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- Materials and Methods
Background: We previously demonstrated, in a small sample, steeper age-related gray matter shrinkage in treatment naïve alcohol-dependent (TxN) men compared to nonalcoholic controls, but could not separate out the contributions of age and lifetime duration of alcohol use (which were highly correlated) to this effect. In the current study, we have quadrupled the sample size and expanded it to include both men and women to try to replicate and extend the previous findings and to separate the contributions of age and alcohol use to the phenomenon.
Methods: In the current study, we examine cortical gray matter volumes in 18- to 50-year-old TxN (n = 84) versus age and gender comparable controls (n = 67). We used a new Region of Interest Analysis method which accounts for differences in sulcal and gyral enfolding between individuals (Fein et al., 2009a).
Results: We found greater age-related gray matter shrinkage in TxN than in controls. Partial correlation analysis showed that the effect was a function of age and not lifetime alcohol burden.
Conclusions: Implications of the findings are discussed in terms of their contribution toward our knowledge of differences between different subpopulations of alcoholics and in terms of their implications for the morbidity of alcohol dependence in an aging national population.
There is an ever-growing body of evidence documenting the adverse effects of alcohol dependence on the brain. Structural magnetic resonance imaging has revealed an association between alcohol dependence and cortical gray matter shrinkage (Sachdev et al., 2008), and hazardous drinking alone has been shown to damage the brain (Garcia-Valdecasas-Campelo et al., 2007; Jernigan et al., 1991; Kril et al., 1997; Paul et al., 2008). Most studies on the effects of alcohol dependence on brain structure have used treated samples, leading to a bias known as Berkson’s Fallacy (Berkson, 1946, 1955), which arises when the association between variables, such as alcoholism and brain morphology, differs between the sample studied (i.e., treated alcoholics) and the population to which the results are generalized (all alcoholics).
Many previous studies on brain structure in alcohol-dependent individuals agree on finding smaller gray matter volumes in areas of the cerebral cortex, although the localities of these reductions occasionally disagree. In an early MRI study, Jernigan and colleagues (1991) found cerebral gray matter reductions in the frontal, parietal, and mesial temporal lobes of treated alcoholics. Other more recent studies on treated alcoholics have found reductions within the dorsolateral prefrontal cortex and insula (Makris et al., 2008), the precentral gyrus, middle central gyrus, and insula (Mechtcheriakov et al., 2007), and the lateral cortices (Shear et al., 1992). In a recent analysis of middle-aged long-term abstinent alcoholics, we found reduced gray matter volumes in the parietal and occipital lobes (Fein et al., 2009a).
The fact that the majority of the publications on alcohol research are based on a disproportionately large sampling of the treated subset of alcoholics must be considered when extending conclusions to the general alcoholic population. In contrast to treated alcoholics, untreated alcoholics comprise the majority of alcohol-dependent individuals in the United States. According to the 2001 to 2002 National Epidemiologic Survey of Alcoholism and Related Conditions (NESARC), of the 4,422 respondents who met criteria for prior-to-past-year alcohol dependence, only 25.5% reported ever having received treatment (Dawson et al., 2005). In addition to being a majority of the alcohol-dependent population, treatment naive alcoholics have less severe alcoholism (Fein and Landman, 2005), less severe comorbid psychiatric illness (Di Sclafani et al., 2008), evidence less impaired performance on decision-making tasks, and do not suffer from the full extent of the tissue loss seen in treated alcoholics (Gazdzinski et al., 2008). In light of this evidence, generalizing results from studies on treated samples, which comprise the bulk of the current literature, to the general alcohol-dependent population may not be valid.
The relatively few studies done on untreated alcohol-dependent individuals have yielded mixed results. Our 2002 study comparing treatment-naïve alcoholics (N = 24) and light drinkers (N = 17) found no significant group differences in cortical gray matter volumes (Fein et al., 2002), but did find stronger relationship between age and overall cortical gray matter shrinkage in the alcohol-dependent group. In a study by Cardenas and colleagues (2005), actively drinking untreated alcohol-dependent individuals (N = 49) presented with significantly lower gray matter volumes than light drinkers (N = 49) in all lobes except the frontal lobe. In a comparison of treated and untreated alcohol-dependent individuals versus controls, Gazdzinski and colleagues (2008) found numerically but not significantly lower gray matter volumes in the untreated group compared with controls, whereas those in the treated sample had more shrinkage in the frontal, occipital, parietal, and temporal lobes than the untreated sample.
