Evidence for the contribution by the cerebral cortex to 5-hydroxyindoleacetic acid found in the cerebrospinal fluid of cats

Perfusion of artificial CSF from a lateral ventricle to the cerebral cortical subarachnoid space in anaesthetized cats was used to study the contribution of the cerebral cortex to the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in CSF. The technique did not cause rupture of the meninges. The use of [14C]5-HIAA and of probenecid suggested that there was a contribution and also a transport mechanism similar to that in the choroid plexus.     

A long-term follow-up study of cerebrospinal fluid 5-hydroxyindoleacetic acid in delirium

Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) was determined for elderly delirious patients during the acute stage and after a 1-year follow-up period, and the 5-HIAA levels were compared with age-equivalent controls. As compared with the controls, the 5-HIAA levels were significantly higher at the beginning of the index admission in patients with multi-infarct dementia and patients with no apparent CNS disease. The 5-HIAA levels were also higher in the latter subgroup in the 1-year sampling, but no other differences between delirious patients and controls were observed. The one-way procedure showed no differences between the subgroup means of delirious patients when divided according to the severity of cognitive decline or type of delirium in any of the samples. The 5-HIAA levels measured during the index admission correlated with the length of life after delirium suggesting that serotonergic dysfunction may have prognostic significance in delirious patients.     

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.     

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type

The possibility of disturbed dopamine and serotonin metabolism in senile dementia of Alzheimer type was studied. The basal concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were studied in 28 patients with senile dementia of Alzheimer type and in 13 controls of similar age with no neurological disease. The concentrations of HVA were significantly reduced in the dementia patients compared to the concentrations of the controls. The values of HVA were also significantly reduced in the most severely demented patients compared to the less severely demented ones. There was a slight but statistically significant decrease in the 5-HIAA levels in the dementia patients compared to the levels of the controls. The 5-HIAA levels were reduced in the most severely demented patients compared to the controls but not when compared with the less severely demented patients.
It is concluded that in severe forms of senile dementia of Alzheimer type, there is a decrease in the levels of HVA and 5-HIAA in CSF which may reflect a decreased turnover of dopamine and serotonin. Patients diagnosed as senile dementia of Alzheimer type, but with less severe symptoms, had levels of HVA and 5-HIAA similar to controls.     

Seasonal variation of serotonin turnover in human cerebrospinal fluid,depressive symptoms and the role of the 5-HTTLPR

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10⁻⁷) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman''s rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.     

Monoamine metabolites in cerebrospinal fluid of depressive subgroups

Lumbar punctures were performed on 69 patients who met Research Diagnostic Criteria (RDC) for major affective disorder, while they were drug-free and depressed. None of the patients met RDC for alcoholism. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by fluorometry and 3-methoxy-4-hydroxyphenylglycol (MHPG) by gas chromatography. Family histories were ascertained by systematic interviews of patients and their relatives, and diagnoses were made by family history diagnostic criteria (Andreasen et al., 1977). Depressed patients with alcoholism in a first degree relative had significantly lower levels of 5-HIAA and MHPG than patients without a family history of alcoholism (p < 0.05). No difference in HVA levels was found. The metabolite differences remained significant when the influence of sex ratio was considered. These results are in agreement with previous work linking alcoholism to abnormal serotonin metabolism. They provide further biochemical evidence of distinct genetic subtypes of affective disorder along lines suggested by Winokur (1979a, 1979b), and illustrate the usefulness of the family history method in defining patient subgroups.     

Rorschach ratings in depressed and suicidal patients with low levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid

In order to explore the psychodynamics of a previously observed association between a low concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and an increased tendency to suicidal behavior, blind ratings of Rorschach variables were compared between depressed and/or suicidal patients with low (<80 nanomoles/1) and normal (&#62;80 nanomoles/1) CSF 5-HIAA. In 14 patient pairs matched for sex, age, body height, and interview-based ratings of severity of depression, the low 5-HIAA subjects had significantly more anxiety and more hostility in the Rorschach ratings. Their anxiety tolerance was lower, and they were significantly less efficient in their handling of conflict. The results support the hypothesis that biochemical variables may be of importance for certain psychodynamic mechanisms suggested to be relevant for psychopathology, including suicidal behavior.     

Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood. Part I. Glutamic acid decarboxylase activity in cerebrospinal fluid of normal infants and children

Glutamic acid decarboxylase (GAD) activity in the cerebrospinal fluid (CSF) of normal infants (n:14) and children (n:28) was determined by measuring the amount of 14CO2 released from L-[1-14C]-glutamic acid. The mean GAD activity in CSF of infants and children was 5.2 +/- 2.5 pmol CO2 formed/hr/ml. Dividing these subjects into 4 groups according to age, GAD activities in CSF were 5.4 +/- 1.6 pmol CO2 formed/hr/ml in neonates (0-1 m), 3.6 +/- 1.6 pmol CO2 formed/hr/ml in infants (2-12 m), 3.9 +/- 1.1 pmol CO2 formed/hr/ml in young children (2-6 yr) and 7.1 +/- 2.3 pmol CO2 formed/hr/ml in school children (7-16 yr), respectively. In neonates and school children, GAD activities were significantly higher (p less than 0.001) than those in the other age groups. In infants under 6 months of age, a significantly negative correlation between GAD activity in CSF and their ages was recognized (r = -0.52, p less than 0.001). In infants and children ranging from 6 months to 16 years of age, a significantly positive correlation between GAD activity in CSF and their ages was found (r = 0.67, p less than 0.001). These data suggest that high GAD activity in neonates may be due to hypoxia at birth and the activity gradually increases from 6 months to 15 years of age.     

Increased tau protein level in postmortem cerebrospinal fluid

Abstract Microtubule-associated protein tau has been reported to be significantly increased in cerebrospinal fluid (CSF) of the patients with Alzheimer's disease (AD), which suggests that it is possibly a biological marker for the diagnosis of AD. The underlying mechanism of the increased tau level in CSF, however, is not known. In this study, the tau levels were compared between antemortem and postmortem CSF. The postmortem tau levels in CSF were significantly increased in all groups including AD, neurological control, and nondemented control. A striking elevation of CSF tau was observed during the postmortem change with the nondemented subjects. These findings may offer some insight into the understanding of the mechanism of the increased tau level in CSF with AD and other related disorders.     

Elevated 5-S-cysteinyldopamine/homovanillic acid ratio and reduced homovanillic acid in cerebrospinal fluid: possible markers for and potential insights into the pathoetiology of Parkinson's disease

Summary High-performance liquid chromatography with electrochemical detection has been employed to analyze ultrafiltrates of cerebrospinal fluid of Parkinson's Disease (PD) patients and age-matched controls for the dopamine (DA) metabolites homovanillic acid (HVA) and 5-S-cysteinyldopamine (5-S-CyS-DA). The mean level of HVA in the CSF of PD patients, measured 5 days after withdrawal from L-DOPA therapy, was significantly lower than that measured in controls. By contrast, mean levels of 5-S-CyS-DA were not significantly different in the CSF of PD patients taking L-DOPA (PD-LT patients) the same patients 5 days after discontinuing this drug (PD-LW patients) or controls. However, the mean 5-S-CyS-DA/HVA concentration ratio was significantly (p < 0.05) higher in the CSF of PD-LW patients compared to controls. Although the PD patient population employed in this study had been diagnosed with the disease several years previously and had been treated with L-DOPA for prolonged periods of time the results of this study suggest that low CSF levels of HVA and a high 5-S-CyS-DA/HVA ratio together might represent useful markers for early diagnosis of PD. The high 5-S-CyS-DA/HVA ratio observed in the CSF of PD-LW patients also provides support for the hypothesis that the translocation of glutathione or L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra might represent an early event in the pathogenesis of PD.Abbreviations CSF cerebrospinal fluid - CySH L-cysteine - DA dopamine - DA-o-quinone dopamine-o-quinone - L-DOPA 3,4-dihydroxyphenylalanine - DOPAC 3,4-dihydroxyphenylacetic acid - EPI epinephrine - GSH glutathione - GSSG oxidized glutathione - 5-HIAA 5-hydroxyindole-3-acetic acid - HVA homovanillic acid - HO· hydroxyl radical - HPLC-EC high performance liquid chromatography with electrochemical detection - 5-HT 5-hydroxytryptamine (serotonin) - NE norepinephrine - PD Parkinson's disease - PD-LT Parkinson's disease patients taking L-DOPA therapy - PD-LW Parkinson's disease patients withdrawn from L-DOPA therapy for 5 days - 5-S-CyS-DA 5-S-cysteinyldopamine - 5-S-Glu-DA 5-S-glutathionyldopamine - SN substantia nigra - O ₂· Superoxide radical anion     

