Immune Responses in HIV Infection, Alcoholism, and Aging: A Neuroimaging Perspective

  • N. M. Zahr
  • A. Manning-Bog
  • C. Alt
  • E. V. Sullivan
  • A. Pfefferbaum


Biological changes that accrue during normal, healthy aging contribute to behavioral (cognitive and motor) decline attributable to structural and metabolic alterations in the brain. Superimposed on the pattern of the healthy aging brain are the consequences of frequent concomitants of aging such as hypertension and hormone deficiency. Even more complex are the brain modifications that can occur in the presence of comorbidities such as infection with the human immunodeficiency virus (HIV) and alcohol dependence, each of which has independent deleterious effects on selective brain systems. Highly active antiretroviral therapy (HAART) has extended the average life span of individuals infected with HIV [1–3]. Accompanying longevity and improved health with treatment are increased opportunity to initiate or resume high-risk activities such as unsafe drinking (estimates of alcoholism among HIV patients range from 8 to 63 %) [4–9], necessitating the consideration of the cumulative interactions of these disease processes on the aging brain [10].


Human Immunodeficiency Virus White Matter Human Immunodeficiency Virus Infection Human Immunodeficiency Virus Patient Human Immunodeficiency Virus Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



NIAAA AA005965 A.P.; AA012388 A.P. & E.V.S.; AA0012388 R37; AA013521-INIA; AA017347


  1. 1.
    Braithwaite RS, McGinnis KA, Conigliaro J, Maisto SA, Crystal S, Day N, Cook RL, Gordon A, Bridges MW, Seiler JF, Justice AC (2005) A temporal and dose–response association between alcohol consumption and medication adherence among veterans in care. Alcohol Clin Exp Res 29(7):1190–1197PubMedCrossRefGoogle Scholar
  2. 2.
    Everall IP, Hansen LA, Masliah E (2005) The shifting pattern of HIV encephalitis neuropathology. Neurotox Res 8:51–61PubMedCrossRefGoogle Scholar
  3. 3.
    Stein M, Herman DS, Trisvan E, Pirraglia P, Engler P, Anderson BJ (2005) Alcohol use and sexual risk behavior among human immunodeficiency virus-positive persons. Alcohol Clin Exp Res 29(5):837–843PubMedCrossRefGoogle Scholar
  4. 4.
    Cook RL, Sereika SM, Hunt SC, Woodward WC, Erlen JA, Conigliaro J (2001) Problem drinking and medication adherence among persons with HIV infection. J Gen Intern Med 16(2):83–88PubMedCrossRefGoogle Scholar
  5. 5.
    Galvan FH, Bing EG, Fleishman JA, London AS, Caetano R, Burnam MA, Longshore D, Morton SC, Orlando M, Shapiro M (2002) The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV Cost and Services Utilization Study. J Stud Alcohol 63(2):179–186PubMedGoogle Scholar
  6. 6.
    LeFevre F, O’Leary B, Moran M, Mossar M, Yarnold PR, Martin GJ, Glassroth J (1995) Alcohol consumption among HIV-infected patients. J Gen Intern Med 10(8):458–460PubMedCrossRefGoogle Scholar
  7. 7.
    Miguez MJ, Shor-Posner G, Morales G, Rodriguez A, Burbano X (2003) HIV treatment in drug abusers: impact of alcohol use. Addict Biol 8(1):33–37PubMedCrossRefGoogle Scholar
  8. 8.
    Page-Shafer K, Delorenze GN, Satariano WA, Winkelstein W Jr (1996) Comorbidity and survival in HIV-infected men in the San Francisco Men’s Health Survey. Ann Epidemiol 6(5):420–430PubMedCrossRefGoogle Scholar
  9. 9.
    Samet JH, Horton NJ, Meli S, Freedberg KA, Palepu A (2004) Alcohol consumption and antiretroviral adherence among HIV-infected persons with alcohol problems. Alcohol Clin Exp Res 28(4):572–577PubMedCrossRefGoogle Scholar
  10. 10.
    Justice AC, Lasky E, McGinnis KA, Skanderson M, Conigliaro J, Fultz SL, Crothers K, Rabeneck L, Rodriguez-Barradas M, Weissman SB, Bryant K (2006) Medical disease and alcohol use among veterans with human immunodeficiency infection: a comparison of disease measurement strategies. Med Care 44(8 Suppl 2):S52–S60PubMedCrossRefGoogle Scholar
  11. 11.
    Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10(12):826–837PubMedCrossRefGoogle Scholar
  12. 12.
    Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrell MI, Friedlander M (2006) Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J Clin Invest 116(12):3266–3276PubMedCrossRefGoogle Scholar
  13. 13.
    Graeber MB, Streit WJ, Kreutzberg GW (1988) Axotomy of the rat facial nerve leads to increased CR3 complement receptor expression by activated microglial cells. J Neurosci Res 21(1):18–24PubMedCrossRefGoogle Scholar
  14. 14.
    Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20(3):269–287PubMedCrossRefGoogle Scholar
  15. 15.
    Aloisi F (2001) Immune function of microglia. Glia 36(2):165–179PubMedCrossRefGoogle Scholar
  16. 16.
    Aschner M (1998) Astrocytic functions and physiological reactions to injury: the potential to induce and/or exacerbate neuronal dysfunction – a forum position paper. Neurotoxicology 19(1):7–17, discussion 37–38PubMedGoogle Scholar
  17. 17.
    Aschner M, Sonnewald U, Tan KH (2002) Astrocyte modulation of neurotoxic injury. Brain Pathol 12(4):475–481PubMedCrossRefGoogle Scholar
  18. 18.
    Haorah J, Ramirez SH, Floreani N, Gorantla S, Morsey B, Persidsky Y (2008) Mechanism of alcohol-induced oxidative stress and neuronal injury. Free Radic Biol Med 45(11):1542–1550PubMedCrossRefGoogle Scholar
  19. 19.
    Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228PubMedCrossRefGoogle Scholar
  20. 20.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318PubMedCrossRefGoogle Scholar
  21. 21.
    Rump TJ, Abdul Muneer PM, Szlachetka AM, Lamb A, Haorei C, Alikunju S, Xiong H, Keblesh J, Liu J, Zimmerman MC, Jones J, Donohue TM Jr, Persidsky Y, Haorah J (2010) Acetyl-l-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain. Free Radic Biol Med 49(10):1494–1504PubMedCrossRefGoogle Scholar
  22. 22.
    Graeber MB, Li W, Rodriguez ML (2011) Role of microglia in CNS inflammation. FEBS Lett 585(23):3798–3805PubMedCrossRefGoogle Scholar
  23. 23.
    Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76(2):77–98PubMedCrossRefGoogle Scholar
  24. 24.
    Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou J (2006) Cytokines and alcohol. Alcohol Clin Exp Res 30(4):720–730PubMedCrossRefGoogle Scholar
  25. 25.
    Gray F, Chretien F, Vallat-Decouvelaere AV, Scaravilli F (2003) The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 62(5):429–440PubMedGoogle Scholar
  26. 26.
    Langford TD, Letendre SL, Larrea GJ, Masliah E (2003) Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol 13(2):195–210PubMedCrossRefGoogle Scholar
  27. 27.
    Masliah E, DeTeresa RM, Mallory ME, Hansen LA (2000) Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14(1):69–74PubMedCrossRefGoogle Scholar
  28. 28.
    Ghafouri M, Amini S, Khalili K, Sawaya BE (2006) HIV-1 associated dementia: symptoms and causes. Retrovirology 3:28PubMedCrossRefGoogle Scholar
  29. 29.
    Grovit-Ferbas K, Harris-White ME (2010) Thinking about HIV: the intersection of virus, neuroinflammation and cognitive dysfunction. Immunol Res 48(1–3):40–58PubMedCrossRefGoogle Scholar
  30. 30.
    Haase AT (1986) The AIDS lentivirus connection. Microb Pathog 1(1):1–4PubMedCrossRefGoogle Scholar
  31. 31.
    Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410(6831):988–994PubMedCrossRefGoogle Scholar
  32. 32.
    Langford TD, Letendre SL, Marcotte TD, Ellis RJ, McCutchan JA, Grant I, Mallory ME, Hansen LA, Archibald S, Jernigan T, Masliah E (2002) Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 16(7):1019–1029PubMedCrossRefGoogle Scholar
  33. 33.
    Peluso R, Haase A, Stowring L, Edwards M, Ventura P (1985) A Trojan Horse mechanism for the spread of visna virus in monocytes. Virology 147(1):231–236PubMedCrossRefGoogle Scholar
  34. 34.
    Rezai-Zadeh K, Gate D, Town T (2009) CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol 4(4):462–475PubMedCrossRefGoogle Scholar
  35. 35.
    Vazeux R, Brousse N, Jarry A, Henin D, Marche C, Vedrenne C, Mikol J, Wolff M, Michon C, Rozenbaum W et al (1987) AIDS subacute encephalitis. Identification of HIV-infected cells. Am J Pathol 126(3):403–410PubMedGoogle Scholar
  36. 36.
    Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83(18):7089–7093PubMedCrossRefGoogle Scholar
  37. 37.
    Cosenza MA, Zhao ML, Si Q, Lee SC (2002) Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 12(4):442–455PubMedCrossRefGoogle Scholar
  38. 38.
    Fischer-Smith T, Croul S, Adeniyi A, Rybicka K, Morgello S, Khalili K, Rappaport J (2004) Macrophage/microglial accumulation and proliferating cell nuclear antigen expression in the central nervous system in human immunodeficiency virus encephalopathy. Am J Pathol 164(6):2089–2099PubMedCrossRefGoogle Scholar
  39. 39.
    Gendelman HE, Persidsky Y, Ghorpade A, Limoges J, Stins M, Fiala M, Morrisett R (1997) The neuropathogenesis of the AIDS dementia complex. AIDS 11(Suppl A):S35–S45PubMedGoogle Scholar
  40. 40.
    Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5(1):69–81PubMedCrossRefGoogle Scholar
  41. 41.
    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(11):1129–1135PubMedCrossRefGoogle Scholar
  42. 42.
    Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R (2005) Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 111(2):194–213PubMedCrossRefGoogle Scholar
  43. 43.
    Albright AV, Strizki J, Harouse JM, Lavi E, O’Connor M, Gonzalez-Scarano F (1996) HIV-1 infection of cultured human adult oligodendrocytes. Virology 217(1):211–219PubMedCrossRefGoogle Scholar
  44. 44.
    Bagasra O, Lavi E, Bobroski L, Khalili K, Pestaner JP, Tawadros R, Pomerantz RJ (1996) Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry. AIDS 10(6):573–585PubMedCrossRefGoogle Scholar
  45. 45.
    Ensoli F, Cafaro A, Fiorelli V, Vannelli B, Ensoli B, Thiele CJ (1995) HIV-1 infection of primary human neuroblasts. Virology 210(1):221–225PubMedCrossRefGoogle Scholar
  46. 46.
    Mizrachi Y, Rodriguez I, Sweetnam PM, Rubinstein A, Volsky DJ (1994) HIV type 1 infection of human cortical neuronal cells: enhancement by select neuronal growth factors. AIDS Res Hum Retroviruses 10(12):1593–1596PubMedCrossRefGoogle Scholar
  47. 47.
    Nuovo GJ, Gallery F, MacConnell P, Braun A (1994) In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids and tumor necrosis factor-alpha RNA in the central nervous system. Am J Pathol 144(4):659–666PubMedGoogle Scholar
  48. 48.
    Obregon E, Punzon C, Fernandez-Cruz E, Fresno M, Munoz-Fernandez MA (1999) HIV-1 infection induces differentiation of immature neural cells through autocrine tumor necrosis factor and nitric oxide production. Virology 261(2):193–204PubMedCrossRefGoogle Scholar
  49. 49.
