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.     

Age effect on dopamine and serotonin metabolite levels in cerebrospinal fluid

Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in lumbar cerebrospinal fluid from a group of patients ranging in age from 1 week to 45 years. Quantitation of these biogenic amine metabolites was achieved using a gas chromatographic/mass spectrometric technique. The subjects had various specific disorders of the nervous system, though patients with movement disorders and biochemical defects known to affect the neurotransmitter systems examined in this study were specifically avoided. The results indicated a strong inverse correlation in children between CSF HVA and 5-HIAA concentrations and age. The decline in these metabolites with age appeared to be exponential. No significant age effect was observed for MHPG. The results indicate the importance of comparing CSF metabolite levels in children with values in age-matched controls.     

CSF concentration gradients of monoamine metabolites in patients with hydrocephalus.

Concentration gradients of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed in 762 successive CSF fractions (2 ml lumbar CSF) from 15 patients with the adult hydrocephalus syndrome (AHS) and 11 patients with hydrocephalus of other causes (mixed group). A mean volume of 49.6 (SD 11.8) ml CSF was removed in the AHS group and 56.4 (10.2) ml in the mixed group. The CSF was collected with a specially designed carousel fraction collector and the corresponding CSF dynamics were continuously registered by a constant pressure CSF infusion method. Pronounced gradients in CSF HVA and CSF 5-HIAA were seen in both patient groups in the first 25 ml of CSF removed. The concentration curves levelled off, despite the removal of larger amounts of CSF and stabilised at about twice the initial concentrations. This phenomenon has not been described before. Concentrations of HVA and 5-HIAA in the first CSF fraction correlated strongly with concentrations in fractions up to about 40 ml. A positive correlation between the first fraction of CSF HVA and CSF 5-HIAA concentrations and CSF outflow conductance was found in the AHS group. There was no gradient in MHPG. It is suggested that the rostrocaudal gradients in CSF HVA and 5-HIAA may be explained by a downward flow of CSF along the spinal cord with absorption of metabolites occurring during passage. Mixing of CSF from different CSF compartments, extraventricular production sites of CSF, clearance of metabolites to venous blood or extracellular fluid, and CSF outflow conductance are probably important determinants of the plateau phase in patients with hydrocephalus. It is concluded that lumbar CSF does not exclusively reflect the concentrations of HVA, 5-HIAA, or MHPG in the ventricles. It should be noted that these results obtained in patients with hydrocephalus may not be applicable to other groups of patients or normal subjects.     

Monoamine metabolites in CSF and suicidal behavior

Cerebrospinal fluid concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) were measured in 30 psychiatric patients who had attempted suicide and 45 healthy volunteers. The suicide attempters had a significantly lower CSF 5-HIAA level than the controls, especially those who had made more violent attempts. After adjustment for differences in body height and age between controls and patients, the difference in 5-HIAA level became even more marked. Concentrations of 5-HIAA also were lower than normal in suicidal patients who were not diagnosed as depressed at the time of lumbar puncture, while HVA levels were lowered only in the depressives. A follow-up study of these and 89 more patients (depressed and/or suicidal) revealed a 20% mortality by suicide within a year after lumbar puncture in patients with a CSF-HIAA level below the median.     

抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Concentration gradient of CSF monoamine metabolites in children and adolescents

Whether the lumbar cerebrospinal fluid (CSF) concentration gradient of monoamine metabolites found in adults is influenced by age or pubertal status was studied in 26 children ranging from 6.5 to 17.3 years of age. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-power liquid chromatography (HPLC) with electrochemical detection. Eight patients were prepubertal (Tanner stage I). The slopes in units of picomoles/milliliter/milliliter for regression lines for CSF monoamine metabolite concentrations versus milliliter of CSF collected were 5.07 +/- 0.65, 10.13 +/- 2.0, and 0.67 +/- 0.22 for 5-HIAA, HVA, and MHPG, respectively, for the group as a whole. Significant correlations with age, height, weight, or Tanner stage were not found for the HVA or MHPG concentration gradients. Tanner stage and 5-HIAA slope were significantly correlated. Three of eight prepubertal patients had nonsignificant 5-HIAA gradients. CSF studies in pediatric populations must control for aliquot collected, as the size of the gradient could produce differences sufficient to mimic a "positive" clinical study if the aliquots collected are not the same.     

