Abstract
Highly active antiretroviral therapy (HAART) has increased life expectancy among HIV-infected individuals, and by 2015, at least half of all HIV-infected individuals will be over 50 years of age. Neurodegenerative processes associated with aging may be facilitated by HIV-1 infection, resulting in premature brain aging. This review will highlight brain abnormalities in HIV patients in the setting of aging, focusing on recent neuroimaging studies of the structural, physiological, functional and neurochemical changes. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy studies performed during the pre-HAART era or on antiretroviral-naive subjects suggest an accelerated aging process, while those on HAART-treated subjects suggest premature brain atrophy. Diffusion tensor imaging studies yielded conflicting findings on the relationship between HIV and age in neuroasymptomatic individuals. Functional MRI studies found evidence of premature or accelerated aging processes in the brains of HIV subjects. Lastly, many age-related illnesses such as diabetes, stroke, and depression, as well as comorbid substance abuse, may further exacerbate the aging process in the HIV-infected brain, leading to premature or accelerated age-related brain changes. Given the different pathologic or physiologic changes in the brain assessed by the different neuroimaging techniques, using a multimodal approach in longitudinal follow-up studies is recommended for future studies.
Similar content being viewed by others
References
Ances BM, Vaida F, Yeh MJ, Liang CL, Buxton RB, Letendre S, McCutchan JA, Ellis RJ (2010) HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 201:336–340
Ances BM, Vaida F, Cherner M, Yeh MJ, Liang CL, Gardner C, Grant I, Ellis RJ, Buxton RB (2011) HIV and chronic methamphetamine dependence affect cerebral blood flow. J Neuroimmune Pharmacol 6:409–419
Ances BM, Benzinger TL, Christensen JJ, Thomas J, Venkat R, Teshome M, Aldea P, Fagan AM, Holtzman DM, Morris JC, Clifford DB (2012a) 11C-PiB imaging of human immunodeficiency virus-associated neurocognitive disorder. Arch Neurol 69:72–77
Ances BM, Ortega M, Vaida F, Heaps J, Paul R (2012b) Independent effects of HIV, aging, and HAART on brain volumetric measures. J Acquir Immune Defic Syndr 59:469–477
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
Arthurs OJ, Boniface S (2002) How well do we understand the neural origins of the fMRI BOLD signal? Trends Neurosci 25:27–31
Becker JT, Maruca V, Kingsley LA, Sanders JM, Alger JR, Barker PB, Goodkin K, Martin E, Miller EN, Ragin A, Sacktor N, Selnes O (2011) Factors affecting brain structure in men with HIV disease in the post-HAART era. Neuroradiology 54:113–121
Bell J (1998) The neuropathology of adult HIV infection. Rev Neurol 154:816–829
Bonacini M (2011) Alcohol use among patients with HIV infection. Ann Hepatol 10:502–507
Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G (2009) Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharmacol 4:163–174
Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, Visscher BR, Margolick JB, Dobs AS (2005) Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 165:1179–1184
Cardenas VA, Meyerhoff DJ, Studholme C, Kornak J, Rothlind J, Lampiris H, Neuhaus J, Grant RM, Chao LL, Truran D, Weiner MW (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15:324–333
Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA (1999) Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353:2093–2099
Catani M, Cherubini A, Howard R, Tarducci R, Pelliccioli GP, Piccirilli M, Gobbi G, Senin U, Mecocci P (2001) (1)H-MR spectroscopy differentiates mild cognitive impairment from normal brain aging. Neuroreport 12:2315–2317
Chang L, Ernst T, Poland RE, Jenden DJ (1996) In vivo proton magnetic resonance spectroscopy of the normal aging human brain. Life Sci 58:2049–2056
