Cerebrospinal Fluid Biomarkers in Patients With Alcohol Use Disorder and Persistent Cognitive Impairment.

BACKGROUND: The prevalence of cognitive impairment is high among alcohol-dependent patients. Although the clinical presentation of alcohol-related cognitive disorder (ARCD) may resemble that of Alzheimer's disease (AD), the prognosis and treatment of the 2 diseases are different. Cerebrospinal fluid (CSF) biomarkers (tau, phosphorylated tau, and amyloid ß) have high diagnostic accuracy in AD and are currently being used to discriminate between psychiatric disorders and AD, but are not used to diagnose ARCD. The aim of this study was to characterize CSF biomarkers in a homogeneous, cognitively impaired alcohol-dependent population. METHODS: This single-center study was conducted in an addiction medicine department of a Parisian Hospital. We selected patients with documented persistent cognitive impairment whose MoCA (Montreal Cognitive Assessment) score was below 24/30 after at least 1 month of documented inpatient abstinence from alcohol. We measured the CSF biomarkers (tau, phosphorylated tau, and amyloid ß 1-42 and 1-40) in 73 highly impaired alcohol-dependent patients (Alcohol Use Disorders Identification Test score over 11 for women and 12 for men) with. RESULTS: Patients' average age was 60 ± 9.1 years and 45 (61.6%) had a normal CSF profile, 8 (11.0%) had a typical CSF AD profile, and 20 (27.4%) had an intermediate CSF profile. CONCLUSIONS: This study revealed a high prevalence of AD in alcohol-dependent patients with persistent cognitive deficits and several anomalies in their CSF profiles. Thus, it is important to consider AD in the differential diagnosis of persistent cognitive deficits in patients with alcohol dependence and to use CSF biomarkers in addition to imaging and neuropsychological testing to evaluate alcohol-related cognitive impairment.

PCSK9 is Increased in Cerebrospinal Fluid of Individuals With Alcohol Use Disorder.

BACKGROUND: Recent studies have shown that alcohol use affects the regulation and expression of proprotein convertase subtilisin/kexin 9 (PCSK9). While a major role of PCSK9 in hepatic function and lipid regulation has been clearly established, other pleiotropic effects remain poorly understood. Existing research suggests a positive association between PCSK9 expression in the brain and psychopathology, with increased levels of PCSK9 in the cerebrospinal fluid (CSF) of individuals with dementia and epigenetic modifications of PCSK9 associated with alcohol use disorder (AUD). In this study, we hypothesized that chronic alcohol use would increase PCSK9 expression in CSF. METHODS: PCSK9 levels in CSF were measured in individuals with AUD (n = 42) admitted to an inpatient rehabilitation program and controls (n = 25). CSF samples in AUD were assessed at 2 time points, at day 5 and day 21 after admission. Furthermore, plasma samples were collected and measured from the individuals with AUD. RESULTS: PCSK9 in CSF was significantly increased in the AUD group at day 5 and day 21 compared to the controls (p < 0.0001). Plasma PCSK9 levels were correlated positively with CSF PCSK9 levels in AUD (p = 0.0493). CONCLUSIONS: Our data suggest that PCSK9 is elevated in the CSF of individuals with AUD, which may indicate a potential role of PCSK9 in AUD. Additional studies are necessary to further elucidate the functions of PCSK9 in the brain.

MAOA expression predicts vulnerability for alcohol use.

The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.

Cerebrospinal fluid monocyte chemoattractant protein-1 in alcoholics: support for a neuroinflammatory model of chronic alcoholism.

BACKGROUND: Liver inflammation in alcoholism has been hypothesized to influence the development of a neuroinflammatory process in the brain characterized by neurodegeneration and altered cognitive function. Monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) elevations have been noted in the alcoholic brain at autopsy and may have a role in this process. METHODS: We studied cerebrospinal fluid (CSF) levels of MCP-1 as well as interleukin-1ß and tumor necrosis factor-α in 13 healthy volunteers and 28 alcoholics during weeks 1 and 4 following detoxification. Serum liver enzymes were obtained as markers of alcohol-related liver inflammation. RESULTS: Compared to healthy volunteers, MCP-1 levels were significantly higher in alcoholics both on day 4 and day 25 (p < 0.0001). Using multiple regression analysis, we found that MCP-1 concentrations were positively associated with the liver enzymes gamma glutamyltransferase (GGT; p = 0.03) and aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/GOT; p = 0.004). CONCLUSIONS: These preliminary findings are consistent with the hypothesis that neuroinflammation as indexed by CSF MCP-1 is associated with alcohol-induced liver inflammation, as defined by peripheral concentrations of GGT and AST/GOT.

