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Biomedical subjects

F A Wiesel

Publications and source records attributed to F A Wiesel.

At least 55 records · Page 3Linked to original sources
PubMed1990

Positron emission tomographic measurements of cerebral glucose utilization using [1-11C]D-glucose.

Regional CMRglc was measured in seven healthy volunteers with positron emission tomography using [1-11C]D-glucose. Regional CBF was measured using [11C]fluoromethane. The arteriovenous differences of unlabeled glucose and oxygen together with 11C metabolites were also measured. In addition to the loss of [11C]CO2, a loss of acidic 11C metabolites was also detected. A three-compartment model was applied to the tracer data in the time interval 0-24 min. After correction for the loss of 11C metabolites, the tracer method gave an average CMRglc of 26.4 +/- 1.9 (SD) mumol/100 g/min, close to the value obtained with the Fick principle. After correction for the loss of [11C]CO2 only, the tracer method gave 23.6 +/- 2.1 mumol/100 g/min, compatible with (1/6) CMRO2, obtained with the Fick principle. These results and the time course of the loss of acidic 11C metabolites are consistent with the presence of nonoxidative metabolism of glucose that causes an early loss of mainly [11C]lactate after a bolus injection of the tracer. This implies that [1-11C]D-glucose measures the rate of glucose oxidation rather than the total CMRglc. The experiments using [1-11C]D-glucose were compared to five analogous experiments using [U-11C]D-glucose together with [15O]H2O as a flow tracer. After correction for the loss of [11C]CO2, the two glucose tracers gave similar global values of CMRglc and other parameters associated with glucose utilization, but with labeling in the carbon-1 position, the loss of [11C]CO2 was substantially delayed and the contrast between gray and white matter was improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1990

Recent advances in psychiatric brain imaging.

The characterization of neuroreceptor functions in the living human brain has hitherto been hampered by the lack of techniques useful for the measurement of physiologic events within the human brain in vivo. Recent developments in positron emission tomography (PET) has allowed the quantitative tracing of intravenously administered molecules within tissue compartments of the brain. Using ligands binding with high affinity to cerebral neuroreceptors it has been possible to examine not only the distribution but also some quantitative aspects of brain neuroreceptors in living human subjects by the PET technique. By the selection of highly selective ligands for different receptor systems and by labeling them with positron emitting isotopes as 11C or 18F, methods have been developed for the characterization of receptor subtypes for the endogenous ligands dopamine, serotonin, opiates, acetylcholine, glutamate and GABA. The present communication describes the use of 11C-SCH 23390 and 11C-raclopride for the analysis of D1 and D2 dopamine receptors, the benzodiazepine (BZ) antagonist 11C-Ro 15-1788 for benzodiazepine receptors and 11C-nicotine for nicotine receptors. Specificity of binding was verified by using active and inactive stereoenantiomers of the ligands. After the intravenous administration of the ligands quantitative aspects of the receptor binding was calculated using models according to equilibrium or dynamic approaches. Bmax and Kd values for D2 dopamine and BZ receptors could be determined in the brain of healthy human subjects and patients with neuropsychiatric disorders. No alteration of D2 dopamine receptors in the major basal ganglia were found in drug naive schizophrenic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzazepines↗
PubMed1989

Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography.

Positron emission tomography (PET) was used to determine regional brain glucose metabolism in schizophrenic patients (n = 17) before and during neuroleptic treatment. The patients had not been treated with neuroleptics for at least 3 weeks before the first study. All suffered from acute psychotic symptoms and were hospitalized to obtain neuroleptic treatment. After determination of regional brain metabolism without neuroleptic treatment, 11 patients were treated with sulpiride (800 mg/day) and 6 patients were treated with chlorpromazine (400 mg/day) over 5-6 weeks before the second PET investigation. The control group consisted of seven healthy male volunteers, also investigated twice 5 weeks apart. The PET investigation was made with the subject in a resting state. The tracer was uniformly labelled 11C-glucose. The metabolism was determined bilaterally in 15 brain regions cortical, as well as central regions. Metabolic rates differed among the groups. The sulpiride group had lower metabolic rates than the controls and the schizophrenic patients later treated with chlorpromazine. The sulpiride group, in which absolute metabolic rates were determined, were clinically more autistic and chronic than the chlorpromazine group. It was proposed that these facts could explain the lower metabolic rates in the sulpiride group. A significant change in metabolism in relation to drug treatment was only found in one brain region. The selective D2-receptor antagonist sulpiride increased the metabolic rate in the right lentiform nucleus in comparison with the patients treated with chlorpromazine and the controls. Likewise, relative metabolic rates were increased only in the right lentiform nucleus. Negative correlations between intensity of clinical symptoms and metabolism indicated that emotional tone and drive were related to brain metabolism. No correlations were found between drug concentrations and metabolism or clinical symptoms.