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 (2004a) A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age. Neuroimage 23:1336–1347
Chang L, Tomasi D, Yakupov R, Lozar C, Arnold S, Caparelli E, Ernst T (2004b) Adaptation of the attention network in human immunodeficiency virus brain injury. Ann Neurol 56:259–272
Chang L, Cloak C, Patterson K, Grob C, Miller EN, Ernst T (2005a) Enlarged striatum in abstinent methamphetamine abusers: a possible compensatory response. Biol Psychiatry 57:967–974
Chang L, Ernst T, Speck O, Grob CS (2005b) Additive effects of HIV and chronic methamphetamine use on brain metabolite abnormalities. Am J Psychiatry 162:361–369
Chang L, Cloak C, Yakupov R, Ernst T (2006) Combined and independent effects of chronic marijuana use and HIV on brain metabolites. J Neuroimmune Pharmacol 1:65–76
Chang L, Wong V, Nakama H, Watters M, Ramones D, Miller EN, Cloak C, Ernst T (2008a) Greater than age-related changes in brain diffusion of HIV patients after 1 year. J Neuroimmune Pharmacol 3:265–274
Chang L, Yakupov R, Nakama H, Stokes B, Ernst T (2008b) Antiretroviral treatment is associated with increased attentional load-dependent brain activation in HIV patients. J Neuroimmune Pharmacol 3:95–104
Chang L, Andres M, Sadino J, Jiang CS, Nakama H, Miller E, Ernst T (2011) Impact of apolipoprotein E epsilon4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging. Neuroimage 58:1017–1027
Chang L, Feger U, Ernst T (2012) Bioimaging. In: Gendelman H, Grant I, Everall IP, Fox HS, Gelbard HA, Lipton SA, Swindells S (eds) The neurology of AIDS. Oxford University Press, New York, pp 763–797
Chiang MC, 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
Cole JW, Pinto AN, Hebel JR, Buchholz DW, Earley CJ, Johnson CJ, Macko RF, Price TR, Sloan MA, Stern BJ, Wityk RJ, Wozniak MA, Kittner SJ (2004) Acquired immunodeficiency syndrome and the risk of stroke. Stroke 35:51–56
Dagan T, Sable C, Bray J, Gerschenson M (2002) Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: what is the evidence? Mitochondrion 1:397–412
Deeks SG (2011) HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 62:141–155
den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MM (2003) Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46:1604–1610
Dever LL, Oruwari PA, Figueroa WE, O'Donovan CA, Eng RH (2000) Hyperglycemia associated with protease inhibitors in an urban HIV-infected minority patient population. Ann Pharmacother 34:580–584
Dewey J, Hana G, Russell T, Price J, McCaffrey D, Harezlak J, Sem E, Anyanwu JC, Guttmann CR, Navia B, Cohen R, Tate DF (2010) Reliability and validity of MRI-based automated volumetry software relative to auto-assisted manual measurement of subcortical structures in HIV-infected patients from a multisite study. Neuroimage 51:1334–1344
Effros RB, Fletcher CV, Gebo K, Halter JB, Hazzard WR, Horne FM, Huebner RE, Janoff EN, Justice AC, Kuritzkes D, Nayfield SG, Plaeger SF, Schmader KE, Ashworth JR, Campanelli C, Clayton CP, Rada B, Woolard NF, High KP (2008) Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 47:542–553
Ernst T, Chang L (2004) Effect of aging on brain metabolism in antiretroviral-naive HIV patients. AIDS 18(Suppl 1):S61–S67
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
Ernst T, Yakupov R, Nakama H, Crocket G, Cole M, Watters M, Ricardo-Dukelow ML, Chang L (2009) Declined neural efficiency in cognitively stable human immunodeficiency virus patients. Ann Neurol 65:316–325
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 32:1045–1053
Everall I, Luther P, Lantos P (1993) A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia. J Neuropathol 52:561–566
Ghafouri M, Amini S, Khalili K, Sawaya BE (2006) HIV-1 associated dementia: symptoms and causes. Retrovirology 3:28
