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Biomedical subjects

S M Aquilonius

Publications and source records attributed to S M Aquilonius.

At least 73 records · Page 4Linked to original sources
PubMed1990

Striatal kinetics of [11C]-(+)-nomifensine and 6-[18F]fluoro-L-dopa in Parkinson's disease measured with positron emission tomography.

The kinetics in brain of the dopamine reuptake blocking agent [11C]-(+)-nomifensine and the L-dopa analogue 6-[18F]fluoro-L-dopa were compared in 3 patients with idiopathic Parkinson's disease and age-matched healthy volunteers using positron emission tomography. Regional uptake was analyzed and quantified according to a 3-compartment model. Retention of both tracers in striatal regions of the parkinsonian patients were reduced compared with the healthy volunteers mainly in the putamen, while the caudate nucleus was only mildly affected. The reductions were considerably less than the decrease previously reported postmortem for striatal dopamine content in the basal ganglia of patients with Parkinson's disease. A fairly constant ratio between 6-[18F]fluoro-L-dopa utilization and [11C]-(+)-nomifensine binding in the caudate nucleus and the putamen were found in both groups unrelated to the size of the estimated parameters. This indicates that a limiting factor for the utilization of exogenous levodopa in Parkinson's disease may be a reduced transport capacity for the amino acid into the dopaminergic terminals.

Adult↗
PubMed1990

Functional and pharmacokinetic studies of tetrahydroaminoacridine in patients with amyotrophic lateral sclerosis.

Assuming the presence of clinically significant cholinergic hypofunction in amyotrophic lateral scleroses (ALS), seven patients with ALS were treated with 100-200 mg tetrahydroaminoacridine (THA) together with 11 g lecithin daily for up to 7 weeks. In a separate experiment pharmacokinetics and effects on muscle strength and neurophysiological parameters were studied following the injection of 30 mg THA intravenously. Following the injection of THA an increase in muscle strength was observed in two patients. There were no consistent pharmacokinetic differences that could explain the effect on intravenous THA on muscle strength in these two patients. The plasma clearance of THA was high and the oral bioavailability low with large interindividual differences (6-36%). No beneficial effect was seen during oral medication and side-effects were common. There were no conclusive changes observed regarding neurophysiological parameters after drug administration. THA has probably no place in the treatment of ALS.

Administration, Oral↗
PubMed1989

[PET--new ways inside the body].

Using positron-emitting short-lived radionuclide tracers, a wide range of substances can now be labelled without their biological properties being affected. Positron emission tomography (PET) enables the distribution and metabolism of the labelled substance to be studied in different organs. By providing quantitative, locational, functional and biochemical information difficult to obtain by other means, PET opens up new possibilities, both diagnostic, pathophysiological and therapeutic, in a broad spectrum of medical practice. The development of the technique is described, with particular reference to its use at Uppsala.

Abdominal Neoplasms↗
PubMed1989

Localization of monoamine oxidase B in human brain by autoradiographical use of 11C-labelled L-deprenyl.

11C-labelled L-deprenyl in vitro autoradiography was used to study the regional distribution of MAO-B in human brain. 80 microns thick cryosections from two human brains, a 67 years old female and a 58 years old male, were taken on tape/paper and transferred on to a gelatinized glass plate. The sections were then incubated with 34 and 54 nM 11C-L-deprenyl for 15 min and exposed to a film sensitive to high energy radiation for 2 hours. The autoradiograms obtained were analyzed by computerized densiotometry. High 11C-deprenyl binding was found in the caudate nucleus, putamen, thalamus, substantia nigra, medial and lateral geniculate bodies, hippocampus and periaqueductal gray. Moderate to low binding was observed in cerebral cortex. Cerebral cortex and white matter showed the lowest binding. The autoradiographic technique described proved to be a fast and reliable method to investigate the topographic localization of MAO-B in large cryosections of human brain.

Aged↗
PubMed1989

Brain dopaminergic mechanisms in Parkinson's disease evaluated by positron emission tomography.