CSF studies on the relationship between dopamine and 5-hydroxytryptamine in Parkinsonism and other movement disorders.

In Parkinson's disease, the concentration of homovanillic acid (HVA) was reduced in lumbar CSF from patients with idiopathic Parkinsonism (n = 54, P less than 0.05) and post-encephalitic Parkinsonism (n = 19, P less than 0.01). The reduction in the concentrations of 5-hydroxyindolylacetic acid (5-HIAA) was not significant, and there was no alteration in the levels of 4-hydroxy-3-methoxyphenylethylene glycol (MHPG). Treatment with L-dopa increased the concentration of HVA in the CSF (P less than 0.05) but had no effect on the levels of 5-HIAA and MHPG. Carbidopa given in combinations with L-dopa produced similar CSF concentrations of dopa as did L-dopa alone but caused less than half the rise in HVA. Fourteen patients who became functionally independent on treatment with L-dopa had higher 5-HIAA levels than 23 patients who showed no such improvement (P less than 0.001), suggesting that intact 5-hydroxyltryptamine neurones may be important in the therapeutic response to L-dopa. In a variety of movement disorders, the levels of HVA, 5-HIAA, and MHPG were not significantly different from age-matched controls. Treatment with tetrabenazine did not significantly alter the metabolite levels in patients in whom it produced either improvement, or side effects.     

CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls

A total of 114 subjects (41 depressed, 20 schizophrenic, 15 manic, and 38 normal controls) underwent lumbar puncture and their CSF was analyzed for levels of tyrosine, tryptophan, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), choline, gamma-aminobutyric acid (GABA), and calcium. Results showed that depressed patients, particularly those over 40 years of age, had lower levels of GABA than did controls, and that their level of HVA increased with age, while controls' decreased. Schizophrenic subjects tended to have higher levels of 5-HIAA and manic subjects tended to have higher levels of HVA and MHPG. Age-associated changes were found in HVA, 5-HIAA, MHPG, GABA, and choline concentrations.     

CSF monoamine metabolites and MRI brain volumes in alcohol dependence

Correlations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepinephrenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures.     

Relationship between CSF neurotransmitter metabolites and aggressive behavior in Alzheimer's disease

To assess neurochemical correlates of aggressive behavior in Alzheimer's disease (AD) we examined concentrations of homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in lumbar cerebrospinal fluid (CSF) of 11 clinically diagnosed Alzheimer's disease (AD) patients and 12 non-demented age-equivalent controls. There were no significant differences between AD patients and controls in CSF HVA concentrations. However, the CSF 5-HIAA content was significantly lower in AD patients compared to controls. Patients without aggressive behavior had significantly lower concentrations of HVA and 5-HIAA than those with aggression, in whom concentrations were preserved compared to non-demented controls.     

Monoamine metabolites in cerebrospinal fluid during and after acute cerebral ischemia

In order to understand the role of monoamines in cerebral ischemia, 3-methyoxy-4-hydroxyphenylglycol(MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid(HVA), the three major unconjugated monoamine metabolites in cerebrospinal fluid (CSF), of 33 patients and 18 controls were measured with high performance liquid chromatography. Results showed all three metabolites were raised in patients with severe ischemia, but only MHPG and 5-HIAA were elevated significantly, MHPG changes more quickly and regularly as a consequence of cerebral ischemia than the two others. A positive correlation between any pair of metabolites was found in controls and in patients in the first week after stroke, but not at the end of the second week. Computer assisted multivariate analysis indicated 5-HIAA and MHPG correlated more closely with the state of illness in the acute stage, whereas HVA correlated the least. Possible explanations for the changes of CSF levels of amine metabolites are discussed.     

