Concentration gradients of monoamine metabolites in human cerebrospinal fluid.

The monamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), vanillylmandelic acid (VMA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were analysed in CSF from different regions of the CSF system to study the caudocranial concentration gradient of the metabolites. Four consecutive 10 ml fractions of CSF were withdrawn in 17 patients during the course of four minutes. The CSF pressure was monitored through a lumbar cannula because of suspected adult hydrocephalus. A pronounced gradient of the HVA concentration was found with a ratio between the last and the first fraction of 1,7. 5-HIAA showed a slight increase while HMPG and VMA showed no increase at higher levels of the CSF system. The results suggest that lumbar HVA reflects dopaminergic activity in the brain, whereas lumbar 5-HIAA and HMPG/VMA reflect the activity of 5-hydroxytryptamine and noradrenaline secreting neurones in both the brain and the spinal cord.     

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.     

5-Hydroxyindoleacetic acid and homovanillic acid in human cerebrospinal fluid below partial and complete spinal subarachnoid block

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were investigated by lumbar cerebrospinal fluid (CSF) of 21 patients with partial and total spinal subarachnoid block. HVA levels in CSF below a complete block were significantly lower and 5-HIAA levels were signigicantly higher than controls. Below a partial block, HVA levels were normal; 5-HIAA levels were higher than in patients with complete block. Possible explanations for these findings are discussed.     

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.     

Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid.

Concentrations of HVA, 5-HIAA, ascorbic acid, and uric acid in the lumbar and cisternal cerebrospinal fluid (CSF) were measured in psychiatric and neurologically impaired patients. The concentration of HVA is 6.1 times and of 5-HIAA 2.7 times higher in cisternal than in lumbar samples, the cisternal level of uric acid is half that of the lumbar region, but no significant differences were found in ascorbic acid concentrations. Correlation between lumbar and cisternal metabolite concentrations is high for 5-HIAA and ascorbic acid, and is less for HVA and uric acid. In cisternal CSF there is a significant correlation between levels of HVA-5-HIAA, 5-HIAA-ascorbic acid, and 5-HIAA-uric acid. These correlations disappear in lumbar CSF. These findings indicate that extrapolations to cisternal neurotransmitter metabolite concentration from lumbar measures are unwarranted for HVA, but not for 5-HIAA.     

Use of cerebrospinal fluid drawn at pneumoencephalography in the study of monoamine metabolism in man

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in CSF obtained after injection of air during pneumoencephalography (PEG) than in lumbar CSF, as drawn before the injection. There was a high correlation between levels in the `mixed' and lumbar samples of CSF in the case of each of the two acids. The concentration of lumbar HVA, but not that of 5-HIAA, was negatively correlated with CSF pressure. 5-HIAA levels were low in both samples of CSF in a group of epileptics, by comparison with controls. In two patients with Kufs disease and in one with Niemann-Pick disease, the concentration of HVA was very low in the lumbar sample. The application of a standardized PEG technique in the study of monoamine metabolism in man is suggested.     

Monoamine acid metabolites and cerebrospinal fluid dynamics in normal pressure hydrocephalus: preliminary results.

Lumbar and ventricular CSF concentration of homovanillic acid (HVA) and 5-hydroxy-indole-acetic acid (5-HIAA) have been determined in 13 patients admitted to hospital for suspected normal pressure hydrocephalus. Low values of HVA in lumbar CSF were found in all patients with reduced CSF absorption and CSF flow inversion. The HVA lumbar concentration remained low after shunt procedure; it increased if obstruction of the shunt occurred. The ventricular CSF concentration of HVA was normal before surgery; it became higher, in two cases, after surgery. No important variations were found in the lumbar and ventricular CSF concentration of 5-HIAA. The possible mechanisms and diagnostic value of these findings are discussed.     

Monoamine metabolites in the CSF of epileptic patients.

To assess the possible role of amine neurotransmitters in human epilepsy, we measured metabolites of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), dopamine (homovanillic acid [HVA]), and norepinephrine (3-methoxy-4-hydroxyphenylethylene glycol [MHPG]) in the lumbar cerebrospinal fluid (CSF) of patients with partial complex seizures and in neurologic controls. Untreated epileptic patients had lower concentrations of 5-HIAA and HVA in the lumbar CSF than the controls, but the differences were not statistically significant. Among epileptic patients receiving effective antiepileptic drug treatment, the HVA concentration was within the control range. Mean MHPG concentrations were similar in patients and controls. From the epileptic patients whose CSF was obtained at pneumoencephalography we obtained a second sample of CSF that was originally in the basal cisterns. No significant differences between treated and untreated patients were found for any of the three metabolites. The concentrations of HVA and 5-HIAA were higher in cisternal than in lumbar CSF, but there was no such gradient for MHPG.     