The meso-striatal dopamine neurons, essential for the automated control of movements, are primarily affected in patients with P.D. Direct study of the role of this pathway in states of disease has not been possible until recently and the application of PET for the in vivo investigation of dopaminergic mechanisms may serve to demonstrate the potential of the technique. One basic idea has been to work out methods to investigate multiple aspects of dopaminergic function, i.e. presynaptic mechanisms such as re-uptake sites and synthesis of neurotransmitter as well as postsynaptic such as receptor properties. Furthermore, efforts have been made to evaluate dopamine degradating enzymes. Preclinical PET-investigations have regularly been performed in Rhesus monkeys and the hemiparkinsonian model produced by infusing MPTP into one internal carotid artery has been of great value to characterize new 11C-labelled tracers. Today 11C--(+)-nomifensine is used to give a measure of dopamine re-uptake sites, probably reflecting nerve terminals. 11C-labelled L-dopa has now been introduced and can be expected to replace 18F-L-fluorodopa as a physiological tracer for precursor transport and transmitter synthesis. Several ligands are available for the quantitation of dopamine receptors--11C-N-methylspiperone and 11C-raclopride have been used in our studies. 11C-L-selegiline and its "inactive" D-form have been used in clinical PET-studies aimed to evaluate the enzyme MAO-B. A summary of in vivo information of dopaminergic mechanisms in P.D. obtained using the above-mentioned tracers and PET is presented.

Brain↗
PubMed1989

Screening for neurotrophic disturbances in amyotrophic lateral sclerosis.

Neurotrophic activities in human serum and post-mortem muscle and spinal cord of possible relevance to pathophysiological mechanisms in amyotrophic lateral sclerosis (ALS) were studied. Tests included in vitro assays for nerve fibre outgrowth from sympathetic ganglia and for survival promotion of dissociated ciliary neurons, both types of neurons, of chicken embryo origin. Extracts of postmortem biceps muscle promoted survival of ciliary neurons in a dose-dependent manner. Half-maximum effect was found at a protein concentration of about 450 micrograms/ml for both ALS and control muscle. Ventral horn extracts were about 5 times as efficient as muscle in promoting neuron survival, again with no differences seen between control and ALS samples. Sera from patients suffering from ALS as well as normal sera did not enhance survival of ciliary neurons to any considerable extent, nor did they induce fibre outgrowth from sympathetic ganglia. Both groups of sera, if present above 5% in the medium, suppressed fibre outgrowth induced by added nerve growth factor (NGF). Sera from some of the ALS patients impaired survival in dissociated ciliary neurons supported by a trophic activity in choroid extract. The results do not indicate major neurotrophic deficits as the cause of ALS disease but suggest that a neurotoxic mechanism may be involved.

Aged↗
PubMed1988

Autoradiographic distribution of [3H]acetylcholine binding sites in the cervical spinal cord of man and some other species.

The distribution of [3H]acetylcholine ([3H]ACh) and [3H]ACh co-incubated with 1-mM nicotine (muscarinic receptor), and [3H]ACh co-incubated with 1.5 microM atropine (nicotinic receptor) binding sites were studied in man and compared to monkey, cat and rat using quantitative in vitro autoradiography. The highest density of total [3H]ACh binding sites was found in laminae II-III, IX (motor neuron areas) and X close to the central canal. The distribution pattern of the muscarinic cholinergic binding sites was similar to that of the total cholinergic binding. In general the number of nicotinic binding sites in the spinal cord was relatively small. The largest number of such binding sites was found in laminae II-III of the dorsal horn and in laminae X around the central canal. It is evident that the spinal cord has a 2-3 times higher number of muscarinic than of nicotinic cholinergic receptors.

Acetylcholine↗
PubMed1988

Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers.

We have produced in one monkey a unilateral lesion of the dopaminergic nigrostriatal pathway by slowly infusing 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) into the right internal carotid artery, resulting in contralateral hemiparkinsonism. This procedure was combined with a series of positron emission tomography scans before and after the lesion, using several dopaminergic tracers in parallel. We show that specific binding of [11C]nomifensine in the lesioned striatum disappears to a large extent (80-90%) as a result of the lesion, indicating a corresponding loss of striatal dopamine re-uptake binding sites and thus of the dopamine nerve terminal pool. The uptake of radioactivity in the striatum contralateral to the lesion remained unchanged. In parallel, an early increase in ipsilateral [11C]raclopride binding, indicating upregulation of dopamine D2 receptors, was seen following the presynaptic lesion. [11C]Deprenyl uptake, indicating monoamine oxidase type B enzyme concentration, did not change after the lesion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

In vivo and in vitro receptor autoradiography of the human brain using an 11C-labelled benzodiazepine analogue.