    Radja F, Kay DG, Albrecht S, Jolicoeur P (2003) Oligodendrocyte-specific expression of human immunodeficiency virus type 1 Nef in transgenic mice leads to vacuolar myelopathy and alters oligodendrocyte phenotype in vitro. J Virol 77(21):11745–11753PubMedCrossRefGoogle Scholar
  50. 50.
    Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson RT, Glass JD (1996) Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol 39(6):705–711PubMedCrossRefGoogle Scholar
  51. 51.
    Trillo-Pazos G, Diamanturos A, Rislove L, Menza T, Chao W, Belem P, Sadiq S, Morgello S, Sharer L, Volsky DJ (2003) Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 13(2):144–154PubMedCrossRefGoogle Scholar
  52. 52.
    Gendelman HE, Baldwin T, Baca-Regen L, Swindells S, Loomis L, Skurkovich S (1994) Regulation of HIV1 replication by interferon alpha: from laboratory bench to bedside. Res Immunol 145(8–9):679–684, discussion 684–685PubMedCrossRefGoogle Scholar
  53. 53.
    Langford D, Masliah E (2001) Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS. Brain Pathol 11(3):306–312PubMedCrossRefGoogle Scholar
  54. 54.
    Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202(1–2):13–23PubMedCrossRefGoogle Scholar
  55. 55.
    Pulliam L, Herndier BG, Tang NM, McGrath MS (1991) Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 87(2):503–512PubMedCrossRefGoogle Scholar
  56. 56.
    Wiley CA (2003) Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 13(3):415, author reply 415–416PubMedCrossRefGoogle Scholar
  57. 57.
    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 152:987–994PubMedGoogle Scholar
  58. 58.
    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. Arch Neurol 50(3):250–255PubMedCrossRefGoogle Scholar
  59. 59.
    Symonds LL, Archibald SL, Grant I, Zisook S, Jernigan TL (1999) Does an increase in sulcal or ventricular fluid predict where brain tissue is lost? J Neuroimaging 9(4):201–209PubMedGoogle Scholar
  60. 60.
    Di Sclafani V, Mackay RD, Meyerhoff DJ, Norman D, Weiner MW, Fein G (1997) Brain atrophy in HIV infection is more strongly associated with CDC clinical stage than with cognitive impairment. J Int Neuropsychol Soc 3(3):276–287PubMedGoogle Scholar
  61. 61.
    Thompson PM, Dutton RA, Hayashi KM, Lu A, Lee SE, Lee JY, Lopez OL, Aizenstein HJ, Toga AW, Becker JT (2006) 3D mapping of ventricular and corpus callosum abnormalities in HIV/AIDS. Neuroimage 31:12–23PubMedCrossRefGoogle Scholar
  62. 62.
    Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, McCutchan JA, Taylor MJ, Kelly MD, Ellis RJ, Wolfson T, Velin R, Marcotte TD, Hesselink JR, Jernigan TL, Chandler J, Wallace M, Abramson I (1995) The HNRC 500 – neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1(3):231–251PubMedCrossRefGoogle Scholar
  63. 63.
    Stout J, Ellis R, Jernigan T, Archibald S, Abramson I, Wolfson T, McCutchan J, Wallace M, Atkinson J, Grant I (1998) Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. Arch Neurol 55:161–168PubMedCrossRefGoogle Scholar
  64. 64.
    Dal Pan GJ, McArthur JH, Aylward E, Selnes OA, Nance-Sproson TE, Kumar AJ, Mellits ED, McArthur JC (1992) Patterns of cerebral atrophy in HIV-1-infected individuals – results of a quantitative MRI analysis. Neurology 42(11):2125–2130PubMedCrossRefGoogle Scholar
  65. 65.
    Manji H, Connolly S, McAllister R, Valentine AR, Kendall BE, Fell M, Durrance P, Thompson AJ, Newman S, Weller IVD, Harrison MJG (1994) Serial MRI of the brain in asymptomatic patients infected with HIV: results from the UCMSM/Medical Research Council neurology cohort. J Neurol Neurosurg Psychiatry 57(2):144–149PubMedCrossRefGoogle Scholar
  66. 66.
    Pfefferbaum A, Rosenbloom M, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Sullivan EV (2012) Regional brain structural dysmorphology in HIV infection: effects of AIDS, alcoholism, and age. Biol Psychiatry May 28. [Epub ahead of print]Google Scholar
  67. 67.
    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(1):239–251PubMedCrossRefGoogle Scholar
  68. 68.
    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 USA 102(43):15647–15652PubMedCrossRefGoogle Scholar
  69. 69.
    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(3):369–376PubMedCrossRefGoogle Scholar
  70. 70.
    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(1):44–60PubMedCrossRefGoogle Scholar
  71. 71.
    Sullivan EV, Rosenbloom MJ, Rohlfing T, Kemper CA, Deresinski S, Pfefferbaum A (2011) Pontocerebellar contribution to ataxia and psychomotor slowing in HIV infection without dementia. Brain Imaging Behav 5:12–24PubMedCrossRefGoogle Scholar
  72. 72.
    Klunder AD, Chiang MC, Dutton RA, Lee SE, Toga AW, Lopez OL, Aizenstein HJ, Becker JT, Thompson PM (2008) Mapping cerebellar degeneration in HIV/AIDS. Neuroreport 19(17):1655–1659PubMedCrossRefGoogle Scholar
  73. 73.
    Schuff N, Amend DL, Knowlton R, Norman D, Fein G, Weiner MW (1999) Age-related metabolite changes and volume loss in the hippocampus by magnetic resonance spectroscopy and imaging. Neurobiol Aging 20(3):279–285PubMedCrossRefGoogle Scholar
  74. 74.
    Adle-Biassette H, Chretien F, Wingertsmann L, Hery C, Ereau T, Scaravilli F, Tardieu M, Gray F (1999) Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage. Neuropathol Appl Neurobiol 25(2):123–133PubMedCrossRefGoogle Scholar
  75. 75.
    An SF, Giometto B, Scaravilli T, Tavolato B, Gray F, Scaravilli F (1996) Programmed cell death in brains of HIV-1-positive AIDS and pre-AIDS patients. Acta Neuropathol 91(2):169–173PubMedCrossRefGoogle Scholar
  76. 76.
    Everall I, Luthert P, Lantos P (1993) A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia. J Neuropathol Exp Neurol 52(6):561–566PubMedCrossRefGoogle Scholar
  77. 77.
    Reyes MG, Faraldi F, Senseng CS, Flowers C, Fariello R (1991) Nigral degeneration in acquired immune deficiency syndrome (AIDS). Acta Neuropathol 82(1):39–44PubMedCrossRefGoogle Scholar
  78. 78.
    Graus F, Ribalta T, Abos J, Alom J, Cruz-Sanchez F, Mallolas J, Miro JM, Cardesa A, Tolosa E (1990) Subacute cerebellar syndrome as the first manifestation of AIDS dementia complex. Acta Neurol Scand 81(2):118–120PubMedCrossRefGoogle Scholar
  79. 79.
    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(3):1638–1648PubMedCrossRefGoogle Scholar
  80. 80.
    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(5):625–633PubMedCrossRefGoogle Scholar
  81. 81.
    Meyerhoff DJ (2001) Effects of alcohol and HIV infection on the central nervous system. Alcohol Res Health 25:288–298PubMedGoogle Scholar
  82. 82.
    Meyerhoff DJ, Bloomer C, Cardenas V, Norman D, Weiner MW, Fein G (1999) Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 52(5):995–1003PubMedCrossRefGoogle Scholar
  83. 83.
    Pfefferbaum A, Rosenbloom M, Sullivan EV (2002) Alcoholism and AIDS: magnetic resonance imaging approaches for detecting interactive neuropathology. Alcohol Clin Exp Res 26(7):1031–1046PubMedCrossRefGoogle Scholar
  84. 84.
    Everall IP, Luthert PJ, Lantos PL (1991) Neuronal loss in the frontal cortex in HIV infection. Lancet 337(8750):1119–1121PubMedCrossRefGoogle Scholar
  85. 85.
    Everall IP, Luthert PJ, Lantos PL (1993) Neuronal number and volume alterations in the neocortex of HIV infected individuals. J Neurol Neurosurg Psychiatry 56(5):481–486PubMedCrossRefGoogle Scholar
  86. 86.
    Ketzler S, Weis S, Haug H, Budka H (1990) Loss of neurons in the frontal cortex in AIDS brains. Acta Neuropathol (Berl) 80(1):92–94CrossRefGoogle Scholar
  87. 87.
    Pulliam L, Rempel H, Sun B, Abadjian L, Calosing C, Meyerhoff DJ (2011) A peripheral monocyte interferon phenotype in HIV infection correlates with a decrease in magnetic resonance spectroscopy metabolite concentrations. AIDS 25(14):1721–1726PubMedCrossRefGoogle Scholar
  88. 88.
    Wilkinson I, Paley M, Miszkiel K, Hall-Craggs M, Kendall B, Chinn R, Harrison M (1997) Cerebral volumes and spectroscopic proton metabolites on MR: is sex important? Magn Reson Imaging 15:243–248PubMedCrossRefGoogle Scholar
  89. 89.
    Chang L, Ernst T, St Hillaire C, Conant K (2004) Antiretroviral treatment alters relationship between MCP-1 and neurometabolites in HIV patients. Antivir Ther 9(3):431–440PubMedGoogle Scholar
  90. 90.
    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 8:17–26PubMedGoogle Scholar
  91. 91.
    Budka H (1991) The definition of HIV-specific neuropathology. Acta Pathol Jpn 41(3):182–191PubMedGoogle Scholar
  92. 92.
    Budka H (1997) Neuropathology of myelitis, myelopathy, and spinal infections in AIDS. Neuroimaging Clin N Am (Neuroimaging of AIDS II) 7(3):639–650Google Scholar
  93. 93.
    Ferrari CC, Depino AM, Prada F, Muraro N, Campbell S, Podhajcer O, Perry VH, Anthony DC, Pitossi FJ (2004) Reversible demyelination, blood–brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain. Am J Pathol 165(5):1827–1837PubMedCrossRefGoogle Scholar
  94. 94.
    Giometto B, An SF, Groves M, Scaravilli T, Geddes JF, Miller R, Tavolato B, Beckett AA, Scaravilli F (1997) Accumulation of beta-amyloid precursor protein in HIV encephalitis: relationship with neuropsychological abnormalities. Ann Neurol 42(1):34–40PubMedCrossRefGoogle Scholar
  95. 95.
    Gray F, Belec L, Chretien F, Dubreuil-Lemaire ML, Ricolfi F, Wingertsmann L, Poron F, Gherardi R (1998) Acute, relapsing brain oedema with diffuse blood–brain barrier alteration and axonal damage in the acquired immunodeficiency syndrome. Neuropathol Appl Neurobiol 24(3):209–216PubMedCrossRefGoogle Scholar
  96. 96.
    Hartung HP, Jung S, Stoll G, Zielasek J, Schmidt B, Archelos JJ, Toyka KV (1992) Inflammatory mediators in demyelinating disorders of the CNS and PNS. J Neuroimmunol 40(2–3):197–210PubMedCrossRefGoogle Scholar
  97. 97.
    Kim TS, Perlman S (2005) Viral expression of CCL2 is sufficient to induce demyelination in RAG1−/− mice infected with a neurotropic coronavirus. J Virol 79(11):7113–7120PubMedCrossRefGoogle Scholar
  98. 98.
    Medana IM, Esiri MM (2003) Axonal damage: a key predictor of outcome in human CNS diseases. Brain 126(Pt 3):515–530PubMedCrossRefGoogle Scholar
  99. 99.
    Raja F, Sherriff FE, Morris CS, Bridges LR, Esiri MM (1997) Cerebral white matter damage in HIV infection demonstrated using beta-amyloid precursor protein immunoreactivity. Acta Neuropathol 93(2):184–189PubMedCrossRefGoogle Scholar
  100. 100.
