Effects of alcoholism on family Effects of alcoholism on the brain Effects of alcoholism on family members Effects of alcoholism on the brain and body Effects of alcoholism on relationships Effects of alcoholism on marriage Effects of alcoholism on body E. Evidence for a Gender-Related Effect of Alcoholism on Brain Volumes, American Journal of Psychiatry

When we adjusted brain volumes for intracranial volume, it was possible to include all four groups in a single analysis. The results are shown in Table 4. All of the brain ratios, except for ventricular volume/(intracranial volume–ventricular volume), differed significantly between alcoholics and comparison subjects (ANOVA, main effect for diagnosis). The alcoholics had a larger proportion of their intracranial volume occupied by CSF than the comparison subjects and had a smaller proportion of intracranial gray and white matter than comparison subjects. Effects of alcoholism.

There was a significant interaction between diagnosis and gender in the analysis of gray matter ratio. Simple contrast tests within genders between alcoholics and nonalcoholics indicated that the difference between the groups was due to alcoholic women having a smaller proportion of gray matter than nonalcoholic women ( Table 4 ). In contrast, alcoholic men had only a slightly smaller ratio of gray matter to remainder of intracranial volume than nonalcoholic men ( Table 4 ).

There were no significant interactions between gender and diagnosis for CSF or white matter ratios. However, there was a significant interaction between diagnosis and gender in the analysis of ventricular ratios. Simple contrast tests indicated that this interaction was due to the alcoholic women having larger ventricular ratios than the nonalcoholic women ( Table 4 ).

The only difference in the ratios between women and men, irrespective of diagnosis, was in the proportion of intracranial volume contents occupied by white matter ( Table 4 ). Women had proportionally less white matter than men. Adjusting for years of education by ANCOVA did not change any of the results. Comparisons between alcoholics who were cigarette smokers and alcoholics who were not smokers revealed no significant differences in brain volume ratios; comparisons between alcoholics with or without a family history of alcoholism also revealed no significant differences. Alcoholics with or without other axis I disorders did not differ in brain volume ratios.

Our results confirm earlier studies showing smaller gray and white matter brain volume among alcoholic men compared with nonalcoholic men (4, 5). In addition, we provide the first evidence, to our knowledge, that alcoholic women have smaller gray and white matter volumes and greater CSF volumes than healthy nonalcoholic women, and that the brain volume differences between alcoholic and nonalcoholic women, particularly in gray matter, are considerably larger than those found between alcoholic and nonalcoholic men. These differences occur despite the fact that the alcoholic women reported fewer years of heavy drinking than the alcoholic men. Our results are consistent with reports that women develop hepatic (2) and cardiac (3) complications of alcoholism earlier in the course of the disease than men do.

One interpretation of these results is that women are more sensitive to brain damage caused by alcoholism than men are. However, this is not the only possible interpretation. Other factors could be involved. It is possible that poor nutrition could lead to differences in brain volume. However, we found no evidence of nutritional differences between the alcoholic men and women. It is also possible that the duration of the interval between last drink and imaging could affect brain volumes. The gray matter volume of alcoholics increases during the first month of abstinence (16). However, in our study, the male and female alcoholic subjects had similar durations of abstinence, making it unlikely that recovery of cortical volume with abstinence could account for the gender differences we observed.

Diseases associated with alcoholism could reduce brain volume, but it is unlikely that this played a role in the differences we observed because medically and neurologically healthy alcoholics were studied. Although we excluded subjects with a history of head injury requiring hospitalization, it is possible that alcoholics experience more frequent minor head trauma not resulting in loss of consciousness or hospitalization than nonalcoholics. It is not known if minor head injuries that do not come to medical attention reduce brain volume or if alcoholic women are more likely to suffer from minor head injury than alcoholic men.

Effects of alcoholism on family Effects of alcoholism on the brain Effects of alcoholism on family members Effects of alcoholism on the brain and body Effects of alcoholism on relationships Effects of alcoholism on marriage Effects of alcoholism on body E

Although we can exclude or at least mitigate many factors other than alcohol consumption as possible causes for the differences in brain volumes we observed, we cannot exclude the possibility that alcoholics, particularly alcoholic women, have smaller brain volumes than nonalcoholics before the onset of alcoholism. Most investigators have assumed that the differences in brain volume between alcoholics and nonalcoholics are caused by the cumulative effects of alcohol neurotoxicity. However, there is little direct evidence for a cumulative dose effect of alcohol on brain volume. Most studies of alcoholics, including ours, have failed to show that lifetime alcohol consumption predicts brain volume (5, 17, 18). This failure may be due to an inherent inaccuracy in self-report of alcohol consumption.

