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N R Sims

Publications and source records attributed to N R Sims.

At least 55 records · Page 3Linked to original sources
PubMed1985

Neurochemical studies of early-onset Alzheimer's disease. Possible influence on treatment.

Multiple neurotransmitter deficits found in recent autopsy studies of patients with Alzheimer's disease may militate against the success of "simple cholinergic replacement" as treatment. To study acetylcholine synthesis, we measured the incorporation of radiolabeled glucose into the transmitter in temporal-cortex specimens obtained at diagnostic craniotomy in 17 young patients with Alzheimer's disease. Synthesis of acetylcholine was significantly correlated with cognitive impairment. These results are consistent with the view that the deficit in the presynaptic cholinergic system is a relatively early change in the development of the clinical features of the disease. Other alterations in noradrenergic cells, some cortical neurons, postsynaptic cortical receptors, and possibly serotoninergic cells may not be closely associated with Alzheimer's disease.

Acetylcholine↗
PubMed1984

Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia.

Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) from control subjects and patients of both presenile and senile age with histologically verified Alzheimer's dementia. CSF HVA increased with age in control but not in Alzheimer patients. HVA and 5-HIAA in the CSF of presenile Alzheimer patients was lower than that of age matched control subjects.

Aged↗
PubMed1983

Amino acid release from biopsy samples of temporal neocortex from patients with Alzheimer's disease.

Tissue prisms prepared from neurosurgical samples of temporal neocortex of Alzheimer and control patients, upon depolarization preferentially released aspartate, glutamate and gamma-aminobutyrate (GABA). The Alzheimer and control samples did not significantly differ in the pattern of amino acid release, although acetylcholine synthesis by the Alzheimer tissue prisms was greatly reduced. There was no correlation between the efflux of any amino and acetylcholine synthesis. These observations suggest that in Alzheimer's disease there are no major changes in the extracellular concentrations of these putative amino acid transmitters.

Acetylcholine↗
PubMed1983

Metabolic processes in Alzheimer's disease: adenine nucleotide content and production of 14CO2 from [U-14C]glucose in vitro in human neocortex.

Samples of neocortex removed at diagnostic craniotomy from patients with Alzheimer's disease and incubated in vitro showed an increased production of 14CO2 from [U-14C]glucose compared with neurosurgical controls. This was a feature of incubations in the presence of both 5 mM K+ (142% control) and 31 mM K+ (126%). Specific labelling of the amino acid pool was unaltered, suggesting that the apparent increase of CO2 production was not merely a reflection of changes in dilution of the radiolabel from glucose. The content of adenine nucleotides was significantly less than control values in the tissue from patients with Alzheimer's disease after in vitro incubations but the adenylate energy charge was unchanged, indicating that normal energy metabolism was not grossly impaired in these preparations.

Acetylcholine↗
PubMed1983

Presynaptic cholinergic dysfunction in patients with dementia.

Indices of presynaptic cholinergic nerve endings were assayed in neocortical biopsy samples from patients with presenile dementia. For those patients in whom Alzheimer's disease was histologically confirmed, [14C]acetylcholine synthesis, choline acetyltransferase activity and choline uptake were all found to be markedly reduced (at least 40%) below mean control values. The changes occurred in samples from both the frontal and temporal lobes and for [14C]acetylcholine synthesis the decrease was similar under conditions of high and low neuronal activity (as assessed by incubations in 31 mM and 5 mM K+ respectively). Samples from other demented patients, in whom the histological features of Alzheimer's disease were not detected, produced values for all three biochemical parameters which were similar to controls. For the total group of patients with presenile dementia there were correlations between values for the three markers of presynaptic cholinergic nerve endings suggestive of a loss of functional activity at these sites in Alzheimer's disease.

Acetylcholine↗
PubMed1983

Biochemical evidence of selective nerve cell changes in the normal ageing human and rat brain.