5-HIAA in cerebrospinal fluid of patients with status epilepticus

Cerebrospinal fluid concentration of 5-hydroxyindolacetic acid (5-HIAA) was determined in 15 patients soon after recovery from status epilepticus. Similarly, patients with generalised epilepsy and persons without epilepsy, serving as controls, were also studied. The level of 5-HIAA was significantly reduced in all epileptic patients with or without status epilepticus, as compared with the nonepileptic control group. However, there was no statistical difference between patients with status epilepticus and those with generalised epilepsy. Among patients with epilepsy, low 5-HIAA levels in CSF could not be correlated with frequency or severity of seizures, or with antiepileptic drugs. A link between CSF 5-HIAA and susceptibility of humans to epilepsy may indicate a possible future therapeutic approach.     

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.     

Butyrylcholinesterase in lumbar and ventricular cerebrospinal fluid

OBJECTIVES: This study establishes reference data for human lumbar CSF butyrylcholinesterase (E.C.3.1.1.8.) activity and investigates the enzyme activity in ventricular CSF. We comment on the relationship between CSF butyrylcholinesterase activity and other laboratory parameters. Subjects and Methods: We investigated 64 lumbar CSF samples obtained from a clinically healthy population and 169 ventricular CSF samples collected from 90 neurosurgical patients. RESULTS: The reference range we recommend for lumbar CSF butyrylcholinesterase activity is 5.4 to 17.0 nmol/min x ml. The majority of ventricular butyrylcholinesterase activities in our patient subset ranged up to 5 nmol/min x ml. CONCLUSIONS: We established the relative influence of serum and CNS components on total CSF butyrylcholinesterase activity. The CNS fraction predominates the total butyrylcholinesterase activity in normal lumbar CSF. In ventricular CSF enzyme influx from serum outweighs the CNS component.     

Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5HIAA and HVA

The degenerative type of progressive myoclonus epilepsy (PME) is a hereditary disease with grand mal seizures, stimulus sensitive myoclonus, characteristic EEG and mental deterioration in the late stage. GABAergic antiepileptic drugs are the most effective ones in this disease, with an unknown etiology. In this study, the GABA concentration in the CSF of 15 PME patients was measured and compared with values of sex- and age-matched epileptic controls. It was correlated with the concentrations of 5HIAA and HVA in the CSF, which were determined earlier from the same patients. The GABA concentration in the PME patients was statistically significantly decreased, to about 75% of that of the epileptic controls. It correlated with HVA and 5HIAA concentrations in the PME patients, but not in the epileptic controls. It is unknown whether these findings are related to the primary cause of PME or whether they are only secondary, owing to a loss of respective neurons or synapses.     

Antidepressant effect of femoxetine and desipramine and relationship to the concentration of amine metabolites in cerebrospinal fluid

The antidepressant and biochemical effects of femoxetine, a selective serotonin uptake inhibitor, and desipramine, a selective nor-adrenaline uptake inhibitor, have been compared in a double–blind study in 42 outpatients with depressive illness. The patients were allocated at random to treatment with either 600 mg femoxetine or 150 mg desipramine daily for 6 weeks. The total depression score showed a significant decrease in both groups, indicating an overall improvement in depressive symptoms. The patients treated with femoxetine reported significantly less severe anticholinergic effects during the whole treatment period than the desipramine patients. Both drugs decreased the level of 5-HIAA in CSF, whereas no consistent changes were found in the HMPG and HVA levels. The pretreatment level of the metabolites had no predictive value for the outcome of the treatment with either drug. No significant correlation was found between therapeutic effect and the plasma concentration of the active compounds.     