Adult↗
PubMed1989

D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics.

Using positron emission tomography and the selective ligands 11C-SCH23390 and 11C-raclopride, central D1- and D2-dopamine receptor occupancy was determined in schizophrenic patients treated with clinical doses of classical and atypical neuroleptics. Treatment with ten chemically distinct classical neuroleptics resulted in a 65-89% occupancy of D2-dopamine receptors. This finding represents strong support for the hypothesis that the mechanism of action of antipsychotic drugs is indeed related to a substantial degree of D2-dopamine receptor occupancy. In two patients treated with the atypical neuroleptic clozapine, 300 mg b.i.d. and 150 mg b.i.d., the D2-dopamine receptor occupancy was 65 and 40%, respectively. D1-dopamine receptor occupancy was determined in six antipsychotic drug-treated patients. No D1-dopamine receptor occupancy was found in patients treated with sulpiride and perphenazine, compounds known to be selective D2-dopamine receptor antagonists. The highest D1-dopamine receptor occupancy, 42%, was found in the patient treated with clozapine 150 mg b.i.d. The effects of the atypical neuroleptic clozapine may be related to a combined effect on both D1- and D2-dopamine receptors.

Antipsychotic Agents↗
PubMed1989

Monoamine metabolites and amino acids in serum from schizophrenic patients before and during sulpiride treatment.

Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18-42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (starting with 400, 800 or 1200 mg) according to a double blind randomized administration schedule. The monoamine metabolites (MAM) homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before treatment and once a week during treatment. There were no significant differences between healthy controls and schizophrenic patients in serum levels of monoamine metabolites and amino acids before treatment. There was no dose-response effect of sulpiride on serum levels of the monoamine metabolites or the amino acids. The results are therefore based on the whole group of patients. During treatment the HMPG levels were reduced at all points in time. The serum level of HVA was significantly reduced after 6 weeks. The 5-HIAA and the amino acid levels were not changed during treatment. There were no significant correlations among the monoamine metabolites before treatment. During treatment, however, significant correlations were found among MAM and amino acids. Since the biochemical findings during the treatment were not related to the dose or the concentration of sulpiride the results may be related to secondary biochemical effects of sulpiride and/or to changes in the clinical state following treatment.

Adolescent↗
PubMed1989

Clinical melperone treatment blocks D2-dopamine receptors in the human brain as determined by PET.

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.

Adult↗
PubMed1989

Positron emission tomography in psychiatry.

Positron emission tomography permits the study of human brain function. With a positron labelled tracer and a model for quantitation, regional brain metabolism and neuroreceptor characteristics can be determined with PET. Schizophrenia is the most extensively studied psychiatric disorder. Most studies have demonstrated decreased metabolic rates in wide areas of the brain. It is proposed that the metabolic changes observed in the brains of schizophrenic patients are due to a fundamental change in neuronal function. Fewer studies have been performed in other psychiatric disorders. Bipolar depressed patients probably have a decreased brain metabolism. Obsessive compulsive and panic disorders (if sensitive to lactate) have an increased brain metabolism. This is probably also the case for female anorectic patients. Alcohol dependent subjects with a long duration of abuse may have a decreased brain metabolism. Neuroreceptor studies with PET have in one study of psychotropic drug naive schizophrenic patients demonstrated an increase of D2-dopamine receptors. In another study no difference between controls and patients was found. Treatment of schizophrenic patients with conventional doses of neuroleptic drugs results in a D2 receptor occupancy of 65 to 85 per cent, suggesting that there is no need for high dose treatment in schizophrenic patients. The studies reviewed clearly demonstrate that PET is a valuable tool in psychiatric research.

Brain↗
PubMed1988

Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers.

The concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and glutamate were determined in cerebrospinal fluid (CSF) and serum in 10 healthy volunteers. The monoamine metabolites were measured by mass fragmentography and the glutamate by high-performance liquid chromatography. The level of glutamate in CSF was low (0.34 +/- 0.14 nmol/ml) in comparison with previously published values. The concentrations of monoamine metabolites in CSF were in close agreement with earlier findings. There were negative correlations between the concentrations of HVA (r = -0.82, p less than 0.01) and 5-HIAA (r = -0.77, p less than 0.01) and glutamate in CSF, but not in serum. The serum levels of HMPG and glutamate were negatively correlated (r = -0.95, p less than 0.001), but not the CSF levels. The HMPG levels in serum and CSF were positively correlated (r = 0.94, p less than 0.001), but not the HVA and the 5-HIAA levels. The serum and CSF levels of glutamate were positively correlated (r = 0.67, p less than 0.05). The results indicate relationships among the metabolism of dopamine, serotonin, and glutamate in the brain and between the metabolism of noradrenaline and glutamate in peripheral tissue.

Adult↗
PubMed1988

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.

Adult↗
PubMed1988

PET scanning--a new tool in clinical psychopharmacology.

Quantitative methods were developed for the determination of dopamine and benzodiazepine receptor characteristics in the living human brain by positron emission tomography (PET). As ligands, the 11C-labelled analogues of the selective antagonists of dopamine receptor subtypes, SCH 23390 and raclopride, and the benzodiazepine antagonist, Ro 15-1788, were used. Tracer amounts of the ligands were injected intravenously into healthy volunteers and schizophrenic patients. The distribution of ligand indicated high densities of D1 as well as D2 dopamine receptors in the basal ganglia. Binding of [11C]-SCH 23390 was also significant in the neocortex where it was shown to represent binding to D1 as well as to 5-HT2 serotonin receptors. High densities of specific benzodiazepine receptor binding were obtained in most neocortical brain areas and in the cerebellum. Using saturation procedures, Bmax and Kd values could be obtained for D2 and benzodiazepine receptors. A comparison of D2 receptor densities in drug-naive schizophrenic patients and healthy volunteers demonstrated similar receptor characteristics in the major basal ganglia in these groups of subjects. Different chemical classes of conventional and unconventional antipsychotic drugs produced a 65%-85% occupancy of D2 receptors when given in clinical doses to schizophrenic patients. High does of diazepam produced a marked occupancy of benzodiazepine receptors during the first hours after oral administration to healthy volunteers. These in vivo methods should be valuable tools for the further analysis of the effects of drug on neuroreceptors in the living brain of neuropsychiatric patients.

Animals↗
PubMed1988

An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.

Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were "very much" or "much" improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

Acute Disease↗
PubMed1988

PET determination of regional cerebral glucose metabolism in alcohol-dependent men and healthy controls using 11C-glucose.

Regional brain glucose metabolism was determined in 9 male alcohol-dependent inpatients and 12 male healthy controls. All the patients were socially impaired by the alcohol abuse. All the subjects had abstained from alcohol and drugs for more than four weeks before entering the study. Brain glucose metabolism was determined by positron emission tomography (PET) with 11C-glucose as the tracer. Regions of interest were drawn on displayed computed tomographic (CT) images of the brain. Regions were transferred to corresponding PET slices, allowing the determination of regional glucose metabolism. In the healthy volunteers there was a reduction in glucose metabolism with age. In 11 of the 19 brain regions examined, the alcoholics had a 20% to 30% lower glucose metabolism than the controls. This was true for both cortical and subcortical structures. The distribution of relative regional metabolic rates indicated that parietal cortical areas were most affected. Atrophic changes as shown by CT were not correlated to the reduced metabolism in the alcohol-dependent patients.

Adult↗
PubMed1987

Decreased tyrosine transport in fibroblasts from schizophrenic patients.

Amino acid transport was studied in vitro in cultured fibroblasts from schizophrenic patients and controls. An isolated decrease in the transport capacity (Vmax) for tyrosine was observed in cells from the patients. The Km for tyrosine transport was unaffected. The kinetic parameters for phenylalanine, tryptophan, leucine and glycine transport did not differ between patients and controls. Competitive inhibition among the amino acids transported by the L-system and its exchange properties were normal in cells from the patients. No differences in intracellular levels of amino acids between patients and controls were observed. The decreased tyrosine transport in the cells from schizophrenic patients appears not to be related to any known amino acid transport system and may reflect a more general defect in plasma membrane function in schizophrenia.

Biological Transport, Active↗