Relationship between liver function and brain shrinkage in patients with alcohol dependence.

BACKGROUND: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence. METHODS: We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as hematocrit (Hct) and albumin were assayed shortly after admission. Magnetic resonance imaging examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage. RESULTS: Patients with alcohol dependence had lower BV, and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), brain ratio (BR), and higher cerebrospinal fluid ratio ratio (CSFR) compared with their healthy counterparts. Age and sex were significantly correlated with some BV measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with BV indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage. CONCLUSIONS: Our results showed that the higher levels of liver function indices, especially GGT, correlated with BV shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.

Correlation of pre-morbid alcoholism and changes in the level of biogenic amine metabolites in cerebrospinal fluid of accute brain infarction patients.

BACKGROUND: The disorder of biogenic amine metabolism (serotonin - 5-HT and dopamine - DA) is expected in the brain (neuron) damage caused by acute ischemia. It is known that long-term abuse of ethyl-alcohol damages the quality of neurons diffusely in the brain. Cerebrospinal fluid (CSF) and its biochemical content, 5-HT and DA, are reliable indicators of the vitality of neurons. The main objective of this research was to demonstrate that the elevated content of metabolites 5-HT and DA in the CSF in patients with acute brain infarction, who were pre-morbid alcohol-dependent patients, is additionally emphasized by diffusive damage of neuron vitality caused by alcoholism. SUBJECTS AND METHODS: Study sample consists of two groups - 50 alcohol-dependent patients with acute brain infarction under the age of 65 (group A) and 50 patients with acute brain infarction who were not alcohol-dependent (group B). All subjects underwent the same procedure - CSF was taken during admission to the hospital and history was obtained through anamnesis, heteroanamnesis and clinical examinations. RESULTS: Metabolism of DA and metabolic turnover of DA (3, 4 dihydroxyphenylacetic acid + homovanilic acid; DOPAC + HVA) was elevated in the liquor of both patient groups. The statistically significant difference between the groups was found in metabolic turnover of 5-HT (p<0.05), and metabolic turnover of DA (p<0.001). CONCLUSIONS: The metabolic neuron disbalance, i.e. their pathophysiological-biochemical dysfunction as a result of acute brain infarction, is present in a higher degree in patients with pre-morbid long-term alcohol abuse.

Elevated cerebrospinal fluid tau protein levels in Wernicke's encephalopathy.

OBJECTIVE: Limited neuronal cell loss is seen in the neuropathology of Wernicke's encephalopathy (WE), but the extent of neuronal damage has not been well studied. Moreover, there is still a debate as to whether alcohol itself causes brain damage in humans. Although, it is difficult to examine the extent of neuronal damage in living patients, recent studies have revealed that total tau protein levels in the cerebrospinal fluid (CSF) reflect the rate of neuronal degeneration. Therefore, we hypothesized that the elevated CSF total tau in patients with WE was due to neuronal damage and thus we examined CSF total tau protein in patients with WE, as well as in those with alcohol withdrawal delirium (WD) and Korsakoff syndrome (KS). We also examined CSF total tau in nonalcohol dependent patients with Alzheimer's disease (AD) as a disease control. METHODS: CSF samples were obtained from 13 acute WE patients with alcohol dependence, 9 WD patients with alcohol dependence and 16 KS patients with alcohol dependence, and from 20 nonalcohol dependent AD patients. CSF was also obtained from 10 of the WE patients after their disease had progressed to the chronic stage. CSF tau protein levels in all samples were determined by sandwich enzyme-linked immunosorbent assay. Tau phosphorylated at threonine 181 (p-tau(181)) and amyloid beta-protein ending at amino acid 42 (A beta 42) in CSF were also determined for comparison between acute WE with AD. RESULTS: Total tau was significantly elevated in acute WE and decreased on long-term follow-up, but was not elevated in WD or KS. The patterns of p-tau(181) and A beta 42 differed between acute WE and AD. CONCLUSIONS: Intense neuronal cell death occurs transiently in WE, and the mechanism differs from that in AD. Neuronal damage is generally unaccompanied in WD. These results suggest that CSF total tau is a useful biological marker for WE.

Shape deformation of the insula in alcoholics: reduction of left-right asymmetry.

We have investigated shape deformation of the insula to get a viewpoint of how chronic alcohol consumption affects the perisylvian region and compared the deformity pattern between the left and right hemisphere. A landmark-based structural and surface shape analysis of the insula was performed in 20 patients with alcohol dependence and 20 controls matched for age. The shape analysis revealed that the left and right insula follow distinct shape deformation patterns, which resulted in the reduction of left-right asymmetry. The shape deformity was most prominent in the central part of both insula. Our findings indicate that the right and left hemisphere are both affected but shows distinct patterns of deformation in alcohol dependence.

