Decreased plasma concentrations of BDNF and IGF-1 in abstinent patients with alcohol use disorders.
ABSTRACT: The identification of growth factors as potential biomarkers in alcohol addiction may help to understand underlying mechanisms associated with the pathogenesis of alcohol use disorders (AUDs). Previous studies have linked growth factors to neural plasticity in neurocognitive impairment and mental disorders. In order to further clarify the impact of chronic alcohol consumption on circulating growth factors, a cross-sectional study was performed in abstinent AUD patients (alcohol group, N = 91) and healthy control subjects (control group, N = 55) to examine plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-1 binding protein-3 (IGFBP-3). The association of these plasma peptides with relevant AUD-related variables and psychiatric comorbidity was explored. The alcohol group was diagnosed with severe AUD and showed an average of 13 years of problematic use and 10 months of abstinence at the moment of participating in the study. Regarding common medical conditions associated with AUD, we observed an elevated incidence of alcohol-induced liver and pancreas diseases (18.7%) and psychiatric comorbidity (76.9%). Thus, AUD patients displayed a high prevalence of dual diagnosis (39.3%) [mainly depression (19.9%)] and comorbid substance use disorders (40.7%). Plasma BDNF and IGF-1 concentrations were significantly lower in the alcohol group than in the control group (p<0.001). Remarkably, there was a negative association between IGF-1 concentrations and age in the control group (r = -0.52, p<0.001) that was not found in the alcohol group. Concerning AUD-related variables, AUD patients with liver and pancreas diseases showed even lower concentrations of BDNF (p<0.05). In contrast, the changes in plasma concentrations of these peptides were not associated with abstinence, problematic use, AUD severity or lifetime psychiatric comorbidity. These results suggest that further research is necessary to elucidate the role of BDNF in alcohol-induced toxicity and the biological significance of the lack of correlation between age and plasma IGF-1 levels in abstinent AUD patients.
Project description:Lysophosphatidic acid (LPA) species are bioactive lipids participating in neurodevelopmental processes. The aim was to investigate whether the relevant species of LPA were associated with clinical features of alcohol addiction. A total of 55 abstinent alcohol use disorder (AUD) patients were compared with 34 age/sex/body mass index-matched controls. Concentrations of total LPA and 16:0-LPA, 18:0-LPA, 18:1-LPA, 18:2-LPA and 20:4-LPA species were quantified and correlated with neuroplasticity-associated growth factors including brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-2, and neurotrophin-3 (NT-3). AUD patients showed dysexecutive syndrome (22.4%) and memory impairment (32.6%). Total LPA, 16:0-LPA, 18:0-LPA and 18:1-LPA concentrations, were decreased in the AUD group compared to control group. Total LPA, 16:0-LPA, 18:2-LPA and 20:4-LPA concentrations were decreased in men compared to women. Frontal lobe functions correlated with plasma LPA species. Alcohol-cognitive impairments could be related with the deregulation of the LPA species, especially in 16:0-LPA, 18:1-LPA and 20:4-LPA. Concentrations of BDNF correlated with total LPA, 18:2-LPA and 20:4-LPA species. The relation between LPA species and BDNF is interesting in plasticity and neurogenesis functions, their involvement in AUD might serve as a biomarker of cognitive impairment.
Project description:Recent studies have identified biomarkers related to the severity and pathogenesis of cocaine addiction and common comorbid psychiatric disorders. Monitoring these plasma mediators may improve the stratification of cocaine users seeking treatment. Because the neurotrophic factors are involved in neural plasticity, neurogenesis and neuronal survival, we have determined plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 3 (IGFBP-3) in a cross-sectional study with abstinent cocaine users who sought outpatient treatment for cocaine (n = 100) and age/body mass matched controls (n = 85). Participants were assessed with the diagnostic interview 'Psychiatric Research Interview for Substance and Mental Disorders'. Plasma concentrations of these peptides were not different in cocaine users and controls. They were not associated with length of abstinence, duration of cocaine use or cocaine symptom severity. The pathological use of cocaine did not influence the association of IGF-1 with age observed in healthy subjects, but the correlation between IGF-1 and IGFBP-3 was not significantly detected. Correlation analyses were performed between these peptides and other molecules sensitive to addiction: BDNF concentrations were not associated with inflammatory mediators, lipid derivatives or IGF-1 in cocaine users, but correlated with chemokines (fractalkine/CX3CL1 and SDF-1/CXCL12) and N-acyl-ethanolamines (N-palmitoyl-, N-oleoyl-, N-arachidonoyl-, N-linoleoyl- and N-dihomo-?-linolenoyl-ethanolamine) in controls; IGF-1 concentrations only showed association with IGFBP-3 concentrations in controls; and IGFBP-3 was only correlated with N-stearoyl-ethanolamine concentrations in cocaine users. Multiple substance use disorders and life-time comorbid psychopathologies were common in abstinent cocaine users. Interestingly, plasma BDNF concentrations were exclusively found to be decreased in users diagnosed with both primary and cocaine-induced disorders for mood and anxiety disorders. In summary, BDNF, IGF-1 and IGFBP-3 were not affected by a history of pathological use of cocaine supported by the absence of associations with other molecules sensitive to cocaine addiction. However, BDNF was affected by comorbid mood disorders. Further research is necessary to elucidate the role of BDNF and IGF-1 in the transition to cocaine addiction and associated psychiatric comorbidity.
