PubMed Health⌕ Search

Biomedical subjects

J A Edwardson

Publications and source records attributed to J A Edwardson.

At least 19 recordsLinked to original sources
PubMed1995

Risk factors in clinically diagnosed presenile dementia of the Alzheimer type: a case-control study in northern England.

STUDY OBJECTIVE: To investigate the relationship between presenile dementia of the Alzheimer type (PDAT) and family history, medical history, cigarette smoking, and exposure to aluminum. DESIGN: A case-control study in which 109 cases of clinically diagnosed PDAT and 109 controls matched for age and sex were compared for exposure to the risk factors. Odds ratios (ORs) were calculated using McNemar's test. SETTING: The northern health region of England. PATIENTS: Cases comprised those under 65 years diagnosed as having dementia by specialist services, who met clinical algorithm criteria for Alzheimer's disease (AD). Cases were confirmed at interview. MAIN RESULTS: Comparing cases with controls, (ORs) significantly greater than unity were obtained when there was a first degree relative with dementia (OR 2.5, 95% confidence interval 1.05, 6.56), any relative with dementia (OR 2.1, 95% CI 1.01, 4.55), and any relative aged less than 65 with dementia (OR 8.0, 95% CI 1.07, 348). Exposure to moderate levels of cigarette smoking (cumulative) was not significant; nor was exposure to aluminum in drinking water, diet, and medicinal sources. CONCLUSION: In this study of modest statistical power, a family history of dementia was confirmed as a risk factor in PDAT. No significant relationship between exposure to aluminium in water supplies, tea, and antacids was found. What is important, however, is the bioavailability of all dietary aluminium, determined by the concentrations of dissolved silicon in water: this requires further investigation.

Age of Onset↗
PubMed1994

Human IMR-32 neuroblastoma cells as a model cell line in Alzheimer's disease research.

The present study investigated expression and processing of amyloid precursor protein by neuronally differentiated IMR-32 neuroblastoma cells. APP mRNA in these cells was found to consist of approximately 58% APP695, 38% APP751, and < 4% APP770. APP-immunoreactive bands detected in western blots of cellular protein extracts were only detected by anti-APP antibodies to peptides with strong homology to APLP2, suggesting that these bands represent APP-like proteins and not APP itself. This result suggests that previous studies claiming immunodetection of cellular forms of APP may have to be re-evaluated. Four main species of C-terminal truncated, secreted APP were detected in blots of protein extracts from medium conditioned by these cells. The immunoreactive profile of these bands suggested a cleavage site N-terminal to the Lys16-Leu17 bond of alpha-secretase. This, together with differences in number and molecular mass of APP-immunoreactive bands between secreted APP from IMR-32 cells and that from the commonly used PC-12 cells, suggests differences in APP processing between these two neuronally differentiated cell lines. In theory, IMR-32 cells being of human neuronal origin may be a more appropriate cell line to study APP-processing in relation to Alzheimer's disease than the rat phaeochromocytoma PC-12 cell line. Therefore, these detected differences warrant further investigation. Additionally IMR-32 cells under certain tissue culture conditions can form intracellular fibrillary material that reacts with anti-PHF specific antibodies. Neuronally differentiated IMR-32 cells could therefore be used as a model system to investigate possible interactions between APP-processing and PHF formation.

Alzheimer Disease↗
PubMed1994

Alzheimer's-disease-like changes in tau protein processing: association with aluminium accumulation in brains of renal dialysis patients.

Tau protein is a major structural protein of the paired helical filaments (PHFs) found in both neuritic senile plaques and neurofibrillary tangles in Alzheimer's disease (AD). Senile plaques also contain amyloid beta protein (A beta). We did an immunochemical analysis of frontal cortex from 15 dialysis cases, 5 Alzheimer's disease patients, and 6 control cases to see whether AD-like changes in A beta deposition and tau protein were linked to aluminium accumulation. Dialysis patients were used because they are frequently exposed to increased levels of aluminium. 8 of the 15 dialysis cases had insoluble A beta, but there was no association between its presence and the accumulation of aluminium. However, we found AD-like changes in the processing of tau protein. In white matter, truncated tau protein in the PHF-core fraction and endogenously truncated tau in the supernatant fraction were both increased in association with aluminium accumulation in the brain. In grey matter, normal tau protein was depleted and insoluble hyperphosphorylated tau increased in association with aluminium concentration. Protease-resistant PHFs were present in grey matter in 2 dialysis cases, a frequency above that expected for AD in this age group. PHF-core tau in both grey and white matter correlated with decreased levels of normal tau protein in white matter. These findings are consistent with a role for aluminium in the development of AD-like pathology in patients subjected to prolonged aluminium exposure.

