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Clinical and pathological features of alcohol-related brain damage

Abstract

One of the sequelae of chronic alcohol abuse is malnutrition. Importantly, a deficiency in thiamine (vitamin B1) can result in the acute, potentially reversible neurological disorder Wernicke encephalopathy (WE). When WE is recognized, thiamine treatment can elicit a rapid clinical recovery. If WE is left untreated, however, patients can develop Korsakoff syndrome (KS), a severe neurological disorder characterized by anterograde amnesia. Alcohol-related brain damage (ARBD) describes the effects of chronic alcohol consumption on human brain structure and function in the absence of more discrete and well-characterized neurological concomitants of alcoholism such as WE and KS. Through knowledge of both the well-described changes in brain structure and function that are evident in alcohol-related disorders such as WE and KS and the clinical outcomes associated with these changes, researchers have begun to gain a better understanding of ARBD. This Review examines ARBD from the perspective of WE and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions. An awareness of the consequences of chronic alcohol consumption on human behavior and brain structure can enable clinicians to improve detection and treatment of ARBD.

Key Points

  • Alcohol can cause a spectrum of untoward structural and functional changes in the brain

  • The spectrum of disruption includes alcohol-related brain damage at one end and complications such as hepatic encephalopathy, Wernicke encephalopathy, Korsakoff syndrome, Marchiafava–Bignami disease and central pontine myelinolysis at the other

  • The clinical diagnoses of alcohol-related brain damage and even Wernicke encephalopathy can be difficult to make, and many cases of these conditions are missed

  • Changes to the brain associated with alcohol intake are regionally specific and can affect both gray and white matter; some of these changes are reversible with abstinence

  • Pathogenic mechanisms associated with alcoholism are under investigation, with neuroinflammation currently receiving particular attention

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Figure 1: Brain regions targeted by alcohol-related disease.
Figure 2: Interactions between alcohol consumption and thiamine deficiency.
Figure 3: Functions and associated brain regions targeted by alcohol abuse and alcoholism.
Figure 4: Graded brain-volume deficits in alcoholism and its sequelae.

References

  1. Lieber, C. S. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol 34, 9–19 (2004).

    CAS  PubMed  Google Scholar 

  2. Hillbom, M., Juvela, S. & Karttunen, V. Mechanisms of alcohol-related strokes. Novartis Found. Symp. 216, 193–204 (1998).

    CAS  PubMed  Google Scholar 

  3. Victor, M., Adams, R. D. & Collins, G. H. The Wernicke–Korsakoff Syndrome and Related Neurologic Disorders due to Alcoholism and Malnutrition, 2nd edn (F. A. Davis, Philadelphia, 1989).

    Google Scholar 

  4. Zuccoli, G. et al. Neuroimaging findings in alcohol-related encephalopathies. AJR Am. J. Roentgenol. 195, 1378–1384 (2010).

    PubMed  Google Scholar 

  5. Sullivan, E. V. & Pfefferbaum, A. Neuroimaging of the Wernicke–Korsakoff syndrome. Alcohol Alcohol. 44, 155–165 (2009).

    PubMed  Google Scholar 

  6. Oscar-Berman, M. & Marinkovic, K. Alcoholism and the brain: an overview. Alcohol Res. Health 27, 125–133 (2003).

    PubMed  PubMed Central  Google Scholar 

  7. Harper, C. Thiamine (vitamin B1) deficiency and associated brain damage is still common throughout the world and prevention is simple and safe! Eur. J. Neurol. 13, 1078–1082 (2006).

    CAS  PubMed  Google Scholar 

  8. Burns, E. M. et al. Introduction of laparoscopic bariatric surgery in England: observational population cohort study. BMJ 341, c4296 (2010).

    PubMed  Google Scholar 

  9. Thomson, A. D., Cook, C. C., Touquet, R. & Henry, J. A. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and emergency department. Alcohol Alcohol. 37, 513–521 (2002).

    CAS  PubMed  Google Scholar 

  10. Sechi, G. & Serra, A. Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 6, 442–455 (2007).

    CAS  PubMed  Google Scholar 

  11. Thomson, A. D., Jeyasingham, M. D., Pratt, O. E. & Shaw, G. K. Nutrition and alcoholic encephalopathies. Acta Med. Scand. 717 (Suppl.), 55–65 (1987).

    CAS  Google Scholar 

  12. Todd, K. G. & Butterworth, R. F. Early microglial response in experimental thiamine deficiency: an immunohistochemical analysis. Glia 25, 190–198 (1999).

    CAS  PubMed  Google Scholar 

  13. Lieber, C. S. Relationships between nutrition, alcohol use, and liver disease. Alcohol Res. Health 27, 220–231 (2003).

    PubMed  PubMed Central  Google Scholar 

  14. Thomson, A. D. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke–Korsakoff syndrome. Alcohol Alcohol. 35 (Suppl.), 2–7 (2000).

    CAS  Google Scholar 

  15. Martin, P. R., Singleton, C. K. & Hiller-Sturmhofel, S. The role of thiamine deficiency in alcoholic brain disease. Alcohol Res. Health 27, 134–142 (2003).

    PubMed  PubMed Central  Google Scholar 

  16. Galvin, R. et al. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur. J. Neurol. 17, 1408–1418 (2010).

    CAS  PubMed  Google Scholar 

  17. Harper, C. The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? J. Neuropathol. Exp. Neurol. 57, 101–110 (1998).

