Relationships of Cerebrospinal Fluid Alzheimer's Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms.

The noradrenergic and dopaminergic systems are affected in Alzheimer's disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine ß-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called -1021C/T or -970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181, p-tau199, and p-tau231), amyloid-ß42 (Aß42), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aß42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aß42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

Central nervous system serotonin and clustering of hostility, psychosocial, metabolic, and cardiovascular endophenotypes in men.

OBJECTIVE: To use measures of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and genotype of a functional polymorphism of the monoamine oxidase A gene promoter (MAOA-uVNTR) to study the role of central nervous system (CNS) serotonin in clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes. METHODS: In 86 healthy male volunteers, we evaluated CSF levels of the primary serotonin metabolite 5HIAA and MAOA-uVNTR genotype for association with a panel of 29 variables assessing hostility, other psychosocial, metabolic, and cardiovascular endophenotypes. RESULTS: The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those of men with less active alleles for 15 of the 29 endophenotypes. MAOA-uVNTR genotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, body mass index, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles. CONCLUSIONS: These findings indicate that, in men, indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, whereas decreased CNS serotonin function is associated with a less favorable profile.

Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression.

OBJECTIVE: Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy. METHODS: In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF. RESULTS: AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD. CONCLUSION: The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.

Energy substrate metabolism among habitually violent alcoholic offenders having antisocial personality disorder.

A large proportion of violent offences in Western countries are attributable to antisocial personality disorder (APD). Several studies have shown abnormal lipid, carbohydrate and low cerebrospinal fluid (CSF) monoamine metabolite levels in habitually violent alcoholic offenders with APD, but it is not clear how these biochemical abnormalities are related to each other in this disorder. We aimed to study energy substrate metabolism among habitually violent offenders with APD. Insulin sensitivity (euglycemic insulin clamp), basal energy expenditure (indirect calorimetry), and CSF 5-hydroxyindoleacetic acid (5-HIAA) measurements were performed on 96 habitually violent antisocial male alcoholic offenders and on 40 normal male controls. Habitually violent, incarcerated offenders with APD had significantly lower non-oxidative glucose metabolism, basal glucagon, and free fatty acids when compared with normal controls, but glucose oxidation and CSF 5-HIAA did not differ markedly between these groups. The effect sizes for lower non-oxidative glucose metabolism among incarcerated and non-incarcerated APD subjects were 0.73 and 0.51, respectively, when compared with controls, indicating that this finding was not explained by incarceration. Habitually violent offenders with APD have markedly lower glucagon and non-oxidative glucose metabolism when compared with healthy controls, and these findings were more strongly associated with habitual violent offending than low CSF 5-HIAA levels, a well-established marker for impulsive violent behavior. Follow-up studies are needed to confirm if abnormal glucose and lipid metabolism can be used to predict violent offending over the course of the APD offender's life span.

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.

Relationship of MAO-A promoter (u-VNTR) and COMT (V158M) gene polymorphisms to CSF monoamine metabolites levels in a psychiatric sample of caucasians: A preliminary report.

Monoamine oxidase A gene promoter (MAOA-uVNTR) and catechol-O-methyltransferase V158M (COMT-V158M) gene functional polymorphisms are reported to be associated with impulsive-aggression, but a biological intermediate effect remains to be determined. This study assessed the association of these polymorphisms with cerebrospinal fluid (CSF) monoamine metabolites as endophenotypes. Ninety-eight Caucasian psychiatric subjects were assessed for Axis I and II diagnosis. Subjects were genotyped for the functional polymorphisms, MAOA-uVNTR and COMT-V158M. CSF was obtained by lumbar puncture. Relationships of the two polymorphism to monoamine metabolites: HVA, 5-HIAA, and MHPG were examined. The higher-expressing MAOA-uVNTR genotype was associated with higher CSF-HVA levels in males only (n = 46) (195.80 pmol/ml, SD = 61.64 vs. 161.13, SD = 50.23, respectively; P = 0.042). No association was found with diagnosis. COMT-V158M had no association with CSF monoamine metabolites. The association of MAOA-uVNTR with dopaminergic activity in males is a preliminary finding that needs to be replicated in a larger sample of Caucasian males and relationships sought with clinical phenotypes. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Platelet monoamine oxidase activity in a nonhuman primate model of type 2 excessive alcohol consumption.

