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.

N(epsilon)(gamma-glutamyl)lysine in cerebrospinal fluid marks Alzheimer type and vascular dementia.

N(epsilon)(gamma-glutamyl)lysine isodipeptide is released from the breakdown of proteins cross-linked by transglutaminase enzymes. Transglutaminase activation is a marker of apoptosis and elevated isodipeptide concentrations in body fluids might correlate with the intensity of apoptotic cell turnover. The concentration of N(epsilon)(gamma-glutamyl)lysine was measured in the cerebrospinal fluid (CSF) of patients with probable Alzheimer's disease (n = 14) and vascular type dementia (n = 11) and compared with not demented surgical controls (n = 17). Baseline levels of 26-62 nM/l (mean 37.9 +/- 8.7 SD) free isodipeptide were detected in control patients. CSF isodipeptide levels showed significant elevation in vascular (mean 95.6 +/- 45.1 SD) as well as Alzheimer patients (176.6 +/- 77.1 SD). Isodipeptide concentrations above 120 nM/l were 72% specific and 77% sensitive to Alzheimer's dementia, although the difference between the two dementias was statistically insignificant (p > 0.05). Determination of CSF N(epsilon)(gamma-glutamyl)lysine isodipeptide concentration offers a novel method for measurement of neurodegeneration in primary and mixed dementias.

The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions.

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steady-state conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone/9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be a useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

Monoamine metabolites in the CSF of conscious unrestrained cats.

The dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured repeatedly over a period of up to 5 months at different sites of the brain ventricular system in unrestrained, awake cats. Samples of 10 microliter CSF were analyzed by high pressure liquid chromatography and subsequent electrochemical detection. Concentrations were in the range of 30-130 ng/ml for DOPAC, 110-340 ng/ml for 5-HIAA and 180-750 ng/ml for HVA. The monoamine metabolites were constant even over a period of several months if measured in the same animal but there was a marked interindividual variation. A marked gradient for monoamine metabolites was found when CSF samples from frontal sites of the lateral ventricle were compared to CSF samples from the dorsal lateral ventricle. The concentrations of DOPAC and HVA were higher at frontal sites.

Purine metabolites in the CSF in presenile and senile dementia of Alzheimer type, and in multi infarct dementia.

Concentrations of hypoxanthine, xanthine, uric acid and creatinine were measured in CSF of patients suffering form presenile and senile dementia of Alzheimer type (PDAT, SDAT) and multi infarct dementia (MID) and in a reference group of young neurotic patients. There was no difference in hypoxanthine concentration, but there was a marked elevation of xanthine concentration in each dementia group, independent of the type of dementia. There was a significant elevation of uric acid in SDAT and MID but not in PDAT. The concentration of uric acid was higher in MID than in SDAT. There was a higher level of creatinine in the dementia groups, but no difference was seen among the dementia groups. These results are discussed in order to better interpret the etiology and the differentiated diagnosis of the types of dementia.

Ascorbic acid in cerebrospinal fluid - a possible protection against free radicals in the brain.

The function of ascorbic acid in living organisms is complex. Previous studies emphasize its protective role against harmful effect of free radicals, and its presence is necessary for the function of numerous enzymes. Ascorbic acid is a powerful reducing agent due to its dienol molecular structure, which is not present in the oxidized form, dehydroascorbic acid. The ratio of ascorbic acid and dehydroascorbic acid might be a marker of oxidative-reductive processes. We measured and compared the level of ascorbic acid and dehydroascorbic acid in the plasma of healthy persons and those of senile dementia patients, who represent pathological aging of the brain. In senile dementia patients, ascorbic acid and dehydroascorbic acid levels were also measured in the cerebrospinal fluid. Concentrations were determined by high performance liquid chromatography with electrochemical detection. In the plasma of senile dementia patients, very low ascorbic acid levels were found (ca. 30% of the healthy control). In lumbar cerebrospinal fluid, the concentration of ascorbic acid is 2.7 times higher compared to that of the plasma level. After intravenous infusion of ascorbic acid, a slow but marked increase of the concentration in the cerebrospinal fluid was measured. Our results support an active transport process for ascorbic acid through the blood-CSF barrier. Ascorbic acid level might be an important factor representing the protection of the central nervous system against free radicals.

Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia.

