Biomedical subjects
Publications and source records attributed to S M Aquilonius.
Papers published between 1980 and 1986 reporting PET scans performed on patients with dementia are reviewed. Application of PET in clinical practice is limited to date. However, PET methods contribute to clarify pathophysiology of the dementias. Some possibilities for future investigations are outlined but progress will be slow due to the complexities of the technique.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective potent neurotoxin which has induced a syndrome similar to parkinsonism both in man and in monkeys. At autopsy degeneration of pigmented nerve cells in the pars compacta of the substantia nigra has been confirmed. The regional distribution of intravenously administered 1-(11C-methyl)-4-phenyl-1,2,3,6-tetrahydropyridine (11C-MPTP) in the brain of Rhesus monkeys was studied by positron emission tomography and the whole body distribution in mice was documented by autoradiography and by impulse counting of selected tissues. A very rapid and high uptake of 11C-MPTP derived radioactivity was seen in areas corresponding to striatum and midbrain, including the substantia nigra area. No elimination from these regions was seen during the study period of 2 h. The uptake was in the order of 7-8 times the homogenous distribution of the radioactivity in the monkey. The uptake was generally high also in other regions of the brain, but there some elimination could be distinguished. Pretreatment of the monkey with spiperone, a selective dopamine receptor antagonist, did not alter uptake nor the kinetics of the 11C-MPTP derived radioactivity. Thus 11C-MPTP does not have a high affinity for postsynaptic dopamine receptors. A remarkably high uptake of 11C-MPTP derived radioactivity was seen in the eye of the monkey. The selective uptake of radioactivity in the eye was also confirmed in pigmented but not in albino mice. The melanin affinity of MPTP may cause high intracellular concentrations of the compound or its metabolites in the melanin containing nerve cells in substantia nigra, which may explain the serious vulnerability of these neurons to MPTP.
A method for processing human postmortem material for application of autoradiography to large cryosections is described. Whole organ or tissue slices 5 mm thick are frozen between copper plates cooled with liquid nitrogen. They are subsequently embedded in carboxymethyl-cellulose, and 40- to 80-microns sections are taken up on adhesive tape and paper and transferred to gelatinized glass plates. Two procedures for incubation of large sections are described. The method is exemplified by autoradiographs of human brain hemisphere ([ 3H]quinuclidinylbenzilate) and whole biceps muscle ([ 3H]alpha-bungarotoxin).
This report is based on the use of L-dopa-containing drugs within 24 Swedish counties in the period 1977-1984. The mean utilization of these drugs in Sweden in 1984 was 1.46 defined daily doses (DDD)/day X 10(3) inhabitants (inh). As Parkinson's disease is virtually the only condition for which these drugs are prescribed, it seems highly probable that the determining factor for their use today is the prevalence of the disease. The exceptionally high utilization (2.34 DDD/day X 10(3) inh) of L-dopa-containing drugs in the county of Gävleborg, warranted further analyses of subareas in this particular county. The use is discussed in relation to environmental factors.
Seven patients with amyotrophic lateral sclerosis participated in a double-blind cross-over trial of oral physostigmine and neostigmine (10 and 45 mg/day, respectively, for 3 days). Six of the patients were also given intravenous injections (1 and 1.5 mg, respectively) of the drugs in an open trial. No significant effects on muscle strength or neurophysiological parameters were observed.
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Binding sites for the receptor ligands 3H-quinuclidinylbenzilate, 3H-alpha-bungarotoxin (3H-alpha-Btx), 3H-etorphine and 3H-strychnine were localized autoradiographically at cervical, thoracic and lumbar levels of spinal cords from post-mortem human control subjects and subjects with amyotrophic lateral sclerosis (ALS). The highest densities of muscarinic binding sites were found in the motor neuron areas and in the substantia gelatinosa, while the grey matter binding was very low within Clarke's column. Both 3H-alpha-Btx and opioid receptor binding sites were numerous within the substantia gelatinosa, while glycine receptor binding sites were more uniformly distributed within the spinal grey matter. In ALS cases, muscarinic receptor binding sites were markedly reduced in motor neuron areas and slightly reduced in the dorsal horn, while the other binding sites studied were relatively unchanged.
The morphological distribution of acetylcholine receptors in the whole biceps brachii muscle from a patient with amyotrophic lateral sclerosis (ALS) and from a control patient was studied by in vitro autoradiography with 3H-alpha-bungarotoxin (alpha-Btx). In ALS, 3H-alpha-Btx binding occurred over the entire muscle, while in the control case the binding was restricted to the motor end-plate region.
The morphological distribution of acetylcholine receptors in rat tibialis anterior and soleus muscles after a cryoinjury of the sciatic nerve was studied by in vitro autoradiography with 3H-alpha-bungarotoxin (3H-alpha-Btx). Tibialis anterior from rats intoxicated with acrylamide was also investigated by this technique. A computer system was used for densitometry and colour coding of the autoradiographs. In normal muscle, 3H-alpha-Btx binding was observed only at the motor endplates. From the second day after the nerve lesion the area of binding spread from the motor endplate region towards the muscle-tendon regions and on the 16th day almost all parts of the muscles showed increased binding. The binding had begun to decrease in the middle parts of the muscles on the 20th day and on the 30th day binding was observed only in the motor endplate area. Tibialis anterior from rats intoxicated with acrylamide (total dose 1100 mg X kg-1) showed 3H-alpha-Btx binding over the entire muscle.
