Reduced brain delivery of homovanillic acid to cerebrospinal fluid during human aging

BACKGROUND: Markers of human brain dopamine metabolism are reported to decline with age. However, the cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA), a major dopamine metabolite, is reported to not change or to increase in elderly individuals. OBJECTIVE: To estimate the rate of delivery of HVA from the brain to CSF, taking into account the HVA concentration gradient in the spinal subarachnoid space and CSF flow. METHODS: Homovanillic acid concentrations were measured in 5 serial 6-mL aliquots of CSF removed from the L3-4 or L4-5 interspaces of 7 healthy young (mean +/- SD age, 28.7 +/- 4.6 years) subjects and 7 healthy elderly (mean +/- SD age, 77.1 +/- 6.3 years) subjects. Cisterna magna HVA concentrations were estimated from the slopes of the HVA concentrations along the spinal subarachnoid space. The products of cisternal HVA concentrations and published values for CSF flow were used to estimate lower limits for brain delivery of HVA to CSF, according to the Fick principle. RESULTS: The mean +/- SD HVA concentration in the initial lumbar CSF sample in the young subjects, 116 +/- 66 pmol/mL, did not differ significantly from 140 +/- 86 pmol/mL in the elderly subjects. Estimated cisternal HVA concentrations equaled 704 and 640 pmol/mL, respectively, in the young and elderly subjects. Multiplying these concentrations by CSF flow rates of 591 and 294 mL/d, respectively, gave lower limits for rates of delivery of HVA from the brain to CSF. These rates equaled 416 and 175 nmol/d, respectively. CONCLUSION: A 50% decline in the lower limit for the rate of HVA delivery from the brain to CSF in elderly individuals is consistent with other evidence that brain dopaminergic neurotransmission declines with age.     

Lumbar cerebrospinal fluid homovanillic acid concentrations are higher in female than male non-human primates

Concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were determined in lumbar cerebrospinal fluid from intact male and female Macaca nemestrina. Concentrations of homovanillic acid, but not 5-hydroxyindoleacetic acid were significantly higher in the females under baseline conditions. Following probenecid treatment, 5-hydroxyindoleacetic acid concentrations were significantly elevated over baseline conditions in both sexes although only homovanillic acid concentrations were significantly higher in the female monkeys.     

Variations of homovanillic acid levels in ventricular cerebrospinal fluid

We studied the nycterohemeral variations of homovanillic acid (HVA) in ventricular cerebrospinal fluid (CSF) in 24 patients undergoing monitoring of intracranial pressure as part of the normotensive hydrocephalus (NTH) work-up. CSF samples were obtained every 4 h in each patient. The mean individual values of HVA in the ventricular CSF ranged from 133 to 421 ng/ml, and they could not be correlated to any clinical feature. The intraindividual levels of HVA were stable throughout 24 hours, with a variation coefficient inferior to 10% in 63% of cases, and inferior to 20% in all the patients.     

d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians

The D-amino acid oxidase activator (DAOA) protein regulates the function of D-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of D-3,4-dihydroxyphenylalanine (D-DOPA) and D-serine. D-DOPA is converted to L-3,4-DOPA, a precursor of dopamine, whereas D-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.     

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.     

Effect of folic acid by mouth on cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentration

Administration of 30 mg folic acid by mouth caused a significant fall in cerebrospinal fluid homovanillic acid concentration in 11 subjects. There was no significant change of 5-hydroxyindoleacetic acid concentration. The fall was less marked in five patients on anticonvulsant medication and failed to reach statistical significance. Neither homovanillic acid nor 5-hydroxyindoleacetic acid concentrations changed significantly when 15 mg folic acid was given in divided dosage for one, two, and four weeks. The effect appeared to be related to the height of serum-folate levels reached and to be independent of cerebrospinal fluid-folate levels, which did not change significantly. Possible mechanisms and their potential therapeutic application are discussed.     

