alto, California, USA

    Yuen Tso

  12. Tufts University School of Medicine, Boston, Massachusetts, USA

    Bradford Navia

Authors
  1. Ronald A Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaroslaw Harezlak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Assawin Gongvatana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven Buchthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giovanni Schifitto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Uraina Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Tate
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jeffery Alger
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mark Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jianhui Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Elyse Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eric Daar
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Deborah McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yuen Tso
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Constantin T Yiannoutsos
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Bradford Navia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ronald A Cohen or Bradford Navia.

Additional information

The authors would like to acknowledge and express their appreciation for the efforts on all the MRS consortium sites involved in this multicenter project, including the Colorado Clinical and Translational Research Institute (RR025780, Sokol, RJ), Principal Investigator [PI], and the staff, clinicians, and investigators from these sites that made this study possible. The authors also appreciate the support of the National Institutes of Health who provide the support and funding for this research, including R01 NS036524 “Proton MRS Studies of Cerebral Injury in HIV Infection” (Brad Navia, PI); R01 MH074368 “Age Effects on HIV-Associated Brain Dysfunction” (Ronald Cohen, PI).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cohen, R.A., Harezlak, J., Gongvatana, A. et al. Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. Journal of NeuroVirology 16, 435–444 (2010). https://doi.org/10.1007/BF03210849

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03210849

Keywords

Search

Navigation