Cross-sectional studies, like this study and earlier studies, are not ideal for detecting cumulative neurotoxic effects. Unfortunately, longitudinal studies of brain volume loss in alcoholism have been rare. In 1998, Pfefferbaum and co-workers (19) examined brain volume loss in 16 alcoholic men over a period of 5 years and found that the rate of gray matter volume loss was predicted by estimated alcohol consumption over the interval. This study suggests that there may be a dose-effect relationship between alcohol consumption and reduction in brain volume. However, the results of Pfefferbaum et al. need to be confirmed with larger study groups that include both men and women as well as younger alcoholics.

Given our uncertainty regarding the causes of smaller brains among alcoholics, it is prudent to consider explanations for both why alcoholic women might be more sensitive to alcohol-induced brain damage and why they might have smaller brains even before alcohol exposure. Women may develop organ damage earlier in the course of alcoholism than men because they achieve higher blood alcohol concentrations for a given dose of alcohol. Smaller body size, lower proportion of total body water (20), and lower concentrations of alcohol dehydrogenase in the lining of the gut (21) all lead to higher blood alcohol concentrations per standard alcohol-containing drink in women than in men. The alcoholic women in our study group reported fewer years of heavy drinking than the alcoholic men. However, their estimates of total lifetime alcohol consumption, although lower, were not significantly lower than the men’s estimates. Furthermore, alcoholic men and women reported drinking virtually identical amounts of alcohol during the 6 months preceding admission, suggesting that during this period the alcoholic women may have achieved higher blood alcohol concentrations on each day they drank than the men did.

Animal studies (22) suggest that alcohol may exert a toxic effect only after the blood alcohol concentration exceeds a certain threshold. Individual genetic, metabolic, dietary, and other biological factors may all influence this threshold. A threshold model would predict that, as a group, women would show greater alcohol-induced brain damage than men because women would be likely to exceed any blood alcohol concentration threshold more often than men. In addition to an individual blood alcohol concentration threshold for toxicity, gender, independent of its effects on blood alcohol concentration, must be considered as well. Even when blood alcohol concentration is controlled, female rats develop more severe alcohol-induced liver injury than male rats (23). Gender-based hormonal differences may affect the threshold for alcohol toxicity or act to modify the brain’s response to alcohol and its metabolites.

Although the evidence for alcohol neurotoxicity as the cause of gender differences in brain volume among alcoholics is not conclusive, it is stronger than the evidence for pre-alcoholism differences. No studies have examined the brain volumes of children at risk for alcoholism before they begin drinking, and no longitudinal imaging studies of individuals at risk for alcoholism have been conducted. Although there is no direct evidence of smaller brain volumes among individuals at risk for alcoholism, there is evidence that emotional trauma during childhood is associated with smaller intracranial volume and brain volume (24). Since alcoholic women report a higher rate of emotional trauma during childhood than alcoholic men (25), it is possible that this could contribute to differences in pre-alcoholism brain volume. However, we have found that the presence or absence of posttraumatic stress disorder does not influence hippocampal volume among alcoholic women (26). Further studies are needed to understand the effects of emotional trauma on the developing brain and the adult brain. Genetic influences also may affect pre-alcoholism brain volume.

Despite our inability to specify the causes of smaller brain volume among alcoholics, our results support two conclusions. First, alcoholic women have proportionally smaller brains after fewer years of heavy drinking than alcoholic men. Second, a smaller brain volume is present among alcoholic women by early in the fourth decade of life. Although the alcoholics in our study did not show clinically apparent cognitive dysfunction, more sensitive testing may have revealed impairment (27). The effects of significant brain volume reduction in early middle age on future cognitive ability are unknown. Likewise, the impact of brain volume reduction on the ability to maintain sobriety is also unknown.

Effects of alcoholism on family Effects of alcoholism on the brain Effects of alcoholism on family members Effects of alcoholism on the brain and body Effects of alcoholism on relationships Effects of alcoholism on marriage Effects of alcoholism on body E

Received Oct. 19, 1999; revision received Feb. 25, 2000; accepted March 24, 2000. From the Section on Electrophysiology and Brain Imaging, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. Address reprint requests to Dr. Hommer, NIAAA, NIH, Rm. 3C103, 10 Center Dr., MSC 1256, Bethesda, MD 20892-1256; danh@lcs.niaaa.nih.gov (e-mail). Funded by the Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism. The authors thank Michael Kerich for computer system management and programming, Elizabeth Israel for database management, and Mary Dufour, M.D., for her comments on an earlier version of this article. They also thank the nursing and social work staff of the Alcohol Treatment Unit of the NIH Clinical Center.

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