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Biomedical subjects

S M Aquilonius

Publications and source records attributed to S M Aquilonius.

At least 37 records · Page 2Linked to original sources
PubMed1996

Levodopa-induced changes in synaptic dopamine in patients with Parkinson's disease as measured by [11C]raclopride displacement and PET.

Changes in striatal binding of [11C]raclopride, a dopamine D2 receptor antagonist, induced by acute levodopa administration, were evaluated with PET in 10 patients with idiopathic Parkinson's disease (PD). The patients were scanned on two occasions: drug-free and 15 minutes after a 5-minute intravenous infusion of 3 mg/kg levodopa. Levodopa administration produced reductions in striatal [11C]raclopride uptake index with a rostrocaudal gradient. The most pronounced reduction was found in the posterior putamen (to 82% of baseline), followed by the anterior putamen (to 88% of baseline) and the caudate nucleus (to 94% of baseline). The magnitude of [11C]raclopride uptake index reduction correlated with drug-free disability. Moreover, in four hemiparkinsonian patients, a reduction in [11C]raclopride uptake index was measured in the putamen contralateral to the parkinsonian symptoms. The present results demonstrate a positive correlation between striatal dopaminergic nerve-terminal deficiency and the capacity for levodopa to increase synaptic dopamine and displace [11C]raclopride binding, which corresponds to an accelerated amine turnover in dopamine-depleted striatal tissue. We therefore suggest that dopaminergic degeneration in PD is paralleled by a progressive acceleration of amine turnover. This mechanistic consequence of nigrostriatal degeneration, the selective restoration of synaptic dopaminergic neurotransmission in denervated striatal subregions, may explain the effectiveness of levodopa in producing symptomatic benefits in early PD. However, we also suggest that in the vastly denervated striatum, as in advanced PD, an excessive acceleration of amine turnover results in swings in levodopa-induced synaptic dopamine levels that are far beyond normal. This phenomenon most likely plays a key role in the pathogenesis underlying the development of motor-response complications in PD.

Aged↗
PubMed1995

Neurological Wilson's disease studied with magnetic resonance imaging and with positron emission tomography using dopaminergic markers.

Four patients with neurological Wilson's disease were investigated using magnetic resonance imaging (MRI) and positron emission tomography (PET). All patients had dystonia as their major clinical manifestation but also had dysarthria and at the presentation of the disease had choreoathetoid movements in at least one limb. A multitracer approach with PET was used to visualize various aspects of dopaminergic function; [11C]-(+)-nomifensine (NMF), [11C]raclopride (RAC) and [11C]-L-DOPA (one patient). Correlation analysis of RAC and NMF binding as well as putamen/caudate uptake ratios showed corresponding reductions. The patient investigated with [11C]-L-DOPA had a normal striatal uptake. Generally, structural changes as shown by MRI corresponded to reductions both in NMF and RAC binding. There was no evident correspondence between PET findings and the severity of clinical symptoms seen in the individual patient. In two patients with discrete neurological impairment at the time of investigation, PET showed serious presynaptic dopaminergic lesions in the putamen. Our data suggest that the striatal degeneration seen in Wilson's disease comprises a complex pathology involving both afferent and efferent projections. The discrete neurological impairment seen in some patients with gross striatal pathology might be due to concomitant lesions in functionally counteracting basal ganglia circuits.

Adult↗
PubMed1994

Double blind cross over trial with deprenyl in amyotrophic lateral sclerosis.

In this paper we present results from a double blind cross over trial with deprenyl, a selective and irreversible monoamine oxidase-B (MAO-B) inhibitor, in 10 patients suffering from amyotrophic lateral sclerosis. The patients were randomised in such a way that half of the patients started with the active drug and half with the placebo treatment. Each patient was given 10 mg deprenyl (eldepryl, 10 mg tablets) per day for 12 weeks and then placebo for the same length of time. There was a drug free period of 12 weeks between the courses. The neurological status of the patients were evaluated every six weeks by using Norris, spinal and bulbar scores and it was observed that all cases deteriorated in their clinical status during the 36 weeks of the controlled study. MAO-B activity in blood platelets was completely inhibited during treatment with deprenyl. In the preliminary analysis performed so far, no obvious retardation in the progress of the disease could be observed with deprenyl treatment.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Monoamine oxidase-B in motor cortex and spinal cord in amyotrophic lateral sclerosis studied by quantitative autoradiography.

