Alcohol-dependent Group Research Articles

Altered Mitochondrial DNA Copy Number and Telomere Length in Patients with Substance Use Disorder: Correlation with Age, Sex, and Chronic Diseases.

Substance use disorder (SUD) is a complex condition involving psychological, sociocultural, and genetic factors. In this study, we examined the alternations in mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) and their relationship to demographic, medical, heredity, and substance use characteristics in patients with SUD and healthy controls. We investigated a total cohort of 54 participants: 21 healthy individuals, 17 patients with alcohol dependence (AD), and 16 patients with drug dependence (DD). TL and mtDNAcn were measured using quantitative real-time PCR, with statistical methods used to assess the association between variables. We observed a significant decrease in mtDNAcn in both SUD groups, particularly associated with chronic diseases in the AD group. No significant differences in TL were found among the three groups. Sex-associated analysis revealed a significant mtDNAcn reduction in the DD males and elevated TL in AD males compared to control males. Correlation analyses showed associations between the two biomarkers and age, sex, and chronic diseases. Our findings suggest that leukocyte mtDNAcn is a more sensitive marker than TL in patients with SUD, indicating sex-specific patterns of alterations. These findings require confirmation through larger cohort recruitment.

Interactions between overweight/obesity and alcohol dependence impact human brain white matter microstructure: evidence from DTI.

There is inconsistent evidence for an association of obesity with white matter microstructural alterations. Such inconsistent findings may be related to the cumulative effects of obesity and alcohol dependence. This study aimed to investigate the possible interactions between alcohol dependence and overweight/obesity on white matter microstructure in the human brain. A total of 60 inpatients with alcohol dependence during early abstinence (44 normal weight and 16 overweight/obese) and 65 controls (42 normal weight and 23 overweight/obese) were included. The diffusion tensor imaging (DTI) measures [fractional anisotropy (FA) and radial diffusivity (RD)] of the white matter microstructure were compared between groups. We observed significant interactive effects between alcohol dependence and overweight/obesity on DTI measures in several tracts. The DTI measures were not significantly different between the overweight/obese and normal-weight groups (although widespread trends of increased FA and decreased RD were observed) among controls. However, among the alcohol-dependent patients, the overweight/obese group had widespread reductions in FA and widespread increases in RD, most of which significantly differed from the normal-weight group; among those with overweight/obesity, the alcohol-dependent group had widespread reductions in FA and widespread increases in RD, most of which were significantly different from the control group. This study found significant interactive effects between overweight/obesity and alcohol dependence on white matter microstructure, indicating that these two controllable factors may synergistically impact white matter microstructure and disrupt structural connectivity in the human brain.

Exploring heart rate variability in alcohol-dependent subjects using frequency-domain analysis

Background: Alcohol-seeking behavior despite being aware of its adverse effects is defined as alcohol dependence (AD). AD syndrome is a cluster of physiological, behavioral, psychological, and perceptual phenomena that develop subsequent to chronic alcohol ingestion. Ethanol is a potent central nervous system depressant that causes toxic damage to the vasomotor and cardiac autonomic nerve fibers which leads to autonomic imbalance leading to arrhythmias and sudden cardiac deaths. Recording and analyzing the heart rate variability (HRV) using the frequency-domain method delineate the autonomic imbalance in alcoholic individuals which may be due to reduced parasympathetic activity and/or sympathetic hyperactivity. Aims and Objectives: The aim of the study was to assess and compare the cardiac autonomic function between the AD group and the non-alcoholic control group using the frequency domain method of HRV. Materials and Methods: A total of 55 alcohol-dependent individuals in the age group of 20–55 years were selected from the psychiatry outpatient department, based on the International Classification of Diseases-10 (Diagnostic and Statistical Manual -IV) criteria as the study population. Fifty-five age and gender-matched healthy volunteers from the master health check-up scheme from the Department of Community Medicine were selected as the control population. Institutional Ethical Committee clearance was obtained. After obtaining informed written consent from the individuals, the short-term 5 min HRV was recorded in the supine position with eyes closed. The results were analyzed and interpreted. Statistical analysis was done using the software Statistical Package for the Social Sciences version 21.0. Results: The frequency domain parameters high frequency (HF) which is a specific marker of parasympathetic activity was significantly reduced, and low frequency (LF) which is a marker of sympathetic activity was significantly increased in the alcoholic group compared to the non-alcoholic group, respectively. The LF: HF ratio which denotes sympathetic-vagal balance was increased in the alcohol-dependent group. Conclusion: HF was decreased, LF and LF: HF ratio was increased in alcoholic-dependent individuals indicating autonomic imbalance with reduced parasympathetic activity and increased sympathetic activity which suggests that alcohol affects the cardiac autonomic status. This concludes that the frequency domain method of HRV could be used as a short-term non-invasive test to assess cardiac autonomic dysfunction in alcohol-dependent individuals.