    Arese M, Ferrandi C, Primo L, Camussi G, Bussolino F (2001) HIV-1 Tat protein stimulates in vivo vascular permeability and lymphomononuclear cell recruitment. J Immunol 166(2):1380–1388PubMedGoogle Scholar
  101. 101.
    McMurtray A, Nakamoto B, Shikuma C, Valcour V (2008) Cortical atrophy and white matter hyperintensities in HIV: the Hawaii Aging with HIV Cohort Study. J Stroke Cerebrovasc Dis 17(4):212–217PubMedCrossRefGoogle Scholar
  102. 102.
    Ernst T, Chang L, Witt M, Walot I, Aronow H, Leonido-Yee M, Singer E (1999) Progressive multifocal leukoencephalopathy and human immunodeficiency virus-associated white matter lesions in AIDS: magnetization transfer MR imaging. Radiology 210(2):539–543PubMedGoogle Scholar
  103. 103.
    Thurnher MM, Post MJ, Rieger A, Kleibl-Popov C, Loewe C, Schindler E (2001) Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol 22(5):977–984PubMedGoogle Scholar
  104. 104.
    Navia BA, Gonzalez RG (1997) Functional imaging of the AIDS dementia complex and the metabolic pathology of the HIV-1 infected brain. Neuroimaging Clin N Am 7(3):431–445PubMedGoogle Scholar
  105. 105.
    Chen Y, An H, Zhu H, Stone T, Smith JK, Hall C, Bullitt E, Shen D, Lin W (2009) White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients. Neuroimage 47(4):1154–1162PubMedCrossRefGoogle Scholar
  106. 106.
    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(1–2):147–152PubMedCrossRefGoogle Scholar
  107. 107.
    Filippi CG, Ulug AM, Ryan E, Ferrando SJ, van Gorp W (2001) Diffusion tensor imaging of patients with HIV and normal-appearing white matter on MR images of the brain. AJNR Am J Neuroradiol 22(2):277–283PubMedGoogle Scholar
  108. 108.
    Pomara N, Crandall DT, Choi SJ, Johnson G, Lim KO (2001) White matter abnormalities in HIV-1 infection: a diffusion tensor imaging study. Psychiatry Res 106:15–24PubMedCrossRefGoogle Scholar
  109. 109.
    Thurnher MM, Castillo M, Stadler A, Rieger A, Schmid B, Sundgren PC (2005) Diffusion-tensor MR imaging of the brain in human immunodeficiency virus-positive patients. AJNR Am J Neuroradiol 26(9):2275–2281PubMedGoogle Scholar
  110. 110.
    Pfefferbaum A, Rosenbloom MJ, Rohlfing T, Kemper CA, Deresinski S, Sullivan EV (2009) Frontostriatal fiber bundle compromise in HIV infection without dementia. AIDS 23(15):1977–1985PubMedCrossRefGoogle Scholar
  111. 111.
    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(2):187–195PubMedCrossRefGoogle Scholar
  112. 112.
    Pfefferbaum A, Rosenbloom MJ, Adalsteinsson E, Sullivan EV (2007) Diffusion tensor imaging with quantitative fiber tracking in HIV infection and alcoholism comorbidity: synergistic white matter damage. Brain 130:48–64PubMedCrossRefGoogle Scholar
  113. 113.
    Ragin AB, Storey P, Cohen BA, Epstein LG, Edelman RR (2004) Whole brain diffusion tensor imaging in HIV-associated cognitive impairment. AJNR Am J Neuroradiol 25(2):195–200PubMedGoogle Scholar
  114. 114.
    Crabbe JC (2002) Alcohol and genetics: new models. Am J Med Genet 114(8):969–974PubMedCrossRefGoogle Scholar
  115. 115.
    Porjesz B, Begleiter H, Reich T, Vaneerdewegh P, Edenberg H, Foroud T, Goate A, Litke A, Chorlian D, Stimus A, Rice J, Blangero J, Almasy L, Sorbell J, Bauer L, Kuperman S, O’Connor S, Rohrbaugh J (1998) Amplitude of visual P3 event-related potential as a phenotypic marker for a predisposition to alcoholism: preliminary-results from the COGA project. Alcohol Clin Exp Res 22(6):1317–1323PubMedGoogle Scholar
  116. 116.
    Ceballos NA, Nixon SJ, Phillips JA, Tivis R (2003) Semantic processing in alcoholics with and without antisocial symptomatology. J Stud Alcohol 64(2):286–291PubMedGoogle Scholar
  117. 117.
    Grant BF, Stinson FS, Dawson DA, Chou SP, Ruan WJ, Pickering RP (2004) Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the United States: results from the National Epidemiologic Survey on alcohol and related conditions. Arch Gen Psychiatry 61(4):361–368PubMedCrossRefGoogle Scholar
  118. 118.
    Kessler RC, Chiu WT, Demler O, Walters EE (2005) Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62(6):617–627PubMedCrossRefGoogle Scholar
  119. 119.
    Harding A, Halliday G, Caine D, Kril J (2000) Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 123(Pt 1):141–154PubMedCrossRefGoogle Scholar
  120. 120.
    Cullen KM, Halliday GM, Caine D, Kril JJ (1997) The nucleus basalis (Ch4) in the alcoholic Wernicke–Korsakoff syndrome: reduced cell number in both amnesic and non-amnesic patients. J Neurol Neurosurg Psychiatry 63(3):315–320PubMedCrossRefGoogle Scholar
  121. 121.
    Baker K, Harding A, Halliday G, Kril J, Harper C (1999) Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke’s encephalopathy. Neuroscience 91(2):429–438PubMedCrossRefGoogle Scholar
  122. 122.
    Harper C (1998) The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? J Neuropathol Exp Neurol 57(2):101–110PubMedCrossRefGoogle Scholar
  123. 123.
    Harper CG, Kril JJ, Daly JM (1987) Are we drinking our neurones away? Br Med J 294:534–536CrossRefGoogle Scholar
  124. 124.
    Kril JJ, Harper CG (1989) Neuronal counts from four cortical regions of the alcoholic brain. Acta Neuropathol (Berl) 79:200–204CrossRefGoogle Scholar
  125. 125.
    Harper C, Dixon G, Sheedy D, Garrick T (2003) Neuropathological alterations in alcoholic brains. Studies arising from the New South Wales Tissue Resource Centre. Prog Neuropsychopharmacol Biol Psychiatry 27(6):951–961PubMedCrossRefGoogle Scholar
  126. 126.
    Harding AJ, Wong A, Svoboda M, Kril JJ, Halliday GM (1997) Chronic alcohol consumption does not cause hippocampal neuron loss in humans. Hippocampus 7(1):78–87PubMedCrossRefGoogle Scholar
  127. 127.
    Kril JJ, Halliday GM, Svoboda MD, Cartwright H (1997) The cerebral cortex is damaged in chronic alcoholics. Neuroscience 79(4):983–998PubMedCrossRefGoogle Scholar
  128. 128.
    McMullen PA, Saint-Cyr JA, Carlen PL (1984) Morphological alterations in the rat CA1 hippocampal pyramidal cell dendrites resulting from chronic ethanol consumption and withdrawal. J Comp Neurol 225:111–118PubMedCrossRefGoogle Scholar
  129. 129.
    Pentney R, Mullan B, Felong A, Dlugos C (2002) The total numbers of cerebellar granule neurons in young and aged Fischer 344 and Wistar-Kyoto rats do not change as a result of lengthy ethanol treatment. Cerebellum 1:79–89PubMedCrossRefGoogle Scholar
  130. 130.
    Pentney RJ (1993) Alterations in the structure of the cerebellum after long-term ethanol consumption. In: Hunt WA, Nixon SJ (eds) Alcohol-induced brain damage: NIAAA Research Monograph No. 22. National Institute of Health, Rockville, pp 249–276Google Scholar
  131. 131.
    Phillips SC, Harper CG, Kril J (1987) A quantitative histological study of the cerebellar vermis in alcoholic patients. Brain 110:301–314PubMedCrossRefGoogle Scholar
  132. 132.
    Tabbaa S, Dlugos C, Pentney R (1999) The number of granule cells and spine density on Purkinje cells in aged, ethanol-fed rats. Alcohol 17(3):253–260PubMedCrossRefGoogle Scholar
  133. 133.
    Torvik A, Torp S (1986) The prevalence of alcoholic cerebellar atrophy: a morphometric and histological study of an autopsy material. J Neurol Sci 75:43–51PubMedCrossRefGoogle Scholar
  134. 134.
    Harper C, Kril J (1994) An introduction to alcohol-induced brain damage and its causes. Alcohol Alcohol Suppl 2:237–243PubMedGoogle Scholar
  135. 135.
    Harper C, Corbett D (1990) Changes in the basal dendrites of cortical pyramidal cells from alcoholic patients – a quantitative golgi study. J Neurol Neurosurg Psychiatry 53(10):856–861PubMedCrossRefGoogle Scholar
  136. 136.
    Ikegami Y, Goodenough S, Inoue Y, Dodd PR, Wilce PA, Matsumoto I (2003) Increased TUNEL positive cells in human alcoholic brains. Neurosci Lett 349(3):201–205PubMedCrossRefGoogle Scholar
  137. 137.
    Oscar-Berman M, Marinkovic K (2007) Alcohol: effects on neurobehavioral functions and the brain. Neuropsychol Rev 17(3):239–257PubMedCrossRefGoogle Scholar
  138. 138.
    Sullivan EV, Pfefferbaum A (2005) Neurocircuitry in alcoholism: a substrate of disruption and repair. Psychopharmacology (Berl) 180:583–594CrossRefGoogle Scholar
  139. 139.
    Zahr NM, Kaufman KL, Harper CG (2011) Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol 7(5):284–294PubMedCrossRefGoogle Scholar
  140. 140.
    Jernigan TL, Butters N, DiTraglia G, Schafer K, Smith T, Irwin M, Grant I, Schuckit M, Cermak L (1991) Reduced cerebral grey matter observed in alcoholics using magnetic resonance imaging. Alcohol Clin Exp Res 15(3):418–427PubMedCrossRefGoogle Scholar
  141. 141.
    Pfefferbaum A, Lim KO, Zipursky RB, Mathalon DH, Rosenbloom MJ, Lane B, Ha CN, Sullivan EV (1992) Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 16(6):1078–1089PubMedCrossRefGoogle Scholar
  142. 142.
    De Bellis MD, Narasimhan A, Thatcher DL, Keshavan MS, Soloff P, Clark DB (2005) Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders. Alcohol Clin Exp Res 29(9):1590–1600PubMedCrossRefGoogle Scholar
  143. 143.
    Sullivan EV, Deshmukh A, Desmond JE, Lim KO, Pfefferbaum A (2000) Cerebellar volume decline in normal aging, alcoholism, and Korsakoff’s syndrome: relation to ataxia. Neuropsychology 14(3):341–352PubMedCrossRefGoogle Scholar
  144. 144.
    Agartz I, Momenan R, Rawlings RR, Kerich MJ, Hommer DW (1999) Hippocampal volume in patients with alcohol dependence. Arch Gen Psychiatry 56:356–363PubMedCrossRefGoogle Scholar
  145. 145.
    Sullivan EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A (1995) Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcohol Clin Exp Res 19:110–122PubMedCrossRefGoogle Scholar
  146. 146.
    Davila MD, Shear PK, Lane B, Sullivan EV, Pfefferbaum A (1994) Mammillary body and cerebellar shrinkage in chronic alcoholics: an MRI and neuropsychological study. Neuropsychology 8:433–444CrossRefGoogle Scholar
  147. 147.
    Shear PK, Sullivan EV, Lane B, Pfefferbaum A (1996) Mammillary body and cerebellar shrinkage in chronic alcoholics with and without amnesia. Alcohol Clin Exp Res 20(8):1489–1495PubMedCrossRefGoogle Scholar
  148. 148.