OBJECTIVE: Low platelet monoamine oxidase (MAO) activity is associated with "type 2 alcoholism." MAO activity is also affected by cigarette smoking. Since most alcoholics are smokers, it is difficult to evaluate the possible effect of platelet MAO activity on alcoholism independently of the effects of smoking. The authors investigated the relationship between platelet MAO activity and excessive alcohol consumption in rhesus macaques. METHOD: Platelet MAO activity and CSF metabolite concentrations were measured. The authors also investigated level of voluntary alcohol intake and social dominance rank. RESULTS: Subjects with low platelet MAO activity consumed alcohol to excess, had low CSF 5-hydroxyindoleacetic acid concentrations, and were less competent socially. CONCLUSIONS: These findings show that nonhuman primates that exhibit type 2-like alcohol features display low platelet MAO activity and support the notion that platelet MAO activity is a biologic marker for central serotonergic activity. The results also challenge the hypothesis that low platelet MAO activity in type 2 alcoholism is simply an artifact of smoking.

Relapse in violent crime in relation to cerebrospinal fluid monoamine metabolites (5-HIAA, HVA and HMPG) in male forensic psychiatric patients convicted of murder: a 16-year follow-up.

OBJECTIVE: Our purpose was to investigate if low levels of cerebrospinal fluid (CSF) monoamine metabolites of 5-HIAA, HVA and HMPG predict relapse in violent crimes. METHOD: Relapse in crime and level of CSF monoamine metabolites (5-HIAA, HVA and HMPG) was studied in a group of 29 murderers. The follow-up was 16 years. RESULTS: Fourteen of the 29 murderers were convicted of crime; nine of them committed violent crimes; one was convicted of a new murder. The differences in mean CSF monoamine metabolites were lower in subjects who relapsed into any type of crime, but only the difference in mean CSF HVA was statistically significant. CONCLUSION: The risk to commit new murder is very small in males who earlier have been convicted of murder. Low levels of CSF HVA is associated with an increased risk for relapse in any type of crime.

Cognitive and biochemical processes in depressed adult outpatients: a test of the circular process model.

The circular process model is a psychobiological model of depression, in which it is postulated that catecholamines and negative cognitions interact to influence depression. Since its publication, there have been no empirical tests to support or refute the model. This study tested the model in 92 depressed adult outpatients with non-bipolar non-psychotic depression. There were no significant bivariate correlations among the biochemical and cognitive measures. However, the interactive model was supported by results of two out of three hierarchical regression analyses, in which the biochemical-by-cognitive interactive terms significantly predicted depression after the main effects of each variable were accounted for. These findings show sufficient evidence in support of the Circular Process Model to warrant further testing over the treatment period.

Serotonin and aggression in children.

Research consistently indicates that in animals and adults, reduced central serotonergic (5-HT) function is associated with increased aggression. This relationship has been elucidated via cerebrospinal fluid monoamine metabolite levels, hormonal responses to pharmacologic challenge using serotonergic probes, platelet receptor binding studies, and, more recently, through molecular genetic approaches. In contrast, studies examining the relationship of 5-HT to aggression in children have been characterized by inconsistent findings. The literature examining the relationship between central 5-HT function and aggression is reviewed. Several hypotheses that might account for the discrepancies in the child literature are examined.

Family psychiatric history, cerebrospinal fluid monoamine metabolites, and temperament in infants.

BACKGROUND: Variations in cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, and homovanillic acid have been associated with behavioral abnormalities in nonhuman primates, and with psychopathology in studies of children and adults. METHODS: We assayed monoamine metabolites in "left-over" spinal fluid from 167 neurologically normal newborn infants (0-3 months of age), and later (at age 18-21 months of age) obtained their family psychiatric histories and assessed their temperament using the Colorado Childhood Temperament Inventory (CCTI). RESULTS: Family history of antisocial personality disorder predicted significantly lower scores for soothability (p = .003) at 18-21 months. There were no statistically significant associations between newborn monoamine metabolite levels and any aspect of temperament on the CCTI. CONCLUSIONS: These findings suggest complex relationships between genetic liability for psychiatric disorders and CSF monoamine metabolite levels; those relationships do not seem to be mediated by infant temperament. It appears likely that interindividual differences in monoamine metabolite levels change over the course of development in humans.

Clinical characteristics and biological parameters in temperamental clusters of suicide attempters.