Cell-type brain-region specific changes in prefrontal cortex of a mouse model of alcohol dependence

The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive alcohol use associated with alcohol dependence and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) and Visium spatial gene expression profiling on the medial prefrontal cortex (mPFC) obtained from C57BL/6 J mice exposed to the two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models phenotypes of alcohol dependence including escalation of alcohol drinking. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Dysregulated modules and their hub genes suggest novel understudied targets for studying molecular mechanisms contributing to the alcohol dependence state. A subtype of inhibitory neurons was the most alcohol-sensitive cell type and contained a downregulated gene co-expression module; the hub gene for this module is Cpa6, a gene previously identified by GWAS to be associated with excessive alcohol consumption. We identified an astrocytic Gpc5 module significantly upregulated in the alcohol-dependent group. To our knowledge, there are no studies linking Cpa6 and Gpc5 to the alcohol-dependent phenotype. We also identified neuroinflammation related gene expression changes in multiple cell types, specifically enriched in microglia, further implicating neuroinflammation in the escalation of alcohol drinking. Here, we present a comprehensive atlas of cell-type specific alcohol dependence mediated gene expression changes in the mPFC and identify novel cell type-specific targets implicated in alcohol dependence.

A Comparative Assessment of Comprehensive Trail Making Test and Wisconsin Card Sorting Test Among Alcohol Dependence Patients

Introduction: Alcohol, when used frequently, accelerates the ageing process, causes brain damage, and results in a reduced volume of grey and white matter, leading to frontal lobe abnormalities. The neurotoxicity resulting from alcohol overuse affects the higher functions of the brain. This study aimed to evaluate the effect of alcohol dependence on the executive functioning of the brain. Methods: This study was carried out as a case-control study among 60 patients with alcohol dependence and 60 controls. Assessment of executive function was carried out using the Comprehensive trail-making test (CTMT) and the Wisconsin card sorting test (WCST). Comparison between the alcohol dependence group and normal healthy controls were calculated using the Mann-Whitney U test as data followed a non-parametric distribution. Results: The mean age of the participants among the cases and controls was 38.3±5.5 years and 37.8±5.4 years, respectively. The results showed a significant difference in both WCST and CTMT between cases and controls (p<0.05). Conclusion: This study concludes that there was an impaired performance in executive functions in alcohol- dependence patients in early abstinence compared to normal controls showing frontal lobe impairment in alcohol-dependence patients.

Predicting ADHD in alcohol dependence using polygenic risk scores for ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high degree of comorbidity, including substance misuse. We aimed to assess whether ADHD polygenic risk scores (PRS) could predict ADHD diagnosis in alcohol dependence (AD). ADHD PRS were generated for 1223 AD subjects with ADHD diagnosis information and 1818 healthy controls. ADHD PRS distributions were compared to evaluate the differences between healthy controls and AD cases with and without ADHD. We found increased ADHD PRS means in the AD cohort with ADHD (mean 0.30, standard deviation (SD) 0.92; p = 3.9 × 10-6); and without ADHD (mean - 0.00, SD 1.00; p = 5.2 × 10-5) compared to the healthy control subjects (mean - 0.17, SD 0.99). The ADHD PRS means differed within the AD group with a higher ADHD PRS mean in those with ADHD, odds ratio (OR) 1.34, confidence interval (CI) 1.10 to 1.65; p = 0.002. This study showed a positive relationship between ADHD PRS and risk of ADHD in individuals with co-occurring AD indicating that ADHD PRS may have utility in identifying individuals that are at a higher or lower risk of ADHD. Further larger studies need to be conducted to confirm the reliability of the results before ADHD PRS can be considered as a robust biomarker for diagnosis.

Serum metabolomics analysis in patients with alcohol dependence.

