CSF MHPG Research Articles

Cerebrospinal fluid monoamine metabolite concentrations in suicide attempt: A meta-analysis.

The purpose of this meta-analysis was to critically examine the data from individual studies on CSF neurotransmitter metabolites to see whether there were consistencies in the results of the comparison of suicide attempters and psychiatric controls and of the comparison of attempted suicides using violent versus nonviolent methods. Systematic literature search across different electronic databases using PubMed/Google Scholar/EMBASE/Cochrane library was conducted for studies that reported concentration of CSF-neurotransmitter metabolites: 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxy phenylglycol (MHPG) in suicide attempters, from January'1981 to November'2020. Standardized mean differences (SMDs) and corresponding 95 % confidence interval (CIs) were deduced for outcome measures. I2 statistics were used to assess heterogeneity within studies. Data were analyzed using STATA software. A total of 36 studies (N = 1987 attempted suicide and N = 1235 psychiatry control) were included for the meta-analysis. We found CSF levels of all the 3 metabolites i.e. 5-HIAA (SMD= -0.43; 95 %CI: -0.61, -0.24), HVA (SMD= -0.16; 95 %CI: -0.33, -0.00) and MHPG (SMD= -0.33; 95 %CI: -0.71, -0.05) were lower in suicide attempters. While the findings were consistent for 5-HIAA, they were inconsistent for the HVA and MHPG. CSF levels of 5-HIAA (SMD= -0.66; 95 %; CI: -1.01, -0.31), HVA (SMD= -0.14; 95 %CI: -0.45, 0.16) and MHPG (SMD= -0.12; 95 %CI: -0.56, 0.31) were significantly lower in violent suicide attempters than non-violent attempters. No significant publication bias found in any study. We found a significant association between lower levels of CSF 5-HIAA in suicide attempters, particularly the violent ones, compared to psychiatric controls, whereas findings from CSF HVA and MHPG were inconsistent.

Monoamine metabolites in ventricular CSF of children with posterior fossa tumors: correlation with tumor histology and cognitive functioning

The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are involved in the regulation of multiple neuronal functions, and changes in monoamine concentrations in the CSF have been detected in several disorders. The aim of the present study was to investigate the role of biogenic amines in the ventricular CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning. Twenty-two children with posterior fossa tumors who were treated surgically at Children's Hospital "Agia Sofia" were studied. Patients ranged in age from 5.5 to 15 years. The study population included patients who suffered from hydrocephalus and were treated by ventriculoperitoneal shunt placement. During the operation for shunt placement, a CSF sample was obtained for the assessment of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Simultaneously, a blood sample was also obtained for assessment of the same metabolites in the serum. The concentration of vanillylmandelic acid (VMA) was evaluated in 24-hour urine samples in 11 patients. Cerebrospinal fluid from a control group of children was also studied. Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC). Twelve patients suffered from astrocytomas, 9 from medulloblastomas, and 1 from an ependymoma. The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas. Twenty-four-hour urine samples of VMA were significantly higher in patients with astrocytomas compared with patients with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC and there was a trend toward a significant negative correlation with the total WISC score. Homovanillic acid in CSF was positively correlated with the performance scale of the WISC. There was a significant correlation between HVA and MHPG levels in CSF. The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum. Twenty-four-hour urine VMA samples were statistically significantly correlated with HVA concentration in both CSF and serum, with MHPG in CSF, and with 5-HIAA in serum. This study showed that children with posterior fossa tumors have differences in the levels of monoamine metabolites in CSF. Further studies with a larger number of patients are obviously needed to verify these observations as well as studies to correlate the monoamine metabolite levels with the neuropsychological and behavioral findings in children with posterior fossa tumors.