    Sullivan EV, Deshmukh A, Desmond JE, Mathalon DH, Rosenbloom MJ, Lim KO, Pfefferbaum A (2000) Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia. Arch Gen Psychiatry 57(9):894–902PubMedCrossRefGoogle Scholar
  149. 149.
    Sullivan EV, Rosenbloom MJ, Serventi KL, Deshmukh A, Pfefferbaum A (2003) Effects of alcohol dependence comorbidity and anti-psychotic medication on volumes of the thalamus and pons in schizophrenia. Am J Psychiatry 160:1110–1116PubMedCrossRefGoogle Scholar
  150. 150.
    Pfefferbaum A, Rosenbloom MJ, Serventi K, Sullivan EV (2002) Corpus callosum, pons and cortical white matter in alcoholic women. Alcohol Clin Exp Res 26:400–405PubMedCrossRefGoogle Scholar
  151. 151.
    Sullivan EV (2003) Compromised pontocerebellar and cerebellothalamocortical systems: speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism. Alcohol Clin Exp Res 27(9):1409–1419PubMedCrossRefGoogle Scholar
  152. 152.
    Bendszus M, Weijers HG, Wiesbeck G, Warmuth-Metz M, Bartsch AJ, Engels S, Boning J, Solymosi L (2001) Sequential MR imaging and proton MR spectroscopy in patients who underwent recent detoxification for chronic alcoholism: correlation with clinical and neuropsychological data. AJNR Am J Neuroradiol 22(10):1926–1932PubMedGoogle Scholar
  153. 153.
    Fein G, Meyerhoff D, Di Sclafani V, Ezekiel F, Poole N, MacKay S, Dillon WP, Constans J-M, Weiner MW (1994) 1H magnetic resonance spectroscopic imaging separates neuronal from glial changes in alcohol-related brain atrophy. In: Lancaster F (ed) Alcohol and glial cells, NIAAA Research Monograph # 27. US Government Printing Office, Bethesda, pp 227–241Google Scholar
  154. 154.
    Jagannathan NR, Desai NG, Raghunathan P (1996) Brain metabolite changes in alcoholism: an in vivo proton magnetic resonance spectroscopy (MRS) study. Magn Reson Imaging 14:553–557PubMedCrossRefGoogle Scholar
  155. 155.
    Meyerhoff DJ, Blumenfeld R, Truran D, Lindgren J, Flenniken D, Cardenas V, Chao LL, Rothlind J, Studholme C, Weiner MW (2004) Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites. Alcohol Clin Exp Res 28(4):650–661PubMedCrossRefGoogle Scholar
  156. 156.
    Schweinsburg B, Taylor M, Videen J, Alhassoon O, Patterson T, Grant I (2000) Elevated myo-inositol in gray matter of recently detoxified but not long-term abstinent alcoholics: a preliminary MR spectroscopy study. Alcohol Clin Exp Res 24:699–705PubMedCrossRefGoogle Scholar
  157. 157.
    Seitz D, Widmann U, Seeger U, Nagele T, Klose U, Mann K, Grodd W (1999) Localized proton magnetic resonance spectroscopy of the cerebellum in detoxifying alcoholics. Alcohol Clin Exp Res 23(1):158–163PubMedCrossRefGoogle Scholar
  158. 158.
    Parks MH, Dawant BM, Riddle WR, Hartmann SL, Dietrich MS, Nickel MK, Price RR, Martin PR (2002) Longitudinal brain metabolic characterization of chronic alcoholics with proton magnetic resonance spectroscopy. Alcohol Clin Exp Res 26(9):1368–1380PubMedCrossRefGoogle Scholar
  159. 159.
    Biller A, Bartsch AJ, Homola G, Solymosi L, Bendszus M (2009) The effect of ethanol on human brain metabolites longitudinally characterized by proton MR spectroscopy. J Cereb Blood Flow Metab 29:891–902PubMedCrossRefGoogle Scholar
  160. 160.
    Durazzo TC, Gazdzinski S, Banys P, Meyerhoff DJ (2004) Cigarette smoking exacerbates chronic alcohol-induced brain damage: a preliminary metabolite imaging study. Alcohol Clin Exp Res 28(12):1849–1860PubMedCrossRefGoogle Scholar
  161. 161.
    Ende G, Walter S, Welzel H, Demirakca T, Wokrina T, Ruf M, Ulrich M, Diehl A, Henn FA, Mann K (2006) Alcohol consumption significantly influences the MR signal of frontal choline-containing compounds. Neuroimage 32(2):740–746PubMedCrossRefGoogle Scholar
  162. 162.
    Li Z, Vance DE (2008) Phosphatidylcholine and choline homeostasis. J Lipid Res 49(6):1187–1194PubMedCrossRefGoogle Scholar
  163. 163.
    Djuricic B, Olson SR, Assaf HM, Whittingham TS, Lust WD, Drewes LR (1991) Formation of free choline in brain tissue during in vitro energy deprivation. J Cereb Blood Flow Metab 11(2):308–313PubMedCrossRefGoogle Scholar
  164. 164.
    Klein J, Koppen A, Loffelholz K, Schmitthenner J (1992) Uptake and metabolism of choline by rat brain after acute choline administration. J Neurochem 58(3):870–876PubMedCrossRefGoogle Scholar
  165. 165.
    Scremin OU, Jenden DJ (1989) Focal ischemia enhances choline output and decreases acetylcholine output from rat cerebral cortex. Stroke 20(1):92–95PubMedCrossRefGoogle Scholar
  166. 166.
    De Stefano N, Bartolozzi ML, Guidi L, Stromillo ML, Federico A (2005) Magnetic resonance spectroscopy as a measure of brain damage in multiple sclerosis. J Neurol Sci 233(1–2):203–208PubMedCrossRefGoogle Scholar
  167. 167.
    Alling C, Bostrom K (1980) Demyelination of the mamillary bodies in alcoholism. A combined morphological and biochemical study. Acta Neuropathol (Berl) 50:77–80CrossRefGoogle Scholar
  168. 168.
    Badsberg-Jensen G, Pakkenberg B (1993) Do alcoholics drink their neurons away? Lancet 342(8881):1201–1204CrossRefGoogle Scholar
  169. 169.
    De la Monte SM (1988) Disproportionate atrophy of cerebral white matter in chronic alcoholics. Arch Neurol 45:990–992PubMedCrossRefGoogle Scholar
  170. 170.
    Harper C, Kril JJ (1989) Patterns of neuronal loss in the cerebral cortex in chronic alcoholic patients. J Neurol Sci 92:81–89PubMedCrossRefGoogle Scholar
  171. 171.
    Harper CG, Kril JJ (1988) Corpus callosal thickness in alcoholics. Br J Addict 83:577–580PubMedCrossRefGoogle Scholar
  172. 172.
    Harper CG, Kril JJ, Holloway RL (1985) Brain shrinkage in chronic alcoholics: a pathological study. Br Med J 290:501–504CrossRefGoogle Scholar
  173. 173.
    Hommer D, Momenan R, Rawlings R, Ragan P, Williams W, Rio D, Eckardt M (1996) Decreased corpus callosum size among alcoholic women. Arch Neurol 53(4):359–363PubMedCrossRefGoogle Scholar
  174. 174.
    Estruch R, Nicolas JM, Salamero M, Aragon C, Sacanella E, Fernandez-Sola J, Urbano-Marquez A (1997) Atrophy of the corpus callosum in chronic alcoholism. J Neurol Sci 146(2):145–151PubMedCrossRefGoogle Scholar
  175. 175.
    Hommer DW, Momenan R, Kaiser E, Rawlings RR (2001) Evidence for a gender-related effect of alcoholism on brain volumes. Am J Psychiatry 158(2):198–204PubMedCrossRefGoogle Scholar
  176. 176.
    Pfefferbaum A, Lim KO, Desmond JE, Sullivan EV (1996) Thinning of the corpus callosum in older alcoholic men: a magnetic resonance imaging study. Alcohol Clin Exp Res 20(4):752–757PubMedCrossRefGoogle Scholar
  177. 177.
    Pfefferbaum A, Lim KO, Rosenbloom MJ (1992) Structural imaging of the brain in chronic alcoholism. In: Zakhari S, Witt E (eds) Imaging in alcohol research: NIAAA Research Monograph No. 21. U.S. Dept Health and Human Services, Rockville, pp 99–120Google Scholar
  178. 178.
    Pfefferbaum A, Sullivan EV, Mathalon DH, Lim KO (1997) Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics. Alcohol Clin Exp Res 21(3):521–529PubMedCrossRefGoogle Scholar
  179. 179.
    Anstey KJ, Jorm AF, Reglade-Meslin C, Maller J, Kumar R, von Sanden C, Windsor TD, Rodgers B, Wen W, Sachdev P (2006) Weekly alcohol consumption, brain atrophy, and white matter hyperintensities in a community-based sample aged 60 to 64 years. Psychosom Med 68(5):778–785PubMedCrossRefGoogle Scholar
  180. 180.
    den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, van Duijn CM, Hofman A, Breteler MM (2004) Alcohol intake in relation to brain magnetic resonance imaging findings in older persons without dementia. Am J Clin Nutr 80(4):992–997Google Scholar
  181. 181.
    Fein G, Shimotsu R, Di Sclafani V, Barakos J, Harper C (2009) Increased white matter signal hyperintensities in long-term abstinent alcoholics compared with nonalcoholic controls. Alcohol Clin Exp Res 33(1):70–78PubMedCrossRefGoogle Scholar
  182. 182.
    Mukamal KJ, Longstreth WT Jr, Mittleman MA, Crum RM, Siscovick DS (2001) Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older audlts: the Cardiovascular Health Study. Stroke 32:1939–1946PubMedCrossRefGoogle Scholar
  183. 183.
    Basile AM, Pantoni L, Pracucci G, Asplund K, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D (2006) Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (Leukoaraiosis and Disability in the Elderly) Study. Cerebrovasc Dis 21(5–6):315–322PubMedCrossRefGoogle Scholar
  184. 184.
    Ovbiagele B, Saver JL (2006) Cerebral white matter hyperintensities on MRI: current concepts and therapeutic implications. Cerebrovasc Dis 22(2–3):83–90PubMedCrossRefGoogle Scholar
  185. 185.
    Rossi R, Boccardi M, Sabattoli F, Galluzzi S, Alaimo G, Testa C, Frisoni GB (2006) Topographic correspondence between white matter hyperintensities and brain atrophy. J Neurol 253(7):919–927PubMedCrossRefGoogle Scholar
  186. 186.
    Kiechl S, Willeit J, Rungger G, Egger G, Oberhollenzer F, Bonora E (1998) Alcohol consumption and atherosclerosis: what is the relation? Prospective results from the Bruneck Study. Stroke 29(5):900–907PubMedCrossRefGoogle Scholar
  187. 187.
    Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WT Jr, Mittleman MA, Siscovick DS (2003) Prospective study of alcohol consumption and risk of dementia in older adults. JAMA 289(11):1405–1413PubMedCrossRefGoogle Scholar
  188. 188.
    Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ (1999) Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 319(7224):1523–1528PubMedCrossRefGoogle Scholar
  189. 189.
    Ruitenberg A, van Swieten JC, Witteman JC, Mehta KM, van Duijn CM, Hofman A, Breteler MM (2002) Alcohol consumption and risk of dementia: the Rotterdam Study. Lancet 359(9303):281–286PubMedCrossRefGoogle Scholar
  190. 190.
    de Leeuw FE, de Groot JC, Bots ML, Witteman JC, Oudkerk M, Hofman A, van Gijn J, Breteler MM (2000) Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study. J Neurol 247(4):291–296PubMedCrossRefGoogle Scholar
  191. 191.
    Pfefferbaum A, Adalsteinsson E, Sullivan EV (2006) Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women. Biol Psychiatry 59(4):364–372PubMedCrossRefGoogle Scholar
  192. 192.