    CAS  PubMed  Google Scholar 

  18. Butters, N. The Wernicke–Korsakoff syndrome: a review of psychological, neuropathological and etiological factors. Curr. Alcohol. 8, 205–232 (1981).

    CAS  PubMed  Google Scholar 

  19. Feinberg, I., Fein, G., Price, L. J., Jernigan, T. L. & Floyd, T. C. in Aging in the 1980s: Psychological Issues (ed. Poon, L. W.) 71–77 (American Psychological Association, Washington D. C., 1980).

    Google Scholar 

  20. Butters, N. & Brandt, J. in Recent Developments in Alcoholism Vol. 3 (ed. Galanter, M.) 207–226 (Plenum Publishing, New York, 1985).

    Google Scholar 

  21. Harper, C. G., Giles, M. & Finlay-Jones, R. Clinical signs in the Wernicke–Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J. Neurol. Neurosurg. Psychiatry 49, 341–345 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Caine, D., Halliday, G. M., Kril, J. J. & Harper, C. G. Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy. J. Neurol. Neurosurg. Psychiatry 62, 51–60 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fama, R., Marsh, L. & Sullivan, E. V. Dissociation of remote and anterograde memory impairment and neural correlates in alcoholic Korsakoff syndrome. J. Int. Neuropsychol. Soc. 10, 427–441 (2004).

    PubMed  Google Scholar 

  24. Fama, R., Pfefferbaum, A. & Sullivan, E. V. Visuoperceptual priming in alcoholic Korsakoff syndrome. Alcohol. Clin. Exp. Res. 30, 680–687 (2006).

    PubMed  Google Scholar 

  25. Sullivan, E. V., Deshmukh, A., Desmond, J. E., Lim, K. O. & Pfefferbaum, A. Cerebellar volume decline in normal aging, alcoholism, and Korsakoff's syndrome: relation to ataxia. Neuropsychology 14, 341–352 (2000).

    CAS  PubMed  Google Scholar 

  26. Kopelman, M. D., Thomson, A. D., Guerrini, I. & Marshall, E. J. The Korsakoff syndrome: clinical aspects, psychology and treatment. Alcohol Alcohol. 44, 148–154 (2009).

    PubMed  Google Scholar 

  27. Oscar-Berman, M. & Ellis, R. J. Cognitive deficits related to memory impairments in alcoholism. Recent Dev. Alcohol. 5, 59–80 (1987).

    CAS  PubMed  Google Scholar 

  28. Dirksen, C. L., Howard, J. A., Cronin-Golomb, A. & Oscar-Berman, M. Patterns of prefrontal dysfunction in alcoholics with and without Korsakoff's syndrome, patients with Parkinson's disease, and patients with rupture and repair of the anterior communicating artery. Neuropsychiatr. Dis. Treat. 2, 327–339 (2006).

    PubMed  PubMed Central  Google Scholar 

  29. Oscar-Berman, M. in Review of NIAAA's Neuroscience and Behavioral Research Portfolio, NIAAA Research Monograph No. 34 (eds Noronha, A., Eckardt, M. & Warren, K.) 437–472 (NIH, Bethesda, 2000).

    Google Scholar 

  30. Giancola, P. R. & Moss, H. B. Executive cognitive functioning in alcohol use disorders. Recent Dev. Alcohol. 14, 227–251 (1998).

    CAS  PubMed  Google Scholar 

  31. Bates, M. E., Bowden, S. C. & Barry, D. Neurocognitive impairment associated with alcohol use disorders: implications for treatment. Exp. Clin. Psychopharmacol. 10, 193–212 (2002).

    CAS  PubMed  Google Scholar 

  32. Oscar-Berman, M. & Marinkovic, K. Alcohol: effects on neurobehavioral functions and the brain. Neuropsychol. Rev. 17, 239–257 (2007).

    PubMed  PubMed Central  Google Scholar 

  33. Sullivan, E. V., Harris, R. A. & Pfefferbaum, A. Alcohol's effects on brain and behavior. Alco. Res. Health 33, 127–143 (2010).

    Google Scholar 

  34. Green, A. et al. The effect of moderate to heavy alcohol consumption on neuropsychological performance as measured by the repeatable battery for the assessment of neuropsychological status. Alcohol. Clin. Exp. Res. 34, 443–450 (2010).

    PubMed  Google Scholar 

  35. Bowden, S. C. Separating cognitive impairment in neurologically asymptomatic alcoholism from Wernicke–Korsakoff Syndrome: is the neuropsychological distinction justified? Psychol. Bull. 10 7, 355–366 (1990).

    Google Scholar 

  36. Squire, L. & Butters, N. (eds) Neuropsychology of Memory 2nd edn (Guilford Press, New York, 1992).

    Google Scholar 

  37. Pitel, A. L. et al. Episodic and working memory deficits in alcoholic Korsakoff patients: the continuity theory revisited. Alcohol. Clin. Exp. Res. 32, 1229–1241 (2008).

    PubMed  Google Scholar 

  38. Sullivan, E. V. et al. Disruption of frontocerebellar circuitry and function in alcoholism. Alcohol. Clin. Exp. Res. 27, 301–309 (2003).

    PubMed  Google Scholar 

  39. Pitel, A. L. et al. Signs of preclinical Wernicke's encephalopathy and thiamine levels as predictors of neuropsychological deficits in alcoholism without Korsakoff's syndrome. Neuropsychopharmacology 36, 580–588 (2011).