Aspects of influx and efflux of homovanillic acid of rat cerebrospinal fluid

In rats, different methods of perfusion (lumbar-cisternal or ventricular-cisternal) with artificial cerebrospinal fluid were performed at velocities of about 30 and 180 μl/min. Levels of homovanillic acid (HVA) in the outflow were assayed with a semi-automated fluorimetric technique.Intravenous administration of 20 μg HVA did not substantially enhance the outflow of this acid, indicating that in our preparations HVA found in the perfusate is of central origin. In the lumbar-cisternal preparation probenecid (200 mg/kg, i.p.) was found to inhibit the efflux of a significant fraction of HVA added to the medium, at both perfusion rates. The proportion of HVA eliminated by a probenecid sensitive transport was much higher at the lower rate of perfusion. Following probenecid the increase of endogenous HVA in the ventricular-cisternal perfusate was higher at a lower rate of perfusion.We determined the turnover rate of HVA in the whole brain and compared this value with the HVA outflow in the various preparations. The highest efflux of HVA was found in the ventricular-cisternal preparation during probenecid treatment and did not appear to be dependent upon the rate of perfusion. A maximal value of 3.5% of HVA formed in the central nervous system was found to be released into the cerebrospinal fluid.     

Pentachlorophenol concentrations in human cerebrospinal fluid

Pentachlorophenol (PCP) is a widely applied insecticide and fungicide, particularly in wood preservation. Significant amounts of this compound have been reported in human serum, adipose tissue and urine. PCP is even found in people not occupationally exposed to this toxin or not living in PCP-treated log-houses. Substantial concentrations of this possible neurotoxic agent were detected in the cerebrospinal fluid (CSF) of 16 neurologic patients as measured by a high resolution gas chromatographic method using electron capture detection. This is the first report on PCP levels in (human) CSF. The observed level in CSF ranged from 0.24 up to 2.03 micrograms/L (ppb), with an average value of 0.75 +/- 0.49. The cerebrospinal fluid level did not correlate with the serum PCP concentration nor with the protein level of the cerebrospinal fluid.     

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.     

Nonhomogeneous distribution of 5-hydroxyindoleacetic acid and homovanillic acid in the lumbar cerebrospinal fluid of man

The volume of the lumbar sac measured in 4 subjects was found to be 15.5 ml. Exactly 15 ml of lumbar cerebrospinal fluid (L-CSF) was permitted to flow freely out during a lumbar puncture in 20 neurological patients and small samples of the L-CSF were collected in the beginning (sample 1), at the middle (sample 2), and at the end (sample 3) of this procedure either for 5-HIAA or HVA measurement. The concentrations of 5-HIAA and HVA increased in an exponential manner from sample 1 to sample 3. These results indicate that CSF in the lumbar sac is not a homogeneous fluid as is generally believed and that certain rules have to be followed in the sampling of the L-CSF to obtain reproducible biochemical data.     

On the origin of homovanillic acid (HVA) in the cerebrospinal fluid

Summary The contribution of homovanillic acid by the caudate nuclei to the cerebrospinal fluid has been assessed quantitatively on the basis of available clinical-neurochemical and animal-experimental data. A considerable fraction of the caudatal tissue may be involved in this function.     

Failure of cerebrospinal fluid homovanillic acid to predict levodopa response in Parkinson''s disease

Lumbar cerebrospinal fluid homovanillic acid levels were estimated in 60 patients with Parkinsonism before and during levodopa treatment. There was a slight negative correlation between pretreatment CSF homovanillic acid levels and disability. There was no correlation between pretreatment homovanillic acid levels and clinical response to levodopa. Patients with high pretreatment levels did as well as those with depressed levels. High (normal or near normal) levels of CSF homovanillic acid in a patient with Parkinsonism do not necessarily indicate that the Parkinsonism will not respond to levodopa. These patients should receive the benefit of a trial of levodopa. There was also no correlation between homovanillic acid level during tratment and improvement. Patients with minimal increases in CSF homovanillic acid responded as well as those with greater elevations. Failure of levodopa to increase CSF homovanillic acid significantly does not indicate that the patient will not respond to levodopa and that levodopa should be discontinued. Other factors, such as vitamin B₆ consumption, should be investigated.     

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.     

The content of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid of patients with acute schizophrenia

The level of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid were determied in a group of acute untreated schizophrenic patients and an age-matched group of other acute phychiatric patients as controls. No significant differences could be shown between the patients and the controls. When all paranoid patients are compared to all non-paranoid patients of the series, those patients with dominant paranoid thought content and/or paranoid hallucinations had a significantly higher level of HVA (p < 0.01) than the patients with no manifest paranoid symptomatology.