Alcohol dependence (AD) is a chronic recurrent mental disease caused by long-term drinking. It is one of the most prevalent public health problems. However, AD diagnosis lacks objective biomarkers. This study was aimed to shed some light on potential biomarkers of AD patients by investigating the serum metabolomics profiles of AD patients and the controls. Liquid chromatography-mass spectrometry (LC-MS) was used to detect the serum metabolites of 29 AD patients (AD) and 28 controls. Six samples were set aside as the validation set (Control: n = 3; AD group: n = 3), and the remaining were used as the training set (Control: n = 26; AD group: n = 25). Principal component analysis (PCA) and partial least squares discriminant analysis (PCA-DA) were performed to analyze the training set samples. The metabolic pathways were analyzed using the MetPA database. The signal pathways with pathway impact >0.2, value of p <0.05, and FDR < 0.05 were selected. From the screened pathways, the metabolites whose levels changed by at least 3-fold were screened. The metabolites with no numerical overlap in their concentrations in the AD and the control groups were screened out and verified with the validation set. The serum metabolomic profiles of the control and the AD groups were significantly different. We identified six significantly altered metabolic signal pathways, including protein digestion and absorption; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; linoleic acid metabolism; butanoate metabolism; and GABAergic synapse. In these six signal pathways, the levels of 28 metabolites were found to be significantly altered. Of these, the alterations of 11 metabolites changed by at least 3-fold compared to the control group. Of these 11 metabolites, those with no numerical overlap in their concentrations between the AD and the control groups were GABA, 4-hydroxybutanoic acid, L-glutamic acid, citric acid and L-glutamine. The metabolite profile of the AD group was significantly different from that of the control group. GABA, 4-hydroxybutanoic acid, L-glutamic acid, citric acid, and L-glutamine could be used as potential diagnostic markers for AD.

Diurnal changes of the oral microbiome in patients with alcohol dependence.

Saliva secretion and oral microbiota change in rhythm with our biological clock. Dysbiosis of the oral microbiome and alcohol consumption have a two-way interactive impact, but little is known about whether the oral microbiome undergoes diurnal changes in composition and function during the daytime in patients with alcohol dependence (AD). The impact of alcohol consumption on the diurnal salivary microbiome was examined in a case-control study of 32 AD patients and 21 healthy control (HC) subjects. We tested the changes in microbial composition and individual taxon abundance by 16S rRNA gene sequencing. The present study is the first report showing that alcohol consumption enhanced the richness of the salivary microbiome and lowered the evenness. The composition of the oral microbiota changed significantly in alcohol-dependent patients. Additionally, certain genera were enriched in the AD group, including Actinomyces, Leptotrichia, Sphaerochaeta and Cyanobacteria, all of which have pathogenic effects on the host. There is a correlation between liver enzymes and oral microbiota. KEGG function analysis also showed obvious alterations during the daytime. Alcohol drinking influences diurnal changes in the oral microbiota, leading to flora disturbance and related functional impairment. In particular, the diurnal changes of the oral microbiota may open avenues for potential interventions that can relieve the detrimental consequences of AD.

Alcohol-induced brain deficit in alcohol dependence.

Although numerous adverse effects of alcohol addiction on health, behavior, and brain function were widely reported, the neurobiological mechanism of alcohol dependence remains largely unknown. In this study, a total of twenty-nine patients with alcohol dependence and twenty-nine status-matched normal controls (NCs) were recruited. Percent amplitude of fluctuation (PerAF) was applied to identify alcohol-related brain activity deficits. We found that alcohol dependence was associated with widespread differences in the left orbitofrontal cortex, right higher visual cortex, right supramarginal gyrus, right postcentral gyrus, and bilateral cerebellum posterior lobe with decreased PerAF, but no brain areas with increased PerAF differences were found. ROC curve showed that decreased PerAF revealed extremely high discriminatory power with a high AUC value of 0.953, as well as a high degree of sensitivity (96.6%) and specificity (86.2%), in distinguishing patients with alcohol dependence from NCs. In the alcohol dependence group, the amount of daily alcohol consumption showed significant negative correlations with the right cerebellum posterior lobe and right higher visual cortex. These findings suggest that the cerebellar-visual-orbitofrontal circuit was disturbed by alcohol dependence. The proposed new method of PerAF may be served as a potential biomarker to identify the regional brain activity deficits of alcohol dependence.

Association between Vitamin D and Cognitive Deficiency in Alcohol Dependence.