Adult↗
PubMed1994

Transferrin receptors in the parkinsonian midbrain.

Several hypotheses have been put forward to explain the pathogenesis of Parkinson's disease (PD) and recently it has been suggested that alterations in iron homeostasis may be implicated. Because of the central role of the transferrin receptor in providing access of iron to cells, we have studied the distribution and density of transferrin receptors using [3H]-transferrin ([3H]-Tf) binding and tritium film autoradiography in the normal and PD midbrain. High levels of [3H]-Tf binding were found in the dorsal raphé, oculomotor nucleus and periaqueductal grey whilst lower levels of [3H]-Tf binding were found in the tegmentum, red nucleus and substantia nigra. Significant reductions in binding were found in the substantia nigra, red nucleus and oculomotor nucleus in PD, the reductions in [3H]-Tf binding being similar to the loss of nigral neurons in PD. The data suggest that the increased iron content of surviving nigral neurons may reflect a compensatory metabolic response rather than abnormal transferrin receptor expression.

Adult↗
PubMed1994

Transferrin receptors in the normal human hippocampus and in Alzheimer's disease.

Several lines of evidence suggest that aluminium may play a role in the pathogenesis of Alzheimer's disease (AD). The iron transport protein transferrin is the major transport protein for aluminium, and aluminium gains access to cells by means of a specific cell surface transferrin receptor. We have assessed the distribution of transferrin receptors in the normal and AD hippocampal formation using [3H]-transferrin ([3H]-Tf) binding and tritium film autoradiography, in order to assess the role of the transferrin receptor in AD. In normal brain, [3H]-Tf binding was highest in the pyramidal cell layers with CA2 > dentate gyrus granule cell layer > or = CA1 > CA3 > or = CA4 > subiculum > parahippocampal gyrus. In AD, significant reductions in [3H]-Tf binding were found in CA1, CA2 and CA4 pyramidal cell layers. The reduced [3H]-Tf binding in AD may, however, be due to poor pre-mortem agonal states which correlated with reduced [3H]-Tf binding. The discrepancy between the distribution of transferrin receptors in the hippocampus and those areas which are prone to the formation of senile plaques and neurofibrillary tangles suggests that if transferrin-mediated uptake of aluminium in AD/SDAT is significant in the pathogenesis of this disorder, it is not the only determinant of Alzheimer-type neuropathology.

Aged↗
PubMed1994

Non-haem iron histochemistry of the normal and Alzheimer's disease hippocampus.

Increased free radical production may occur in Alzheimer's disease (AD). In view of the central role of iron in free radical reactions we have investigated the distribution of non-haem iron in the hippocampal formation in normal control individuals and in patients with AD. In controls, non-haem iron was principally associated with glial elements and the neuropil, with highest levels in the stratum radiatum/lacunosum, fimbria, alveus and oriens layers. Except for the subiculum, the pyramidal cell layers and the granule cell layer showed little or no non-haem iron staining. Intensity of staining was in the order of subiculum >> CA2 and adjacent regions of CA3 > CA4 > the remainder of CA3 > CA1. In the hippocampus in AD, iron was associated with cells containing neurofibrillary tangles (NFT) and was present in glial cells and neurites of senile plaques (SP). These findings were most pronounced in CA1 pyramidal cell layer and subicular complex although not all NFT or SP were stained. Since the NFT and SP staining for non-haem iron appears to be associated with glial cells, the association of non-haem iron with the pathological stigmata of AD may be a secondary response of glial cells, in particular microglia, to neuronal damage.

Aged↗
PubMed1994

Iron histochemistry of the substantia nigra in Parkinson's disease.

Raised tissue iron levels in the substantia nigra in Parkinson's disease (PD) suggests that altered iron homeostasis may underly the disorder. We have therefore investigated the distribution of non-haem iron in the normal and PD substantia nigra, using a sensitive histochemical procedure, to assess the pathogenic potential of this metal. In control cases non-haem iron staining was highest in the substantia nigra zona reticulata (SNr) and associated with the neuropil, oligodendrocytes, astrocytes and non-pigmented neurones. The substantia nigra zona compacta (SNc) showed lower non-haem iron staining than the SNr, with generalized impregnation of the neuropil and occasional non-haem iron-positive oligodendrocytes and astrocytes. The pigmented dopaminergic neurones were unstained, often present in areas of neuropil with low iron reactivity. In PD the SNc showed increased iron staining of the neuropil with many iron-positive microglial cells associated with extracellular melanin. The remaining dopaminergic neurones were unstained, though many of the non-pigmented neurones of the SNr were iron-positive.

