Abstract
Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.
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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
Archibald SL, Masliah E, Fennema-Notestine C, Marcotte TD, Ellis RJ, McCutchan JA, Heaton RK, Grant I, Mallory M, Miller A, Jernigan TL (2004) Correlation of in vivo neuroimaging abnormalities with postmortem human immunodeficiency virus encephalitis and dendritic loss. Arch Neurol 61:369–376
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
Cardenas V, Meyerhoff D, Studholme C, Kornak J, Rothlind J, Lampiris H, Neuhaus J, Grant R, Chao L, Truran D, Weiner M (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15(4):324–333
Chang L, Speck O, Miller EN, Braun J, Jovicich J, Koch C, Itti L, Ernst T (2001) Neural correlates of attention and working memory deficits in HIV patients. Neurology 57:1001–1007
Chang L, Ernst T, Witt MD, Ames N, Gaiefsky M, Miller E (2002) Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naive HIV patients. Neuroimage 17:1638–1648
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
Chang L, Ernst T, Speck O, Grob CS (2005) Additive effects of HIV and chronic methamphetamine use on brain metabolite abnormalities. Am J Psychiatry 162:361–369
Cloak CC, Chang L, Ernst T (2004) Increased frontal white matter diffusion is associated with glial metabolites and psychomotor slowing in HIV. J Neuroimmunol 157:147–152
Cohen RA, Harezlak J, Schifitto G, Hana G, Clark U, Gongvatana A, Paul R, Taylor M, Thompson P, Alger J, Brown M, Zhong J, Campbell T, Singer E, Daar E, McMahon D, Tso Y, Yiannoutsos CT, Navia B (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
Crews L, Patrick C, Achim CL, Everall IP, Masliah E (2009) Molecular pathology of neuro-AIDS (CNS-HIV). Int J Mol Sci 10:1045–1063
Cysique LA, Brew BJ (2009) Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review. Neuropsychol Rev 19:169–185
Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44
Ernst T, Chang L, Jovicich J, Ames N, Arnold S (2002) Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients. Neurology 59:1343–1349
Ernst T, Chang L, Arnold S (2003) Increased glial metabolites predict increased working memory network activation in HIV brain injury. Neuroimage 19:1686–1693
Fennema-Notestine C, Gamst AC, Quinn BT, Pacheco J, Jernigan TL, Thal L, Buckner R, Killiany R, Blacker D, Dale AM, Fischl B, Dickerson B, Gollub RL (2007) Feasibility of multi-site clinical structural neuroimaging studies of aging using legacy data. Neuroinformatics 5:235–245
Giancola ML, Lorenzini P, Balestra P, Larussa D, Baldini F, Corpolongo A, Narciso P, Bellagamba R, Tozzi V, Antinori A (2006) Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 41:332–337
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, CHARTER Group (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–2096
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
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
Hestad K, McArthur JH, Dal Pan GJ, Selnes OA, Nance-Sproson TE, Aylward E, Mathews VP, McArthur JC (1993) Regional brain atrophy in HIV-1 infection: association with specific neuropsychological test performance. Acta Neurol Scand 88:112–118
Jacobsen LK, Giedd JN, Gottschalk C, Kosten TR, Krystal JH (2001) Quantitative morphology of the caudate and putamen in patients with cocaine dependence. Am J Psychiatry 158:486–489
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
Jernigan TL, Archibald SL, Fennema-Notestine C, Gamst AC, Stout JC, Bonner J, Hesselink JR (2001) Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging 22:581–594
Jernigan TL, Gamst AC, Archibald SL, Fennema-Notestine C, Mindt MR, Marcotte TD, Heaton RK, Ellis RJ, Grant I (2005) Effects of methamphetamine dependence and HIV infection on cerebral morphology. Am J Psychiatry 162:1461–1472
Kieburtz K, Ketonen L, Cox C, Grossman H, Holloway R, Booth H, Hickey C, Feigin A, Caine ED (1996) Cognitive performance and regional brain volume in human immunodeficiency virus type 1 infection. Arch Neurol 53:155–158
Letendre SL, Cherner M, Ellis RJ, Marquie-Beck J, Gragg B, Marcotte T, Heaton RK, McCutchan JA, Grant I (2005) The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance: biological correlates of disease. Aids 19(Suppl 3):S72–S78
Levin HS, Williams DH, Borucki MJ, Hillman GR, Williams JB, Guinto FC Jr, Amparo EG, Crow WN, Pollard RB (1990) Magnetic resonance imaging and neuropsychological findings in human immunodeficiency virus infection. J Acquir Immune Defic Syndr 3:757–762
Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997) Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16:187–198
Patel SH, Kolson DL, Glosser G, Matozzo I, Ge Y, Babb JS, Mannon LJ, Grossman RI (2002) Correlation between percentage of brain parenchymal volume and neurocognitive performance in HIV-infected patients. AJNR Am J Neuroradiol 23:543–549
Paul R, Cohen R, Navia B, Tashima K (2002) Relationships between cognition and structural neuroimaging findings in adults with human immunodeficiency virus type-1. Neurosci Biobehav Rev 26:353–359
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
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
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
Sevigny JJ, Albert SM, McDermott MP, Schifitto G, McArthur JC, Sacktor N, Conant K, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Marder K, Epstein LG (2007) An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. Arch Neurol 64:97–102
Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97
Stout JC, Ellis RJ, Jernigan TL, Archibald SL, Abramson I, Wolfson T, McCutchan JA, Wallace MR, Atkinson JH, Grant I (1998) Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group. Arch Neurol 55:161–168
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
Taylor MJ, Schweinsburg BC, Alhassoon OM, Gongvatana A, Brown GG, Young-Casey C, Letendre SL, Grant I (2007) Effects of human immunodeficiency virus and methamphetamine on cerebral metabolites measured with magnetic resonance spectroscopy. J Neurovirol 13:150–159
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
Tozzi V, Bellagamba R, Castiglione F, Amendola A, Ivanovic J, Nicastri E, Libertone R, D’Offizi G, Liuzzi G, Gori C, Forbici F, D’Arrigo R, Bertoli A, Salvatori MF, Capobianchi MR, Antinori A, Perno CF, Narciso P (2008a) Plasma HIV RNA decline and emergence of drug resistance mutations among patients with multiple virologic failures receiving resistance testing-guided HAART. AIDS Res Hum Retroviruses 24:787–796
Tozzi V, Libertone R, Liuzzi G (2008b) HIV pharmacogenetics in clinical practice: recent achievements and future challenges. Curr HIV Res 6:544–554
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
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The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) is supported by award N01 MH22005 from the National Institutes of Health.
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The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University, Mount Sinai School of Medicine, University of California, San Diego, University of Texas, Galveston, University of Washington, Seattle, Washington University, St. Louis and is headquartered at the University of California, San Diego and includes: Director: Igor Grant, M.D.; Co-Directors: J. Allen McCutchan, M.D., Ronald J. Ellis, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D., Terry Alexander, R.N.; Laboratory, Pharmacology and Immunology Component: Scott Letendre, M.D. (P.I.), Edmund Capparelli, Pharm.D.; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Steven Paul Woods, Psy.D., Matthew Dawson; Virology Component: Joseph K. Wong, M.D. (P.I.); Imaging Component: Christine Fennema-Notestine, Ph.D. (P.I.), Terry L., Jernigan, Ph.D., Michael J. Taylor, Ph.D., Rebecca J. Theilmann, Ph.D., John Hesselink, M.D.; Data Management Unit: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman; Statistics Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Protocol Coordinating Component: Thomas D. Marcotte, Ph.D. (P.I.), Rodney von Jaeger, M.P.H.; Johns Hopkins University Site: Justin McArthur (P.I.), Mary Smith; Mount Sinai School of Medicine Site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P., Cheuk Tang, Ph.D., and Thomas Naidich, M,D.; University of California, San Diego Site: J. Allen McCutchan, M.D. (P.I.), Will Toperoff, N.P..; University of Washington, Seattle Site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Kenneth Maravilla, MD, KC Stegbauer, Ph.D.; Trudy Jones, M.N., A.R.N.P.; University of Texas, Galveston Site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N., Gregory Chaljub, M.D.; and Washington University, St. Louis Site: David Clifford, M.D. (P.I.), Muhammad Al-Lozi, M.D., Mengesha Teshome, M.D.
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Jernigan, T.L., Archibald, S.L., Fennema-Notestine, C. et al. Clinical factors related to brain structure in HIV: the CHARTER study. J. Neurovirol. 17, 248–257 (2011). https://doi.org/10.1007/s13365-011-0032-7
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DOI: https://doi.org/10.1007/s13365-011-0032-7