It has long been known that alcoholism is associated with both brain and liver damage. We recruited 124 patients with alcohol dependence and 111 healthy control subjects and measured both hepatic and brain markers pf injury. Gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as hematocrit (Hct) and Albumin were assayed shortly after admission. MRI examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. The patients with alcohol dependence had lower brain volume (BV), and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), and brain ratio (BR) and higher CSF ratio (CSFR) compared to their healthy counterparts. Age and sex were significantly correlated with some brain volume measurements in both patient and control groups. Body mass index (BMI), Hct and serum GGT level were significantly correlated with some brain volume indices in the patient group. No biological variables were correlated with brain volume indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients, but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female pati====nts were significantly correlated with brain shrinkage. Our results showed that liver function was correlated with brain volume shrinkage in patients with alcohol dependence, but not in controls. Especially, serum GGT level outweighed aging effect on brain shrinkage in female patients(1). We have completed specific investigations of frontal lobe volume in alcoholics and controls. Alcoholics appear to have smaller frontal lobe volumes than controls. This reduction in frontal volume is restricted to the mesial surface of the right frontal lobe. We have also found that among healthy subjects that the tendency to devalue delayed rewards (delay discounting), which is considered an excellent laboratory measure of impulsivity, is associated with shrinkage of the lateral surface of the frontal lobes. The lateral frontal lobe is the same region that has been shown to be activated during delayed discounting tasks during functional imaging. Thus our results are consistent with the functional neuroanatomy of human impulsivity and may be important in understanding brain differences associated with risk for the development of substance abuse. We have used voxel-based morphometry (VBM) to confirm the reductions in frontal lobe volume we have observed among alcoholics. To do this we are performing two independent analyses. One involves the use of VBM as implemented in FSL software to measure gray matter volume. The other uses measurements of cortical thickness implemented in both FSL and AFNI. These automated results confirm our previous purely volume-based results that most of the brain damage among alcoholics is present in the frontal lobes. In addition, the cortical thickness analysis reveals a region of decreased cortical thickness in the insular cortex of alcoholics (Steckler et.al., in press). Alcoholism is often associated with impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric MRI to compare different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs). Caucasian men (n =54), ages 24-55, who had participated in National Institutes of Alcohol Abuse and Alcoholism treatment programs, were grouped together as IPV-ADs (n=27), non-violent ADs (n=14) and HCs (n=13). The MRI scan was performed at least 3 weeks from the participant's last alcohol use. T1-weighted images were used to measure the volumes of intracranial space, gray and white matter, orbitofrontal cortex, medial prefrontal cortex, lateral prefrontal cortex, and six subcortical structures. Results revealed that IPV-ADs, compared with non-violent ADs and HCs, had a significant volume reduction in the right amygdala. No significant volumetric difference was found in other structures. This finding suggests that structural deficits in the right amygdala may underlie impulsive types of aggression often seen in alcohol-dependent patients with a history of IPV. It adds to a growing literature suggesting that there are fundamental differences between alcohol-dependent patients with and without IPV (2). We have used the PET methods of racloride displacement to investigate the genetics of dopamine release induced by intravenous alcohol administration. We found that a functional polymorphism of a gene coding for a type of brain opiate receptor (OPRM1 A118G) is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and (11)C-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. Carries of the more common allele of OPRM1 did not show measurable dopamine release following intravenous alcohol. These results are consistent with the idea that the 118G allele of the human opiate receptor may be a risk factor for the development of alcoholism or a marker for the utility of opiate receptor blockade as a treatment for alcoholism (3). In collaboration with Dr. Ramchandanis section we have examined the effects of alcohol on Growth hormone (GH)-insulin-like growth factor-1 (IGF-1). This study examined the effects of intravenous alcohol on the GH-IGF-1 axis and gonadal hormone concentrations, and the influence of age and sex on their regulation. Acute intravenous infusion of alcohol resulted in changes in gonadal hormones that differed by sex. Change in free testosterone showed a significant treatment baseline interaction (p <0.001), indicating that alcohol-induced suppression of testosterone occurred predominantly in men. On the other hand, change in estradiol showed a significant treatment sex interaction (p = 0.028), indicating that alcohol-induced increases in estradiol occurred predominantly in women. There was a trend for alcohol-induced decreases in IGF-1 levels. Change in GH showed a significant main effect of baseline (p <0.001) and a trend for treatment by baseline interaction, suggesting an alcohol-induced decrease in individuals with high baseline GH values. There was also a significant main effect of sex (p = 0.046) indicating that men had greater changes in GH across treatment compared with women. Alcohol appears to induced a complex pattern of hormonal responses that varies between younger and older men and women. Some of the observed sex-based differences may help improve our understanding of the greater susceptibility to alcohol-related hepatic damage seen in women (4).

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2012
Total Cost
$1,008,738
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
Zip Code
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