    PubMed  Google Scholar 

  40. Victor, M., Adams, R. D. & Collins, G. H. The Wernicke–Korsakoff Syndrome (F. A. Davis, Philadelphia, 1971).

    Google Scholar 

  41. Harper, C. G. & Blumbergs, P. C. Brain weights in alcoholics. J. Neurol. Neurosurg. Psychiatry 45, 838–840 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Skullerud, K. Variations in the size of the human brain. Influence of age, sex, body length, body mass index, alcoholism, Alzheimer changes, and cerebral atherosclerosis. Acta Neurol. Scand. 102, 1–94 (1985).

    CAS  Google Scholar 

  43. Harper, C. G. & Kril, J. J. in Alcohol Induced Brain Damage: NIAAA Research Monograph No. 22 (eds Hunt, W. A. & Nixon, S. J.) 39–69 (NIH, Rockville, 1993).

    Google Scholar 

  44. Harper, C. G., Kril, J. J. & Holloway, R. L. Brain shrinkage in chronic alcoholics: a pathological study. Br. Med. J. 290, 501–504 (1985).

    CAS  Google Scholar 

  45. De la Monte, S. M. Disproportionate atrophy of cerebral white matter in chronic alcoholics. Arch. Neurol. 45, 990–992 (1988).

    CAS  PubMed  Google Scholar 

  46. Harper, C. & Kril, J. J. Brain atrophy in chronic alcoholic patients: a quantitative pathological study. J. Neurol. Neurosurg. Psychiatry 48, 211–217 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kril, J. J. & Butterworth, R. F. Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease. Hepatology 26, 837–841 (1997).

    CAS  PubMed  Google Scholar 

  48. Phillips, S. C., Harper, C. G. & Kril, J. A quantitative histological study of the cerebellar vermis in alcoholic patients. Brain 110, 301–314 (1987).

    PubMed  Google Scholar 

  49. Harper, C. G. & Kril, J. J. Corpus callosal thickness in alcoholics. Br. J. Addict. 83, 577–580 (1988).

    CAS  PubMed  Google Scholar 

  50. Tarnowska-Dziduszko, E., Bertrand, E. & Szpak, G. Morphological changes in the corpus callosum in chronic alcoholism. Folia Neuropathol. 33, 25–29 (1995).

    CAS  PubMed  Google Scholar 

  51. Lee, S. T., Jung, Y. M., Na, D. L., Park, S. H. & Kim, M. Corpus callosum atrophy in Wernicke's encephalopathy. J. Neuroimaging 15, 367–372 (2005).

    PubMed  Google Scholar 

  52. Harper, C. et al. The pathophysiology of 'brain shrinkage' in alcoholics structural and molecular changes and clinical implications. Alcohol. Clin. Exp. Res. 29, 1106–1115 (2005).

    Google Scholar 

  53. Harding, A., Halliday, G., Caine, D. & Kril, J. Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 12 3, 141–154 (2000).

    Google Scholar 

  54. Cullen, K. M., Halliday, G. M., Caine, D. & Kril, J. J. 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, 315–320 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Baker, K., Harding, A., Halliday, G., Kril, J. & Harper, C. Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy. Neuroscience 91, 429–438 (1999).

    CAS  PubMed  Google Scholar 

  56. Harper, C. & Kril, J. An introduction to alcohol-induced brain damage and its causes. Alcohol Alcohol. 2 (Suppl.), 237–243 (1994).

    CAS  Google Scholar 

  57. Kril, J. J., Halliday, G. M., Svoboda, M. D. & Cartwright, H. The cerebral cortex is damaged in chronic alcoholics. Neuroscience 79, 983–998 (1997).

    CAS  PubMed  Google Scholar 

  58. Harper, C. & Corbett, D. Changes in the basal dendrites of cortical pyramidal cells from alcoholic patients—a quantitative Golgi study. J. Neurol. Neurosurg. Psychiatry 53, 856–861 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. McMullen, P. A., Saint-Cyr, J. A. & Carlen, P. L. Morphological alterations in the rat CA1 hippocampal pyramidal cell dendrites resulting from chronic ethanol consumption and withdrawal. J. Comp. Neurol. 225, 111–118 (1984).

    CAS  PubMed  Google Scholar 

  60. Harding, A. J., Halliday, G. M., Ng, J. L., Harper, C. G. & Kril, J. J. Loss of vasopressin-immunoreactive neurons in alcoholics is dose-related and time-dependent. Neuroscience 72, 699–708 (1996).

    CAS  PubMed  Google Scholar 

  61. Harper, C., Dixon, G., Sheedy, D. & Garrick, T. Neuropathological alterations in alcoholic brains. Studies arising from the New South Wales Tissue Resource Centre. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 951–961 (2003).

    CAS  PubMed  Google Scholar 

  62. Harding, A. J., Wong, A., Svoboda, M., Kril, J. J. & Halliday, G. M. Chronic alcohol consumption does not cause hippocampal neuron loss in humans. Hippocampus 7, 78–87 (1997).

    CAS  PubMed  Google Scholar 

  63. Baker, K. G., Halliday, G. M., Kril, J. J. & Harper, C. G. Chronic alcoholics without Wernicke–Korsakoff syndrome or cirrhosis do not lose serotonergic neurons in the dorsal raphe nucleus. Alcohol. Clin. Exp. Res. 20, 61–66 (1996).

