Chronic alcohol depended patients have a significant reduction in brain volume and concomitant neurobehavioral deficits which may recover during abstinence. However, the pathophysiology of these well-documented findings remains to be elucidated. Using proton magnetic resonance spectroscopy [MRS], which allows noninvasive quantitation in vivo of brain metabolites within anatomically localized volumes of interest [VOI], we have found an increase with duration of abstinence in the concentration of MR visible choline [Cho]- containing compounds relative to the neuronal marker, n-acetylaspartate [NAA], within the midline cerebellum of alcoholic patients. Our preliminary data suggest that the ratio Cho/NAA may be related to clinical variables, particularly to the severity of brain dysfunction. We propose to characterize the longitudinal course of these metabolic changes in regions of the brain recognized to be sensitive to alcohol-induced damage (cerebellar vermis, frontal cortex, and frontal white matter). Alcohol dependent patients will be studied using proton MRS when signs of acute alcohol withdrawal have abated (within 3 to 5 days of their last consumption of alcohol), after 3 weeks of inpatient monitored abstinence, and 9 weeks after discharge from hospital. High resolution MR images will be acquired concurrently to determine the contributions to the intracranial volume of gray matter, white matter, and cerebrospinal fluid, the volume of the cerebellum, and the tissue composition of each VOI. Also, cognitive (attention, psychomotor speed, and memory) and cerebellar (postural sway) functions will be evaluated. Healthy controls will also be studied at the same time intervals as the alcoholics to account for potential MRS/MRI repositioning error and learning effects of neurobehavioral testing. After 3 weeks of monitored abstinence, a comprehensive neuropsychological test battery will be administered to determine whether patients have enduring, clinically meaningful cognitive dysfunction. The longitudinal progression and interrelationships among metabolic characteristics of brain VOIs, volumetric changes, cognitive/cerebellar functions, and relevant clinical variables will be analyzed. If our hypotheses are confirmed, it would implicate white matter injury in the pathophysiology of alcohol-induced brain damage, and an increase in Cho-containing compounds in the recovery of CNS functions observed with abstinence. In the future, it may be possible to chemically identify the exact compounds involved by in vitro studies using autopsied human brain tissue or using available preclinical animal models, with significant implica-tions for prevention, differential diagnosis, and treatment of organic mental disorders associated with alcoholism.