CSF Tau, Aβ42, and MHPG Differentiate Dementia with Lewy Bodies from Alzheimer's Disease

Differentiating dementia with Lewy bodies (DLB) from Alzheimer's Disease (AD) can be difficult because of the substantial overlap in clinical features. Since deficits in serotonergic and dopaminergic pathways seem more pronounced in DLB patients, we investigated whether cerebrospinal fluid (CSF) analysis of neurotransmitter metabolites, in addition to brain-specific proteins, may improve the differentiation between DLB and AD. We retrospectively compared CSF concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the brain-specific proteins total tau (t-tau), phosphorylated tau protein (p-tau), and amyloid-β42 (Aβ42) in 45 patients with AD (mean age 71.6 years; 34 (76%) men; 44 probable AD, 1 definite) and 23 patients with DLB (mean age 71.6 years; 18 (78%) men; 6 possible DLB, 16 probable, 1 definite). The concentrations of all neurotransmitter metabolites, as well as those for t-tau and p-tau protein, were significantly lower in DLB compared to AD, irrespective of the diagnostic certainty (i.e., possible or probable). The currently used combination of Aβ42, p-tau, and t-tau yielded a sensitivity of 92.9% and a specificity of 90%. The addition of MHPG resulted in an increased sensitivity of 97.6% and a specificity of 95% for the discrimination between DLB and AD. In conclusion, the combination of MHPG and the brain specific proteins t-tau, p-tau, and Aβ42 in CSF were associated with the clinical diagnosis of DLB and discriminated between AD and DLB with high diagnostic accuracy, suggesting this combination as a potential biomarker for DLB.

Influence of parenting style on the offspring's behaviour and CSF monoamine metabolite levels in crossfostered and noncrossfostered female rhesus macaques

We investigated the association between variation in parenting style and the offspring's behaviour and CSF monoamine metabolite (5-HIAA, HVA, and MHPG) levels in rhesus monkeys. Study subjects were 25 two-year-old females reared by their biological mothers and 15 same-aged females that were crossfostered at birth and reared by unrelated mothers. Subjects that were rejected more by their mothers in the first 6 months of life engaged in more solitary play and had lower CSF concentrations of 5-HIAA than subjects that were rejected less. The relation between these variables was generally similar in crossfostered and noncrossfostered females. CSF levels of 5-HIAA were negatively correlated with rates of scratching, a behavioural indicator of anxiety. These results suggest that that early exposure to high rates of maternal rejection can result in higher anxiety later in life, and that this effect may be mediated by serotonergic mechanisms. Variation in maternal protectiveness did not affect offspring behaviour and neither protectiveness nor rejection affected CSF levels of HVA and MHPG. CSF levels of MHPG, however, were negatively correlated with solitary play behaviour and avoidance of other individuals, suggesting that individuals with lower CSF MHPG were more fearful and socially phobic than those with higher CSF MHPG. Taken together, these findings suggest that individual differences in anxiety and fearfulness in young rhesus monkeys are accounted for, at least in part, by variation in CSF levels of monoamine metabolites, and that the development of brain monoamine systems, particularly serotonin, can be affected by early exposure to variable maternal behaviour.

Relationships among CSF monoamine metabolite levels, alcohol sensitivity, and alcohol‐related aggression in rhesus macaques

AbstractA relationship between alcohol intake and aggressive behavior has been demonstrated in both associational and laboratory studies. Among the factors that contribute to aggression during intoxication are a history of violence and the level of alcohol‐induced stimulation. In humans, excessive alcohol intake and alcoholism are predicted by decreased sensitivity, or a low level of response (LOR), to alcohol. In addition, aggressive behavior, LOR, and alcoholism have been attributed to CNS serotonergic dysfunction. Given that they are both related to diminished CNS serotonin, in this study we wanted to determine whether a low LOR to alcohol would be associated with aggression during intoxication in rhesus macaques. Adolescent rhesus macaques (N=115) received an intravenous dose of ethanol (2.2g/kg) and were scored for their levels of response for 30 minutes. Following provocation by an investigator, animals were then scored for aggressive behaviors (lunges, open‐mouth threats, stares, head‐bobs, and barks) for five minutes. At the approximate age of five years, animals were entered into a free‐access alcohol consumption study, during which they were allowed voluntary access for one hour/day, four days/week to aspartame‐sweetened alcohol or vehicle. Alcohol intake for each subject was determined using a computerized collar, which was detected by a station system that measured individual subject consumption rates. Data were analyzed using regression analyses and t‐tests. Decreased sensitivity to alcohol, alcohol‐induced increases in CSF MHPG, and pre‐alcohol CSF levels of 5–HIAA were associated independently with aggression during intoxication (r= −0.32, P= 0.0006 , r = − 0.29, P=0.01, and r= −0.21, P=0.02, respectively). High rates of alcohol‐related aggression predicted future alcohol consumption (r=0.27, p=0.004), even after controlling for rearing condition and monoamine metabolite concentrations, previously shown in these animals to predict alcohol consumption. By investigating the relationships between LOR, central catecholamine reactivity and function, and alcohol‐induced aggression in alcohol‐naïve nonhuman primates, this report provides evidence that alcohol‐induced stimulation and neurotransmitter‐linked predisposition to impulsive aggression independently contribute to aggression during intoxication. This paper further emphasizes the importance of the nonhuman primate model for studying susceptibility to alcohol‐related aggression and alcoholism, because variables such as prior exposure to alcohol are difficult to control in human subjects. Aggr. Behav. 29:288–301, 2003. © 2003 Wiley‐Liss, Inc.

