Kristina Bayerlein

Evidence of Increased Homocysteine Levels in Alcoholism: The Franconian Alcoholism Research Studies (FARS)

BACKGROUND A limited number of investigations have studied clearly defined patients with alcoholism and blood alcohol concentrations with their correlation to plasma homocysteine values and differentiated actively drinking patients from those with early abstinence. Therefore, this power analysis-based study was undertaken to determine whether plasma homocysteine levels are evidently altered in actively drinking alcoholic patients and patients with early abstinence. METHODS Two groups of patients with an established diagnosis of alcohol dependence. For both groups, a power of 90% (alpha = 0.05) was applied. Group A comprised 144 consecutively admitted actively drinking patients with alcoholism. Group B consisted of 56 patients with alcoholism who had abstained from alcohol for 24 to 72 hr before admission to the hospital. RESULTS Plasma homocysteine levels were significantly (t test: df = 198, t = -8.6, p < 0.0001) higher at admission when comparing group A with group B. The highly increased homocysteine levels in actively drinking patients with alcoholism were based on a strong significant positive correlation with the blood alcohol concentration (multiple regression analysis, p < 0.0001). CONCLUSIONS Plasma homocysteine levels are evidently altered in actively drinking patients with alcoholism. Even though it has been described, the authors found no evidence for an increase of homocysteine levels in alcoholic patients with early abstinence. The current results emphasize the proposed pathogenetic role of increased plasma homocysteine levels in alcohol-related disorders (i.e., brain atrophy, alcohol withdrawal seizures).

Elevated alpha synuclein mRNA levels are associated with craving in patients with alcoholism.

BACKGROUND Alpha synuclein has been found elevated in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. METHODS The alpha synuclein mRNA expression level was measured by quantitative polymerase chain reaction in the blood of 75 male alcoholics and 69 nondrinking healthy control subjects. Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale total score, including subscales for obsessive and compulsive craving. RESULTS The alpha synuclein expression in patients with alcoholism (2.79 DeltaCT; SD = 1.69; p = .021) was significantly higher when compared with healthy control subjects (2.20 DeltaCT; SD = 1.59). Increased alpha synuclein levels significantly predict Obsessive-Compulsive Drinking Scale total score (odds ratio = 1.44, 95% confidence interval: 1.01-2.06, p = .042) and especially Obsessive-Compulsive Drinking Scale obsessive subscale (odds ratio = 1.74, 95% confidence interval: 1.18-2.58, p = .005) but not Obsessive-Compulsive Drinking Scale compulsive subscale alcohol craving. CONCLUSIONS Higher levels of alpha synuclein are associated with an increase in alcohol craving. The present results provide a novel pathophysiological approach to the explanation of craving mechanisms.

α‐Synuclein Protein Levels Are Increased in Alcoholic Patients and Are Linked to Craving

BACKGROUND Alpha synuclein has been found to be increased in dopamine neurones of cocaine abusers and in rats whose alcohol preference is inbred. Furthermore, increased alpha-synuclein messenger RNA expression has been linked to craving in patients with alcoholism. The aim of the current study was to investigate whether protein levels of alpha synuclein in alcoholics are changed and possibly influence alcohol craving. METHODS The alpha-synuclein protein expression level was measured by enzyme-linked immunosorbent assay in the serum of 49 male alcoholics and 50 nondrinking healthy controls. Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale total score, including subscales for obsessive and compulsive craving. RESULTS Alpha-synuclein protein expression in patients with alcoholism (14.33 ng/ml; SD, 13.01 ng/ml) was significantly higher (t test, T = 3.66, p < 0.0001) when compared with that of healthy controls (5.92 ng/ml; SD, 9.72 ng/ml). Using a multivariate analysis, all craving scores (Obsessive-Compulsive Drinking Scale total score and obsessive and compulsive subscale scores) in alcoholics were significantly associated with their alpha-synuclein protein levels (multiple linear regression, p < 0.014). CONCLUSIONS To our knowledge, this is the first study evaluating alpha-synuclein protein expression in alcoholics. The current study provides further evidence of altered alpha-synuclein levels in patients with alcoholism and their linkage to alcohol craving. Because alpha synuclein is involved in the modulation of dopaminergic neurotransmission, these results deliver further pathophysiological explanations of craving mechanisms.

Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism

Summary.Higher plasma homocysteine levels have been found in actively drinking alcoholics as well as in early abstinent patients. Furthermore, elevated homocysteine levels are associated with cognitive decline in dementia and in healthy elderly people. The aim of this prospective study was to investigate a possible association between homocysteine serum levels and clinically well known cognitive deficits during alcohol withdrawal. We examined 89 patients (67 men, 22 women) during early withdrawal treatment. Cognitive function was assessed using the c.I.-Test. Patients with cognitive deficits showed significantly higher homocysteine serum levels (Mann-Whitney-U, p = 0.004) than patients without cognitive deficits, while the difference in blood alcohol concentration was not significant. Using logistic regression analysis, cognitive deficits were best predicted by high homocysteine serum levels (Wald χ2 = 4.071, OR = 1.043, 95% CI 1.001–1.086, p<0.05), which was confirmed by Receiver Operating Curves (AUC = 0.68, 95% CI = 0.57–0.79, p = 0.004). The present results show first evidence of an association between elevated plasma homocysteine levels in alcoholics and cognition deficits in patients undergoing alcohol withdrawal.

Leptin is associated with craving in females with alcoholism

The appetite and weight regulating peptide leptin was associated recently with alcohol craving during withdrawal. Nevertheless, correlations were only significant with craving displayed on the visual analogue scale for maximum craving during the previous week (VAS), and not if assessed with the highly validated Obsessive Compulsive Drinking Scale (OCDS). The objective of the following study, therefore, is to elucidate further the associations between the leptin system and craving concepts during alcohol withdrawal. A sufficiently large sample size should allow multiple statistical subgroup and confounder analyses. We prospectively investigated 102 chronic alcoholic inpatients (23 females, 79 males) during withdrawal on days 0 (admission), 1, 2 and days 7 ‐ 10. In addition to the statistical analysis of the total sample, females and males were to be analysed separately. For detecting associations between leptin levels and craving scores multiple regression analysis was performed. Plasma leptin levels were determined, and craving for ethanol was assessed by both the OCDS and the VAS. Leptin plasma levels significantly increased during alcohol withdrawal compared to day 0, while all craving scores decreased. Body mass corrected leptin plasma levels predicted craving on day 0 in the OCDS total score (R  = 0.55, F  = 7.91, df = 1.19, p  < 0.05) and in the OCDS obsessive subscore (R  = 0.57, F < = 8.48, df = 1.19, p  < 0.05) in females. Neither in males nor in the total population did multiple regression analysis reveal any significant results. Leptin levels seem to change during inpatient alcohol withdrawal. In a multivariate model, correlations between leptin levels and the highly validated craving scores of the OCDS can only be assumed in females. Hence, gender differences have to be taken into account when searching for neurobiological models of alcohol craving.

Low digit ratio 2D:4D in alcohol dependent patients.

The ratio of the lengths of the second and fourth finger (2D∶4D) has been described as reflecting the degree of prenatal androgen exposure in humans. 2D∶4D is smaller for males than females and is associated with traits such as left-handedness, physical aggression, attention-deficit-hyperactivity disorder and a genetic polymorphism of the androgen receptor. All of these traits are known to be correlated to the vulnerability for alcohol dependency. We therefore hypothesized low 2D∶4D in patients with alcohol dependency. In the present study on 131 patients suffering from alcohol dependency and 185 healthy volunteers, we found that alcohol dependent patients had smaller 2D∶4D ratios compared to controls with preserved sexual dimorphism but with reduced right-left differences. The detection of alcohol dependency based on 2D∶4D ratios was most accurate using the right hand of males (ROC-analysis: AUC 0.725, sensitivity 0.667, specificity 0.723). These findings provide novel insights into the role of prenatal androgen exposure in the development of alcohol dependency and for the use of 2D∶4D as a possible trait marker in identifying patients with alcohol dependency.

An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures

Summary:  Purpose: Higher homocysteine levels were found in actively drinking patients with alcohol dependence. Recent studies have shown that high homocysteine levels are associated with alcohol‐withdrawal seizures. The aim of the present study was to calculate the best predictive cutoff value of plasma homocysteine levels in actively drinking alcoholics (n = 88) with first‐onset alcohol‐withdrawal seizures.