Cortisol concentrations, stress-coping styles after withdrawal and long-term abstinence in alcohol dependence.

Alcohol-dependent patients face a substantial risk of relapse after detoxification. A major risk factor for relapse is stress which is reflected biologically by various physiological changes that include an activation of the hypothalamic-pituitary-adrenal (HPA) axis and release of glucocorticoids. The prospective study examined cortisol concentrations and stress-coping styles in relation to abstinence 1 year following discharge from treatment. Cortisol concentrations were measured in the plasma of 46 alcohol-dependent patients (12 women) on initial presentation for treatment (day 1), and again in plasma and in cerebrospinal fluid (CSF) after 6 weeks of abstinence (day 40). These results were compared with those of 26 age- and sex-matched, healthy control subjects. After withdrawal, the patients completed a comprehensive baseline assessment including a stress-coping questionnaire (Stressverarbeitungsfragebogen SVF120) and were monitored for 1 year after discharge. Negative stress-coping styles (e.g. flight, resignation) positively correlated with higher cortisol concentration in plasma and in CSF after withdrawal (day 40). Compared with relapsers after 1 year, abstainers had significantly lower levels for cortisol in CSF, whereas the stress-coping styles did not differ between abstainers and relapsers in this sample. These findings suggest that relatively stable personality traits like stress-coping styles have no measurable influence on abstinence. The lower cortisol concentration in CSF as an indicator for HPA axis functioning is associated with long-term abstinence in detoxified alcoholics.

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index.

Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenaline. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N=278) and controls (N=227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P=0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P<0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

CSF monoamine patterns in pathological gamblers and healthy controls.

Previous reports on compounds in the cerebrospinal fluid (CSF) of pathological gamblers have focused on disturbed NA, DA and 5-HT function in the central nervous system. We have analysed precursors, transmitters and transmitter metabolites in 3 x 6 ml of CSF obtained from one female and 11 male pathological gamblers and 11 healthy male controls lumbar punctured at the L4-5 level after 8 h of fasting without preceding strict bedrest. Pathological gamblers displayed lower CSF levels of tryptophan and 5-HT while the opposite was the case for 5-HIAA, tyrosine, DA, HVA, DOPAC and HMPG. In contrast to previous studies, the NA level did not differ between pathological gamblers and healthy controls. A disrupted CSF gradient was noted for tryptophan, 5-HT, DA, HVA, DOPAC, NA and HMPG, but only in pathological gamblers. A disrupted gradient was found for 5-HIAA in both pathological gamblers and healthy controls. The results are in line with the presence of altered indoleamine and catecholamine function in pathological gamblers as well as an altered CSF transport from the brain to the lumbar compartment in such gamblers.

The diagnostic value of tau protein, beta-amyloid (1-42) and their ratio for the discrimination of alcohol-related cognitive disorders from Alzheimer's disease in the early stages.

BACKGROUND: Chronic and heavy alcohol abuse or dependence may result in impaired cognition and dementia. The increased risk of Alzheimer's disease (AD) in older individuals interferes with the differential diagnosis, especially when dealing with elderly patients with a long history of alcohol abuse. The aim of the present study was to evaluate the diagnostic value of the putative cerebrospinal fluid (CSF) biomarkers tau, beta-amyloid 1-42 (Abeta42) and their ratio in differentiating alcohol related cognitive disorder (ARCD) from AD. METHODS: Double-sandwich ELISA (Innotest htau antigen and beta-Amyloid (1-42), Innogenetics) were used to quantify the above markers in a total of 20 patients with ARCD, 33 AD patients with mild to moderate dementia and 50 mentally intact subjects. RESULTS: Tau protein successfully differentiated AD from normal ageing with 96% specificity and 93.9% sensitivity and from ARCD with 95% specificity, and 87.9% sensitivity. Abeta42 alone had a specificity of 88% and a sensitivity of 69.7% in differentiating AD from normal ageing, while the corresponding values for differentiating AD from ARCD were 80% and 84.8% respectively. The tau/Abeta42 ratio was better than tau alone for differentiating AD from normal ageing (specificity 94%, sensitivity 97%) and better than any of the candidate markers alone, for differentiating AD from ARCD (specificity 100%, sensitivity 97%). CONCLUSIONS: The combined use of CSF tau and Abeta42 may be a useful tool in the differential diagnosis of ARCD from AD, especially in the early stages, where diagnostic uncertainty is greater.