    CAS  PubMed  Google Scholar 

  64. Jernigan, T. L. et al. Reduced cerebral grey matter observed in alcoholics using magnetic resonance imaging. Alcohol. Clin. Exp. Res. 15, 418–427 (1991).

    CAS  PubMed  Google Scholar 

  65. Sullivan, E. V. et al. In vivo mammillary body volume deficits in amnesic and nonamnesic alcoholics. Alcohol. Clin. Exp. Res. 23, 1629–1636 (1999).

    CAS  PubMed  Google Scholar 

  66. Sheedy, D., Lara, A., Garrick, T. & Harper, C. Size of mamillary bodies in health and disease: useful measurements in neuroradiological diagnosis of Wernicke's encephalopathy. Alcohol. Clin. Exp. Res. 23, 1624–1628 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Shear, P. K., Sullivan, E. V., Lane, B. & Pfefferbaum, A. Mammillary body and cerebellar shrinkage in chronic alcoholics with and without amnesia. Alcohol. Clin. Exp. Res. 20, 1489–1495 (1996).

    CAS  PubMed  Google Scholar 

  68. Jernigan, T. L., Schafer, K., Butters, N. & Cermak, L. S. Magnetic resonance imaging of alcoholic Korsakoff patients. Neuropsychopharmacology 4, 175–186 (1991).

    CAS  PubMed  Google Scholar 

  69. Lenz, V. et al. Value of MRI findings in Gayet–Wernicke encephalopathy [French]. J. Neuroradiol. 29, 153–160 (2002).

    CAS  PubMed  Google Scholar 

  70. Pfefferbaum, A. et al. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol. Clin. Exp. Res. 16, 1078–1089 (1992).

    CAS  PubMed  Google Scholar 

  71. Pfefferbaum, A., Sullivan, E. V., Mathalon, D. H. & Lim, K. O. Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics. Alcohol. Clin. Exp. Res. 21, 521–529 (1997).

    CAS  PubMed  Google Scholar 

  72. Cardenas, V. A., Studholme, C., Gazdzinski, S., Durazzo, T. C. & Meyerhoff, D. J. Deformation-based morphometry of brain changes in alcohol dependence and abstinence. Neuroimage 34, 879–887 (2007).

    PubMed  Google Scholar 

  73. Pfefferbaum, A. et al. Increase in brain cerebrospinal fluid volume is greater in older than in younger alcoholic patients: a replication study and CT/MRI comparison. Psychiatry Res. 50, 257–274 (1993).

    CAS  PubMed  Google Scholar 

  74. Pfefferbaum, A., Lim, K. O., Desmond, J. E. & Sullivan, E. V. Thinning of the corpus callosum in older alcoholic men: a magnetic resonance imaging study. Alcohol. Clin. Exp. Res. 20, 752–757 (1996).

    CAS  PubMed  Google Scholar 

  75. Estruch, R. et al. Atrophy of the corpus callosum in chronic alcoholism. J. Neurol. Sci. 146, 145–151 (1997).

    CAS  PubMed  Google Scholar 

  76. Sullivan, E. V. et al. Cerebellar volume deficits and neuropsychological function in alcoholics [abstract]. Alcohol. Clin. Exp. Res. 22, 63A (1998).

  77. Agartz, I., Momenan, R., Rawlings, R. R., Kerich, M. J. & Hommer, D. W. Hippocampal volume in patients with alcohol dependence. Arch. Gen. Psychiatry 56, 356–363 (1999).

    CAS  PubMed  Google Scholar 

  78. Sullivan, E. V., Marsh, L., Mathalon, D. H., Lim, K. O. & Pfefferbaum, A. Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcohol. Clin. Exp. Res. 19, 110–122 (1995).

    CAS  PubMed  Google Scholar 

  79. Blansjaar, B., Vielvoye, G., van Dijk, J. & Rijnders, R. Similar brain lesions in alcoholics and Korsakoff patients: MRI, psychometric and clinical findings. Clin. Neurol. Neurosurg. 93, 197–203 (1992).

    Google Scholar 

  80. O'Neill, J., Cardenas, V. A. & Meyerhoff, D. J. Effects of abstinence on the brain: quantitative magnetic resonance imaging and magnetic resonance spectroscopic imaging in chronic alcohol abuse. Alcohol. Clin. Exp. Res. 25, 1673–1682 (2001).

    CAS  PubMed  Google Scholar 

  81. Pfefferbaum, A., Adalsteinsson, E. & Sullivan, E. V. Dysmorphology and microstructural degradation of the corpus callosum: interaction of age and alcoholism. Neurobiol. Aging 27, 994–1009 (2006).

    CAS  PubMed  Google Scholar 

  82. Schroth, G., Naegele, T., Klose, U., Mann, K. & Petersen, D. Reversible brain shrinkage in abstinent alcoholics, measured by MRI. Neuroradiology 30, 385–389 (1988).

    CAS  PubMed  Google Scholar 

  83. Carlen, P. L., Wilkinson, D. A., Wortzman, G. & Holgate, R. Partially reversible cerebral atrophy and functional improvement in recently abstinent alcoholics. Can. J. Neurol. Sci. 11, 441–446 (1984).

    CAS  PubMed  Google Scholar 

  84. Schweinsburg, B. C. et al. Chemical pathology in brain white matter of recently detoxified alcoholics: a 1H magnetic resonance spectroscopy investigation of alcohol-associated frontal lobe injury. Alcohol. Clin. Exp. Res. 25, 924–934 (2001).