Free amino acid levels were measured in cerebrospinal fluid (CSF) from demented patients (D, n = 30) suffering from presenile and senile dementia of Alzheimer type (PDAT, n = 7; SDAT, n = 9), multi-infarct dementia (MID, n = 14) and a reference sample group consisting of young neurotic patients (R, n = 16). Comparing the amino acid levels in the dementia subgroups, significantly higher alanine, methionine, phenylalanine and tyrosine levels were found both in MID and SDAT vs. PDAT. No difference was seen between SDAT and MID. Compared to the reference sample group, higher glycine levels were found in each dementia subgroup; higher alanine, methionine and ornithine levels in MID, and SDAT; and higher phenylalanine levels in MID. In PDAT the level of tyrosine was lower. Coefficients of correlation were calculated between amino acid levels and age, and the findings in the reference sample groups were divergent from those observed in dementia. The differences observed are discussed in terms of amino acid, carbohydrate and neurotransmitter metabolism.

Dementias, psychological tests, and neurotransmitters.

A preliminary investigation was made of data of intelligence quotient, dementia quotients, objective profile analysis of MAWI (Hungarian standardized version of WAIS) in patients suffering from multi infarct, primary degenerative and alcoholic dementia (MID, PDD, Alc. D). Homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) were measured in lumbar cerebrospinal fluid (CSF) from patients with presenile dementia and senile dementia of Alzheimer's type (PDAT and SDAT) and multi infarct dementia. They were compared to controls and to each other. Alcoholic dementia can be differentiated from other types of dementia mainly by the values of verbal and practical quotients (VQ/PQ), Hewson Index 5 and by the objective profile analysis. MID can hardly be differentiated from PDD, but the objective profile analysis can help, mainly subtests 1 and 3 of MAWI. No decrease was found in the concentrations of HVA and 5-HIAA in lumbar CSF of demented patients compared to controls, but there was an elevation in 5-HIAA concentration.

Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid.

The purine metabolites hypoxanthine, xanthine and urate as well as creatinine were measured in cerebrospinal fluid (CSF) from two groups of patients and a reference sample group. In one of the patient groups lumbar CSF was collected in 2 ml portions until a total volume of 14 ml was withdrawn. Every second portion was analysed for its content of the metabolites in focus. In the other patient group both cisternal CSF and a fixed volume (20 ml) of lumbar CSF were obtained and analysed. An increase in concentration of hypoxanthine, xanthine and creatinine and a decrease in urate concentration was found in the successive CSF specimens. The mean individual increase in hypoxanthine concentration between the first and the last 2 ml portion was as high as 39.6%, while it was lower for xanthine, 21.5%, and creatinine, 6.7%. The decrease in urate concentration was 17.2%. The results from the other patient group were in good agreement with these findings. The concentrations in the cisternal CSF was 162% of that in lumbar CSF for hypoxanthine, 155% for xanthine, 123% for creatinine and 80% for urate. Mechanisms behind inter- and intraindividual differences in gradients are discussed.

[First Hungarian experiences with positron emission tomography (PET) studies. Members of the PET working group]. / Elsö hazai tapasztalatok pozitron emissziós tomográfiás (PET) vizsgálatokkal. PET munkacsoport tagjai.

Diagnostic investigations commenced on the 28th of June 1994 in Hungary's and Central Europe's first PET Centre at the University Medical School of Debrecen. The Centre is equipped with a GE 4096 Plus whole body PET scanner. A metabolic tracer, 18F-deoxy-D-glucose (FDG), was used in the investigations. During the first 15 months 249 PET investigations were made in the Centre of which 242 were diagnostic and 7 normal subjects served as control for the patient studies with brain scans. The number of oncological indications (intra- and extracranial tumours, Hodgkin's lymphomas) was n = 105 (43.4% of the 242 diagnostic examinations), neurological investigations (without intracranial tumours) formed the dominant group (n = 117; 48.3%), whereas the number of cardiological indications was 20 (8.3%). The oncological studies included those of intracranial tumours (n = 76; 31.4%); thyroid tumours (n = 9; 3.7%); Hodgkin's lymphomas (n = 7; 2.9%) and other extracranial tumours (n = 13; 5.4%). The distribution of different neurological and psychiatric investigations was as follows: localization of focal epileptogen zone (n = 60; 24.8%); differential diagnosis of dementias (n = 30; 12.4%); exploration of cerebrovascular diseases (n = 10; 4.1%); and other neurological diseases (n = 17; 7.0%). The main objective of the cardiological PET investigations was the exploration of viable myocardium. The present paper overviews both the procedures (including administrative issues, as well) and the results of the first 249 FDG-PET investigations.