CSF monoamine metabolites in dementia of the Alzheimer type and controls: Evidence for lower levels of homovanillic acid and 5-hydroxyindoleacetic acid in patients

The monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) were measured in 15 patients with dementia of the Alzheimer type (DAT) and 48 controls by means of a sensitive liquid chromotagraphic method. Relative to a large group of control subjects, the mean CSF 5-HIAA and HVA levels in patients with DAT appeared to be significantly lower. This finding appeared to be sex-related, in that the decrease in CSF monoamine metabolite levels could be attributed predominantly to male patients. A statistically significant relationship was found between 5-HIAA and HVA in both patients and controls. Linear regression analysis revealed a statistically significant positive relationship between age and CSF HVA in female controls only. No relationship was found between 5-HIAA and age either in patients or in controls. It is concluded that CSF 5-HIAA and HVA levels are decreased in male patients with DAT, probably signalling a sex-related change in serotonin and probably dopamine functioning in the central nervous system.     

Self-rated childhood emotional neglect and CSF monoamine indices in abstinent cocaine-abusing adults: possible implications for suicidal behavior

Non-human primate studies suggest that early environmental influences may have an enduring effect on central serotonin function. Therefore, it was decided to examine in humans whether childhood trauma might be related to cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) as an adult. A total of 29 withdrawn cocaine-dependent patients completed the Childhood Trauma Questionnaire. They also had a lumbar puncture for determination of CSF concentrations of 5-HIAA. CSF concentrations of the dopamine metabolite homovanillic acid (HVA) were also determined. Childhood emotional neglect scores showed significant negative correlations with CSF levels of 5-HIAA and HVA, and patients with emotional neglect scores above the median had significantly lower CSF 5-HIAA and HVA levels than patients with emotional neglect scores at or below the median. These findings suggest the possibility that childhood trauma may have an effect on central monoamine function as an adult.     

Brain MRI,lumbar CSF monoamine concentrations,and clinical descriptors of patients with spinocerebellar ataxia mutations.

OBJECTIVES: To serially assess changes in lumbar CSF biogenic amines, radiographic characteristics, and neurological signs in 34 patients with dominantly inherited ataxia. METHODS: Mutational analysis was used to identify genetic subgroups. Annual assessment of lumbar CSF monoamine metabolites using a gas chromatographic/mass spectrometric method and morphometric measurements of the cerebellum, pons, and the cervical spinal cord on MRI were analysed for each patient and compared with normal controls. RESULTS: Patients with CAG trinucleotide repeat expansions on chromosome 6p (mutSCA1) and chromosome 14q (mutSCA3) had only about one half the normal concentrations of lumbar CSF homovanillic acid (HVA) whereas, 5-hydroxyindoleacetic acid (5-HIAA) concentrations were similar to those in age matched normal subjects. The HVA and 5-HIAA concentrations in clinically similar patients without mutSCA1 or mutSCA3 were normal. One year after the first study, HVA concentrations were reduced by a mean of 22% regardless of the patient''s SCA mutation. Abnormalities on MRI were consistent with a spinopontine atrophy in patients with mutSCA3, spinopontocerebellar atrophy in patients with mutSCA1, and "pure" cerebellar atrophy in patients without these mutations. CONCLUSIONS: Quantitative MRI measurements were not useful in monitoring progression of disease but lumbar CSF HVA concentrations and total scores on a revised version of the ataxia clinical rating scale seemed to progress in parallel.     

Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer''s dementia.

Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) from control subjects and patients of both presenile and senile age with histologically verified Alzheimer's dementia. CSF HVA increased with age in control but not in Alzheimer patients. HVA and 5-HIAA in the CSF of presenile Alzheimer patients was lower than that of age matched control subjects.     