Hypoglycemia-induced elevation of immunoreactive beta-endorphin level in cerebrospinal fluid in the cat

Under pentobarbital anesthesia, β-endorphin levels in cat cerebrospinal fluid (CSF) were studied by a sensitive radioimmunoassay combined with a gel column chromatograph. Immunoreactive β-endorphin (IR-β-EP) levels in cat CSF significantly increased during insulin-induced hypoglycemia along with the elevation of its peripheral plasma levels. The entry of systematically administered β-endorphin into CSF is, if of any effect, negligible in these experimental conditions. Such an increase of IR-β-EP in CSF, therefore, might reflect its release form the brain into cerebroventricular spaces during insulin-induced hypoglycemia.     

Increased levels of TRH in cerebrospinal fluid from patients with endogenous depression.

(1) A radioimmunoassay of thyrotropin releasing hormone (TRH) in cerebrospinal fluid (CSF) has been developed. The lower detection limit was 2.0 pg/ml. (2) The concentration of TRH in lumbar fluid from 20 patients with various neurological diseases averaged 5.4 pg/ml (1.9–10.7). In 2 patients the concentration was below detection limit. (3) The TRH concentration was not related to sex or age. (4) In 15 patients with endogenous depression the concentration was elevated (p<0.01), before electroconvulsive treatment (24.2 pg/ml, range: 6.9–187) as well as after such therapy (14.4 pg/ml, range 6.0–31.0). The values before and after treatment were not significantly different. (5) The concentration of TRH was not correlated to the serum thyrotropin (TSH) response to 200 μg TRH i.v. (6) Changes in TRH concentration were also unrelated to changes in the TSH response to TRH and to the clinical outcome after 6 months of observation.     

The effect of valproic acid on the 5-hydroxyindoleacetic, homovanillic and lactic acid levels of cerebrospinal fluid

In this study the cisternal cerebrospinal fluid (CSF) contents of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were sequentially measured in free-moving rats which were administered 50–500 mg·kg⁻¹ valproic acid. Animals receiving 100–500 mg·kg⁻¹ valproic acid showed significant increases in CSF 5-HIAA and HVA content, with maximal accumulation rates of 1.80–2.10 and 0.25–0.30 nmol·ml⁻¹·h⁻¹, repectively, being reached at the 250 mg·kg⁻¹ dose. The combination of valproic acid 500 mg·kg⁻¹ and probenecid 300 mg·kg⁻¹ failed to increase the accumulation rates of 5-HIAA and HVA over those seen with valproic acid 500 mg·kg⁻¹ or probenecid 300 mg·kg⁻¹ alone. This pattern of change indicates that valproic acid and probenecid share a common site of action in blocking the clearance of 5-HIAA and HVA from CSF. The tranquillizer diazepam produced progressive increases in CSF 5-HIAA and HVA content which suggested a similar action to that of valproic acid and probenecid. The anticonvulsants phenytoin and phenobarbital produced selective increases in 5-HIAA, whereas the tranquillizer chlorpromazine produced proportionally larger increases in HVA, changes which seem to indicate a more selective effect of these drugs on the serotonergic or dopaminergic systems, respectively. Valproic acid was associated with increases in CSF lactate which occurred in the absence of similar increases of blood or tissue lactate. This indicated that valproic acid, like probenecid, can inhibit the monocar☐ylic acid transport system which removes lactate from the CSF.     

Amino acid concentrations in cerebrospinal fluid of patients with multiple sclerosis

As oligodendrocytes have binding sites for excitatory amino acids (glutamate, aspartate, serine, etc.), a role of these molecules in demyelinating disorders is possible. We measured the levels of amino acids in the cerebrospinal fluid (CSF) of patients with multiple sclerosis in comparison with CSF obtained by myelography from patients with lower back pain. There were no significant differences in the CSF concentrations of these amino acids between the two groups. Normal concentrations of excitotoxins do not exclude the role of these molecules in demyelinating disorders.