Aged↗
PubMed1993

Effect of silicon on gastrointestinal absorption of aluminium.

The reported geographical association between Alzheimer's disease and levels of aluminium (Al) in water supplies may reflect the inverse relation between Al and silicon (Si) concentrations in water, and the potential for Si to reduce the bioavailability of the metal. We tested this hypothesis using isotopic 26Al tracer administered orally to five healthy volunteers in the presence and absence of Si. Dissolved Si, at a concentration found in some water supplies (100 mumol/L), reduced the peak plasma 26Al concentration to 15% of the value obtained in the absence of Si. The results indicate that dissolved Si is an important factor in limiting the absorption of dietary Al.

Administration, Oral↗
PubMed1992

Iron and aluminium in relation to brain ferritin in normal individuals and Alzheimer's-disease and chronic renal-dialysis patients.

Ferritin has been isolated and its subunit composition, iron and aluminium content determined in the cerebral cortex and cerebellum of normal individuals and in the cerebral cortex of Alzheimer's-disease and renal-dialysis patients. An e.l.i.s.a. for ferritin has been developed and the ferritin, non-haem iron and aluminium content of the parietal cortex were determined in normal individuals and Alzheimer's-disease patients. It was found that ferritin from the cerebral cortex and cerebellum of normal individuals had a high H-subunit content, similar to that of heart ferritin. The subunit composition of ferritin isolated from the cerebral cortex was not significantly altered in Alzheimer's-disease or renal-dialysis patients. Ferritin from the cerebral cortex of normal individuals had only approx. 1500 atoms of iron per molecule and the iron content of ferritin was not significantly changed in Alzheimer's-disease or renal-dialysis patients. Ferritin isolated from the cerebral cortex of normal, Alzheimer's-disease and renal-dialysis patients had less than 9 atoms of aluminium per molecule. The failure to find increased concentrations of aluminium associated with ferritin in dialysis patients, who had markedly increased concentrations of aluminium in the cerebral cortex, shows that aluminium does not accumulate in ferritin in vivo. This has important implications for the toxicity of aluminium, since it implies that cells are unable to detoxify aluminium by the same mechanism as that available for iron. Comparison of the concentrations of ferritin, aluminium and iron in the parietal cortex from normal and Alzheimer's-disease patients showed that, whereas the concentration of aluminium was not increased, both ferritin and iron were significantly increased in Alzheimer's disease.

Aged↗
PubMed1992

Matching-to-sample deficits in patients with senile dementias of the Alzheimer and Lewy body types.

Using a computerized matching-to-sample task, nonverbal visual recognition memory was studied in two groups of patients suffering from senile dementia of the Alzheimer type or the recently described senile dementia of the Lewy body type. The patients' cognitive abilities had been shown to be similar according to a number of standard psychometric tests. The two groups did not differ with respect to simultaneous matching-to-sample performance, although both were impaired relative to control. The group with senile dementia of the Lewy body type was severely impaired, relative to the group with senile dementia of the Alzheimer type, when delays (delayed matching to sample) were introduced. The findings suggest that short-term mnemonic processes, mediated by temporal lobe structures, could be more severely affected in senile dementia of the Lewy body type.

Aged↗
PubMed1992

Aluminium accumulation, beta-amyloid deposition and neurofibrillary changes in the central nervous system.

Deposition of beta-amyloid and the formation of neurofibrillary tangles (NFTs) are central to the aetiopathogenesis of Alzheimer's disease (AD). The possible effects of aluminium on these processes have been investigated in patients with renal failure who are exposed chronically to high blood levels of aluminium. Focal accumulation of aluminium was observed in neurons with high densities of transferrin receptors, indicating transferrin-mediated uptake, in regions such as cortex and hippocampus which are selectively vulnerable in AD. Increased staining for the beta-amyloid precursor protein (APP) in cortical pyramidal neurons was evident in the majority of renal patients and immature senile plaques were present in 30% of cases, suggesting that aluminium may induce or accelerate beta-amyloid deposition. The absence of neurofibrillary changes in this group of renal patients indicates that aluminium does not directly cause the formation of NFTs. The brain aluminium content was not raised in neuropathologically assessed cases of AD and we have been unable to confirm claims of defective transferrin binding in this disorder. If aluminium contributes to the development of sporadic AD, it must do so indirectly, perhaps via effects on the synthesis or metabolism of APP, or by contributing generally to the age-related attrition of neurons and thus reducing the threshold for deficits produced by more specific disease-related processes.

Aluminum↗
PubMed1992

Germanium-68 as a possible marker for silicon transport in rat brain.