Atrophy with ageing of human whole brain, entire temporal lobe, and caudate nucleus was assessed in autopsy specimens, by biochemical techniques. Only the caudate nucleus showed changes. Markers for several neurotransmitter systems were also examined for changes with age. In neocortex and temporal lobe of human brain, small decreases were detected in markers of cholinergic nerve terminals, whereas a large decrease (79%) occurred in the caudate nucleus. Findings were similar in striatum from 3--33-month-old rats. No change occurred in binding of [3H]quinuclidinyl benzilate by human samples. Markers of serotonergic terminals were also unchanged in human and rat brain. By contrast, binding of [3H]lysergic acid diethylamide and [3H]serotonin was decreased (32-81%) in human neocortex and temporal lobe, but not in caudate nucleus. A 43% loss of a marker of gamma-aminobutyrate terminals occurred in human neocortex, while [3H]muscimol binding increased (179%). No changes were detected in markers of catecholamine synapses in temporal lobe or rat striatum. Hence, with human ageing there appears to be a loss of markers of gamma-aminobutyrate neurones intrinsic to neocortex and acetylcholine cells intrinsic to the caudate nucleus, as well as a change in postsynaptic serotonin receptors in neocortex. These losses are accompanied by relative preservation of markers of ascending projections from basal forebrain and brain stem.

Aged↗
PubMed1983

Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease.

Markers of serotonin synapses in entire temporal lobe and frontal and temporal neocortex were examined for changes in Alzheimer's disease by use of both neurosurgical and autopsy samples. Uptake of [3H]serotonin, binding of [3H]imipramine, and content of indolamines were all significantly reduced, indicating that serotonin nerve terminals are affected. Binding of [3H]serotonin was also reduced, whereas that of [3H]quinuclidinyl benzilate, [3H]muscimol, and [3H]dihydroalprenolol were unaltered. When the Alzheimer's samples were subdivided according to age, the reduction in [3H]serotonin binding was a feature of only autopsy samples from younger patients. In contrast, presynaptic cholinergic activity was reduced in all groups of Alzheimer's samples, including neurosurgical specimens. Five markers, thought to reflect cerebral atrophy, cytoplasm, nerve cell membrane, and neuronal perikarya were measured in the entire temporal lobe. In Alzheimer's disease the reductions (mean 25%, range 20-35%) were thought to be too large to be due only to loss of structures associated with the presumed cholinergic perikarya in the basal forebrain and monoamine neurones in the brain stem.

Acetylcholine↗
PubMed1982

Stimulation of acetylcholine synthesis by blockade of presynaptic muscarinic inhibitory autoreceptors: observations in rat and human brain preparations and comparison with the effect of choline.

The central presynaptic muscarinic inhibitory autoreceptor has been monitored by measuring the effects of muscarinic agents on acetylcholine (ACh) synthesis by rat and human neocortical tissue prisms. Quinuclidinyl benzilate (QNB), the antimuscarinic which of 20 tested caused the most marked stimulation of ACh synthesis in rat, significantly increased ACh synthesis in human prisms over a range or concentrations of 0.1 microM-10 microM. This data provides the first evidence that human brain contains presynaptic muscarinic receptors. However, the most marked effect of QNB was to increase synthesis to only 112% of control (value without drug) which was much less than in rat (to 140% of control). ACh synthesis is reduced to 50% of control in neocortex from Alzheimer patients so none of the antimuscarinics tested seem to be potentially capable of appreciably reversing this deficit. A high concentration of choline (10 mM) stimulated synthesis in rat prisms to about the same extent as QNB. Moreover, the ACh precursor was at least as effective in stimulating synthesis in human prisms (including those from a patient with Alzheimer's disease). This suggests that an elevated intracellular concentration of choline is likely to be much more effective than an antimuscarinic agent in stimulating synthesis in Alzheimer brain.

Acetylcholine↗
PubMed1982

Production of [14C]acetylcholine and [14C]carbon dioxide from [U-14C]glucose in tissue prisms from aging rat brain.

Production of [14C]acetylcholine and 14CO2 was examined by using tissue prisms from neocortex, hippocampus, and striatum from rats aged approximately 5 months, 13 months, and 27 months. [14C]Acetylcholine synthesis in the striatum showed highly significant decreases with age for measurements in the presence of both 5 mM- and 31 mM-K+, contrasting with the lack of significant change in 14CO2 production in this region. The neocortex and hippocampus showed only small changes, especially when comparison was made between 13-month and senescent animals. Measurements of the release of [14C]acetylcholine and influence of atropine on this release confirmed the relative stability with age of the cholinergic system in the neocortex.