    Pfefferbaum A, Sullivan EV (2002) Microstructural but not macrostructural disruption of white matter in women with chronic alcoholism. Neuroimage 15:708–718PubMedCrossRefGoogle Scholar
  193. 193.
    Pfefferbaum A, Sullivan EV (2005) Disruption of brain white matter microstructure by excessive intracellular and extracellular fluid in alcoholism: evidence from diffusion tensor imaging. Neuropsychopharmacology 30(2):423–432PubMedCrossRefGoogle Scholar
  194. 194.
    Pfefferbaum A, Sullivan EV, Hedehus M, Adalsteinsson E, Lim KO, Moseley M (2000) In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism. Alcohol Clin Exp Res 24(8):1214–1221PubMedCrossRefGoogle Scholar
  195. 195.
    Pfefferbaum A, Rosenbloom MJ, Fama R, Sassoon SA, Sullivan EV (2010) Transcallosal white matter degradation detected with quantitative fiber tracking in alcoholic men and women: selective relations to dissociable functions. Alcohol Clin Exp Res 34(7):1201–1211PubMedGoogle Scholar
  196. 196.
    Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH, Armstrong RC (2005) Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 26(1):132–140PubMedCrossRefGoogle Scholar
  197. 197.
    Pfefferbaum A, Rosenbloom M, Rohlfing T, Sullivan EV (2009) Degradation of association and projection white matter systems in alcoholism detected with quantitative fiber tracking. Biol Psychiatry 65(8):680–690PubMedCrossRefGoogle Scholar
  198. 198.
    Lewohl J, Wang L, Miles M, Zhang L, Dodd P, Harris R (2000) Gene expression in human alcoholism: microarray analysis of frontal cortex. Alcohol Clin Exp Res 24:1873–1882PubMedCrossRefGoogle Scholar
  199. 199.
    Mayfield RD, Lewohl JM, Dodd PR, Herlihy A, Liu J, Harris RA (2002) Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics. J Neurochem 81(4):802–813PubMedCrossRefGoogle Scholar
  200. 200.
    Hasin DS, Liu X, Alderson D, Grant BF (2006) DSM-IV alcohol dependence: a categorical or dimensional phenotype? Psychol Med 36(12):1695–16705PubMedCrossRefGoogle Scholar
  201. 201.
    Lewohl JM, Wixey J, Harper CG, Dodd PR (2005) Expression of MBP, PLP, MAG, CNP, and GFAP in the human alcoholic brain. Alcohol Clin Exp Res 29(9):1698–1705PubMedCrossRefGoogle Scholar
  202. 202.
    Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT (2008) Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflammation 5:10PubMedCrossRefGoogle Scholar
  203. 203.
    Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279(2):1415–1421PubMedCrossRefGoogle Scholar
  204. 204.
    Valles SL, Blanco AM, Pascual M, Guerri C (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14(4):365–371PubMedCrossRefGoogle Scholar
  205. 205.
    Knapp DJ, Crews FT (1999) Induction of cyclooxygenase-2 in brain during acute and chronic ethanol treatment and ethanol withdrawal. Alcohol Clin Exp Res 23(4):633–643PubMedCrossRefGoogle Scholar
  206. 206.
    Choi DK, Lee H, Jeong J, Lim B, Suk K (2005) Differential effects of ethanol on glial signal transduction initiated by lipopolysaccharide and interferon-gamma. J Neurosci Res 82(2):225–231PubMedCrossRefGoogle Scholar
  207. 207.
    Deaciuc IV (1997) Alcohol and cytokine networks. Alcohol 14(5):421–430PubMedCrossRefGoogle Scholar
  208. 208.
    Fleming S, Toratani S, Shea-Donohue T, Kashiwabara Y, Vogel SN, Metcalf ES (2001) Pro- and anti-inflammatory gene expression in the murine small intestine and liver after chronic exposure to alcohol. Alcohol Clin Exp Res 25(4):579–589PubMedCrossRefGoogle Scholar
  209. 209.
    Frost RA, Nystrom G, Burrows PV, Lang CH (2005) Temporal differences in the ability of ethanol to modulate endotoxin-induced increases in inflammatory cytokines in muscle under in vivo conditions. Alcohol Clin Exp Res 29(7):1247–1256PubMedCrossRefGoogle Scholar
  210. 210.
    Jarvelainen HA, Fang C, Ingelman-Sundberg M, Lindros KO (1999) Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines. Hepatology 29(5):1503–1510PubMedCrossRefGoogle Scholar
  211. 211.
    Leevy CB, Elbeshbeshy HA (2005) Immunology of alcoholic liver disease. Clin Liver Dis 9(1):55–66PubMedCrossRefGoogle Scholar
  212. 212.
    McClain CJ, Song Z, Barve SS, Hill DB, Deaciuc I (2004) Recent advances in alcoholic liver disease. IV. Dysregulated cytokine metabolism in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 287(3):G497–G502PubMedCrossRefGoogle Scholar
  213. 213.
    Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, Ludwiczek O, Shawcross D, Zoller H, Alisa A, Mookerjee RP, Graziadei I, Datz C, Trauner M, Schuppan D, Obrist P, Vogel W, Williams R (2003) Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol 38(4):419–425PubMedCrossRefGoogle Scholar
  214. 214.
    Karuppagounder SS, Shi Q, Xu H, Gibson GE (2007) Changes in inflammatory processes associated with selective vulnerability following mild impairment of oxidative metabolism. Neurobiol Dis 26(2):353–362PubMedCrossRefGoogle Scholar
  215. 215.
    Todd KG, Butterworth RF (1999) Early microglial response in experimental thiamine deficiency: an immunohistochemical analysis. Glia 25(2):190–198PubMedCrossRefGoogle Scholar
  216. 216.
    Vemuganti R, Kalluri H, Yi JH, Bowen KK, Hazell AS (2006) Gene expression changes in thalamus and inferior colliculus associated with inflammation, cellular stress, metabolism and structural damage in thiamine deficiency. Eur J Neurosci 23(5):1172–1188PubMedCrossRefGoogle Scholar
  217. 217.
    He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210(2):349–358PubMedCrossRefGoogle Scholar
  218. 218.
    Fernandez-Lizarbe S, Pascual M, Guerri C (2009) Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol 183(7):4733–4744PubMedCrossRefGoogle Scholar
  219. 219.
    Mandrekar P, Dolganiuc A, Bellerose G, Kodys K, Romics L, Nizamani R, Szabo G (2002) Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation? Alcohol Clin Exp Res 26(11):1609–1614PubMedGoogle Scholar
  220. 220.
    Wu Y, Lousberg EL, Moldenhauer LM, Hayball JD, Coller JK, Rice KC, Watkins LR, Somogyi AA, Hutchinson MR (2012) Inhibiting the TLR4-MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol-induced sedation and motor impairment in mice. Br J Pharmacol 165(5):1319–1329PubMedCrossRefGoogle Scholar
  221. 221.
    Pascual M, Balino P, Alfonso-Loeches S, Aragon CM, Guerri C (2011) Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun 25(Suppl 1):S80–S91PubMedCrossRefGoogle Scholar
  222. 222.
    Alfonso-Loeches S, Pascual M, Gomez-Pinedo U, Pascual-Lucas M, Renau-Piqueras J, Guerri C (2012) Toll-like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse. Glia 60(6):948–964PubMedCrossRefGoogle Scholar
  223. 223.
    Li X, Jiang S, Tapping RI (2010) Toll-like receptor signaling in cell proliferation and survival. Cytokine 49(1):1–9PubMedCrossRefGoogle Scholar
  224. 224.
    Mao XR, Moerman-Herzog AM, Chen Y, Barger SW (2009) Unique aspects of tran­scriptional regulation in neurons – nuances in NFkappaB and Sp1-related factors. J Neuroinflammation 6:16PubMedCrossRefGoogle Scholar
  225. 225.
    Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260PubMedCrossRefGoogle Scholar
  226. 226.
    Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866PubMedCrossRefGoogle Scholar
  227. 227.
    Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6(10):1072–1078PubMedCrossRefGoogle Scholar
  228. 228.
    Mattson MP, Culmsee C, Yu Z, Camandola S (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 74(2):443–456PubMedCrossRefGoogle Scholar
  229. 229.
    Crews F, Nixon K, Kim D, Joseph J, Shukitt-Hale B, Qin L, Zou J (2006) BHT blocks NF-kappaB activation and ethanol-induced brain damage. Alcohol Clin Exp Res 30(11):1938–1949PubMedCrossRefGoogle Scholar
  230. 230.
    Ward RJ, Zhang Y, Crichton RR, Piret B, Piette J, de Witte P (1996) Identification of the nuclear transcription factor NFkappaB in rat after in vivo ethanol administration. FEBS Lett 389(2):119–122PubMedCrossRefGoogle Scholar
  231. 231.
    Zou J, Crews F (2006) CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. Cell Mol Neurobiol 26:385–405PubMedCrossRefGoogle Scholar
  232. 232.
    Zou J, Crews F (2010) Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-kappaB and proinflammatory cytokines. Alcohol Clin Exp Res 34(5):777–789PubMedCrossRefGoogle Scholar
  233. 233.
    Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 35(2):151–159PubMedCrossRefGoogle Scholar
  234. 234.
    Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prullage M, Pfeiffer J, Lindecke A, Staiger V, Israel A, Kaltschmidt C, Memet S (2006) NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol 26(8):2936–2946PubMedCrossRefGoogle Scholar
  235. 235.
    Wang J, Fu XQ, Lei WL, Wang T, Sheng AL, Luo ZG (2010) Nuclear factor kappaB controls acetylcholine receptor clustering at the neuromuscular junction. J Neurosci 30(33):11104–11113PubMedCrossRefGoogle Scholar
  236. 236.
    Obernier JA, White AM, Swartzwelder HS, Crews FT (2002) Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharmacol Biochem Behav 72(3):521–532PubMedCrossRefGoogle Scholar
  237. 237.
    Cagnin A, Gerhard A, Banati RB (2002) In vivo imaging of neuroinflammation. Eur Neuropsychopharmacol 12(6):581–586PubMedCrossRefGoogle Scholar
  238. 238.
    Ward RJ, Colivicchi MA, Allen R, Schol F, Lallemand F, de Witte P, Ballini C, Corte LD, Dexter D (2009) Neuro-inflammation induced in the hippocampus of ‘binge drinking’ rats may be mediated by elevated extracellular glutamate content. J Neurochem 111(5):1119–1128PubMedCrossRefGoogle Scholar
  239. 239.
    Riikonen J, Jaatinen P, Rintala J, Porsti I, Karjala K, Hervonen A (2002) Intermittent ethanol exposure increases the number of cerebellar microglia. Alcohol Alcohol 37(5):421–426PubMedGoogle Scholar
  240. 240.
    Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C (2010) Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci 30(24):8285–8295PubMedCrossRefGoogle Scholar
  241. 241.
    Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 57(1):1–9PubMedCrossRefGoogle Scholar
  242. 242.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170PubMedCrossRefGoogle Scholar
  243. 243.
    Milligan CE, Cunningham TJ, Levitt P (1991) Differential immunochemical markers reveal the normal distribution of brain macrophages and microglia in the developing rat brain. J Comp Neurol 314(1):125–135PubMedCrossRefGoogle Scholar
  244. 244.
    Savchenko VL, McKanna JA, Nikonenko IR, Skibo GG (2000) Microglia and astrocytes in the adult rat brain: comparative immunocytochemical analysis demonstrates the efficacy of lipocortin 1 immunoreactivity. Neuroscience 96(1):195–203PubMedCrossRefGoogle Scholar
  245. 245.
    Shapiro LA, Wang L, Ribak CE (2008) Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia 49(Suppl 2):33–41PubMedCrossRefGoogle Scholar
  246. 246.
    Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65(3):199–203PubMedGoogle Scholar
  247. 247.