    CAS  PubMed  Google Scholar 

  85. Fein, G., Meyerhoff, D. J. & Weiner, M. W. Magnetic resonance spectroscopy of the brain in alcohol abuse. Alcohol Health Res. World 19, 3056–3314 (1995).

    Google Scholar 

  86. Jagannathan, N. R., Desai, N. G. & Raghunathan, P. Brain metabolite changes in alcoholism: An in vivo proton magnetic resonance spectroscopy (MRS) study. Magn. Reson. Imaging 14, 553–557 (1996).

    CAS  PubMed  Google Scholar 

  87. Seitz, D. et al. Localized proton magnetic resonance spectroscopy of the cerebellum in detoxifying alcoholics. Alcohol. Clin. Exp. Res. 2 3, 158–163 (1999).

    Google Scholar 

  88. Durazzo, T. C., Gazdzinski, S., Rothlind, J. C., Banys, P. & Meyerhoff, D. J. Brain metabolite concentrations and neurocognition during short-term recovery from alcohol dependence: preliminary evidence of the effects of concurrent chronic cigarette smoking. Alcohol. Clin. Exp. Res. 30, 539–551 (2006).

    CAS  PubMed  Google Scholar 

  89. Martin, P. R. et al. Brain proton magnetic resonance spectroscopy studies in recently abstinent alcoholics. Alcohol. Clin. Exp. Res. 19, 1078–1082 (1995).

    CAS  PubMed  Google Scholar 

  90. Bartsch, A. J. et al. Manifestations of early brain recovery associated with abstinence from alcoholism. Brain 130, 36–47 (2007).

    PubMed  Google Scholar 

  91. Shear, P. K., Jernigan, T. L. & Butters, N. Volumetric magnetic resonance imaging quantification of longitudinal brain changes in abstinent alcoholics. Alcohol. Clin. Exp. Res. 18, 172–176 (1994).

    CAS  PubMed  Google Scholar 

  92. Pfefferbaum, A. et al. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapsed alcoholics. Alcohol. Clin. Exp. Res. 19, 1177–1191 (1995).

    CAS  PubMed  Google Scholar 

  93. Gazdzinski, S., Durazzo, T. C. & Meyerhoff, D. J. Temporal dynamics and determinants of whole brain tissue volume changes during recovery from alcohol dependence. Drug Alcohol Depend. 78, 263–273 (2005).

    CAS  PubMed  Google Scholar 

  94. Sullivan, E. V. & Marsh, L. Hippocampal volume deficits in alcoholic Korsakoff's syndrome. Neurology 61, 1716–1719 (2003).

    PubMed  Google Scholar 

  95. Kim, E. et al. Mammillothalamic functional connectivity and memory function in Wernicke's encephalopathy. Brain 132, 369–376 (2009).

    PubMed  Google Scholar 

  96. Schulte, T., Sullivan, E. V., Muller-Oehring, E. M., Adalsteinsson, E. & Pfefferbaum, A. Corpus callosal microstructural integrity influences interhemispheric processing: a diffusion tensor imaging study. Cereb. Cortex 15, 1384–1392 (2005).

    CAS  PubMed  Google Scholar 

  97. Pfefferbaum, A., Adalsteinsson, E. & Sullivan, E. V. Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women. Biol. Psychiatry 59, 364–372 (2006).

    PubMed  Google Scholar 

  98. Pfefferbaum, A., Adalsteinsson, E. & Sullivan, E. V. Dysmorphology and microstructural degradation of the corpus callosum: interaction of age and alcoholism. Neurobiol. Aging 27, 994–1009 (2006).

    CAS  PubMed  Google Scholar 

  99. Sullivan, E. V. Compromised pontocerebellar and cerebellothalamocortical systems: speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism. Alcohol. Clin. Exp. Res. 27, 1409–1419 (2003).

    PubMed  Google Scholar 

  100. Leiner, H. C., Leiner, A. L. & Dow, R. S. Cognitive and language functions of the human cerebellum. Trends Neurosci. 16, 444–447 (1993).

    CAS  PubMed  Google Scholar 

  101. Chanraud, S. et al. Diffusion tensor tractography in mesencephalic bundles: relation to mental flexibility in detoxified alcohol-dependent subjects. Neuropsychopharmacology 34, 1223–1232 (2009).

    PubMed  Google Scholar 

  102. Zahr, N. M., Pitel, A. L., Chanraud, S. & Sullivan, E. V. Contributions of studies on alcohol use disorders to undrestanding cerebellar function. Neuropsychol. Rev. 20, 280–289 (2010).

    PubMed  PubMed Central  Google Scholar 

  103. Parks, M. H. et al. Longitudinal brain metabolic characterization of chronic alcoholics with proton magnetic resonance spectroscopy. Alcohol. Clin. Exp. Res. 26, 1368–1380 (2002).

    CAS  PubMed  Google Scholar 

  104. Schmahmann, J. & Sherman, J. The cerebellar cognitive affective syndrome. Brain 121, 561–579 (1998).

    PubMed  Google Scholar 

  105. Meyerhoff, D. J. Brain spectroscopic imaging, morphometry, and cognition in social drinkers and recovering alcoholics. Alcohol. Clin. Exp. Res. 29, 153–154 (2005).