The changes of monoamine metabolites in CSF of patients with cerebral stroke]

For understanding of the role of monoamines in cerebral ischemia, 3-methoxy-4-hydroxyphenylglycol (MHPG), hydroxyindoleacetic acid (5HIAA) homovanillic acid (HVA) the three major monoamine metabolites in CSF of 33 patients and 18 controls were measured with high-performance liquid chromatography. Results showed MHPG was more sensitive to cerebral ischemia than the two others. All three metabolites were elevated in patients with severe ischemia but only MHPG and 5-HIAA were significantly elevated. A positive correlation between any two of metabolites was found in controls and in patients in the first week after stroke but altered at the end of the second week. Computer assisted multivariate analysis indicated 5-HIAA might contribute more to the state of illness in the acute stage while HVA the least. Clinically, MHPG appeared to be the most significant element on reflecting the degree of the damage and the prognosis of the disease among the metabolites.     

CSF monoamine metabolites in schizophrenic patients

The monoamine metabolites 3-methoxy-4-hydroxyphenyglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 16 psychiatrically health controls and in 28 schizophrenic patients. There was no difference in CSF MHPG and HVA levels between the group of patients and the controls. CSF levels of 5-HIAA were significantly lower in schizophrenic patients than in controls. Differential analysis of patients with and without neuroleptics revealed that these findings were not due to drug treatment. Positive correlations were found between the level of 5-HIAA and the items: hallucinatory behaviour, grandiosity, and tension as rated on the Brief Psychiatric Rating Scale. As 5-HIAA CSF data are controversial for nosological entities, the search for correlations between 5-HIAA and individual psychopathological variables could provide more specific indices for psychiatric diagnosis, treatment or prophylaxis.     

CSF monoamine metabolites in mania

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.     

Spinal reflexes and the concentrations of 5-HIAA, MHPG, and HVA in lumbar cereborspinal fluid after spinal lesions in man.

Descending bulbospinal pathways that employ specific neurotransmitter substances are known to be capable of modulating segmental reflex activity in the experimental animal. To determine whether this might also occur in man correlations have been sought between the activity in spinal reflex pathways and the lumbar cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) in 12 patients with complete or virtually complete spinal lesions. The concentrations of 5-HIAA and MHPG in lumbar CSF ARE REDUCED AFTER COMPLETE OR VIRTUALLY COMPLETE SPINAL LESIONS IN MAN. This may occur within 18 days of the lesion. MHPG concentrations appear to be inversely related to the level of the lesion. The HVA concentration in lumbar CSF is reduced when there is obstruction of the CSF pathways. No relationship could be demonstrated between the concentrations of 5-HIAA or MHPG in lumbar CSF and the activity in the spinal monosynaptic pathway (estimated from the proportion of the motoneurone pool activated by the Achilles tendon reflex or H reflex) or the activity of a spinal inhibitory mechanism (estimated by the degree of vibratory inhibition of the monosynaptic reflex). Patients with a tonic vibration reflex (TVR) tended to have higher MHPG levels. There appeared to be an association between low CSF HVA and enhanced vibratory inhibition of the monosynaptic reflex in the nine patients whose spinal lesions were complete.     

Monoamine metabolites in cerebrospinal fluid in multiple sclerosis.

The concentrations of homovanillic acid (HVA), 5-hydroxyindolylacetic acid (5-HIAA), and 4-hydroxy, 3-methoxyphenylethylene glycol (MHPG) were estimated in the lumbar cerebrospinal fluid (CSF) of control subjects and in some patients who probably, and others who definitely, suffered from multiple sclerosis (MS). In the control group, the concentration of HVA was lower in people who underwent lumbar puncture having fasted and been recumbent for 12 hours before the procedure than in those from whom CSF was obtained under non-standardised conditions. These studies demonstrate that a standardised procedure for lumbar puncture is required in order to obtain meaningful results. In patients suffering from MS the CSF 5-HIAA concentrations were significantly lower than in comparable controls but the HVA concentrations did not differ. There was no relationship between metabolite concentrations, site of lesion, the duration of the disease, gamma-globulin levels nor the occurrence of relapse within the previous month.     