    Zahr NM, Luong R, Sullivan EV, Pfefferbaum A (2010) Measurement of serum, liver, and brain cytokine induction, thiamine levels, and hepatopathology in rats exposed to a 4-day alcohol binge protocol. Alcohol Clin Exp Res 34(11):1858–1870PubMedCrossRefGoogle Scholar
  248. 248.
    O’Connor JJ, Coogan AN (1999) Actions of the pro-inflammatory cytokine IL-1 beta on central synaptic transmission. Exp Physiol 84(4):601–614PubMedCrossRefGoogle Scholar
  249. 249.
    Ross FM, Allan SM, Rothwell NJ, Verkhratsky A (2003) A dual role for interleukin-1 in LTP in mouse hippocampal slices. J Neuroimmunol 144(1–2):61–67PubMedCrossRefGoogle Scholar
  250. 250.
    Semple BD, Kossmann T, Morganti-Kossmann MC (2010) Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 30(3):459–473PubMedCrossRefGoogle Scholar
  251. 251.
    Szelenyi J, Kiss JP, Puskas E, Szelenyi M, Vizi ES (2000) Contribution of differently localized alpha 2- and beta-adrenoceptors in the modulation of TNF-alpha and IL-10 production in endotoxemic mice. Ann N Y Acad Sci 917:145–153PubMedCrossRefGoogle Scholar
  252. 252.
    Pickering M, Cumiskey D, O’Connor JJ (2005) Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol 90(5):663–670PubMedCrossRefGoogle Scholar
  253. 253.
    Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295(5563):2282–2285PubMedCrossRefGoogle Scholar
  254. 254.
    Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25(12):3219–3228PubMedCrossRefGoogle Scholar
  255. 255.
    Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440(7087):1054–1059PubMedCrossRefGoogle Scholar
  256. 256.
    Rabbitt P, Scott M, Lunn M, Thacker N, Lowe C, Pendleton N, Horan M, Jackson A (2007) White matter lesions account for all age-related declines in speed but not in intelligence. Neuropsychology 21(3):363–370PubMedCrossRefGoogle Scholar
  257. 257.
    Kramer JH, Blusewicz MJ, Preston KA (1989) The premature aging hypothesis: old before its time? J Consult Clin Psychol 57(2):257–262PubMedCrossRefGoogle Scholar
  258. 258.
    Reuter-Lorenz PA, Stanczak L, Miller AC (1999) Neural recruitment and cognitive aging: two hemispheres are better than one, especially as you age. Psychol Sci 10:494–500CrossRefGoogle Scholar
  259. 259.
    Blatter DD, Bigler ED, Gale SD, Johnson SC, Anderson C, Burnett BM, Parker N, Kurth S, Horn S (1995) Quantitative volumetric analysis of brain MRI: normative database spanning five decades of life. AJNR Am J Neuroradiol 16(2):241–245PubMedGoogle Scholar
  260. 260.
    Courchesne E, Chisum HJ, Townsend J, Cowles A, Covington J, Egaas B, Harwood M, Hinds S, Press GA (2000) Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology 216(3):672–682PubMedGoogle Scholar
  261. 261.
    Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001) A voxel-based morphometric study of ageing in 465 normal adult brains. Neuroimage 14:21–36PubMedCrossRefGoogle Scholar
  262. 262.
    Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO (1994) A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol 51:874–887PubMedCrossRefGoogle Scholar
  263. 263.
    Raz N, Gunning FM, Head D, Dupuis JH, McQuain J, Briggs SD, Loken WJ, Thornton AE, Acker JD (1997) Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex 7(3):268–282PubMedCrossRefGoogle Scholar
  264. 264.
    Sowell ER, Thompson PM, Toga AW (2004) Mapping changes in the human cortex throughout the span of life. Neuroscientist 10(4):372–392PubMedCrossRefGoogle Scholar
  265. 265.
    Sullivan EV, Rosenbloom MJ, Serventi KL, Pfefferbaum A (2004) Effects of age and sex on volumes of the thalamus, pons, and cortex. Neurobiol Aging 25:185–192PubMedCrossRefGoogle Scholar
  266. 266.
    Taki Y, Kinomura S, Sato K, Goto R, Inoue K, Okada K, Ono S, Kawashima R, Fukuda H (2006) Both global gray matter volume and regional gray matter volume negatively correlate with lifetime alcohol intake in non-alcohol-dependent Japanese men: a volumetric analysis and a voxel-based morphometry. Alcohol Clin Exp Res 30(6):1045–1050PubMedCrossRefGoogle Scholar
  267. 267.
    Liu RS, Lemieux L, Bell GS, Sisodiya SM, Shorvon SD, Sander JW, Duncan JS (2003) A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis. Neuroimage 20(1):22–33PubMedCrossRefGoogle Scholar
  268. 268.
    Pfefferbaum A, Sullivan EV, Rosenbloom MJ, Mathalon DH, Lim KO (1998) A controlled study of cortical gray matter and ventricular changes in alcoholic men over a five year interval. Arch Gen Psychiatry 55(10):905–912PubMedCrossRefGoogle Scholar
  269. 269.
    Raz N, Rodrigue KM, Kennedy KM, Acker JD (2007) Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults. Neuropsychology 21(2):149–157PubMedCrossRefGoogle Scholar
  270. 270.
    Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C (2003) Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J Neurosci 23(8):3295–3301PubMedGoogle Scholar
  271. 271.
    Raz N, Gunning-Dixon F, Head D, Rodrigue K, Williamson A, Acker J (2004) Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume. Neurobiol Aging 25(3):377–396PubMedCrossRefGoogle Scholar
  272. 272.
    Tang Y, Whitman GT, Lopez I, Baloh RW (2001) Brain volume changes on longitudinal magnetic resonance imaging in normal older people. J Neuroimaging 11(4):393–400PubMedCrossRefGoogle Scholar
  273. 273.
    Luft AR, Skalej M, Schulz JB, Welte D, Kolb R, Burk K, Klockgether T, Voight K (1999) Patterns of age-related shrinkage in cerebellum and brainstem observed in vivo using three-dimensional MRI volumetry. Cereb Cortex 9(7):712–721PubMedCrossRefGoogle Scholar
  274. 274.
    Oguro H, Okada K, Yamaguchi S, Kobayashi S (1998) Sex differences in morphology of the brain stem and cerebellum with normal ageing. Neuroradiology 40(12):788–792PubMedCrossRefGoogle Scholar
  275. 275.
    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 15:1676–1689PubMedCrossRefGoogle Scholar
  276. 276.
    Sullivan EV, Deshmukh A, De Rosa E, Rosenbloom MJ, Pfefferbaum A (2005) Striatal and forebrain nuclei volumes: contribution to motor function and working memory deficits in alcoholism. Biol Psychiatry 57(7):768–776PubMedCrossRefGoogle Scholar
  277. 277.
    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(4):581–594PubMedCrossRefGoogle Scholar
  278. 278.
    Walhovd KB, Fjell AM, Reinvang I, Lundervold A, Dale AM, Eilertsen DE, Quinn BT, Salat D, Makris N, Fischl B (2005) Effects of age on volumes of cortex, white matter and subcortical structures. Neurobiol Aging 26(9):1261–1270, discussion 1275–1278PubMedCrossRefGoogle Scholar
  279. 279.
    Driesen NR, Raz N (1995) The influence of sex, age, and handedness on corpus callosum morphology: a meta-analysis. Psychobiology 23(3):240–247Google Scholar
  280. 280.
    Raz N, Gunning-Dixon F, Head D, Williamson A, Acker JD (2001) Age and sex differences in the cerebellum and the ventral pons: a prospective MR study of healthy adults. AJNR Am J Neuroradiol 22(6):1161–1167PubMedGoogle Scholar
  281. 281.
    Sullivan EV, Pfefferbaum A, Adalsteinsson E, Swan GE, Carmelli D (2002) Differential rates of regional change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men. Cereb Cortex 12:438–445PubMedCrossRefGoogle Scholar
  282. 282.
    Van Petten C (2004) Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: review and meta-analysis. Neuropsychologia 42:1394–1413PubMedCrossRefGoogle Scholar
  283. 283.
    Sullivan EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A (1995) Age-related decline in MRI volumes of temporal lobe gray matter but not hippocampus. Neurobiol Aging 16(4):591–606PubMedCrossRefGoogle Scholar
  284. 284.
    Sullivan EV, Marsh L, Pfefferbaum A (2005) Preservation of hippocampal volume through adulthood in healthy men and women. Neurobiol Aging 26:1093–1098PubMedCrossRefGoogle Scholar
  285. 285.
    Sullivan EV, Pfefferbaum A, Swan GE, Carmelli D (2001) Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment. Hippocampus 11:754–762PubMedCrossRefGoogle Scholar
  286. 286.
    Golomb J, De Leon MJ, Kluger A, George AE, Tarshish C, Ferris SH (1993) Hippocampal atrophy in normal aging: an association with recent memory impairment. Arch Neurol 50(9):967–973PubMedCrossRefGoogle Scholar
  287. 287.
    Braak H, Braak E (1994) Morphological criteria for the recognition of Alzheimer’s disease and the distribution pattern of cortical changes related to this disorder. Neurobiol Aging 15:355–356PubMedCrossRefGoogle Scholar
  288. 288.
    Hyman BT, Gomezisla T (1994) Alzheimer’s disease is a laminar, regional, and neural system specific disease, not a global brain disease. Neurobiol Aging 15(3):353–354PubMedCrossRefGoogle Scholar
  289. 289.
    Lippa CF, Hamos JE, Pulaski-Salo D, DeGennaro LJ, Drachman DA (1992) Alzheimer’s disease and aging: effects on perforant pathway perikarya and synapses. Neurobiol Aging 13(3):405–411PubMedCrossRefGoogle Scholar
  290. 290.
    West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344(8925):769–772PubMedCrossRefGoogle Scholar
  291. 291.
    Adalsteinsson E, Sullivan EV, Kleinhans N, Spielman DM, Pfefferbaum A (2000) Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer’s disease. Lancet 355:1696–1697PubMedCrossRefGoogle Scholar
  292. 292.
    Grachev ID, Apkarian AV (2000) Chemical heterogeneity of the living human brain: a proton MR spectroscopy study on the effects of sex, age, and brain region. Neuroimage 11(5 Pt 1):554–563PubMedCrossRefGoogle Scholar
  293. 293.
    Kwo-On-Yuen PF, Newmark RD, Budinger TF, Kaye JA, Ball MJ, Jagust WJ (1994) Brain N-acetyl-l-aspartic acid in Alzheimer’s disease: a proton magnetic resonance spectroscopy study. Brain Res 667(2):167–174PubMedCrossRefGoogle Scholar
  294. 294.
    Pfefferbaum A, Adalsteinsson E, Spielman D, Sullivan EV, Lim KO (1999) In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: effects of normal aging. Magn Reson Med 41(2):276–284PubMedCrossRefGoogle Scholar
  295. 295.
    Saunders D, Howe F, van den Boogaart A, Griffiths J, Brown M (1999) Aging of the adult human brain: in vivo quantitation of metabolite content with proton magnetic resonance spectroscopy. J Magn Reson Imaging 9(5):711–716PubMedCrossRefGoogle Scholar
  296. 296.
    Sijens PE, den Heijer T, Origgi D, Vermeer SE, Breteler MM, Hofman A, Oudkerk M (2003) Brain changes with aging: MR spectroscopy at supraventricular plane shows differences between women and men. Radiology 226(3):889–896PubMedCrossRefGoogle Scholar
  297. 297.
    Kaiser LG, Schuff N, Cashdollar N, Weiner MW (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4T. Neurobiol Aging 26(5):665–672PubMedCrossRefGoogle Scholar
  298. 298.
    Chang L, Ernst T, Poland RE, Jenden DJ (1996) In vivo proton magnetic resonance spectroscopy of the normal aging human brain. Life Sci 58(22):2049–2056PubMedCrossRefGoogle Scholar
  299. 299.