High correlation between salivary MHPG and CSF MHPG.

Determination of 3-methoxy-4-hydroxy-phenylglycol (MHPG) as a major metabolite of noradrenaline may reflect changes in noradrenergic activity dependent on psychiatric illness and drug therapy. This study was designed to investigate the relationship between CSF and salivary MHPG, and thus the utility of saliva MHPG as a marker for CSF MHPG. Twenty-one paired samples of saliva and CSF were assayed for MHPG by solid-phase extraction and HPLC-ED. Salivary MHPG was highly positively correlated with CSF MHPG ( P<0.001). This finding supports the use of salivary MHPG as an index for CSF MHPG, and enhances the usefulness of salivary MHPG measurements as a non-invasive approach for clinical studies investigating noradrenergic systems.

538. Elevation in CSF CRH and reduction in CSF MHPG during pregnancy

538. Elevation in CSF CRH and reduction in CSF MHPG during pregnancy

Altered Dopamine Activity after Recovery from Restricting-Type Anorexia Nervosa

When ill, women with eating disorders have disturbances of mood and behavior and alterations of catecholamine activity. It is not known whether these alterations are cause or consequence of pathological eating behaviors. To avoid confounding effects of pathologic eating behavior, we studied women who were recovered (>1 year, normal weight, regular menstrual cycles, no restricting eating pattern, no bingeing or purging) from anorexia nervosa (AN) and bulimia nervosa (BN) compared to healthy control women. Recovered AN women had significantly lower height-adjusted weight than did recovered BN women. CSF HVA (pmol/ml ± SD), a major metabolite of dopamine, was significantly lower (p < .02) in six restricting-type AN women (131 ± 49) compared to 19 BN women (216 ± 73) and at a trend (p < .08) less than 13 bulimic-type AN women (209 ± 53, p < .06) and 18 control women (202 ± 57, p < .08). These four groups had similar values for CSF MHPG, a norepinephrine metabolite. Dopamine neuronal function has been associated with motor activity, reward, and novelty seeking. These behaviors are altered in restricting-type AN compared to other eating disorder subtypes. A trait-related disturbance of dopamine metabolism may contribute to a vulnerability to develop this sub-type of eating disorder.

Susceptibility to neuroleptic malignant syndrome in Parkinson's disease.

To determine susceptibility to neuroleptic malignant syndrome (NMS) in patients with PD in relation to central monoamine metabolism. CSF levels of homovanillic acid (HVA), 3-methoxy-4-hydroxy phenyletilene glycol (MHPG), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in 98 PD patients (mean age, 77.2 years), including 11 patients with a prior NMS-like episode, by high-performance liquid chromatography with electrochemical detection. Patients with a previous NMS-like episode had worse parkinsonian disability as measured by Hoehn & Yahr scale (3.7 +/- 0.8 versus 3.0 +/- 1.1; p = 0.038) and lower CSF HVA levels (20.9 +/- 17.3 versus 44.7 +/- 22.2 ng/mL; p = 0.001) compared to those without, despite similar age, disease duration, and daily dosages of antiparkinsonian drugs between groups. Logistic regression analysis showed that the CSF HVA level (p = 0.008), but not 5-HIAA level (p = 0.621), was significantly and independently related to NMS, and that the MHPG level (p = 0.070) was tendentially associated with the disorder. Odds ratios (95% confidence intervals) corresponding to 10 ng/mL increment in CSF HVA, MHPG, and 5-HIAA levels were 0.30 (0.13 to 0.73), 4.03 (0.89 to 18.2) and 1.29 (0.47 to 3.58), respectively. Central dopaminergic and possible noradrenergic activity contributes to NMS development in an elderly population of PD patients. Measuring CSF levels of monoamine metabolites may provide a means for identifying NMS susceptibility in PD patients.