Aberrant monoamine metabolite levels in CSF and family history of schizophrenia. Their relationships in schizophrenic patients

In 36 drug-free schizophrenic patients, lumbar CSF was analyzed by mass fragmentography for the major monoaminergic transmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). High or deviant concentrations of 5-HIAA were significantly related to a family history of schizophrenia. For patients with deviant 5-HIAA levels, the probability for a family history of schizophrenia was eight times higher than in subjects with normal values. High concentrations of HVA also tended to be significantly related to a family history of schizoprenia. The majority of schizophrenic patients, who lacked family history for the disorder, had normal monoamine metabolite concentrations in CSF. The results suggest a coupling between biochemical variables related to central serotonin and dopamine metabolism and forms of schizophrenia that have a familial disposition.     

Variations in CSF monoamine metabolites according to the season of birth

The cerebrospinal fluid (CSF) concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as well as their ratios and correlations were analyzed in relation to the season of birth. The sample consisted of 241 drug-free patients participating in psychobiological programs and comprising the DSM-III-R diagnoses of mood, anxiety and adjustment disorders. Significant season-of-birth variations were found even after adjusting for sex, age, height, the diagnostic category and the month of lumbar puncture. Those born during February to April had significantly lower values of 5-HIAA. Values of HVA and of the ratios HVA/5-HIAA and HVA/MHPG were significantly higher for those born during October to January. Correlation coefficients also showed season-of-birth variations. These results may provide an important link for the season-of-birth variations reported for several neuropsychiatric disorders.     

Tryptophan and biogenic amine metabolites in post-mortem human cisternal fluid: effects of post-mortem interval and agonal time.

Cisternal fluid (CF) tryptophan (TRP), 5-hydroxyindole-3-acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were measured from 40 adult cadavers. They were divided into 4 groups (n = 10 in each group), with samples taken 2, 4, 10 and 24 h after death. The CF concentrations of TRP and all determined biogenic amine metabolites were distinctly higher than in lumbar CSF during life, and concentrations of 5-HIAA were also higher in post-mortem samples than in cisternal or ventricular CSF in living humans. The means of the samples of 5-HIAA, DOPAC, HVA and MHPG were not statistically significantly different over time, but some trends were evident. TRP concentrations in CF increased linearly with time (from 4.6 to 23.6 mumol/l, P less than 0.001). CF DOPAC and HVA concentrations were dependent on agonal time and dopamine infusions. Our results imply that both ante-mortem and post-mortem conditions may influence monoamine metabolite and TRP concentrations in CF. These conditions should be accounted for in studies using post-mortem samples to study differences between patient groups in CNS neurochemistry.     

CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis

Levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF, and norepinephrine (NE), epinephrine (E), vanillylmandelic acid, normetanephrine, metanephrine, and MHPG in the urine, were measured in 151 hospitalized patients with affective disorders and in 80 healthy controls following a two-week drug-free period. Unipolar and bipolar depressed subjects differed only in NE and E levels. Compared with controls, depressed subjects had higher CSF MHPG levels, women had higher 5-HIAA levels, and men had lower HVA levels. All urinary metabolites were elevated in depression and mania, with the exception of MHPG. The patterns of NE-E differences discriminated among the forms of affective disorders. These data suggest an imbalance of monoamine transmission in depression, characterized by the hyperactive sympathetic nervous system and adrenal medulla. However, MHPG may not be the measure of choice to reflect this imbalance, necessitating measurement of total body monoamine output.