    Leary SM, Brex PA, MacManus DG, Parker GJ, Barker GJ, Miller DH, Thompson AJ (2000) A (1)H magnetic resonance spectroscopy study of aging in parietal white matter: implications for trials in multiple sclerosis. Magn Reson Imaging 18(4):455–459PubMedCrossRefGoogle Scholar
  300. 300.
    Meyerhoff DJ, MacKay S, Constans JM, Norman D, Van Dyke C, Fein G, Weiner MW (1994) Axonal injury and membrane alterations in Alzheimer’s disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol 36(1):40–47PubMedCrossRefGoogle Scholar
  301. 301.
    Costa MO, Lacerda MT, Garcia Otaduy MC, Cerri GG, Da Costa LC (2002) Proton magnetic resonance spectroscopy: normal findings in the cerebellar hemisphere in childhood. Pediatr Radiol 32(11):787–792PubMedCrossRefGoogle Scholar
  302. 302.
    Fazekas F, Niederkorn K, Schmidt R, Offenbacher H, Horner S, Bertha G, Lechner H (1988) White matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. Stroke 19(10):1285–1288PubMedCrossRefGoogle Scholar
  303. 303.
    Kuller LH, Longstreth WT Jr, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr (2004) White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke 35(8):1821–1825PubMedCrossRefGoogle Scholar
  304. 304.
    Longstreth WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, Enright PL, O’Leary D, Fried L (1996) Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the cardiovascular health study. Stroke 27(8):1274–1282PubMedCrossRefGoogle Scholar
  305. 305.
    Hachinski VC, Potter P, Merskey H (1987) Leuko-araiosis. Arch Neurol 44(1):21–23PubMedCrossRefGoogle Scholar
  306. 306.
    Inzitari D (2003) Leukoaraiosis: an independent risk factor for stroke? Stroke 34(8):2067–2071PubMedCrossRefGoogle Scholar
  307. 307.
    Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC (2002) Subcortical ischaemic vascular dementia. Lancet Neurol 1(7):426–436PubMedCrossRefGoogle Scholar
  308. 308.
    Young VG, Halliday GM, Kril JJ (2008) Neuropathologic correlates of white matter hyperintensities. Neurology 71(11):804–811PubMedCrossRefGoogle Scholar
  309. 309.
    Marcus J, Gardener H, Rundek T, Elkind MS, Sacco RL, Decarli C, Wright CB (2011) Baseline and longitudinal increases in diastolic blood pressure are associated with greater white matter hyperintensity volume: the northern Manhattan study. Stroke 42(9):2639–2641PubMedCrossRefGoogle Scholar
  310. 310.
    Raz N, Yang Y, Dahle CL, Land S (2012) Volume of white matter hyperintensities in healthy adults: contribution of age, vascular risk factors, and inflammation-related genetic variants. Biochim Biophys Acta 1822(3):361–369PubMedCrossRefGoogle Scholar
  311. 311.
    Schmidt R, Grazer A, Enzinger C, Ropele S, Homayoon N, Pluta-Fuerst A, Schwingenschuh P, Katschnig P, Cavalieri M, Schmidt H, Langkammer C, Ebner F, Fazekas F (2011) MRI-detected white matter lesions: do they really matter? J Neural Transm 118(5):673–681PubMedCrossRefGoogle Scholar
  312. 312.
    Bhagat YA, Beaulieu C (2004) Diffusion anisotropy in subcortical white matter and cortical gray matter: changes with aging and the role of CSF-suppression. J Magn Reson Imaging 20(2):216–227PubMedCrossRefGoogle Scholar
  313. 313.
    Head D, Buckner RL, Shimony JS, Williams LE, Akbudak E, Conturo TE, McAvoy M, Morris JC, Snyder AZ (2004) Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. Cereb Cortex 14(4):410–423PubMedCrossRefGoogle Scholar
  314. 314.
    Pfefferbaum A, Adalsteinsson E, Sullivan EV (2005) Frontal circuitry degradation marks healthy adult aging: evidence from diffusion tensor imaging. Neuroimage 26(3):891–899PubMedCrossRefGoogle Scholar
  315. 315.
    Pfefferbaum A, Sullivan EV (2003) Increased brain white matter diffusivity in normal adult aging: relationship to anisotropy and partial voluming. Magn Reson Med 49:953–961PubMedCrossRefGoogle Scholar
  316. 316.
    Pfefferbaum A, Sullivan EV, Hedehus M, Lim KO, Adalsteinsson E, Moseley M (2000) Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging. Magn Reson Med 44(2):259–268PubMedCrossRefGoogle Scholar
  317. 317.
    Salat DH, Tuch DS, Greve DN, van der Kouwe AJ, Hevelone ND, Zaleta AK, Rosen BR, Fischl B, Corkin S, Rosas HD, Dale AM (2005) Age-related alterations in white matter microstructure measured by diffusion tensor imaging. Neurobiol Aging 26(8):1215–1227PubMedCrossRefGoogle Scholar
  318. 318.
    Sullivan EV, Adalsteinsson E, Hedehus M, Ju C, Moseley M, Lim KO, Pfefferbaum A (2001) Equivalent disruption of regional white matter microstructure in aging healthy men and women. Neuroreport 12(22):99–104PubMedCrossRefGoogle Scholar
  319. 319.
    Sullivan EV, Rohlfing T, Pfefferbaum A (2010) Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: relations to timed performance. Neurobiol Aging 31:464–481PubMedCrossRefGoogle Scholar
  320. 320.
    Angelie E, Bonmartin A, Boudraa A, Gonnaud PM, Mallet JJ, Sappey-Marinier D (2001) Regional differences and metabolic changes in normal aging of the human brain: proton MR spectroscopic imaging study. AJNR Am J Neuroradiol 22(1):119–127PubMedGoogle Scholar
  321. 321.
    Soher BJ, Hurd RE, Sailasuta N, Barker PB (1996) Quantitation of automated single-voxel proton MRS using cerebral water as an internal reference. Magn Reson Med 36(3):335–339PubMedCrossRefGoogle Scholar
  322. 322.
    Moats RA, Ernst T, Shonk TK, Ross BD (1994) Abnormal cerebral metabolite concentrations in patients with probable Alzheimer’s disease. Magn Reson Med 32:110–115PubMedCrossRefGoogle Scholar
  323. 323.
    Moreno-Torres A, Pujol J, Soriano-Mas C, Deus J, Iranzo A, Santamaria J (2005) Age-related metabolic changes in the upper brainstem tegmentum by MR spectroscopy. Neurobiol Aging 26(7):1051–1059PubMedCrossRefGoogle Scholar
  324. 324.
    Arfanakis K, Haughton VM, Carew JD, Rogers BP, Dempsey RJ, Meyerand ME (2002) Diffusion tensor MR imaging in diffuse axonal injury. AJNR Am J Neuroradiol 23:794–802PubMedGoogle Scholar
  325. 325.
    Peters A, Sethares C (2002) Aging and the myelinated fibers in prefrontal cortex and corpus callosum of the monkey. J Comp Neurol 442(3):277–291PubMedCrossRefGoogle Scholar
  326. 326.
    Peters A, Sethares C (2003) Is there remyelination during aging of the primate central nervous system? J Comp Neurol 460(2):238–254PubMedCrossRefGoogle Scholar
  327. 327.
    Peters A, Sethares C, Killiany RJ (2001) Effects of age on the thickness of myelin sheaths in monkey primary visual cortex. J Comp Neurol 435(2):241–248PubMedCrossRefGoogle Scholar
  328. 328.
    Wang DS, Bennett DA, Mufson EJ, Mattila P, Cochran E, Dickson DW (2004) Contribution of changes in ubiquitin and myelin basic protein to age-related cognitive decline. Neurosci Res 48(1):93–100PubMedCrossRefGoogle Scholar
  329. 329.
    Dilger RN, Johnson RW (2008) Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 84(4):932–939PubMedCrossRefGoogle Scholar
  330. 330.
    Long JM, Kalehua AN, Muth NJ, Calhoun ME, Jucker M, Hengemihle JM, Ingram DK, Mouton PR (1998) Stereological analysis of astrocyte and microglia in aging mouse hippocampus. Neurobiol Aging 19(5):497–503PubMedCrossRefGoogle Scholar
  331. 331.
    Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9(4):339–349PubMedCrossRefGoogle Scholar
  332. 332.
    Streit WJ, Sparks DL (1997) Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med (Berl) 75(2):130–138CrossRefGoogle Scholar
  333. 333.
    Sheffield LG, Berman NE (1998) Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging 19(1):47–55PubMedCrossRefGoogle Scholar
  334. 334.
    Sloane JA, Hollander W, Moss MB, Rosene DL, Abraham CR (1999) Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol Aging 20(4):395–405PubMedCrossRefGoogle Scholar
  335. 335.
    Ogura K, Ogawa M, Yoshida M (1994) Effects of ageing on microglia in the normal rat brain: immunohistochemical observations. Neuroreport 5(10):1224–1226PubMedCrossRefGoogle Scholar
  336. 336.
    Perry VH, Matyszak MK, Fearn S (1993) Altered antigen expression of microglia in the aged rodent CNS. Glia 7(1):60–67PubMedCrossRefGoogle Scholar
  337. 337.
    Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19(10):1329–1331PubMedGoogle Scholar
  338. 338.
    Williams K, Ulvestad E, Waage A, Antel JP, McLaurin J (1994) Activation of adult human derived microglia by myelin phagocytosis in vitro. J Neurosci Res 38(4):433–443PubMedCrossRefGoogle Scholar
  339. 339.
    Mosley K, Cuzner ML (1996) Receptor-mediated phagocytosis of myelin by macrophages and microglia: effect of opsonization and receptor blocking agents. Neurochem Res 21(4):481–487PubMedCrossRefGoogle Scholar
  340. 340.
    Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW (2008) Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 22(3):301–311PubMedCrossRefGoogle Scholar
  341. 341.
    Barrientos RM, Higgins EA, Biedenkapp JC, Sprunger DB, Wright-Hardesty KJ, Watkins LR, Rudy JW, Maier SF (2006) Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 27(5):723–732PubMedCrossRefGoogle Scholar
  342. 342.
    DiPatre PL, Gelman BB (1997) Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus. J Neuropathol Exp Neurol 56(2):143–149PubMedCrossRefGoogle Scholar
  343. 343.
    Godbout JP, Johnson RW (2006) Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Neurol Clin 24(3):521–538PubMedCrossRefGoogle Scholar
  344. 344.
    Perry VH (2010) Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol 120(3):277–286PubMedCrossRefGoogle Scholar
  345. 345.
    Xie Z, Morgan TE, Rozovsky I, Finch CE (2003) Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp Neurol 182(1):135–141PubMedCrossRefGoogle Scholar
  346. 346.
    Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ (2012) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 33(1):195.e1–12CrossRefGoogle Scholar
  347. 347.
    Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9(4):183–192PubMedCrossRefGoogle Scholar
  348. 348.
    Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55(4):412–424PubMedCrossRefGoogle Scholar
  349. 349.
    Potula R, Haorah J, Knipe B, Leibhart J, Chrastil J, Heilman D, Dou H, Reddy R, Ghorpade A, Persidsky Y (2006) Alcohol abuse enhances neuroinflammation and impairs immune responses in an animal model of human immunodeficiency virus-1 encephalitis. Am J Pathol 168(4):1335–1344PubMedCrossRefGoogle Scholar
  350. 350.
    Szabo G (1999) Consequences of alcohol consumption on host defence. Alcohol Alcohol 34(6):830–841PubMedGoogle Scholar
  351. 351.
    Wang X, Douglas SD, Metzger DS, Guo CJ, Li Y, O’Brien CP, Song L, Davis-Vogal A, Ho WZ (2002) Alcohol potentiates HIV-1 infection of human blood mononuclear phagocytes. Alcohol Clin Exp Res 26(12):1880–1886PubMedCrossRefGoogle Scholar
  352. 352.