In vitro autoradiography of an 11C-labelled ligand, Ro 15-1788, has been used to visualize benzodiazepine binding sites in large human brain cryo-sections. In parallel, using the same radioligand, an in vivo study of a human healthy volunteer was performed, by means of positron emission tomography (PET). The in vitro and in vivo mapping of the ligand demonstrated a very similar binding pattern, although the poor resolution of PET precluded a full discrimination of fine details. The 11C-autoradiograms showed good spatial resolution, even with distinction of different layers in the cerebral and cerebellar cortex. In a separate experiment, the spatial resolution of 11C-autoradiography was found to be 180 microns, using 80-microns-thick cryo-sections. It is emphasized that in vitro and in vivo studies of the same radioligand give complementary information, which is valuable in the assessment of PET images.

Aged↗
PubMed1988

Monoamine re-uptake sites in the human brain evaluated in vivo by means of 11C-nomifensine and positron emission tomography: the effects of age and Parkinson's disease.

Six patients with Parkinson's disease, selected to cover a range of clinical features, and 7 healthy volunteers aged 24-81 years, were examined by positron emission tomography after i.v. injection of racemic 11C-nomifensine, a catecholamine re-uptake blocking drug. After injection the radiotracer, radioactivity was rapidly distributed to the brain. The highest accumulation of radioactivity was found in areas rich in dopaminergic and noradrenergic innervation, such as the striatum and the thalamus. In regions with negligible dopaminergic and noradrenergic innervation, such as the cerebellum, radioactivity was lower and evenly distributed. In all investigated brain regions a marked age-related decline in 11C-nomifensine-derived radioactivity relative to the cerebellum was observed in the group of healthy volunteers. Parkinsonian patients did not show such a decline with age. In the group of parkinsonian patients with mainly unilateral involvement, the contralateral putamen exhibited the most pronounced decrease. Only the 3 parkinsonian patients aged 63 and younger showed markedly lower 11C-nomifensine binding in striatal areas than age-matched healthy volunteers. 11C-nomifensine seems to be a valuable tool for investigating noradrenergic and dopaminergic re-uptake sites in vivo. Further achievements will most likely be made when the active enantiomer becomes available.

Adult↗
PubMed1987

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography.

In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11C-nomifensine was administered i.v. in trace amounts (10-50 micrograms) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the time-course of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

Aged↗
PubMed1987

Dopamine receptor properties in Parkinson's disease and Huntington's chorea evaluated by positron emission tomography using 11C-N-methyl-spiperone.

Dopaminergic receptor properties in the striatum of patients with Parkinson's disease (PD) and Huntington's chorea (HD) were studied by positron emission tomography (PET), using 11C-N-methyl-spiperone as a dopamine D2 receptor ligand. The time-dependent regional radioactive uptake in the caudate nucleus and the putamen was measured and fitted to a 3-compartment pharmacokinetic model. The rate constant k3 for specific binding to the receptor compartment in the striatum was determined in relation to the binding in regions with a low density of specific binding sites, such as the cerebellum and the frontal cortex . k3, which is a measure of the receptor density, was reduced in one patient with HD but less affected in PD in comparison with healthy controls. The pattern of k3 values calculated from the 6 PD patients is discussed in relation to any side-to-side differences in dopamine receptor densities in hemiparkinsonism and to possible "hypersensitivity" of dopamine receptors in the early stage of the disease and down-regulation in more advanced disease.

Aged↗
PubMed1987

Positron emission tomography (PET) in the study of dopamine receptors in the primate brain: evaluation of a kinetic model using 11C-N-methyl-spiperone.

The regional kinetics of 11C-N-methyl-spiperone (11C-NMSP) are described in the monkey brain under tracer conditions and after displacement and protection experiments. The primary aim of the study was to investigate different methodological problems associated with use of 11C-NMSP in the quantitation of receptor properties before applying the method in clinical research. Special emphasis was placed on the evaluation of different mathematical approximations of a general compartment model. Different mathematical procedures are described and the results indicate that the approximations performed are reasonable. The simplest method for obtaining a reliable measurement of the rate constant k3 (which is approximately equal to proportional to the number of receptors) and k4 (the receptor dissociation rate constant) uses the radioactivity in the cerebellum as a measure of the tissue concentration of ligand equilibrating with the receptor compartment.

Animals↗