Project description:Alcohol use disorder (AUD) is among the most stigmatized health conditions and is frequently comorbid with mood, anxiety, and drug use disorders. Theoretical frameworks have conceptualized stigma-related stress as a predictor of psychiatric disorders. We described profiles of psychiatric comorbidity among people with AUD and compared levels of perceived alcohol stigma across profiles.Cross-sectional data were analyzed from a general population sample of U.S. adults with past-year DSM-5 AUD (n = 3,368) from the National Epidemiologic Survey on Alcohol and Related Conditions, which was collected from 2001 to 2005. Empirically derived psychiatric comorbidity profiles were established with latent class analysis, and mean levels of perceived alcohol stigma were compared across the latent classes while adjusting for sociodemographic characteristics and AUD severity.Four classes of psychiatric comorbidity emerged within this AUD sample, including those with: (i) high comorbidity, reflecting internalizing (i.e., mood and anxiety disorders) and externalizing (i.e., antisocial personality and drug use disorders) disorders; (ii) externalizing comorbidity; (iii) internalizing comorbidity; and (iv) no comorbidity. Perceived alcohol stigma was significantly higher in those with internalizing comorbidity (but not those with high comorbidity) as compared to those with no comorbidity or externalizing comorbidity.Perceived stigma, as manifested by anticipations of social rejection and discrimination, may increase risk of internalizing psychiatric comorbidity. Alternatively, internalizing psychiatric comorbidity could sensitize affected individuals to perceive more negative attitudes toward them. Future research is needed to understand causal and bidirectional associations between alcohol stigma and psychiatric comorbidity.
Project description:<b>Rationale:</b> Both attention deficit-/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) are accompanied by deficits in response inhibition. Furthermore, the prevalence of comorbidity of ADHD and AUD is high. However, there is a lack of research on whether the same neuronal subprocesses of inhibition (i.e., interference inhibition, action withholding and action cancellation) exhibit deficits in both psychiatric disorders. <b>Methods:</b> We examined these three neural subprocesses of response inhibition in patient groups and healthy controls: non-medicated individuals with ADHD (ADHD; <i>N</i> = 16), recently detoxified and abstinent individuals with alcohol use disorder (AUD; <i>N</i> = 15), and healthy controls (HC; <i>N</i> = 15). A hybrid response inhibition task covering interference inhibition, action withholding, and action cancellation was applied using a 3T functional magnetic resonance imaging (fMRI). <b>Results:</b> Individuals with ADHD showed an overall stronger hypoactivation in attention related brain areas compared to AUD or HC during action withholding. Further, this hypoactivation was more accentuated during action cancellation. Individuals with AUD recruited a broader network, including the striatum, compared to HC during action withholding. During action cancellation, however, they showed hypoactivation in motor regions. Additionally, specific neural activation profiles regarding group and subprocess became apparent. <b>Conclusions:</b> Even though deficits in response inhibition are related to both ADHD and AUD, neural activation and recruited networks during response inhibition differ regarding both neuronal subprocesses and examined groups. While a replication of this study is needed in a larger sample, the results suggest that tasks have to be carefully selected when examining neural activation patterns of response inhibition either in research on various psychiatric disorders or transdiagnostic questions.
Project description:The lack of effective treatments and a high rate of relapse in cocaine addiction constitute a major health problem. The present study was conducted to examine the expression of tryptophan-derived metabolites in the context of cocaine addiction and psychiatric comorbidity, which is common in addicted subjects. Abstinent patients with cocaine use disorder (CUD) and control subjects were recruited for a cross-sectional study. Participants were assessed with a semi-structured diagnostic interview (PRISM) based on DSM-IV-TR for substance and mental disorders. Plasma concentrations of tryptophan metabolites and their association with relevant CUD-related variables and psychiatric comorbidity were explored. We observed decreased plasma kynurenic acid concentrations in the cocaine group, however no associations between CUD-related variables and tryptophan-derived metabolites were found. In contrast, 5-HT concentrations were increased in CUD-patients and the diagnosis of different psychiatric disorders in the cocaine group was related to higher plasma 5-HT concentrations compared with non-comorbid patients. Therefore, while changes in plasma kynurenic acid concentrations appear to be directly associated with lifetime CUD, changes in 5-HT concentrations are associated with psychiatric comorbidity. These results emphasize the need to find potential biomarkers for a better stratification of cocaine-addicted patients in order to develop therapeutic approaches to prevent cocaine relapse.