Gongvatana A, Cohen RA, Correia S, Devlin KN, Miles J, Kang H, Ombao H, Navia B, Laidlaw DH, Tashima KT (2011) Clinical contributors to cerebral white matter integrity in HIV-infected individuals. J Neurovirol 17:477–486
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713
Gray F, Scaravilli F, Everall I, Chretien F, An S, Boche D, Adle-Biassette H, Wingertsmann L, Durigon M, Hurtrel B, Chiodi F, Bell J, Lantos P (1996) Neuropathology of early HIV-1 infection. Brain Pathol 6:1–15
Haase AT (1986) Pathogenesis of lentivirus infections. Nature 322:130–136
Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Alger J, Singer E, Campbell T, Yiannoutsos C, Cohen R, Navia B (2011) Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 25:625–633
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
Kaul M, Zheng J, Okamoto S, Gendelman HE, Lipton SA (2005) HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ 12(Suppl 1):878–892
Langford D, Adame A, Grigorian A, Grant I, McCutchan JA, Ellis RJ, Marcotte TD, Masliah E (2003) Patterns of selective neuronal damage in methamphetamine-user AIDS patients. J Acquir Immune Defic Syndr 34:467–474
Lepore N, Brun C, Chou YY, Chiang MC, Dutton RA, Hayashi KM, Luders E, Lopez OL, Aizenstein HJ, Toga AW, Becker JT, Thompson PM (2008) Generalized tensor-based morphometry of HIV/AIDS using multivariate statistics on deformation tensors. IEEE Trans Med Imaging 27:129–141
Lim KO, Helpern JA (2002) Neuropsychiatric applications of DTI—a review. NMR Biomed 15:587–593
Madden DJ, Spaniol J, Whiting WL, Bucur B, Provenzale JM, Cabeza R, White LE, Huettel SA (2007) Adult age differences in the functional neuroanatomy of visual attention: a combined fMRI and DTI study. Neurobiol Aging 28:459–476
McBean AM, Li S, Gilbertson DT, Collins AJ (2004) Differences in diabetes prevalence, incidence, and mortality among the elderly of four racial/ethnic groups: Whites, Blacks, Hispanics, and Asians. Diabetes Care 27:2317–2324
Nakama H, Chang L, Fein G, Shimotsu R, Jiang CS, Ernst T (2011) Methamphetamine users show greater than normal age-related cortical gray matter loss. Addiction 106:1474–1483
Navia BA, Cho ES, Petito CK, Price RW (1986) The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525–535
Ostrow DG (1994) Substance abuse and HIV infection. Psychiatr Clin North Am 17:69–89
Ovbiagele B, Nath A (2011) Increasing incidence of ischemic stroke in patients with HIV infection. Neurology 76:444–450
Palacios R, Merchante N, Macias J, Gonzalez M, Castillo J, Ruiz J, Marquez M, Gomez-Mateos J, Pineda JA, Santos J (2006) Incidence of and risk factors for insulin resistance in treatment-naive HIV-infected patients 48 weeks after starting highly active antiretroviral therapy. Antivir Ther 11:529–535
Pfefferbaum A, Adalsteinsson E, Sullivan EV (2005) Cortical NAA deficits in HIV infection without dementia: influence of alcoholism comorbidity. Neuropsychopharmacology 30:1392–1399
Pfefferbaum A, Rosenbloom MJ, Rohlfing T, Adalsteinsson E, Kemper CA, Deresinski S, Sullivan EV (2006) Contribution of alcoholism to brain dysmorphology in HIV infection: effects on the ventricles and corpus callosum. Neuroimage 33:239–251
Pfefferbaum A, Rosenbloom MJ, Adalsteinsson E, Sullivan EV (2007) Diffusion tensor imaging with quantitative fibre tracking in HIV infection and alcoholism comorbidity: synergistic white matter damage. Brain 130:48–64
Pfefferbaum A, Rosenbloom MJ, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Sullivan EV (2012) Regional brain structural dysmorphology in human immunodeficiency virus infection: effects of acquired immune deficiency syndrome, alcoholism, and age. Biol Psychiatry. doi:10.1016/j.biopsych.2012.02.018
Pomara N, Crandall D, Choi S, Johnson G, Lim K (2001) White matter abnormalities in HIV-1 infection: a diffusion tensor imaging study. Psychiatry Res 106:15–24