Silicon (Si) is an essential trace element normally present in brain and cerebrospinal fluid, although the mechanism by which it enters and distributes in brain is largely unknown. Due to the short radioactive half-life of 31Si (156 min) we have investigated the use of 68Germanium (68-Ge, half-life 282 days) as a possible marker for Si transport in rat brain over longer periods than are possible with 31Si. Adult male anaesthetised rats were given a bolus of 68Ge I.V. and arterial blood samples taken during experiments that lasted between 5 min and 3 days. At termination, the brain was removed and analysed for radioactivity as were the plasma samples. Data were analyzed by Graphical Analysis which showed that the blood-brain barrier permeability to 68Ge (Kin approximately 10(-4) ml/min/g) is similar to that for many non protein-bound electrolytes in plasma and that 68Ge fluxes across cerebral capillaries are bidirectional. The autoradiographic distribution of 68Ge in brain was homogenous. Our results are in agreement with those of previous studies using 31Si or 68Ge, which suggest 68Ge may be a useful marker for Si when investigating the role of this element in conditions such as neurodegenerative diseases.

Animals↗
PubMed1992

Distribution of transferrin receptors in relation to cytochrome oxidase activity in the human spinal cord, lower brainstem and cerebellum.

Neuronal activity and oxidative energy metabolism are tightly coupled. There is evidence that cytochrome oxidase, the terminal enzyme of the electron transport chain, can serve as a metabolic marker of neuronal activity. All the respiratory chain enzymes have iron containing prosthetic groups and therefore represent an important component of iron utilisation. Since iron entry into cells is mediated by the transferrin receptor, this receptor may also serve as marker of neuronal activity. The histochemical distribution of cytochrome oxidase has therefore been compared with the autoradiographic distribution of the transferrin receptor in the human spinal cord, brainstem and cerebellum. Cytochrome oxidase activity showed a very similar pattern of distribution to the transferrin receptor in the spinal cord, brainstem and cerebellum. The highest levels of cytochrome oxidase activity and transferrin receptor binding were associated with; in the spinal cord, the substantia gelatinosa, laminae II and III and the motor neurones; in the medulla and pons, the spinal trigeminal nucleus, hypoglossal nucleus, dorsal motor nucleus of the vagus, inferior and superior olives, nucleus praepositus, nucleus paramedianus, central grey, superior central nuclei and locus coeruleus; in the cerebellum, the molecular layer. The results suggest that the transferrin receptor may provide a useful marker of total neuronal respiratory activity.

Aged↗
PubMed1992

The imaging and quantification of aluminium in the human brain using dynamic secondary ion mass spectrometry (SIMS).

Dynamic secondary ion mass spectrometry (SIMS) has been utilised to study the post-mortem distribution of aluminium in air-dried frozen sections from unfixed, unstained human brain in order to minimise contamination of the tissue and avoid redistribution and extraction of endogenous tissue aluminium. Substrates, sputter-coated with silver, were found to be free of focal aluminum surface contamination and thus minimised substrate induced artefacts in the tissue aluminium ion image. SIMS imaging of aluminium secondary ions at a mass resolution that eliminated the major molecular interferences, combined with a photomontage technique provided a unique strategy for studying aluminium distribution in tissue unrivalled by other spatially resolved microanalytical techniques such as laser microprobe mass spectrometry or X-ray microanalysis. Using this strategy, high densities of focal aluminium accumulations have been demonstrated in the cerebral cortex of the majority of chronic renal dialysis patients studied. In contrast, such aluminium accumulations were absent in control patients. SIMS imaging of aluminium appeared to provide much better discrimination between the dialysis patient group and the control group than one of the most widely used techniques for measuring aluminium in bulk samples, graphite furnace atomic absorption spectrometry. Preliminary studies have shown the feasibility of quantifying focal aluminium SIMS images obtained from brain tissue using aluminium-loaded brain homogenates as reference standards.

Adult↗
PubMed1992

Gastrointestinal absorption of aluminium in Alzheimer's disease: response to aluminium citrate.

Alzheimer's disease (AD) has been linked to genetic defects on chromosome 21 in some families, but most elderly cases appear to be sporadic and may, at least in part, involve environmental risk factors. Several lines of evidence suggest that aluminium may be involved in the aetiology of AD. However, despite universal exposure to aluminium in the diet, only some people develop the disease. We have developed a test of aluminium absorption using an aluminium citrate drink, to examine the hypothesis that sufferers from AD show increased aluminium absorption. In a younger group of AD patients aluminium absorption was significantly raised compared with age-matched controls. Aluminium absorption increased with age in the control group but was not significantly raised in older AD patients when compared with age-matched controls.

Adult↗