A potential confounding factor in alcohol research is normal age-related brain shrinkage accompanied by declines in mental abilities. It is widely accepted that brain volume is lost in normal aging, and the total lifetime alcohol consumption often correlates with age due to longer periods of drinking. While the cumulative effects of long periods of drinking may be difficult to separate from the normal atrophic effects of age, the effects of extended periods of heavy drinking have been shown to independently contribute to brain volume declines. Early CT- and MRI-based studies by Pfefferbaum and colleagues (1992, 1993) reported that the rate of age-related brain tissue loss, measured by decreases in gray matter and white matter or increases in cerebrospinal fluid, is larger in older alcoholics than in younger alcoholics compared with controls. A later study by the same group found that alcoholics ranging in age from 45 to 63 years had significant gray and white matter deficits compared with age-matched controls, and significantly more volume loss in the prefrontal cortex compared to younger alcoholics between 26 and 44 years old (Pfefferbaum et al., 1997). The presence of the age-related differences despite the lack of group differences in disease duration and total estimated lifetime alcohol consumption in the cohort studied led Pfefferbaum and colleagues to the conclusion that the accelerated age-related brain volume declines in older alcoholics was due to the increased vulnerability of the aging brain rather than a cumulative effect of alcohol consumed.
The purpose of the current study was to assess volumetric differences in the cerebral cortex of treatment-naïve alcoholics (TxN) compared to light- or nondrinking nonalcoholic controls using structural MRI. Our previous study on a separate sample of TxN men found greater age-related volume reductions in TxN than in controls. There was a strong inverse association between brain size and lifetime duration of alcohol use, but because the duration of alcohol use was highly correlated with age, these measures were highly confounded in this sample (n = 24), and could not be disentangled. Moreover, we did not find any associations between regional cortical gray matter volumes with total or average lifetime alcohol consumption, supporting our previous assertion that treated and untreated alcoholics come from different populations. With the larger sample size of the current study (NTxN = 84, Ncontrols = 67), we hoped to further explore the relationship between age and cortical gray matter volumes in both male and female alcoholics versus controls, and to have power to separate the contributions of age and alcohol use measures to this association.
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- Materials and Methods
The major finding of this study is the presence of greater than normal age-related cortical gray matter volume reduction in TxN that is independent of lifetime alcohol consumption (average and total). In contrast, the effect of lifetime alcohol consumption on brain shrinkage was the result of its high correlation with age. These results are consistent with a synergistic effect of heavy alcohol use and aging on gray matter shrinkage in TxN. In our previous study on treated long-term abstinent alcoholics (LTAA, on average 10 to 15 years older than the current study) (Fein et al., 2009a), we noticed separate and additive effects of alcohol dependence and aging on localized gray matter shrinkage. It is impossible to say whether the difference in findings between the 2 studies is the result of the greater age of the LTAA cohort, their longer period of alcohol dependence, or their greater severity of alcohol dependence (Fein and Landman, 2005) and comorbid psychiatric disorders (Di Sclafani et al., 2008) than TxN in the current study. We are now gathering data on a TxN sample of comparable age to the LTAA sample.
The fact that we did not find any significant overall or regional gray matter reductions in the alcohol-dependent sample replicates the result from our previous study (Fein et al., 2002), supporting the hypothesis that the neurological effects on nontreatment seeking alcohol-dependent individuals are less severe than in those who seek treatment. Similarly, we did not find any significant associations within the TxN between average lifetime alcohol dose and cranium size-adjusted cortical gray matter volumes. However, unlike the previous study, we were able to determine that the accelerated decrease in cortical gray matter volume within the TxN was a function of age that was independent of any alcohol consumption measures.