There are still not enough findings to elucidate how exactly alcohol use impairs cognitive abilities. Some studies have shown that there is a link between alcohol intake and vitamin D levels, but these findings are inconsistent so further research is needed. The aim of this study was to investigate the association between serum vitamin D levels and cognitive impairment in alcohol-dependent individuals. A case-control study was carried out including a total of N = 132 respondents with a medical history of alcoholism, and healthy volunteers. The Montreal Cognitive Assessment (MoCa) and Addenbrooke’s Cognitive Examination-Revised (ACE-R) screening tools were used for cognitive status assessment and serum vitamin D levels analysis (blood samples of respondents). Significant difference (p = 0.022), was found in vitamin D levels in the alcohol-dependent group with cognitive deficiency 13.7 ± 9.4 (ng/mL), alcohol-dependent group without cognitive deficiency 19.5 ± 11.2 (ng/mL) and healthy controls 19.9 ± 11.1 (ng/mL), respectively. Furthermore, vitamin D levels were significantly different across all groups based on MoCa (p = 0.016) and ACE-R (p = 0.004) scores. All three groups exhibited vitamin D deficiency. A significant correlation was found between vitamin D deficiency and cognitive impairment, but it yielded no significant difference in alcohol-dependent individuals.

Alterations in white matter microstructure in alcohol and alcohol‐polydrug dependence: Associations with lifetime alcohol and nicotine exposure

Evidence suggests that alcohol dependence (AD) is associated with microstructural deficits in white matter, but the relationship with lifetime alcohol exposure and the impact of polydrug dependence is not well understood. Using diffusion tensor magnetic resonance (MR) imaging, we examined white matter microstructure in relation to alcohol and polydrug dependence using data from the Imperial College Cambridge Manchester (ICCAM) platform study. Tract‐based spatial statistics were used to examine fractional anisotropy (FA) in a cohort of abstinent AD participants, most of whom had a lifetime history of dependence to nicotine. A further subgroup also had a lifetime history of dependence to cocaine and/or opiates. Individuals with AD had lower FA throughout the corpus callosum, and negative associations with alcohol and nicotine exposure were found. A group‐by‐age interaction effect was found showing greater reductions with age in the alcohol‐dependent group within corpus callosum, overlapping with the group difference. We found no evidence of recovery with abstinence. A comparison of alcohol‐only‐ and alcohol‐polydrug‐dependent groups found no differences in FA. Overall, our findings show that AD is associated with lower FA and suggest that these alterations are primarily driven by lifetime alcohol consumption and cigarette smoking, showing no relationship with exposure to other substances such as cocaine, opiates or cannabis. Reductions in FA across the adult lifespan are more pronounced in AD and offer further support for the notion of accelerated ageing in relation to alcohol dependence. These findings highlight there may be lasting structural differences in white matter in alcohol dependence, despite continued abstinence.

Promoter Specific Methylation of SSTR4 is Associated With Alcohol Dependence in Han Chinese Males.

Alcohol dependence (AD), a disease can be affected by environmental factors with epigenetic modification like DNA methylation changes, is one of the most serious and complex public health problems in China and worldwide. Previous findings from our laboratory using the Illumina Infinium Human Methylation450 BeadChip suggested that methylation at the promoter of SSTR4 was one of the major form of DNA modification in alcohol-dependent populations. To investigate whether DNA methylation levels of the SSTR4 promoter influence alcohol-dependent behaviors, genomic DNA was extracted from the peripheral blood sample of 63 subjects with AD and 65 healthy controls, and pyrosequencing was used to verify the results of BeadChip array. Linear regression was used to analyze the correlation between the methylation levels of SSTR4 promoter and the scores of alcohol dependence scales. Gene expression of SSTR4 in brain tissue was obtained from the Genotype-Tissue Expression (GTEx) project and Human Brain Transcriptome database (HBT). We found the methylation levels of SSTR4 in AD group were significantly lower than healthy controls (two-tailed t-test, t = 14.723, p < 0.001). In addition, only weak to moderate correlations between the methylation levels of the SSTR4 promoter region and scale scores of Alcohol Use Disorders Identification Test (AUDIT), Life Events Scale (LES) and Wheatley Stress Profile (WSS) based on linear regression analyses (AUDIT: R 2 = 0.35, p < 0.001; LES: R 2 = 0.27, p < 0.001; WSS: R 2 = 0.49, p < 0.001). The hypomethylated status of SSTR4 may involve in the development of AD and increase the risk of AD persistence in Han Chinese males.