    Google Scholar 

  106. Sullivan, E. V., Rosenbloom, M. J., Lim, K. O. & Pfefferbaum, A. Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: relationships to changes in brain structure. Neuropsychology 14, 178–188 (2000).

    CAS  PubMed  Google Scholar 

  107. Rosenbloom, M. J., Pfefferbaum, A. & Sullivan, E. V. Recovery of short-term memory and psychomotor speed but not postural stability with long-term sobriety in alcoholic women. Neuropsychology 1 8, 589–597 (2004).

    Google Scholar 

  108. Shatz, C. J. MHC class I: an unexpected role in neuronal plasticity. Neuron 64, 40–45 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Luna-Medina, R. et al. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J. Neurosci. 27, 5766–5776 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. He, J. & Crews, F. T. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp. Neurol. 210, 349–358 (2008).

    CAS  PubMed  Google Scholar 

  111. Barres, B. A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430–440 (2008).

    CAS  PubMed  Google Scholar 

  112. Cook, C. C., Hallwood, P. M. & Thomson, A. D. B vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol Alcohol. 33, 317–336 (1998).

    CAS  PubMed  Google Scholar 

  113. Butterworth, R. F., Kril, J. J. & Harper, C. G. Thiamine-dependent enzyme changes in the brains of alcoholics—relationship to the Wernicke–Korsakoff syndrome. Alcohol. Clin. Exp. Res. 17, 1084–1088 (1993).

    CAS  PubMed  Google Scholar 

  114. Morgan, M. Y. Alcohol and nutrition. Br. Med. Bull. 38, 21–29 (1982).

    CAS  PubMed  Google Scholar 

  115. Tallaksen, C. M., Bøhmer, T. & Bell, H. Blood and serum thiamin and thiamin phosphate esters concentrations in patients with alcohol dependence syndrome before and after thiamin treatment. Alcohol. Clin. Exp. Res. 16, 320–325 (1992).

    CAS  PubMed  Google Scholar 

  116. Harper, C., Rodriguez, M., Gold, J. & Perdices, M. The Wernicke–Korsakoff syndrome in Sydney—a prospective necropsy study. Med. J. Aust. 149, 718 (1988).

    CAS  PubMed  Google Scholar 

  117. Blass, J. P. & Gibson, G. E. Abnormality of a thiamine-requiring enzyme in patients with Wernicke–Korsakoff syndrome. N. Engl. J. Med. 297, 1367–1370 (1977).

    CAS  PubMed  Google Scholar 

  118. Mukherjee, A. B. et al. Transketolase abnormality in cultured fibroblasts from familial chronic alcoholic men and their male offspring. J. Clin. Invest. 79, 1039–1043 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Nixon, P. F., Kaczmarek, M. J., Tate, J., Kerr, R. A. & Price, J. An erythrocyte transketolase isoenzyme pattern associated with the Wernicke–Korsakoff syndrome. Eur. J. Clin. Invest. 14, 278–281 (1984).

    CAS  PubMed  Google Scholar 

  120. Coy, J. F. et al. Molecular cloning of tissue-specific transcripts of a transketolase-related gene: implications for the evolution of new vertebrate genes. Genomics 32, 309–316 (1996).

    CAS  PubMed  Google Scholar 

  121. Guerrini, I. et al. Direct genomic PCR sequencing of the high affinity thiamine transporter (SLC19A2) gene identifies three genetic variants in Wernicke Korsakoff syndrome (WKS). Am. J. Med. Genet. B Neuropsychiatr. Genet. 137B, 17–19 (2005).

    PubMed  Google Scholar 

  122. Loh, E. W. et al. Association between variants at the GABAAβ2, GABAAα6 and GABAAγ2 gene cluster and alcohol dependence in a Scottish population. Mol. Psychiatry 4, 539–544 (1999).

    CAS  PubMed  Google Scholar 

  123. Singleton, C. K. & Martin, P. R. Molecular mechanisms of thiamine utilization. Curr. Mol. Med. 1, 197–207 (2001).

    CAS  PubMed  Google Scholar 

  124. Liu, J. et al. Patterns of gene expression in the frontal cortex discriminate alcoholic from nonalcoholic individuals. Neuropsychopharmacology 31, 1574–1582 (2006).

    CAS  PubMed  Google Scholar 

  125. Mayfield, R. D. et al. Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics. J. Neurochem. 81, 802–813 (2002).

    CAS  PubMed  Google Scholar 

  126. Iwamoto, K. et al. Decreased expression of NEFH and PCP4/PEP19 in the prefrontal cortex of alcoholics. Neurosci. Res. 49, 379–385 (2004).

    CAS  PubMed  Google Scholar 

  127. Etheridge, N., Lewohl, J. M., Mayfield, R. D., Harris, R. A. & Dodd, P. R. Synaptic proteome changes in the superior frontal gyrus and occipital cortex of the alcoholic brain. Proteomics Clin. Appl. 3, 730–742 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Sokolov, B. P., Jiang, L., Trivedi, N. S. & Aston, C. Transcription profiling reveals mitochondrial, ubiquitin and signaling systems abnormalities in postmortem brains from subjects with a history of alcohol abuse or dependence. J. Neurosci. Res. 72, 756–767 (2003).

    CAS  PubMed  Google Scholar 

  129. Weimbs, T. & Stoffel, W. Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioester-linked cysteine residues and implications for the membrane topology of PLP. Biochemistry 31, 12289–12296 (1992).