Gender and reproductive effects on cognitive function

creases in symptom scores during high dose MT administration of negative mood (irritability, mood swings, violent feelings, hostility), positive mood (euphoria. energy, sexual arousal), and cognitive impairment (distractibility, forgetfulness, confusion). MT significantly decreased CSF MHPG and significantly increased CSF 5-HIAA. Cognitive impairment was associated with relatively blunted suppression of the pituitary gonadal and pituitary adrenal axes by MT. Changes in plasma dehydroepiandrosterone (DHEA) and CSF HVA accounted for approximately 50% of the variance of MT induced symptoms on stepwise regression analysis. The different biochemical and behavioral profiles exhibited in response to MT suggest that in humans, as in animals, the biological and behavioral response to androgens is context dependent. tion from cell surface receptors to various effectors. They are especially important in the CNS, where they play a major role in the amplification and integration of signals, thereby affecting the functional balance between neurotransmitter systems, and have recently been shown to be modulated by sex steroids, most notably ! 7[~-Estradiol. Although a variety of biochemical effects may contribute to the CNS manifestations of (physiological or pathophysiological) alterations in gonadal steroids, modification of G protein function or content (with the inherent amplification of receptor responses) represents an attractive mechanisms. We are presently conducting a study designed to elucidate biochemical and physiological targets of gonadal in humans. Data will be presented on the effects of these key neuromodulatory hormones on the levels and function of various G protein subtypes.

Increased cerebrospinal fluid dopamine and 3,4-dihydroxyphenylacetic acid levels in Huntington's disease: evidence for an overactive dopaminergic brain transmission.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of patients with Huntington's disease (HD) were measured by HPLC. CSF DA, DOPAC, and MHPG levels were found to be increased in HD patients. Levels of HVA, 5-HIAA, and NA in the CSF of HD patients did not differ from those of controls. Changes in CSF DA and DOPAC levels were consistent with previous findings of increased DA tissue content in some brain areas of patients with HD. These results suggest that CSF DOPAC levels could be a more reliable index of overactive dopaminergic brain systems in HD than CSF HVA levels.

Minipump clorgyline administration and CSF amine metabolites in unrestrained monkeys

The irreversible MAO-A inhibitor clorgyline was administered in doses of 0.5 mg/kg (N = 1), 1 mg/kg (N = 3), and 2 mg/kg (N = 1) to 5 young (age 5.5 to 23.9 months) pigtail ( M. nemestrina) monkeys using a 28-day (Alza 2ML4) osmotic minipump. CSF MHPG, 5-HIAA, HVA, and plasma MHPG were measured before and at approximately weekly intervals after pump implantation. Implants were well torelated. CSF MHPG decreased about 75%, 5-HIAA 30%, and HVA from 30–50% with a tendency to plateau by the second week. Plasma MHPG decreased to undetectable levels. The findings demonstrate that long-term inhibition of MAO-A can be produced in unrestrained monkeys by minipump administered clorgyline. There is an apparently greater effect on the norepinephrine system relative to the serotonin and dopamine systems.

Correlations between cisternal CSF and plasma concentrations of HVA, MHPG, 5-HIAA, DA, and NA

In the present work we compared the levels of HVA, MHPG, 5-HIAA, DA, and NA in cisternal CSF (cCSF) with their plasma concentrations. Our question was whether or not the levels of these substances are in good accordance with the levels in cisternal CSF

Relationship between plasma and cerebrospinal fluid norepinephrine and dopamine metabolites in a nonhuman primate.