Lower CSF homovanillic acid levels in depressed patients with a history of alcoholism.

Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.

[Role of calcium and magnesium ions in cerebrospinal fluid in alcoholic-traumatic coma]. / Rolul determinarii ionilor de calciu si magneziu în LCR în coma etilico-traumatica.

The goal of investigation was to determine the role of calcium and magnesium ions in the cerebrospinal fluid in ethylic-traumatic coma. We measured the level of calcium in the cerebrospinal fluid within simple photometric test and the magnesium level within xylidyl blue photometric test. We found a high mortality in patients with high level of calcium in cerebrospinal fluid and low level of magnesium in cerebrospinal fluid. At patients with ethylic-traumatic coma high levels of calcium in cerebrospinal fluid are caused by the excitatory amino acids cascade and increased of hematoencephalic barrier permeability. Decreased levels of magnesium in cerebrospinal fluid are associated with convulsions and a poor prognosis of the patients. These analyses are very important for establishment of prognosis in patients with ethylic-traumatic coma.

Relationship between cortisol and serotonin metabolites and transporters in alcoholism [correction of alcolholism].

BACKGROUND: Stress hormone activation may induce clinical depression via an interference with central serotonergic neurotransmission. In alcoholics, a reduction in serotonin transporters was associated with clinical depression, and an activation of cortisol secretion is frequently found during detoxification. We assessed the interaction between stress hormone activation, serotonin transporters, monoamine metabolites in the cerebrospinal fluid (CSF), and mood states in male and female alcoholics and healthy control subjects. METHODS: The availability of serotonin transporters was measured with [I-123]beta-CIT and SPECT in the raphe area of the brainstem in 31 alcoholics after four weeks of abstinence and in 25 age-matched healthy volunteers. Concentrations of plasma cortisol were measured on the day of the SPECT scan. Within one week after the SPECT scan, we assessed monoamine metabolites and corticotropin-releasing factor (CRF) in the CSF. RESULTS: Clinical depression was associated with a reduction in serotonin transporter availability among male alcoholics. Among male alcoholics and healthy volunteers, CSF 5-HIAA and plasma cortisol concentrations were inversely correlated with the availability of raphe serotonin transporters and positively correlated with the severity of clinical depression. No significant correlations were observed between raphe serotonin transporters and HVA, MHPG and CRF concentrations in the CSF. CONCLUSION: Our findings support the hypothesis of an interaction between reduced serotonin transporters, stress hormone activation and clinical depression. They confirm the hypothesis that serotonergic neurotransmission dysfunction in alcoholism is limited to male alcoholics. The observed interactions between high cortisol concentrations and reduced serotonin transporter availability warrant further studies in major depression and other neuropsychiatric diseases with implied cortisol activation and serotonergic dysfunction.

Effect of subchronic ethanol treatment on plasma and cerebrospinal fluid leptin levels in rats selectively bred for high and low alcohol preference.

The effect of 5-week voluntary ethanol (EtOH) intake on plasma and cerebrospinal fluid (CSF) leptin levels was determined in adult male Warsaw high EtOH preferring (WHP) and low preferring (WLP) rats. EtOH treatment led to a decrease in leptin CSF concentration in WHP rats when compared to EtOH-naive WHP and control Wistar rats. On the contrary, in EtOH-treated WLP rats, both plasma and CSF leptin levels were increased in comparison with EtOH-naive animals. It can be concluded that EtOH treatment led to different response expressed especially by CSF leptin levels in WHP and WLP animals and it may be related to their genetic predisposition.

Biological markers for suicidal behavior in alcohol dependence.

Alcohol-dependent populations have a high lifetime suicide rate (between 7 and 15%, relative risk = 7), and alcoholism is one of the two psychiatric disorders most frequently found in suicidal cases (between 15 and 25%). Biological factors that would detect patients at risk could thus be of value. Carbohydrate-deficient transferrin, monoamine oxidase B, soluble interleukin-2 receptor and cholesterol have been proposed as markers of suicidal risk in alcohol-dependent patients, although nonspecific and with low predictive value. On the other hand, there is large and convergent data stressing the importance of serotonin dysregulation as increasing the risk for aggressive behaviour toward the self, although it is not clear whether serotonin is involved through the altered behavior inhibition system, enhancement of anxiety and depression, or association with specific subtypes of alcohol-dependence, such as early-onset type II alcoholism. Considering the complex but significant impact of alcohol on serotonin metabolism and turnover, it is likely that serotonin mediates a large part of the proneness of ethanol to commit impulsive-aggressive behavior.