    CAS  PubMed  Google Scholar 

  130. Boison, D. & Stoffel, W. Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. Proc. Natl Acad. Sci. USA 91, 11709–11713 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Lewohl, J. M., Dodd, P. R., Mayfield, R. D. & Harris, R. A. Application of DNA microarrays to study human alcoholism. J. Biomed. Sci. 8, 28–36 (2001).

    CAS  PubMed  Google Scholar 

  132. Matsuda-Matsumoto, H., Iwazaki, T., Kashem, M. A., Harper, C. & Matsumoto, I. Differential protein expression profiles in the hippocampus of human alcoholics. Neurochem. Int. 51, 370–376 (2007).

    CAS  PubMed  Google Scholar 

  133. Alexander-Kaufman, K., Harper, C., Wilce, P. & Matsumoto, I. Cerebellar vermis proteome of chronic alcoholic individuals. Alcohol. Clin. Exp. Res. 31, 1286–1296 (2007).

    CAS  PubMed  Google Scholar 

  134. Alexander-Kaufman, K., Dedova, I., Harper, C. & Matsumoto, I. Proteome analysis of the dorsolateral prefrontal region from healthy individuals. Neurochem. Int. 51, 433–439 (2007).

    CAS  PubMed  Google Scholar 

  135. Alexander-Kaufman, K., James, G., Sheedy, D., Harper, C. & Matsumoto, I. Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study. Mol. Psychiatry 11, 56–65 (2006).

    CAS  PubMed  Google Scholar 

  136. Kashem, M. A., James, G., Harper, C., Wilce, P. & Matsumoto, I. Differential protein expression in the corpus callosum (splenium) of human alcoholics: a proteomics study. Neurochem. Int. 50, 450–459 (2007).

    CAS  PubMed  Google Scholar 

  137. Kashem, M. A., Harper, C. & Matsumoto, I. Differential protein expression in the corpus callosum (genu) of human alcoholics. Neurochem. Int. 53, 1–11 (2008).

    CAS  PubMed  Google Scholar 

  138. Lishman, W. A. Cerebral disorder in alcoholism: syndromes of impairment. Brain 1 04, 1–20 (1981).

    Google Scholar 

  139. Crabbe, J. C. Alcohol and genetics: new models. Am. J. Med. Genet. 114, 969–974 (2002).

    PubMed  Google Scholar 

  140. Chen, Y. C. et al. Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele. Pharmacogenet. Genomics 19, 588–599 (2009).

    CAS  PubMed  Google Scholar 

  141. Enoch, M. A. Genetic and environmental influences on the development of alcoholism: resilience vs. risk. Ann. NY Acad. Sci. 1094, 193–201 (2006).

    PubMed  Google Scholar 

  142. Caspi, A. et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002).

    CAS  PubMed  Google Scholar 

  143. Foley, D. L. et al. Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder. Arch. Gen. Psychiatry 61, 738–744 (2004).

    CAS  PubMed  Google Scholar 

  144. Rangaswamy, M. et al. A functional MRI study of visual oddball: evidence for frontoparietal dysfunction in subjects at risk for alcoholism. Neuroimage 21, 329–339 (2004).

    PubMed  Google Scholar 

  145. Wiers, R. W., Sergeant, J. A. & Gunning, W. B. Psychological mechanisms of enhanced risk of addiction in children of alcoholics: a dual pathway? Acta Paediatr. Suppl. 40 4, 9–13 (1994).

    Google Scholar 

  146. Whipple, S. C. & Noble, E. P. Personality characteristics of alcoholic fathers and their sons. J. Stud. Alcohol 52, 331–337 (1991).

    CAS  PubMed  Google Scholar 

  147. Blum, K. et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J. Psychoactive Drugs 32 (Suppl. i–iv), 1–112 (2000).

    Google Scholar 

  148. Mathalon, D. H., Pfefferbaum, A., Lim, K. O., Rosenbloom, M. J. & Sullivan, E. V. Compounded brain volume deficits in schizophrenia–alcoholism comorbidity. Arch. Gen. Psychiatry 60, 245–252 (2003).

    PubMed  Google Scholar 

  149. Sullivan, E. V. et al. Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia. Arch. Gen. Psychiatry 57, 894–902 (2000).

    CAS  PubMed  Google Scholar 

  150. Krystal, J. H. et al. The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia. Neurotox. Res. 10, 235–252 (2006).

    CAS  PubMed  Google Scholar 

  151. Cargiulo, T. Understanding the health impact of alcohol dependence. Am. J. Health Syst. Pharm. 64, S5–S11 (2007).

    PubMed  Google Scholar 

  152. Ceballos, N. A., Nixon, S. J., Phillips, J. A. & Tivis, R. Semantic processing in alcoholics with and without antisocial symptomatology. J. Stud. Alcohol 64, 286–291 (2003).

    PubMed  Google Scholar 

  153. Grant, B. F. et al. 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, 361–368 (2004).

    PubMed  Google Scholar 

  154. Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch. Gen. Psychiatry 62, 617–627 (2005).

    PubMed  PubMed Central  Google Scholar 

  155. New South Wales Tissue Resource Centre. 'Brain Bank' [online], (2010).

  156. Harper, C. et al. How important are brain banks for alcohol research? Alcohol. Clin. Exp. Res. 27, 310–323 (2003).

    PubMed  Google Scholar 

  157. Pfefferbaum, A., Sullivan, E. V., Adalsteinsson, E., Garrick, T. & Harper, C. Postmortem MR imaging of formalin-fixed human brain. Neuroimage 21, 1585–1595 (2004).