Project description:BACKGROUND AND AIMS:Studies that have included family history of alcohol use disorder (AUD) as a predictor of remission from AUD have yielded few significant results. The goals of this study were to estimate the association of persistent AUD, non-abstinent remission and abstinent remission ('AUD/remission status') in a proband with AUD/remission status in a relative and to test whether this association differed in related and unrelated proband-relative pairs. DESIGN:High-risk family study of alcohol dependence. Probands were recruited from treatment settings and relatives were invited to participate. Baseline assessments occurred between 1991 and 1998 with follow-up between 1996 and 2005. Half of probands were matched with a biological 1st-degree relative with life-time AUD (related group) and half of probands were paired with an unrelated individual with life-time AUD (unrelated group). SETTING:Brooklyn, New York; Indianapolis, Indiana; Iowa City, Iowa; San Diego, California; Farmington, Connecticut; and St Louis, Missouri, USA. PARTICIPANTS:A total of 606 probands (25.7% female, mean age 37.7) with baseline and follow-up data and 606 of their 1st-degree relatives who had life-ime AUDs (45.8% female, mean age 36.2 years). MEASUREMENTS:Persistent AUD, non-abstinent remission and abstinent remission were based on self-report interview data on most recent AUD symptoms and alcohol consumption. Dependent variable was relatives' AUD/remission status. Independent variable was probands' AUD/remission status. FINDINGS:A total of 34.6% of probands and 20.6% of relatives were abstinent and 11.1% of probands and 22.8% of relatives were in non-abstinent remission. AUD/remission status was correlated significantly in related (r = 0.23, P = 0.0037) but not in unrelated pairs. A significant interaction of probands' abstinent remission with a variable representing related (versus unrelated, P = 0.003) pairs suggested a familial association for abstinent remission. In related pairs, individuals with an abstinent proband were more likely to be abstinent themselves than were individuals whose proband had persistent AUD [relative risk ratio = 3.27, 95% confidence interval (CI) = 1.56-6.85, P = 0.002]; this association was not significant in unrelated pairs. CONCLUSIONS:The likelihood of abstinent remission among people with alcohol use disorder appears to be more than three times greater for individuals who are related to an abstinent proband versus those related to a proband with persistent alcohol use disorder.
Project description:Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX-LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical evidence has suggested a role of LPA signaling in alcohol use disorder (AUD) and AUD-related cognitive function. However, the ATX-LPA axis has not been sufficiently investigated in alcoholic liver diseases. An exploratory study was conducted in 136 participants, 66 abstinent patients with AUD seeking treatment for alcohol (alcohol group), and 70 healthy control subjects (control group). The alcohol group was divided according to the presence of comorbid liver diseases (i.e., fatty liver/steatosis, alcoholic steatohepatitis, or cirrhosis). All participants were clinically evaluated, and plasma concentrations of total LPA and ATX were measured using enzyme-linked immunosorbent assays. Data were primarily analyzed using analysis of covariance (ANCOVA) while controlling for age, body mass index, and sex. Logistic regression models were created to assess the association of the ATX-LPA axis and AUD or liver disease. LPA and ATX were log<sub>10</sub>-transformed to fit the assumptions of parametric testing.The main results were as follows: total LPA and ATX concentrations were dysregulated in the alcohol group, and patients with AUD had significantly lower LPA (F<sub>(1,131)</sub> = 10.677, <i>p</i> = 0.001) and higher ATX (F<sub>(1,131)</sub> = 8.327, <i>p</i> = 0.005) concentrations than control subjects; patients with AUD and liver disease had significantly higher ATX concentrations (post hoc test, <i>p</i> < 0.05) than patients with AUD but not liver disease; significant correlations between AUD-related variables and concentrations of LPA and ATX were only found in the non-liver disease subgroup (the duration of alcohol abstinence with LPA and ATX (r = +0.33, <i>p</i> < 0.05); and the severity of AUD with ATX (rho = -0.33, <i>p</i> < 0.05)); and a logistic regression model with LPA, ATX, and AUD-related variables showed an excellent discriminative power (area under the curve (AUC) = 0.915, <i>p</i> < 0.001) for distinguishing patients with AUD and comorbid liver disease. In conclusion, our data show that the ATX-LPA axis is dysregulated in AUD and suggest this lipid signaling, in combination with relevant AUD-related variables, as a reliable biomarker of alcoholic liver diseases.