Acetylcholine↗
PubMed1981

[14C]acetylcholine synthesis and [14C]carbon dioxide production from [U-14C]glucose by tissue prisms from human neocortex.

1. [14C]Acetylcholine synthesis and 14CO2 production from [U-14C]glucose has been measured in tissue prism preparations from human neocortex. 2. Electron micrographs of prisms from human and rat neocortex show that both contain intact synaptic endings with evenly-distributed vesicles and normal-appearing mitochondria, but only poorly preserved cell body structure. 3. Synthesis of [14C]acetylcholine in prisms from rat neocortex is similar to estimates for turnover in vivo. Synthesis in prisms from human neocortex is 18% of that in rat tissue and 64% of that in tissue from baboon neocortex for incubations performed in 31 mM-K+. 4. Investigations of prisms prepared from rat brains stored at 37 degrees C after death revealed that synthesis of [14C]acetylcholine in the presence of 31 mM-K+ was greatly decreased within 30 min of post-mortem incubation, whereas synthesis at 5 mM-K+ and production of 14CO2 at both K+ concentrations were only significantly affected after longer periods. Changes were similar in neocortex and striatum. Thus human autopsy material is unlikely to be suitable for use with this system. 5. Investigations using animal models suggest that [14C]acetylcholine synthesis and 14CO2 production are not affected by surgical or anaesthetic procedures. 6. Neither [14C]acetylcholine synthesis nor 14CO2 production in human prisms was significantly changed with age between 15 and 68 years. 7. Samples from patients with the dementing condition Alzheimer's disease showed a significant decrease in [14C]acetylcholine synthesis to 47% of normal samples and a significant increase of 39% in production of 14CO2.

Acetylcholine↗
PubMed1980

Glucose metabolism and acetylcholine synthesis in relation to neuronal activity in Alzheimer's disease.

The metabolism of (U--14C) glucose and its incorporation into acetylcholine were determined in vitro in fresh cortical biopsy samples from patients with Alzheimer's disease and controls. Synthesis of 14C acetylcholine was significantly reduced (60% and 67% reduction under stimulated and resting conditions, respectively) without significant changes in the overall metabolism of glucose (as measured by 14CO2 production). Acetylcholine synthesis was directly related to the activity of choline acetyltransferase. The changes in cholinergic markers reflected the severity of psychological defects. Acetylcholine synthesis was not reduced in biopsy samples from patients suffering from presenile dementia with no histological evidence of Alzheimer's disease.

Acetylcholine↗
PubMed1979

Detergent activation and solubilization of 2':3'-cyclic nucleotide 3'-phosphodiesterase from isolated myelin and c6 cells.

Several detergents were investigated for their ability to increase activity of 2':3'-cyclic nucleotide 3'-phosphodiesterase in isolated myelin. The ability of Triton X-100 and Sulfobetaine DLH to solubilize the enzyme was also examined. Solubilization with Triton X-100 was only effective in the presence of salt, for example with NaCl 51% of the activity was solubilized. A single extraction with Sulfobetaine DLH yielded slightly more solubilized enzyme and did not require added salt. Both activation and solubilization of 2':3'-cyclic nucleotide 3'-phosphodiesterase appeared to be similarly dependent on detergent concentration, suggesting a common action of the detergent in the two processes. Myelin basic protein was solubilized more readily than the enzyme. In contrast with the enzyme in myelin, 2':3'-cyclic nucleotide 3'-phosphodiesterase activity in C6 cells was not increased in the presence of Triton X-100, and was partially solubilized by either Triton X-100 or NaCl alone. No myelin basic protein could be detected in C6 cells by radioimmunoassay.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1978

A search for the "multiple sclerosis virus"--lack of effect of brain extracts on myelin development in chickens, mice and rats.

Attempts were made to transmit possible infectious agents from tissue of MS patients into three animal species, under conditions designed to enhance the development of such an agent. Myelination was monitored by measuring CNPase activity and myelin basic protein. Although no significant effects were observed, the usefulness of a new assay for CNPase was demonstrated. Nude mice were found to have a lower level of CNPase than their heterozygous littermates.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