Concentration gradients for monoamine metabolites in lumbar cerebrospinal fluid

Summary Concentration gradients in lumbar cerebrospinal fluid (CSF) for the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were studied in 9 healthy controls and 47 neuropsychiatric patients without diseases causing disturbed CSF circulation. In a serial sampling of the first 24 ml of CSF, steep concentration gradients between the first (0–4 th ml) and last (21th–24th ml) portions of CSF were found for HVA (99±59% increase; p<0.001) and 5-HIAA (88±54% increase; p<0.001), while the concentration gradient was slight for HMPG (11±7% increase; p<0.001). The existence of marked concentration gradients for the monoamine metabolites HVA and 5-HIAA gives further evidence for an active transport system for these metabolites and indicates that the lumbar CSF-HVA and 5-HIAA levels reflect the dopamine and serotonin metabolism in the brain. Moreover, the existence of pronounced concentration gradients for HVA and 5-HIAA levels reflect the dopamine and serotonin metabolism in the brain. Moreover, the existence of pronounced concentration gradients for HVA and 5-HIAA stresses the importance of making analyses on a standardized volume of CSF.     

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.     

CSF monoamine metabolites of depressed patients during illness and after recovery

Repeated lumbar punctures in 16 healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven depressed patients, studied during two or three illness periods, the metabolite concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA, but not of HVA, were higher after recovery than during depression. This increase of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite levels were low. The finding constitutes further evidence of a biochemical heterogeneity within the depressive disorders, and suggests that patients whose CSF 5-HIAA is low during a depressive episode may have a less stable serotonin system than other patients with depressive illness.     

Influence of gonadal steroids on human and monkey cerebrospinal fluid homovanillic acid concentrations

The influence of gonadal steroids on central dopaminergic function was assessed by measuring concentrations of the dopamine metabolite homovanillic acid (HVA) in cerebrospinal fluid (CSF) in humans and monkeys. CSF HVA and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured by high performance liquid chromatography with electrochemical detection. Thirteen intact adult female monkeys (Macaca fascicularis) and six ovariectomized monkeys had a lumbar puncture to collect CSF. Ovariectomized monkeys had higher HVA concentrations in their CSF while 5-HIAA levels remained unchanged. In a second experiment, 40 human subjects were divided into six groups as follows: I, women with menses; II, menopaused or ovariectomized women taking estrogens; III, hysterectomized women of unknown hormonal status; IV, menopaused or ovariectomized women; V, women taking dopaminergic drugs or showing signs of parkinsonism; VI, men. CSF was collected by lumbar puncture. 5-HIAA levels were constant. Hysterectomized (III) as well as menopaused or ovariectomized (IV) women had significantly (p less than 0.05) higher CSF HVA concentrations compared to men. While women in group IV were older, those in group III were of the same age as the men. These results provide further evidence for the role of endogenous ovarian factors as modulators of central dopaminergic activity.     

5-Hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid of children with febrile convulsions.

5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by high-performance liquid chromatography (HPLC) in lumbar cerebrospinal fluid (CSF) obtained from febrile children subdivided according to the presence or absence of convulsions. Lumbar puncture was made either early (mean time 2 h) or late (3-6 days) after the febrile convulsion. The level of 5-HIAA was significantly decreased in children early and late after the febrile convulsion as compared with the convulsion-free group, but the HVA level was reduced only early after the febrile convulsion. These results support the hypothesis that a decrease in CSF 5-HIAA may be a biologic marker of susceptibility to convulsions and indicate that the transient decrease in HVA is a secondary phenomenon related to occurrence of convulsions.     

Cerebrospinal fluid monoamine metabolites and suicide

Prospective studies of the serotonergic system and suicide report that low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and a history of attempted suicide predict suicide risk. Low CSF homovanillic acid (HVA) is reported to be associated with past and future lethality of suicide attempts but not with suicide. The interrelationships between monoamine metabolites, violent method, suicide intent and lethality of suicidal behaviour are complex. We hypothesized that CSF 5-HIAA and HVA levels are related to suicide intent, violence and lethality of suicidal behaviour. Fifteen male suicide attempters admitted to a psychiatric ward at the Karolinska University Hospital and eight healthy male volunteers were submitted to lumbar puncture and CSF 5-HIAA and HVA were assayed. Suicide intent with the Beck Suicide Intent Scale (SIS), lethality and violence of suicidal behaviour were assessed. All patients were followed up for causes of death. Six suicides and one fatal accident were identified with death certificates. Mean CSF 5-HIAA but not CSF HVA differed between suicides and survivors. Violent suicides had higher suicide intent and CSF 5-HIAA than non-violent suicides. In violent suicides, CSF 5-HIAA levels were negatively correlated with SIS. Greater suicide intent may be associated with greater aggressive intent and predicts a violent suicide method.     

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.     

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.