The distribution of MAO-B was studied by using an in vitro quantitative autoradiographical method in the post-mortem spinal cord and motor cortex from control and ALS cases. 3H-L-deprenyl was used as a radiotracer. Sections stained with thionine were used to count glial cells. In both control and ALS spinal cords, high density of 3H-L deprenyl binding was observed around the central canal, in the substantia gelatinosa and other grey matter regions. In the ALS cases a pronounced and statistically significant increase of MAO-B was observed in the corticospinal tract, the motor neuron areas and in the ventral white matter. An increase in the number of glial cells in spinal cords from ALS cases was also evident. Moreover, the concentration of MAO-B was highly correlated with glial cell counts in thionine stained sections in various regions of the spinal cord, both in controls and ALS cases. An elevated level of 3H-L-deprenyl binding, in ALS cases, was observed in all the individual laminae of the pre- and post-central gyri of the cerebral cortex. There was no difference in MAO-B concentration between the two groups in the occipital cortex. A substantial increase in the concentration of MAO-B was observed in the white matter of ALS cases. Reactive gliosis has been shown to be associated with neurodegenerative disorders and experimental lesions in animals. The most likely explanation for the increase of MAO-B in ALS and in other neurodegenerative disorders seems to be that the increase is a consequence of the reactive gliosis associated with these disorders.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Reactive gliosis and monoamine oxidase B.

A double-staining method was applied to cryosections of human spinal cord from patients who died with amyotrophic lateral sclerosis (ALS) and corresponding controls in order to investigate cellular content of monoamine oxidase B (MAO-B). 3H-L-Deprenyl emulsion autoradiography was used in combination with histochemical methods for the detection of astrocytes and monocytes/microglia. In the ALS spinal cords an increased number of astrocytes as well as an increased content of MAO-B in reactive species of astrocytes was demonstrated. No significant 3H-L-deprenyl binding was observed in cells derived from the mesoderm, e.g. monocytes or microglia. Furthermore, a sub-population of reactive astrocytes that contained low levels of MAO-B was observed in spinal sections. These findings were further substantiated by studies performed on primary astrocyte cultures.

Amyotrophic Lateral Sclerosis↗
PubMed1994

Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis.

Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for 125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Aged↗
PubMed1993

Monoamine oxidase-B in astrocytes.

In the present report we describe the astrocytic localization and content of monoamine oxidase-B (MAO-B) by means of a 3H-L-deprenyl emulsion autoradiography in primary cultures of rat astrocytes, in cryosectioned astrocytoma surgical specimen, and in cryosections of human spinal cords from patients dying in amyotrophic lateral sclerosis (ALS) and controls. The occurrence of MAO-B enzyme protein depends on the degree of cellular differentiation as demonstrated by studies on astrocytes in primary cultures analyzed at two different stages of maturation. Highly differentiated cells exhibited high relative enzyme concentration whereas glioblasts lacked or showed very low contents of MAO-B enzyme. This was further substantiated by studies performed on human astrocytoma tissue using 3H-L-deprenyl emulsion autoradiography in combination with immunohistochemical detection of glial fibrillary acidic protein (GFAP). Regional increases of MAO-B concentration were found in ALS lumbar sections with quantitative 3H-L-deprenyl autoradiography. On the basis of results obtained from double staining for GFAP and MAO-B, the increase in MAO-B seemed to be due to an increased number of astrocytes as well as an increased content of MAO-B in reactive species of astrocytes. A cell culture model has been used that produces cells with morphology and GFAP-content similar to reactive cells. These astrocytes exhibited high relative content of the MAO-B enzyme protein. In the light of the presented data, taking into account the finding that a subpopulation of reactive cells contained low levels of MAO-B, a heterogeneity among reactive astrocytes was observed.

Amyotrophic Lateral Sclerosis↗
PubMed1993

Differential increases in catecholamine metabolizing enzymes in amyotrophic lateral sclerosis.

The activity of three catecholamine-metabolizing enzymes, monoamine oxidase type A and type B (MAO-A and MAO-B) as well as catechol-O-methyltransferase (COMT), were estimated in homogenates of human spinal cord using radiometric assays. The enzyme activities were determined in postmortem spinal cord tissue from controls and cases with amyotrophic lateral sclerosis (ALS). The activity of MAO-A was below the limit of detectability in both controls and ALS cases. The activities of MAO-B and COMT were evenly distributed at the various spinal levels. The MAO-B activity was substantially elevated in ALS spinal homogenates, whereas only a slight, but not statistically significant, increase in COMT activity was observed. A significant correlation between COMT and MAO-B activities was observed for controls. However, this covariation was not apparent for the ALS cases. These results suggest that the two enzyme proteins are regulated by more complex mechanisms in the spinal cord in amyotrophic lateral sclerosis than simple general increases caused by elevated astroglial cell numbers. In addition, the MAO-A, MAO-B, and COMT activities were estimated in spinal cords from rats treated with the selective MAO-B inhibitor L-deprenyl, a drug with putative neuroprotective effects in neurodegenerative disorders. After 3 weeks of L-deprenyl treatment (0.25 mg/kg/day, sc), the spinal MAO-A and MAO-B activities were decreased by 50 and 80%, respectively. In contrast, the COMT activity was not altered by L-deprenyl administration.