A sample of 215 suicide attempters was categorized in a cluster analysis into four groups according to temperamental trails. Monoamine metabolites in the cerebrospinal fluid were analysed (n = 106). Dexamethasone suppression tests (DST) were performed (n = 154) and the activity of the enzyme monoamine oxidase in platelets (pl-MAO) was assessed (n = 103). Patients belonging to the two clusters with the most deviant temperament profiles (nos 2 and 3) were young and scored high on the Beck Hopelessness Scale and the Suicide Assessment Scale. "Cluster 3" ("neurotic, impulsive, aggressive") patients often had dysthymia and axis II, cluster B diagnoses (e.g. borderline or histrionic personality). "Cluster 2" ("neurotic and introverted") patients often had major depression. The "Cluster 1", with on the whole a normal temperament profile, had significantly higher levels of post-DST cortisol than the other clusters. The "Cluster 4" had a normal temperament profile. Adjustment disorders were most common in "Cluster 1" and "Cluster 4". The monoamine metabolite levels did not differ between the clusters, and the differences in pl-MAO activity disappeared after adjusting for age and gender. The results suggest that temperament profiles in suicide attempters are related to psychiatric diagnoses, suicidality, hopelessness, and post-DST cortisol, but are not predictive of completed suicide.

Platelet MAO-B activity as a marker of behavioural characteristics in dementia disorders.

Both low and high platelet MAO-B (pMAO-B) activity is considered an indicator of increased vulnerability in psychopathology. How the activity of this peripheral enzyme can be linked with the sophisticated functions of the central nervous system (CNS) is not clear; in man, evidence exists that the genetic mechanisms determining the size or capacity of the central serotonin system are common to platelet and brain MAO. In the present study pMAO-B activity was evaluated in demented patients suffering from early-onset Alzheimer's disease (AD), late-onset Alzheimer's disease (SDAT), vascular dementia (VD), and controls. In these dementia categories, the relationship between pMAO-B activity and clinical features, and between pMAO-B activity and cerebrospinal fluid (CSF) monoamine metabolites (3-methoxy-4-hydroxyphenyl-glycol, MHPG; 5-hydroxy-indoleacetic acid, 5-HIAA; homovanillic acid, HVA) was also investigated. pMAO-B activity was significantly higher in SDAT patients, compared to controls and AD. Age, as covariate, failed to show any significant effect, and no association was found between pMAO-B activity and CSF monoamine metabolites. The correlation analysis between pMAO-B and neuropsychological scores showed a highly significant positive relationship with GBS-emotional impairment (N = 40, r = 0.72, p < 0.01) in the SDAT group. This result suggests the importance of platelet MAO-B activity as biological marker also in old-age dementias, namely senile dementia of Alzheimer type, where the increased activity of this enzyme might constitute a marker for vulnerability toward behavioural disturbance, i.e., emotional deterioration.

Biodevelopmental aspects of conduct disorder in boys.

The association between biochemical parameters and conduct disorder (CD) was studied in 22 boys admitted to a residential center. Three-methoxy-4-hydroxyphenylglycol (MHPG) levels were significantly higher in prepubertal CD youth than in pubertal/post pubertal CD youth. Homovanillic acid (HVA) levels were significantly lower in CD youth under age 12.0 years than in non CD youth under age 12.0 years. The implications of these biodevelopmental findings in the study of CD are discussed.

[Natural modulators of the function of the amine oxidase system in the body]. / O prirodnykh moduliatorakh funktsii sistemy aminoksidaz v organizme.

In cerebrospinal fluid (CSF) obtained from patients with chronic alcoholism natural modulators of monoamine oxidase (MAO) activity, containing in human mitochondrial and microsomal fractions or in rat brain mitochondria, have been found. These modulators, which were previously unknown, did not affect the activity of partially purified diamine oxidase from human placenta with 14C-putrescine as a substrate. The MAO modulators from CSF were thermostable (during 3 min at 100 degrees), penetrated through dialysing membrane thus differing from high molecular modulators of MAO previously described. In the system containing membrane bound MAO from human placenta, where the MAO-A is predominating, the modulators studied mostly inhibited deamination of 14C-serotonin. However, in the system containing membrane bound MAO from rat brain with prevalence of the MAO-B, the modulators from human CSF caused either inhibition or stimulation of oxidative deamination of 14C-serotonin or 14C-beta-phenylethylamine used as substrates. The modulators studied were not similar to tribulin (isatin) or quinolinic acid in their effects on catalytic properties of the amine oxidases investigated.

Monoamine oxidase localization in the ependyma and infundibular recess in the catfish Clarias batrachus and its probable significance.

The presence of monoamine oxidase (MAO) in the cerebrospinal fluid (CSF) and MAO positive tracts bridging the CSF and the subependyma strongly suggest the involvement of CSF in the neuroendocrine control of hypophysial function.