Although the brain pathology observed in alcoholism is often referred to as the result of the neurotoxic effects of alcohol, it is not clear to what extent alcohol alone is responsible. The marked variability in neuropathology among alcoholics, even with similar consumption histories, suggests the likelihood is high that factors in addition t excessive alcohol consumption (e.g., dietary deficiency and hematopoietic effects, age at exposure, genetic factors) are determinants of alcoholic brain pathology. With the ability to investigate humans and animal models with common metrics, neuroimaging is a unique in vivo translational approach for examining the enduring effects of alcohol and other factors on the brain. Human studies are hampered by the inability to observe individuals prior to alcohol exposure, precluding knowledge of the brain's premorbid state. Thus, animal models of excessive alcohol exposure enable control over factors uncontrollable in humans. In human alcoholics, we have demonstrated the influence of signs of past occult thiamine deficiency on cognitive status despite lack of relation between current thiamine status and brain structure. By contrast, there is a relation between brain status and indices of macrocytosis in humans with a history of alcohol dependence. In rats, the inferior collicullus (IC) is affected by thiamine deficiency more consistently than other structures, perhaps because of its high capillary density and glucose utilization. The proposed studies are aimed at elucidating factors in addition to alcohol per se that contribute to chronic alcoholic brain damage. The animal studies have led us to propose that deficits in the structural and white matter connectivity integrity of the IC may be an historical marker of past occult thiamine deficiency in humans. The animal studies will test the necessity of achieving alcohol dependence to produce enduring neuropathology with alcohol alone, determine the contribution of advanced age on susceptibility to alcohol damage, and determine if production of macrocytosis is necessary to produce enduring brain compromise in the rat model.
The specific aims are: 1a) In a rat model, determine the necessity for dependence to produce enduring MRI-detectable brain structural and MRS-detectable biochemical changes with chronic intermittent exposure. 1b) Determine the necessity for advanced age, equivalent to human 40+ years old, to produce enduring brain structural and biochemical changes with chronic intermittent exposure. 1c) Determine the necessity for producing macrocytosis to produce enduring brain structural and biochemical changes with chronic intermittent exposure. 2a) In human study, use structural and fiber tracking neuroimaging to assess the integrity of the inferior colliculus, mammillary bodies and the limbic system 2b) Investigate the role of thiamine transporter genotype variants on brain structure and function
The marked variability in the location and extent of brain damage among alcoholics, even with similar consumption histories, suggests that factors in addition to excessive alcohol consumption (e.g., dietary deficiency, age at exposure, genetic factors) are determinants in the development of alcoholic brain pathology. The proposed studies in human alcoholics and a rat model are aimed at elucidating factors, in addition to alcohol per se, that contribute to chronic 'alcoholic brain damage' and related functional impairment and that could be remedied with therapeutic intervention.
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