Anomalies in global network connectivity associated with early recovery from alcohol dependence: A network transcranial magnetic stimulation and electroencephalography study.

Although previous research in alcohol dependent populations identified alterations within local structures of the addiction ‘reward’ circuitry, there is limited research into global features of this network, especially in early recovery. Transcranial magnetic stimulation (TMS) is capable of non‐invasively perturbing the brain network while electroencephalography (EEG) measures the network response. The current study is the first to apply a TMS inhibitory paradigm while utilising network science (graph theory) to quantify network anomalies associated with alcohol dependence. Eleven individuals with alcohol‐dependence (ALD) in early recovery and 16 healthy controls (HC) were administered 75 single pulses and 75 paired‐pulses (inhibitory paradigm) to both the left and right prefrontal cortex (PFC). For each participant, Pearson cross‐correlation was applied to the EEG data and correlation matrices constructed. Global network measures (mean degree, clustering coefficient, local efficiency and global efficiency) were extracted for comparison between groups. Following administration of the inhibitory paired‐pulse TMS to the left PFC, the ALD group exhibited altered mean degree, clustering coefficient, local efficiency and global efficiency compared to HC. Decreases in local efficiency increased the prediction of being in the ALD group, while all network metrics (following paired‐pulse left TMS) were able to adequately discriminate between the groups. In the ALD group, reduced mean degree and global clustering was associated with increased severity of past alcohol use. Our study provides preliminary evidence of altered network topology in patients with alcohol dependence in early recovery. Network anomalies were predictive of high alcohol use and correlated with clinical features of alcohol dependence. Further research using this novel brain mapping technique may identify useful network biomarkers of alcohol dependence and recovery.

Data-driven study on resting-state functional magnetic resonance imaging during early abstinence of alcohol dependence in male patients and its predictive value for relapse

BackgroundAlcohol dependence is a mental disorder with a high relapse rate. However, specific neuroimaging biomarkers have not been determined for alcohol dependence and its relapse. We conducted data-driven research to investigate resting-state functional magnetic resonance imaging (rs-fMRI) during early abstinence from alcohol dependence and its potential ability to predict relapse.MethodsParticipants included 68 alcohol-dependent patients and 68 healthy controls (HCs). The regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) were compared between the alcohol dependence group and the HCs and between the relapse group and the nonrelapse group. The brain regions that presented significantly different ReHo and/or fALFF between the alcohol-dependent patients and HCs and/or between the relapsed and nonrelapsed patients were selected as the seeds to calculate the functional connectivities (FCs).ResultsDuring a 6-month follow-up period, 52.24% of alcohol-dependent patients relapsed. A regression model for differentiating alcohol-dependent patients and HCs showed that reductions in ReHo in the left postcentral region, fALFF in the right fusiform region, and FC in the right fusiform region to the right middle cingulum were independently associated with alcohol dependence, with an area under the receiver operating characteristic curve (AUC) of 0.841. The baseline FC of the left precentral to the left cerebellum of the relapse group was significantly lower than that of the nonrelapse group. The AUC of this FC to predict relapse was 0.774.ConclusionsOur findings contribute to advancing research on the neurobiological etiology and predictive biomarkers for relapse associated with alcohol dependence.

Exploration of the Role of Serine Proteinase Inhibitor A3 in Alcohol Dependence Using Gene Expression Omnibus Database.

Background: Alcohol dependence is an overall health-related challenge; however, the specific mechanisms underlying alcohol dependence remain unclear. Serine proteinase inhibitor A3 (SERPINA3) plays crucial roles in multiple human diseases; however, its role in alcohol dependence clinical practice has not been confirmed.Methods: We screened Gene Expression Omnibus (GEO) expression profiles, and identified differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were generated using STRING and Cytoscape, and the key clustering module was identified using the MCODE plugin. SERPINA3-based target microRNA prediction was performed using online databases. Functional enrichment analysis was performed. Fifty-eight patients with alcohol dependence and 20 healthy controls were recruited. Clinical variables were collected and follow-up was conducted for 8 months for relapse.Results: SERPINA3 was identified as a DEG. ELANE and miR-137 were identified after PPI analysis. The enriched functions and pathways included acute inflammatory response, response to stress, immune response, and terpenoid backbone biosynthesis. SERPINA3 concentrations were significantly elevated in the alcohol dependence group than in healthy controls (P < 0.001). According to the median value of SERPINA3 expression level in alcohol dependence group, patients were divided into high SERPINA3 (≥2677.33 pg/ml, n = 29) and low SERPINA3 groups (<2677.33 pg/ml, n = 29). Binary logistic analysis indicated that IL-6 was statistically significant (P = 0.015) Kaplan-Meier survival analysis did not indicate any difference in event-free survival between patients with low and high SERPINA3 levels (P = 0.489) after 8 months of follow-up. Receiver characteristic curve analysis revealed that SERPINA3 had an area under the curve of 0.921 (P < 0.0001), with a sensitivity and specificity of 93.1 and 80.0%, respectively. Cox regression analysis revealed that aspartate transaminase level was a negative predictor of relapse (β = 0.003; hazard ratio = 1.003; P = 0.03).Conclusions: SERPINA3 level was remarkably elevated in patients with alcohol dependence than healthy controls, indicating that SERPINA3 is correlated with alcohol dependence. However, SERPINA3 may not be a potential predictive marker of relapse with patients in alcohol dependence.