Despite the lack of highly controlled studies on the mechanisms of aging-related brain shrinkage, a number of hypotheses for this phenomenon have been proposed. One is that cerebrovascular changes can contribute to the natural aging of the brain. Decreases in the growth of new capillaries and cerebrovascular blood flow have been known to occur in old age (Sonntag et al., 2007), and evidence suggests that prolonged exposure to glucocorticoids, a hormone released in response to stress, has a negative impact on brain function and may contribute to the age-related decline in brain function (Goosens and Sapolsky, 2007). Calcium ions (Ca2+) have also been associated with neurodegeneration and accelerated aging of the brain. Homeostatic intracellular Ca2+ systems, which are responsible for important transducing processes, have been shown to regulate neuronal death through the process of excitotoxicity (Olney and Ho, 1970), and tend to show dysfunction with increasing age (Toescu, 2007). Finally, oxidative stress (associated with free radical metabolism and inflammation) is thought to play a role in the overall decline of the central nervous system over time.
Alcohol abuse and withdrawal has been found to be associated with elevated glucocorticoid levels in mice and rats (Little et al., 2008) as well as increased oxidative stress in humans (Huang et al., 2009; Lecomte et al., 1994; Peng et al., 2005). Although our data do not provide the information necessary to pinpoint the mechanism responsible for the accelerated age-related decline of the brain in the TxN, it is likely that the heavy drinking in the TxN subjects influenced the concentrations of the neurodegenerative or neuroprotective substrates involved in the associated aging pathway or pathways. However, the fact that we did not see significant effects for cumulative alcohol exposure or average alcohol dose during periods of drinking indicates that the increasing vulnerability of the aging brain to these pathways is a significant reason for this pattern of gray matter volume loss.
Within the white matter, we found no group differences in WMSH severity, in contrast to our finding of increased WMSH in LTAA (Fein et al., 2009b). The absence of any significant group differences in either periventricular or deep WMSH volumes is not surprising, due to the relatively young age of our sample (on average over a decade younger than the sample in our study of long-term abstinent alcoholics). Although age is the most important predictor of WMSH load, appreciable amounts of WMSH are not usually found in individuals under 40 (Awad et al., 1986).
On average, TxN had slightly larger craniums than controls, indicating that TxN may have enjoyed a slightly higher brain reserve capacity than our sample of controls. This is opposite to the finding of reduced intracranial vault size (i.e., cranium size) in early-onset-treated alcoholics (Gilman et al., 2007). Our results are suggestive of a selection bias in TxN toward individuals with higher brain (and cognitive) reserve capacity. These results demonstrate the importance of examining selection bias indicators in complex and demanding studies. This selection bias, if real (note that it was only a trend in the analyses presented here), would attenuate any cognitive effects of alcohol dependence in the TxN sample.
A limitation of this study is that we did not measure tobacco smoking in our samples. There is evidence that smoking is highly associated with white matter damage, and that between 80 and 95% of alcoholics smoke cigarettes (Patten et al., 1996), 3 times higher than among the population as whole. Cigarette smoking is thought to be associated with increased WMSH burden, an indicator of white matter damage, independent of hypertension (Fukuda and Kitani, 1996). Gazdzinski and colleagues (2005) found preliminary evidence that comorbid cigarette smoking in alcoholics accounts for some of the cortical gray matter loss. Moreover, Mon and colleagues (2009) found that cerebral perfusion improved in nonsmoking recovering alcoholics, while this improvement was hindered in alcohol abstainers who continued to smoke.
In conclusion, we found a synergistic effect of alcohol dependence and aging on gray matter shrinkage, implying that the shrinkage will get worse as the TxN sample ages. This has potential important public health consequences, portending increasing brain morbidity of alcoholics as individuals age. Our results in the current study and in our study of elderly LTAA also point out the presence of selection bias in studies of clinical samples of alcoholics, and suggest that such selection bias will make it very difficult to measure the phenomena of increased brain morbidity of alcohol dependence in elderly cohorts. These issues are exacerbated when other neurodegenerative diseases associated with aging (e.g., Alzheimer’s disease, cerebrovascular disease, etc.) add their morbidity to the aging cohort. Nonetheless, the possibility of increased brain morbidity of alcohol dependence in elderly cohorts is a very important area of study, with increasing public health implications as the population of the country ages, and underlines the importance of developing creative and innovative sampling plans to study this phenomenon.