    Wang Y, Watson RR (1995) Is alcohol consumption a cofactor in the development of acquired immunodeficiency syndrome? Alcohol 12(2):105–109PubMedCrossRefGoogle Scholar
  353. 353.
    Chen W, Tang Z, Fortina P, Patel P, Addya S, Surrey S, Acheampong EA, Mukhtar M, Pomerantz RJ (2005) Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways. Virology 334(1):59–73PubMedCrossRefGoogle Scholar
  354. 354.
    Self RL, Mulholland PJ, Harris BR, Nath A, Prendergast MA (2004) Cytotoxic effects of exposure to the human immunodeficiency virus type 1 protein Tat in the hippocampus are enhanced by prior ethanol treatment. Alcohol Clin Exp Res 28(12):1916–1924PubMedCrossRefGoogle Scholar
  355. 355.
    Wu P, Price P, Du B, Hatch WC, Terwilliger EF (1996) Direct cytotoxicity of HIV-1 envelope protein gp120 on human NT neurons. Neuroreport 7(5):1045–1049PubMedCrossRefGoogle Scholar
  356. 356.
    Self RL, Smith KJ, Butler TR, Pauly JR, Prendergast MA (2009) Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 protein trans-activator of transcription exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl-d-aspartate glutamate receptors to produce persisting spatial learning deficits. Neuroscience 163(3):868–876PubMedCrossRefGoogle Scholar
  357. 357.
    Belmadani A, Zou JY, Schipma MJ, Neafsey EJ, Collins MA (2001) Ethanol pre-exposure suppresses HIV-1 glycoprotein 120-induced neuronal degeneration by abrogating endogenous glutamate/Ca2+−mediated neurotoxicity. Neuroscience 104(3):769–781PubMedCrossRefGoogle Scholar
  358. 358.
    Collins MA, Neafsey EJ, Zou JY (2000) HIV-I gpI20 neurotoxicity in brain cultures is prevented by moderate ethanol pretreatment. Neuroreport 11(6):1219–1222PubMedCrossRefGoogle Scholar
  359. 359.
    Belmadani A, Neafsey EJ, Collins MA (2003) Human immunodeficiency virus type 1 gp120 and ethanol coexposure in rat organotypic brain slice cultures: curtailment of gp120-induced neurotoxicity and neurotoxic mediators by moderate but not high ethanol concentrations. J Neurovirol 9(1):45–54PubMedGoogle Scholar
  360. 360.
    Bagby GJ, Stoltz DA, Zhang P, Kolls JK, Brown J, Bohm RP Jr, Rockar R, Purcell J, Murphey-Corb M, Nelson S (2003) The effect of chronic binge ethanol consumption on the primary stage of SIV infection in Rhesus macaques. Alcohol Clin Exp Res 27(3): 495–502PubMedCrossRefGoogle Scholar
  361. 361.
    Poonia B, Nelson S, Bagby GJ, Zhang P, Quniton L, Veazey RS (2006) Chronic alcohol consumption results in higher simian immunodeficiency virus replication in mucosally inoculated Rhesus macaques. AIDS Res Hum Retroviruses 22(6):589–594PubMedCrossRefGoogle Scholar
  362. 362.
    Hudson LC, Colby BA, Meeker RB (2010) Ethanol suppression of peripheral blood mononuclear cell trafficking across brain endothelial cells in immunodeficiency virus infection. HIV AIDS (Auckl) 2:7–18Google Scholar
  363. 363.
    Strazza M, Pirrone V, Wigdahl B, Nonnemacher MR (2011) Breaking down the barrier: the effects of HIV-1 on the blood–brain barrier. Brain Res 1399:96–115PubMedCrossRefGoogle Scholar
  364. 364.
    Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y (2005) Alcohol-induced oxidative stress in brain endothelial cells causes blood–brain barrier dysfunction. J Leukoc Biol 78(6):1223–1232PubMedCrossRefGoogle Scholar
  365. 365.
    Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y (2007) Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood–brain barrier dysfunction. J Neurochem 101(2):566–576PubMedCrossRefGoogle Scholar
  366. 366.
    Ehrlich D, Pirchl M, Humpel C (2012) Effects of long-term moderate ethanol and cholesterol on cognition, cholinergic neurons, inflammation, and vascular impairment in rats. Neuroscience 205:154–166PubMedCrossRefGoogle Scholar
  367. 367.
    Phillips SC, Cragg BG (1982) Weakening of the blood–brain barrier by alcohol-related stresses in the rat. J Neurol Sci 54(2):271–278PubMedCrossRefGoogle Scholar
  368. 368.
    Rosengren LE, Persson LI (1979) Chlorpromazine treatment of blood–brain barrier dysfunction. A quantitative and fluorescence microscopical study on small cerebral stab wounds in the rat. Acta Neuropathol 46(1–2):145–150PubMedCrossRefGoogle Scholar
  369. 369.
    Pratt OE, Rooprai HK, Shaw GK, Thomson AD (1990) The genesis of alcoholic brain tissue injury. Alcohol Alcohol 25(2–3):217–230PubMedGoogle Scholar
  370. 370.
    Thomsen H, Kaatsch HJ, Asmus R (1994) Magnetic resonance imaging of the brain during alcohol absorption and elimination – a study of the “rising tide phenomenon”. Blutalkohol 31(3):178–185PubMedGoogle Scholar
  371. 371.
    Fein G, Biggins CA, MacKay S (1995) Delayed latency of the event-related brain potential P3A component in HIV disease: progressive effects with increasing cognitive impairment. Arch Neurol 52(11):1109–1118PubMedCrossRefGoogle Scholar
  372. 372.
    Green JE, Saveanu RV, Bornstein RA (2004) The effect of previous alcohol abuse on cognitive function in HIV infection. Am J Psychiatry 161(2):249–254PubMedCrossRefGoogle Scholar
  373. 373.
    Rothlind JC, Greenfield TM, Bruce AV, Meyerhoff DJ, Flenniken DL, Lindgren JA, Weiner MW (2005) Heavy alcohol consumption in individuals with HIV infection: effects on neuropsychological performance. J Int Neuropsychol Soc 11(1):70–83PubMedCrossRefGoogle Scholar
  374. 374.
    Meyerhoff DJ, MacKay S, Sappey-Marinier D, Deicken R, Calabrese G, Dillon WP, Weiner MW, Fein G (1995) Effects of chronic alcohol abuse and HIV infection on brain phosphorus metabolites. Alcohol Clin Exp Res 19(3):685–692PubMedCrossRefGoogle Scholar
  375. 375.
    Pfefferbaum A, Adalsteinsson E, Sullivan EV (2005) Cortical NAA deficits in HIV infection without dementia: influence of alcoholism comorbidity. Neuropsychopharmacology 30(7):1392–1399PubMedGoogle Scholar
  376. 376.
    CDC (2005) HIV/AIDS surveillance report, vol 17, AtlantaGoogle Scholar
  377. 377.
    Becker JT, Lopez OL, Dew MA, Aizenstein HJ (2004) Prevalence of cognitive disorders differs as a function of age in HIV virus infection. AIDS 18(Suppl 1):S11–S18PubMedGoogle Scholar
  378. 378.
    Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, Selnes O, Holck P, Grove J, Sacktor N (2004) Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology 63(5):822–827PubMedCrossRefGoogle Scholar
  379. 379.
    Valcour V, Shiramizu B (2004) HIV-associated dementia, mitochondrial dysfunction, and oxidative stress. Mitochondrion 4(2–3):119–129PubMedCrossRefGoogle Scholar
  380. 380.
    Agrawal L, Lu X, Jin Q, Alkhatib G (2006) Anti-HIV therapy: current and future directions. Curr Pharm Des 12(16):2031–2055PubMedCrossRefGoogle Scholar
  381. 381.
    Price TO, Uras F, Banks WA, Ercal N (2006) A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells. Exp Neurol 201(1):193–202PubMedCrossRefGoogle Scholar
  382. 382.
    Reynolds A, Laurie C, Mosley RL, Gendelman HE (2007) Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol 82:297–325PubMedCrossRefGoogle Scholar
  383. 383.
    Visalli V, Muscoli C, Sacco I, Sculco F, Palma E, Costa N, Colica C, Rotiroti D, Mollace V (2007) N-acetylcysteine prevents HIV gp 120-related damage of human cultured astrocytes: correlation with glutamine synthase dysfunction. BMC Neurosci 8:106PubMedCrossRefGoogle Scholar
  384. 384.
    Achim CL, Adame A, Dumaop W, Everall IP, Masliah E (2009) Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J Neuroimmune Pharmacol 4(2):190–199PubMedCrossRefGoogle Scholar
  385. 385.
    Caron M, Auclairt M, Vissian A, Vigouroux C, Capeau J (2008) Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir Ther 13(1):27–38PubMedGoogle Scholar
  386. 386.
    Abraham J, Jang S, Godbout JP, Chen J, Kelley KW, Dantzer R, Johnson RW (2008) Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120. Neurobiol Aging 29(4):614–621PubMedCrossRefGoogle Scholar
  387. 387.
    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(3):336–340PubMedCrossRefGoogle Scholar
  388. 388.
    Chang L, Wong V, Nakama H, Watters M, Ramones D, Miller EN, Cloak C, Ernst T (2008) Greater than age-related changes in brain diffusion of HIV patients after 1 year. J Neuroimmune Pharmacol 3(4):265–274PubMedCrossRefGoogle Scholar
  389. 389.
    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(4):1336–1347PubMedCrossRefGoogle Scholar
  390. 390.
    Ernst T, Chang L (2004) Effect of aging on brain metabolism in antiretroviral-naive HIV patients. AIDS 18(Suppl 1):S61–S67PubMedGoogle Scholar
  391. 391.
    Rigler SK (2000) Alcoholism in the elderly. Am Fam Physician 61(6):1710–1716, 1883–1884, 1887–1888 passimPubMedGoogle Scholar
  392. 392.
    Dlugos CA, Pentney RJ (1997) Morphometric evidence that the total number of synapses on Purkinje neurons of old F344 rats is reduced after long-term ethanol treatment and restored to control levels after recovery. Alcohol Alcohol 32(2):161–172PubMedGoogle Scholar
  393. 393.
    Pentney RJ, Quackenbush LJ (1990) Dendritic hypertrophy in Purkinje neurons of old Fischer 344 rats after long-term ethanol treatment. Alcohol Clin Exp Res 14(6):878–886PubMedCrossRefGoogle Scholar
  394. 394.
    Wiggins RC, Gorman A, Rolsten C, Samorajski T, Ballinger WE, Freund G (1988) Effects of aging and alcohol on the biochemical composition of histologically normal human brain. Metab Brain Dis 3(1):67–80PubMedCrossRefGoogle Scholar
  395. 395.
    Fein G, Shimotsu R, Barakos J (2010) Age-related gray matter shrinkage in a treatment naive actively drinking alcohol-dependent sample. Alcohol Clin Exp Res 34(1):175–182PubMedCrossRefGoogle Scholar
  396. 396.
    Oscar-Berman M (2000) Neuropsychological vulnerabilities in chronic alcoholism. In: Noronha A, Eckardt M, Warren K (eds) Review of NIAAA’s neuroscience and behavioral research portfolio, NIAAA Research Monograph No. 34. National Institutes of Health, Bethesda, pp 437–472Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • N. M. Zahr
    • 1
    • 2
  • A. Manning-Bog
    • 1
  • C. Alt
    • 3
  • E. V. Sullivan
    • 2
  • A. Pfefferbaum
    • 1
    • 2
  1. 1.Policy DivisionSRI InternationalMenlo ParkUSA
  2. 2.Psychiatry and Behavioral SciencesStanford University, School of MedicineStanfordUSA
  3. 3.Biosciences DivisionSRI InternationalMenlo ParkUSA

Personalised recommendations