Major and minor pathways of metabolism in the mammalian CNS result in the formation of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NMN) from norepinephrine (NE), and homovanillic acid (HVA) and 3-methoxytyramine (3-MT) from dopamine (DA), respectively. The correlational relationships between HVA and 3-MT and between MHPG and NMN in primate CSF and plasma have not been described. These relationships may help to elucidate the usefulness of CSF and plasma metabolites as indices of CNS NE and DA activity. In addition, because NMN is unlikely to cross the blood-brain barrier. CSF NMN concentrations would not be confounded by contributions from plasma, which is a major issue with CSF MHPG. We have obtained repeated samples of plasma and CSF from drug-naive male squirrel monkeys and have measured the concentrations of MHPG, HVA, NMN, and 3-MT to define their correlational relationships. For the NE metabolites, significant correlations were obtained for CSF MHPG and NMN (r = 0.806, p less than 0.001), plasma MHPG and CSF NMN (r = 0.753, p less than 0.001), and plasma and CSF MHPG (r = 0.776, p less than 0.001). These results suggest that CSF and plasma MHPG and CSF NMN may reflect gross changes in whole brain steady-state noradrenergic metabolism. Only a single significant relationship was demonstrated for the DA metabolites, with CSF 3-MT correlating with plasma HVA (r = 0.301, p less than 0.025). The results for the DA metabolites probably reflect regional differences in steady-state brain dopaminergic metabolism.

Biogenic amine metabolites in human CSF after hypoxia due to cardiac arrest

The concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) were determined in CSF of patients with hypoxia due to circulatory arrest. Patients were divided into neurologically disabled and recovered according to the Glasgow Coma Scale. CSF was collected 4, 28, 76 and 172 h after commencement of resuscitation and once from control patients subjected to spinal anaesthesia. The initial concentrations of MHPG, 5-HIAA and HVA were significantly higher in a subgroup of neurologically disabled patients who died within 76 h. In recovered patients the concentration of MHPG declined with time to the value of the control group, whereas it increased in neurologically disabled patients. In the latter group the concentration of 5-HIAA also showed an increase with time, whereas in recovered patients it declined after an initial rise. It is concluded that high concentrations of MHPG, 5-HIAA and HVA in CSF may be prognostic for hypoxic brain injury after cardiac arrest.

CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that was followed by replacement with placebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and 5-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.

Intercorrelation of CSF HVA, 5-HIAA, and MHPG before and after probenecid administration

Intercorrelation of CSF HVA, 5-HIAA, and MHPG before and after probenecid administration

Selective attention in Alzheimer's disease: CSF correlates of behavioral impairments

CSF levels of HVA, 5-HIAA, and free MHPG, the major metabolites of dopamine, serotonin, and norepinephrine respectively, were measured in 22 patients with AD. These 22 patients were also administered tests of picture-recognition and attentional focusing as part of an earlier experiment. A significant association between deficits in attentional focusing and reduced levels of free MHPG in CSF was noted. These results suggest that behavioral measures can identify patients with noradrenergic involvement.

CSF‐amine metabolites in depression, dementia and in controls

Lumbar CSF concentration of 5-HIAA, MHPG, and HVA were measured in patients with depression, dementia due to normal pressure hydrocephalus (NPH) and in controls. Moreover, ventricular concentrations of the metabolites were measured in patients with NPH. It was aimed to match patients and controls for age, sex, and body height. Non-parametric statistics were used throughout the study. No differences in lumbar concentrations of CSF 5-HIAA, MHPG and HVA were found between the different diagnostic groups. A ventriculo-lumbar gradient of 5-HIAA and HVA being 4:1 and 5:1, respectively, was found in patients with NPH. No correlation between the difference in ventricular and lumbar concentrations and body height was found, suggesting that body height may be an inaccurate measure for the rostro-caudal gradient. Moreover, no correlation between ventricular and lumbar levels of 5-HIAA and HVA was seen.

Consistent evidence for a biological subtype of depression characterized by low CSF monoamine levels

Analysis of previously published CSF monoamine data has revealed statistical evidence for a biological subtype of depression, characterized by abnormally low CSF-5HIAA and CSF HVA. Using maximum likelihood gaussian mixture analysis we were able to resolve the empirical frequency distributions of both CSF HVA and CSF 5-HIAA into two component normal mixtures. Simultaneous analysis of both CSF 5-HIAA and CSF HVA revealed a two component bivariate normal mixture distribution in which 35% of the depressed patient sample were classified in the low subgroup. No evidence for mixture distributions was found in controls. Analysis of CSF MHPG revealed a single component normal distribution with virtually identical mean and variance in both patients and controls. These results are shown to be virtually identical to parallel analyses conducted on CSF monoamine data collected as part of the NIMH collaborative study on the psychobiology of depression study.