Aged↗
PubMed1993

Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson's disease.

Motor performance of five patients with advanced Parkinson's disease was investigated during their optimum oral therapy (conventional tablets and/or depot capsules) and during a continuous duodenal infusion of levodopa. Due to the low water solubility of the drug, conventional tablets of levodopa+carbidopa (Sinemet) were milled and dispersed in a 1.8% aqueous methylcellulose solution. The dispersion was delivered nasoduodenally by a portable pump. The effect of levodopa in the two dosing regimens was estimated optico-electronically every 15 min and was also evaluated from videorecordings every 30 min and plasma levels of levodopa was regularly measured. Each dosage regimen the was studied twice, at a 2-4 day interval. Duodenal infusion improved motor function in all five patients and the fluctuations were reduced when compared to the oral therapy. Variation in plasma levodopa concentrations was 3-10 fold during oral therapy, while during the infusion a stable concentration was obtained. The therapeutic concentration varied from 0.3-3 ml-1 between patients. The relative bioavailability of levodopa in the solid preparation compared to the dispersion was in all patients 100%. Our results encourage further development of a duodenal infusion system with a levodopa dispersion for clinical use in parkinsonian patients who show severe fluctuation.

Administration, Oral↗
PubMed1993

Magnetic resonance imaging of the brain in Wilson's disease.

Fifteen patients with Wilson's disease were examined, using spin-echo (SE) and gradient-echo (GE) sequences with 0.5 T and 1.5 T magnetic resonance (MR) imagers. They fell into three groups: groups 1 and 2 were examined retrospectively after 3-18 years of treatment, while group 3 was examined prospectively from the start of treatment, after recommencement of treatment, or inadequate treatment. MRI was sensitive to changes in the basal ganglia at sites typical of Wilson's disease and was useful for documenting the effects of treatment. It was found necessary to estimate the relaxation times T1 and T2, to better assess improvement or transient worsening of the disease in the prospective group. Residual cavitation and gliosis could be distinguished in the retrospective group using a subtraction technique.

Adult↗
PubMed1993

The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man.

1. A new method for perfusing a 10 cm segment of jejunum in humans has been used in seven subjects to study the effect of the amino acid L-leucine (40 mM) on the intestinal absorption of levodopa (2.5 mM). The tube contains six channels and has two inflatable balloons, which enable a perfusion of a closed and defined segment of the proximal small intestine. 2. L-leucine decreased the intestinal absorption of levodopa from 40 +/- 19 to 21 +/- 15% but was without effect on the absorption of antipyrine, benserazide and D-glucose. 3. We confirm that levodopa is absorbed by the active transport system normally responsible for the absorption of large neutral amino acids (LNAA) in humans. Oral absorption by passive diffusion, probably by the paracellular route, might also occur for levodopa in the proximal part of the small intestine.

Adult↗
PubMed1993

A pilot trial of dextromethorphan in amyotrophic lateral sclerosis.

Assuming the presence of glutamate-induced neurotoxicity in amyotrophic lateral sclerosis 14 patients were treated with dextromethorphan, an N-methyl-D-aspartate receptor antagonist. The patients were treated with 150 mg dextromethorphan or placebo daily for 12 weeks in a double-blind crossover trial, with a wash out period of 4 weeks between the two treatment periods. Thereafter the surviving patients were treated with 300 mg dextromethorphan daily for up to 6 months in an open trial. No positive effects on clinical or neurophysiological parameters (relative number of axons, and compound muscle action potentials in the abductor digiti minimi muscle) were observed either in the double-blind trial or in the open trial.

Aged↗
PubMed1993

Konzo: a distinct disease entity with selective upper motor neuron damage.

Two Tanzanian patients with konzo were severely disabled by a non-progressive spastic paraparesis, since the sudden onset during an epidemic six years earlier. At the time of onset they had a high dietary intake of cyanide from exclusive consumption of insufficiently processed bitter cassava roots. MRI of brain and spinal cord were normal but motor evoked potentials on magnetic brain stimulation were absent, even in the only slightly affected upper limbs. Other neurophysiological investigations were largely normal but the more affected patient had central visual field defects. Konzo is a distinct disease entity with selective type upper motor neuron damage.

Adult↗