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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010583-02
Application #
2457483
Study Section
Special Emphasis Panel (ZRG4-ALTX-3)
Project Start
1996-08-01
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Parks, Mitchell H; Morgan, Victoria L; Pickens, David R et al. (2003) Brain fMRI activation associated with self-paced finger tapping in chronic alcohol-dependent patients. Alcohol Clin Exp Res 27:704-11
Parks, Mitchell H; Dawant, Benoit M; Riddle, William R et al. (2002) Longitudinal brain metabolic characterization of chronic alcoholics with proton magnetic resonance spectroscopy. Alcohol Clin Exp Res 26:1368-80
Dawant, B M; Hartmann, S L; Pan, Shiyan et al. (2002) Brain atlas deformation in the presence of small and large space-occupying tumors. Comput Aided Surg 7:1-10
Singleton, C K; Martin, P R (2001) Molecular mechanisms of thiamine utilization. Curr Mol Med 1:197-207
Hartmann, S L; Parks, M H; Martin, P R et al. (1999) Automatic 3-D segmentation of internal structures of the head in MR images using a combination of similarity and free-form transformations: Part II, validation on severely atrophied brains. IEEE Trans Med Imaging 18:917-26
Hartmann, S L; Dawant, B M; Parks, M H et al. (1998) Image-guided MR spectroscopy volume of interest localization for longitudinal studies. Comput Med Imaging Graph 22:453-61