Sven-Åke Eckernäs

Biochemical changes in Dementia disorders of Alzheimer type (AD/SDAT)

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.

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

ABSTRACT— Dopaminergic receptor properties in the striatum of patients with Parkinson s disease (PD) and Huntingtons 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.

Topographical localization of choline acetyltransferase within the human spinal cord and a comparison with some other species

Choline acetyltransferase (ChAT), which is known to be a specific marker of cholinergic structures, was assayed in small tissue samples punched out from cryosections of human, bovine, cat and rat spinal cords. The relative distribution patterns of spinal ChAT were similar between the different species. An area of high activity in the ventrolateral part of the ventral horn was found. This activity is probably located in the motor neurons, as it could be traced into the ventral root region. In addition, in the dorsal horn of the cord from man and cow another area with high ChAT activity was found. Subcellular studies suggest that this activity is mainly located at nerve terminals.

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

ABSTRACT— 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 ∼ 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.

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.

Choline therapy in Huntington chorea

Choline chloride was administered orally (3 to 15 gm per day) to five patients with Huntington chorea. A long-lasting dose-dependent elevation of the concentration of free choline in plasma was obtained and the highest plasma concentrations (25 to 30 μmol per liter) were of the same magnitude as those that increase brain acetylcholine content in the rat. However, the choline treatment did not conclusively alter the involuntary movements of these patients.

Free choline in human plasma analysed by simple radio-enzymatic procedure: age distribution and effect of a meal.

Ultrafiltration of plasma was shown to be a simple and rapid method to obtain a stable sample for direct measurement of free choline (Ch) in plasma by a radioenzymatic procedure. Free Ch was analysed in plasma from healthy volunteers fasted 12-15 h and 1 h after a meal. The free Ch concentration was found within narrow limits with a mean of 10.6 +/- 0.4 mumol/l in the fasted subjects and 11.5 +/- 0.3 mumol/l 1 h after a meal. The difference is significant (paired t test, P less than 0.01, n = 23). Dietary influence on the free Ch concentration in human plasma is suggested. In three newborn infants (1-3 min post partum) the Ch concentration in plasma from the umbilical vein was 24.5 +/- 1.9 mumol/l.

Receptor binding and selectivity of three 11C-labelled dopamine receptor antagonists in the brain of rhesus monkeys studied with positron emission tomography

ABSTRACT— The regional distribution of 3 11C‐labelled dopamine receptor antagonists, N‐methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C‐raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D2‐dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C‐N‐methylspiperone and 11C‐clozapine both bound to serotonin receptors in the frontal cortex and to D2‐dopamine receptors in the striatal area. Raclopride was selectively bound to the D2‐dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3‐compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, kon and number of receptors, Bmax, varied from 0.02–0.07 min‐1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the Bmax values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.

Cholinesterase inhibitors lack therapeutic effect in amyotrophic lateral sclerosis. A controlled study of physostigmine versus neostigmine

ABSTRACT Seven patients with amyotrophic lateral sclerosis participated in a doubleblind 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.

Effects of atropine treatment on cortical, striatal and hippocampal high-affinity uptake of choline in the mouse

Abstract Changes in high-affinity uptake of choline (H.A. Ch ) were studied in synaptosomes from different mouse brain regions following intravenous (i.v.) administration of atropine (0.3–30 mg/kg body weight) in vivo . The Ch-uptake was expressed as a Ch-uptake index, defined as the ratio between H.A. Ch and the corresponding choline acetylt-ransferase (ChAt) activity. The Ch-uptake index was highest in the hippocampus and lowest in the striatum. In the hippocampus a dose-dependent increase in this index was found following atropine treatment, while the striatal Ch-uptake index was unaffected by atropine. Atropine given i.v. in a dose of 10 mg/kg induced a 86% increase in V max in synaptosomes from the hippocampus.