Binding of labelled L- quinuclidinylbenzylate was studied in cryosections and homogenates of human and rat spinal cord. For the cryosections an autoradiographic method was used. With both techniques a higher density of muscarinic binding sites was found in rat than in human spinal cord. In the autoradiographs very high densities of muscarinic binding sites were observed in the motor neurone area and in the apical part of the dorsal horn. The latter high density region was not always found in homogenates from dissected tissue samples. The autoradiographic technique has a better resolution for detecting discrete regional variations in the receptor content of the spinal cord.
The distribution of motor endplates in biceps brachii, tibialis anterior, and sartorius muscles from human adults was studied by staining longitudinal cryosections of whole muscle for cholinesterase. A special freezing technique was used to prevent the muscle from cracking before sectioning on a heavy cryostat microtome. The results from a large number of cryosections from biceps brachii and tibialis anterior muscles were analyzed by a computer and the topographical distributions of endplates in different views of the muscles were reconstructed. In the biceps brachii muscle, the endplates formed a fairly distinct, slightly V-shaped band through the middle of the two heads. In the tibialis anterior muscle, the majority of the endplates were superficially distributed along the whole muscle. In the longitudinal sections from the middle part of the muscle, they gave the pattern of a parabola with its apex at the proximal end of the muscle. In the sartorius muscle, the endplates were scattered throughout the muscle and no endplate band was observed. The findings are in accordance with results obtained 30 years ago in investigations of muscle from small children and stillborn infants.
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In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.
Determination of plasma concentration of pyridostigmine in 20 myasthenic patients on maintenance therapy revealed rather small intraindividual variations within a dose interval. The predose concentration varied considerably between different patients and up to seven fold in patients on the same daily dose. No pharmacokinetic interaction between pyridostigmine and neostigmine was found in five patients studied. In six patients the decrement in the deltoid muscle was studied in parallel with determination of the plasma concentrations following administration of pyridostigmine or neostigmine. In these patients the existence of a "bell-shaped" dose response curve is suggested with the maximal effect at a concentration of 30-60 ng/ml for pyridostigmine and 5-15 ng/ml for neostigmine.
The topographic location of the enzyme choline acetyltransferase (ChAT) has recently been determined within the human spinal cord. ChAT, which is regarded as a specific marker of cholinergic structures in nervous tissue, showed an area of high activity in the ventrolateral part of the ventral horn, probably related to motor neurons. In addition, an area of high ChAT activity was found in the apical part of the dorsal horn. As amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of the cortico-spinal tracts and the lower motor neurons, we considered it of value to investigate the involvement of spinal cholinergic structures in this disorder. Substance P is regarded as the transmitter of incoming pain signals to the dorsal horn of the spinal cord, a subject recently reviewed by Marx. As disturbed sensation of pain is not a symptom of ALS, there seemed reason to correlate the spinal concentration of this peptide with the activities of ChAT in ALS.
The acetylcholine synthesizing (ACh-s) activity and the binding of the nicotine ligands 3H-alpha-bungarotoxin (alpha Btx) and 3H-d-tubocurarine (d-TC) were analysed in rat hind limb muscles 1-32 days after denervation. Muscles of the contralateral leg served as controls. ACh-s activity was considerably lower in tibialis anterior as compared to the extensor digitorum longus and the peroneus longus muscles. After denervation there was a rapid decrease in ACh-s activity in parallel to a considerable increase in alpha-Btx binding. The binding of d-TC was essentially unchanged following denervation indicating the special characteristics of the newly formed receptors. ACh-s activity can be differentiated into one specific (choline acetyltransferase) and one unspecific component.
Acetylcholine synthesizing (ACh-s) activity and binding of the nicotinic ligands 3H-alpha-bungarotoxin (alpha-Btx) and 3H-d-tubocurarine (d-TC) were analysed in rat hind limb muscles for up to 6 months after a cryolesion of the sciatic nerve. Muscles of the contralateral leg served as controls. After cryolesion there was a rapid decrease in ACh-s activity parallel to a considerable increase in alpha-Btx binding. A clearcut increase in ACh-s activity was first seen at 32 days and complete restoration in ACh-s activity was seen from 2-3 months postoperatively. From the 16th day there was a rapid decrease in alpha-Btx bindings sites and initial values were seen at the 32nd day postoperatively. D-TC binding sites were relatively unchanged during the experimental period. The first neurophysiological signs of reinnervation were seen at 16 days. The rats were observed to move normally about 2 months postoperatively. Normalization of alpha-Btx binding sites seems to be an earlier sign of reinnervation than normalization of ACh-s activity.