Project description:The goal of this study was to determine whether the plasma leptin, nesfatin-1, cortisol, brain-derived neurotrophic factor (BDNF), and inflammatory cytokines could be used as potential biomarkers for the degree of craving in the alcohol-dependent patients after 1 month of abstinence. A total of 83 patients with alcohol use disorder (AUD) and 61 healthy subjects were assessed. Patients with AUD were selected from Department of Material Dependence, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. The Alcohol Urge questionnaire Scale (AUQ) was used to evaluate the extent of craving for alcohol, and the Michigan Alcoholism Screening Test (MAST), the Fagerstrom Test for Nicotine Dependence (FTND), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) were also assessed in patients with AUD. Enzyme-Linked Immunosorbent Assay (ELISA) was used for the measurement of plasma leptin, nesfatin-1, cortisol, BDNF, Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-? (TNF-?) levels. Compare with healthy controls, the average leptin, leptin/BMI, IL-6, CRP, and TNF-? levels in patients with AUD were significantly increased, while the BDNF levels were significantly decreased. Moreover, the partial correlational analysis showed that the AUQ scores of the alcohol-dependent patients were positively correlated with the plasma leptin levels (r = 0.613, P < 0.001), rather than nesfatin-1 (r = 0.066, P = 0.569) after controlling for age as covariate. Furthermore, plasma nesfatin-1 levels were found to be correlated with the SDS scores (r = 0.366, P = 0.001) in the AUD group. In addition, plasma leptin levels were positively associated with the plasma IL-6 (r = 0.257, P = 0.033), CRP (r = 0.305, P = 0.011), and TNF-? (r = 0.311, P = 0.009) levels, and negatively associated with the BDNF levels (r = -0.245, P = 0.042) in patients with AUD. These results suggest that plasma leptin, but not nesfatin-1, might be a potential biomarker for the degree of craving in alcohol-dependent patients after 1 month of abstinence, the mechanism of which might be related to the dysfunction of the inflammatory cytokines and BDNF levels.
Project description:BACKGROUND:Understanding the comorbidity of alcohol use disorder (AUD) and other psychiatric diagnoses has been a long-standing interest of researchers and mental health professionals. Comorbidity is often examined via the diagnostic co-occurrence of discrete, categorical diagnoses, which is incongruent with increasingly supported dimensional approaches of psychiatric classification and diagnosis, and for AUD more specifically. The present study examined associations between DSM-5 AUD and psychiatric symptoms of other DSM-IV and DSM-5 disorders categorically, and dimensionally organized according to the Hierarchical Taxonomy of Psychopathology (HiTOP) spectra (e.g., Internalizing, Disinhibited Externalizing). METHODS:The comorbidity of AUD with other psychological disorders was examined in 2 independent nationally representative samples of past-year drinkers via an initial examination in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) Wave 2 and replicated in NESARC-III. RESULTS:Analyses focusing on psychopathology symptom counts organized by spectra demonstrated that greater AUD severity was associated with a higher number of symptoms across HiTOP spectra. Traditional categorical analyses also demonstrated increasing prevalence as a monotonic function of DSM-5 AUD severity gradients. CONCLUSIONS:This study indicates that AUD and other psychiatric disorder comorbidity implies increased presence of multiple forms of psychopathology with a corresponding increased number of symptoms across hierarchical spectra. Greater AUD severity increases the likelihood of other psychopathology and, when present, "more severe" presentations. That is, on average, a given disorder (e.g., depression) is more severe when copresenting with an AUD, and increases in severity along with the AUD.
Project description:Neurotrophic growth factors were originally characterized for their support in neuronal differentiation, outgrowth, and survival during development. However, it has been acknowledged that they also play a vital role in the adult brain. Abnormalities in growth factors have been implicated in a variety of neurological and psychiatric disorders, including alcohol use disorder (AUD). This work focuses on the interaction between alcohol and growth factors. We review literature suggesting that several growth factors play a unique role in the regulation of alcohol consumption, and that breakdown in these growth factor systems is linked to the development of AUD. Specifically, we focus on the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), and insulin growth factor 1 (IGF-1). We also review the literature on the potential role of midkine (MDK) and pleiotrophin (PTN) and their receptor, anaplastic lymphoma kinase (ALK), in AUD. We show that alcohol alters the expression of these growth factors or their receptors in brain regions previously implicated in addiction, and that manipulations on these growth factors and their downstream signaling can affect alcohol-drinking behaviors in animal models. We conclude that there is a need for translational and clinical research to assess the therapeutic potential of new pharmacotherapies targeting these systems.