Neurofilament Light Chain Is a Promising Biomarker in Alcohol Dependence.

Background: Alcohol dependence, a global public health problem, leads to structural and functional damage in the brain. Alcohol dependence patients present complex and varied clinical manifestations and live with general complaints existing in contemporary society, making most people with alcohol dependence hard to identify. Therefore, it is important to find potential biomarkers for the diagnosis and evaluation of alcohol dependence. In the study, we explored potential biomarkers for the diagnosis and monitoring of diseases and evaluated brain structural changes in alcohol dependence patients.Methods: Enzyme-linked immunosorbent assay (ELSA) was employed to detect the expression of serum nucleotide-binding oligomerization domain containing 3 (NLRP3) and single-molecule array (Simoa) assay was used to detect the expression of serum neurofilament light (NfL) in 50 alcohol dependence patients and 50 controls with no drinking history. Alcohol consumption was measured by standard drinks. Neuropsychological assessments, including the Montreal cognitive assessment (MoCA), Pittsburgh sleep quality index (PSQI), generalized anxiety disorder (GAD-7), and patient health questionnaire-9 (PHQ-9), were conducted to evaluate cognitive function and psychological state. The degree of white matter lesions (WMLs) was rated using the Fazekas scale based on magnetic resonance imaging analysis. White matter structure was quantified using the voxel-based morphometry method. The correlations between NLRP3 levels, NfL levels, neuropsychological dysfunction, the degree of WMLs, and white matter volume (WMV) were analyzed in alcohol dependence patients.Results: Serum NLRP3 and NfL levels were higher in the alcohol dependence group. NLRP3 levels were irrelevant to monthly alcohol assumption as well as to the MoCA, PSQI, GAD-7, PHQ-9, and Fazekas scale scores and WMV. NfL levels were positively correlated with the PSQI and PHQ-9 scores as well as the degree of WMLs and negatively correlated with the MoCA scores and WMV. No associations were evident between NfL and monthly alcohol assumption and GAD-7 scores in the alcohol dependence group.Conclusion: This study supports the potential value of serum NfL as a non-invasive biomarker in alcohol dependence. The association with neuropsychological dysfunction and degree of WMLs has implications to use NfL as a promising biomarker to assess the severity of brain damage as well as the progression and prognosis of alcohol dependence.

Combinations of alcohol-induced flushing with genetic polymorphisms of alcohol and aldehyde dehydrogenases and the risk of alcohol dependence in Japanese men and women.

The risk of alcohol dependence (AD) in Japanese men and women was evaluated according to combinations of alcohol flushing and aldehyde dehydrogenase-2 (ALDH2, rs671) and alcohol dehydrogenase-1B (ADH1B, rs1229984) genotypes, all of which are known to determine AD susceptibility in Asians. Previous studies have focused on men, since women account for a smaller proportion of AD subjects. Case control studies were conducted between 3721 male and 335 female AD Japanese and 610 male and 406 female controls who were asked about their current or former tendency to experience facial flushing after drinking a glass of beer and underwent ALDH2 and ADH1B genotyping. The time at which alcohol-induced facial flushing tendencies had disappeared in former-flushing AD subjects was also evaluated. Current alcohol flushing, the inactive ALDH2*1/*2 genotype, and the fast-metabolizing ADH1B*2 allele were less frequently found in the AD groups. Although alcohol flushing was strongly influenced by the ALDH2 and ADH1B genotypes, multiple logistic model showed that never or former flushing and the genotype combinations were independent strong risk factors of AD in men and women. Never or former flushing (vs. current flushing) markedly increased the odds ratios of AD in carriers of each of the ALDH2 and ADH1B genotype combinations. The temporal profiles for drinking and flushing in former-flushing AD subjects revealed that the flushing response disappeared soon after or before the start of habitual drinking during young adulthood, regardless of the ALDH2 genotype. Although alcohol flushing is influenced by the ALDH2 and ADH1B genotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for AD. The combination of the alcohol flushing status and the ALDH2 and ADH1B genotypes can provide a better new strategy for AD risk assessment than the alcohol flushing status alone or the genotypes alone in Asian men and women.

Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study.

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [11C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects.

Gene variants and serum levels of synaptic vesicle and presynaptic plasma membrane proteins in alcohol dependence and their relationship with impulsivity and temperament

ABSTRACT Background: Exocytosis-related gene variants have been suggested to be associated with externalizing behaviors. Objective: This study aimed to examine VAMP2 26 bp Ins\Del, synaptotagmin XI (Syt11) rs3820594 and 33-bp promoter, Syntaxin 1A (Syn-1A) rs1569061 and SNAP-25 rs1051312 and rs3746544 polymorphisms, their serum levels and their relationship with impulsivity, temperament in individuals with alcohol dependence (AD) and healthy controls (HC). Methods: The study included 107 individuals with AD and 104 HCs. Single-nucleotide polymorphisms (SNPs) were studied with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and serum levels with ELISA. Michigan Alcohol Screening Test (MAST), Barratt Impulsiveness Scale-11 (BIS-11) and Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) were applied. Results: Syn-1A rs1569061 C allele polymorphism was significantly higher in AD group. Syn-1A rs1569061 C allele was associated with 1.5 times increased risk of AD. All serum levels were significantly higher in the HC group. There was a relationship between Syn-1A rs1569061 polymorphism and BIS-11 motor impulsiveness in the AD group; Syt11 rs3820594 polymorphism and BIS-11 total, TEMPS-A depressive, hyperthymia in the HC group. Discussion: In our study, gene variants and serum levels of synaptic vesicle and presynaptic plasma membrane proteins were related to AD, impulsivity and temperament.

Association of Plasma Pro-Brain-Derived Neurotrophic Factor (proBDNF)/Mature Brain-Derived Neurotrophic Factor (mBDNF) Levels with BDNF Gene Val66Met Polymorphism in Alcohol Dependence.

BackgroundIn a previous study, we reported that pro-brain-derived neurotrophic factor (proBDNF) was involved in the pathology of alcohol dependence, and the single-nucleotide polymorphism (SNP) Val66Met was located at the prodomain of the brain-derived neurotrophic factor gene (BDNF). This polymorphism has been reported to affect intracellular trafficking and activity-dependent secretion of BDNF. Our present research investigated the relationships between the BDNF Val66Met polymorphism and the plasma levels of proBDNF and mature brain-derived neurotrophic factor (mBDNF) in patients with alcohol dependence.Material/MethodsThe BDNF gene Val66Met polymorphism was genotyped in 59 alcohol-dependent patients and 37 age- and sex-matched controls, and the plasma levels of proBDNF and mBDNF were assessed by enzyme-linked immunosorbent assay in all participants.ResultsNo association was found between the BDNF gene Val66Met polymorphism and alcohol dependence (P>0.05). In comparison with the control group, the level of plasma proBDNF in the alcohol-dependence group was notably increased (Z=−2.228, P=0.026), while the level of mBDNF was remarkedly decreased (Z=−2.014, P=0.044). In the alcohol-dependence group, significant associations were not found between the Val66Met polymorphisms and proBDNF and mBDNF plasma levels (P>0.05). The plasma level of proBDNF was positively correlated with the average daily alcohol consumption in the last month (r=0.344, P=0.008) and drinking history (r=0.317, P=0.014), while the plasma level of mBDNF had negative effects (r=−0.361, P=0.005, with the average daily alcohol consumption; r=−0.427, P=0.001, with drinking history).ConclusionsThe BDNF gene Val66Met polymorphism does not appear to affect the secretion of proBDNF and mBDNF in Chinese patients with alcohol dependence. Furthermore, this study reconfirmed that the plasma levels of proBDNF and mBDNF were correlated with the average daily alcohol consumption in the last month and with drinking history.