Prentiss D, Power R, Balmas G, Tzuang G, Israelski DM (2004) Patterns of marijuana use among patients with HIV/AIDS followed in a public health care setting. J Acquir Immune Defic Syndr 35:38–45
Qureshi AI, Janssen RS, Karon JM, Weissman JP, Akbar MS, Safdar K, Frankel MR (1997) Human immunodeficiency virus infection and stroke in young patients. Arch Neurol 54:1150–1153
Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A, Dahle C, Gerstorf D, Acker JD (2005) Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15:1676–1689
Reynolds NR (2009) Cigarette smoking and HIV: more evidence for action. AIDS Educ Prev 21:106–121
Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 18:691–701
Schuitemaker A, van der Doef TF, Boellaard R, van der Flier WM, Yaqub M, Windhorst AD, Barkhof F, Jonker C, Kloet RW, Lammertsma AA, Scheltens P, van Berckel BN (2012) Microglial activation in healthy aging. Neurobiol Aging 33:1067–1072
Smith GH (2005) Opening statement of Senator Gordon H. Smith. Aging hearing: HIV over fifty, exploring the new threat. Senate Committee on Aging, Washington, DC, U.S. Government Printing Office
Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW (2003) Mapping cortical change across the human life span. Nat Neurosci 6:309–315
Sowell ER, Thompson PM, Toga AW (2004) Mapping changes in the human cortex throughout the span of life. Neuroscientist 10:372–392
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
Streit WJ, Xue QS (2010) The brain's aging immune system. Aging Dis 1:254–261
Taylor MJ, Letendre SL, Schweinsburg BC, Alhassoon OM, Brown GG, Gongvatana A, Grant I (2004) Hepatitis C virus infection is associated with reduced white matter N-acetylaspartate in abstinent methamphetamine users. J Int Neuropsychol Soc 10:110–113
Thames AD, Foley J, Panos SE, Singer EJ, Patel SM, El-Saden S, Hinkin CH (2011) Past stimulant abuse is associated with reduced basal ganglia and hippocampal integrity in older HIV+ adults: a diffusion tensor imaging study. J AIDS Clinic Res 2:129. doi:10.4172/2155-6113.1000129
Tiehuis AM, van der Graaf Y, Visseren FL, Vincken KL, Biessels GJ, Appelman AP, Kappelle LJ, Mali WP (2008) Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease. Stroke 39:1600–1603
Tipping B, de Villiers L, Wainwright H, Candy S, Bryer A (2007) Stroke in patients with human immunodeficiency virus infection. J Neurol Neurosurg Psychiatry 78:1320–1324
Tomasi D, Ernst T, Caparelli EC, Chang L (2006) Common deactivation patterns during working memory and visual attention tasks: an intra-subject fMRI study at 4 Tesla. Hum Brain Mapp 27:694–705
Towgood KJ, Pitkanen M, Kulasegaram R, Fradera A, Kumar A, Soni S, Sibtain NA, Reed L, Bradbeer C, Barker GJ, Kopelman MD (2011) 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
Tyler LK, Wright P, Randall B, Marslen-Wilson WD, Stamatakis EA (2010) Reorganization of syntactic processing following left-hemisphere brain damage: does right-hemisphere activity preserve function? Brain 133:3396–3408
Vink D, Aartsen MJ, Comijs HC, Heymans MW, Penninx BW, Stek ML, Deeg DJ, Beekman AT (2009) Onset of anxiety and depression in the aging population: comparison of risk factors in a 9-year prospective study. Am J Geriatr Psychiatry 17:642–652
Walli R, Goebel FD, Demant T (1998) Impaired glucose tolerance and protease inhibitors. Ann Intern Med 129:837–838
Woods SP, Moore DJ, Weber E, Grant I (2009) Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev 19:152–168
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Holt, J.L., Kraft-Terry, S.D. & Chang, L. Neuroimaging studies of the aging HIV-1-infected brain. J. Neurovirol. 18, 291–302 (2012). https://doi.org/10.1007/s13365-012-0114-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-012-0114-1