Alcoholism-Associated Hyperhomocysteinemia and Previous Withdrawal Seizures

BACKGROUND Higher homocysteine levels were found in actively drinking alcoholics as well as in early abstinent patients. Furthermore, it has been shown that high homocysteine levels predicted first-onset alcohol withdrawal seizures. The aim of the present study was to determine plasma homocysteine levels in actively drinking alcoholics and patients with early abstinence in order to evaluate whether there is an additional association between elevated plasma homocysteine levels and a history of alcohol withdrawal seizures. METHODS Two groups of patients with an established diagnosis of alcohol dependence were studied. Group A comprised 56 consecutively admitted alcoholics who had been abstinent from alcohol between 24 to 72 hours before hospitalization. Group B consisted of 144 consecutively recruited alcoholics who were admitted - acutely intoxicated - for withdrawal treatment. Furthermore, groups were divided into two subgroups: patients with and without a history of alcohol withdrawal seizures. RESULTS Alcoholics of GROUP B with a history of withdrawal seizures had significantly (p<.0001) higher homocysteine levels than actively drinking patients without seizures in their history: 42.0 micromol/l (SD 26.4) versus 22.5 micromol/l (SD 11.4). Using a logistic regression analysis, history withdrawal seizures in Group B but not in Group A patients were best predicted by a high homocysteine level at admission (Wald chi2=15.5, p<.0001; odds ratio 1.11, 95% CI 1.05-1.20). CONCLUSIONS Homocysteine levels on admission may be a useful screening method to identify actively drinking patients with a higher risk of alcohol withdrawal seizures.

Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal

The orexins (hypocretins) are neuropeptides deriving from the lateral hypothalamus and may be of importance within the context of drug craving, withdrawal, and relapse. Therefore, the orexin A expression and promoter methylation in peripheral blood cells of 68 patients (41 male and 27 female patients at three different time points during withdrawal and 27 patients during stationary dehabituation therapy) suffering from alcohol dependence were assessed by quantitative reverse transcription-polymerase chain reaction and bisulfite sequencing. There was a statistically significant difference of orexin A expression between the three time points of withdrawal and long-term (LT) abstinence (F=4.16, P=.011). This difference was most prominent in comparison with LT abstinence (t=-3.08, P=.0032). Expression was significantly associated with the severity of withdrawal symptoms measured with the Withdrawal Syndrome Scale for Alcohol and Related Psychoactive Drugs (WSA) (t=2.17, P=.0356). The stronger the withdrawal symptoms, the lower the orexin A expression (F=4.69, P=.036). Body mass index (t=2.15, P=.041), the severity of withdrawal measured with the WSA (t=2.595, P=.0133), craving measured either by the Obsessive Compulsive Drinking Scale (t=2.77, P=.0085) or the Lübecker Craving Questionnaire (t=-2.23, P=.0314) had a significant influence on orexin A expression taking into account mean methylation of the CpG island of the orexin A promoter during withdrawal. Orexin A may be a possible candidate to further elucidate mechanisms of alcohol withdrawal taking into account energy homoeostasis in the circuit of reward and motivation.

Alteration of prolactin serum levels during alcohol withdrawal correlates with craving in female patients

Dopaminergic transmission has been suggested to be a main mechanism mediating reinforcement, withdrawal and craving in alcohol dependency. Dopamine is associated with prolactin secretion, acting as a prolactin inhibitor. The aim of the present study was to investigate whether there is an association between altered prolactin levels and craving during early and late alcohol withdrawal. Therefore, we examined 145 patients suffering from alcohol dependency after admission to the detoxification unit, assessing craving with the Obsessive Compulsive Drinking Scale (OCDS) and measuring prolactin serum levels during early withdrawal (‐EW: day 0 or day 1) and late withdrawal (‐LW: day 7–day 10). We observed a significant influence of the alteration of prolactin during withdrawal on craving in female patients (Spearmans rho, OCDS‐EW: r =−0.607, p =0.001; OCDS‐LW: r =−0.730, p2 =0.530; OCDS‐LW: F =17.091, p2 =0.535). In male patients we did not find any significant results. Our findings support the previously described role of the hypothalamic–pituitary–adrenal (HPA) axis in the neurobiology of alcohol craving and show evidence of an association between increased prolactin serum levels and lower craving during alcohol withdrawal in female patients.