    PubMed  Google Scholar 

  158. Dedova, I. et al. The importance of brain banks for molecular neuropathological research: the New South Wales Tissue Resource Centre experience. Int. J. Mol. Sci. 10, 366–384 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Garrick, T., Azizi, L., Merrick, J. & Harper, C. Brain donation for research, what do people say? Intern. Med. J. 33, 475 (2003).

    CAS  PubMed  Google Scholar 

  160. Glaw, X. M. et al. Brain donation: who and why? Cell Tissue Bank 10, 241–246 (2009).

    PubMed  Google Scholar 

  161. Fein, G. & Landman, B. Treated and treatment-naive alcoholics come from different populations. Alcohol 35, 19–26 (2005).

    PubMed  Google Scholar 

  162. Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003).

    CAS  PubMed  Google Scholar 

  163. Bora, P. S. & Lange, L. G. Molecular mechanism of ethanol metabolism by human brain to fatty acid ethyl esters. Alcohol. Clin. Exp. Res. 1 7, 28–30 (1993).

    Google Scholar 

  164. Coyle, J. T. & Puttfarcken, P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689–695 (1993).

    CAS  PubMed  Google Scholar 

  165. Tsai, G. E. et al. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am. J. Psychiatry 155, 726–732 (1998).

    CAS  PubMed  Google Scholar 

  166. Ikegami, Y. et al. Increased TUNEL positive cells in human alcoholic brains. Neurosci. Lett. 349, 201–205 (2003).

    CAS  PubMed  Google Scholar 

  167. Brooks, P. J. Brain atrophy and neuronal loss in alcoholism: a role for DNA damage? Neurochem. Int. 37, 403–412 (2000).

    CAS  PubMed  Google Scholar 

  168. Climent, E., Pascual, M., Renau-Piqueras, J. & Guerri, C. Ethanol exposure enhances cell death in the developing cerebral cortex: role of brain-derived neurotrophic factor and its signaling pathways. J. Neurosci. Res. 68, 213–225 (2002).

    CAS  PubMed  Google Scholar 

  169. Fadda, F. & Rossetti, Z. L. Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Prog. Neurobiol. 56, 385–431 (1998).

    CAS  PubMed  Google Scholar 

  170. Butterworth, R. F. Hepatic encephalopathy—a serious complication of alcoholic liver disease. Alcohol Res. Health 27, 143–145 (2003).

    PubMed  PubMed Central  Google Scholar 

  171. Felipo, V. & Butterworth, R. F. Neurobiology of ammonia. Prog. Neurobiol. 67, 259–279 (2002).

    CAS  PubMed  Google Scholar 

  172. Zahr, N. M. et al. Glutamate and glutamine changes induced by ethanol treatment in the rat brain detectable at 3T. In Proc. ISMRM 18th Annual Meeting 917 (Stockholm, Sweden, 2010).

    Google Scholar 

  173. Mousseau, D. D., Perney, P., Layrargues, G. P. & Butterworth, R. F. Selective loss of pallidal dopamine D2 receptor density in hepatic encephalopathy. Neurosci. Lett. 162, 192–196 (1993).

    CAS  PubMed  Google Scholar 

  174. Donaldson, J., LaBella, F. S. & Gesser, D. Enhanced autoxidation of dopamine as a possible basis of manganese neurotoxicity. Neurotoxicology 2, 53–64 (1981).

    CAS  PubMed  Google Scholar 

  175. Niemela, O. et al. Antibodies against acetaldehyde-modified protein epitopes in human alcoholics. Hepatology 7, 1210–1214 (1987).

    CAS  PubMed  Google Scholar 

  176. Albano, E. Alcohol, oxidative stress and free radical damage. Proc. Nutr. Soc. 65, 278–290 (2006).

    CAS  PubMed  Google Scholar 

  177. Yokoyama, H. et al. Experimental hepatitis induced by ethanol after immunization with acetaldehyde adducts. Hepatology 1 7, 14–19 (1993).

    Google Scholar 

  178. Horner, M., Behrens, U. J., Worner, T. & Lieber, C. S. Humoral immune response to acetaldehyde adducts in alcoholic patients. Res. Comm. Chem. Pathol. Pharmacol. 54, 3–12 (1996).

    Google Scholar 

  179. Qin, L. et al. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J. Neuroinflammation 5, 10 (2008).

    PubMed  PubMed Central  Google Scholar 

  180. Crews, F. T. & Nixon, K. Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol. 44, 115–127 (2009).

  181. Phillips, S. C. Cytoprotective value of lysine, penicillamine, and pyridoxal phosphate against the neurotoxicity of acetaldehyde. Toxicol. Appl. Pharmacol. 98, 553–560 (1989).

    CAS  PubMed  Google Scholar 

  182. Butterworth, R. F. Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease. Metab. Brain Dis. 10, 1–8 (1995).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank E. V. Sullivan for her invaluable support and advice in preparing this Review. The authors would also like to thank A. Pfefferbaum for contributing the illustrations.

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The authors all contributed to researching data for the article, discussion of content and writing. N. M. Zahr reviewed the manuscript before submission.

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Correspondence to Clive G. Harper.

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Zahr, N., Kaufman, K. & Harper, C. Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol 7, 284–294 (2011). https://doi.org/10.1038/nrneurol.2011.42

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