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J A Edwardson

Publications and source records attributed to J A Edwardson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Gastrointestinal absorption of aluminum is increased in Down's syndrome.

Individuals with Down's Syndrome (DS) develop the neuropathological features of senile dementia of the Alzheimer's type (SDAT) by early middle age. Because of recent evidence that gastrointestinal (GI) aluminum (Al) absorption is increased in patients with SDAT, and that Al may contribute to associated neuropathological changes, we have investigated the GI uptake of Al in patients with DS by two methods. The first measured the absorption of 27Al at concentrations associated with antacid use, in the presence of citrate, using atomic absorption spectrometry. There was no difference between basal blood concentrations of 27Al in 15 DS subjects (36-46 years) and 15 age-matched controls. The mean increase in 27Al blood concentrations 60 minutes after the dose of Al was four times greater in the DS group than in controls (p < 0.001). The second measured GI absorption of 26Al under normal dietary conditions using accelerator mass spectrometry. With 26Al the mean Al absorption in DS subjects (n = 5) exceeded that of controls (n = 4) by a factor of 6 (p < 0.02). Although the mechanisms of enhanced absorption are unknown, the data indicate that similar abnormalities in the GI handling of Al occur in both SDAT and DS suggesting that it may be advisable to minimize dietary exposure to Al in subjects at risk of developing Alzheimer-type pathology.

Adult↗
PubMed1996

Effect of aluminium on expression and processing of amyloid precursor protein.

The environmental agent aluminium has been extensively investigated for a potential role in the aetiology of Alzheimer's disease. Despite many investigations there is at present no definite proof for any involvement. If aluminium is involved it is possible that its action is mediated through interaction with the synthesis or processing of amyloid precursor protein (APP). The present study compared aluminium loaded IMR-32 neuroblastoma cells and rat brains with control cells and brains to determine if aluminium affected APP expression and/or processing. In the IMR-32 model system aluminium had no effect on steady-state APP mRNA levels or on the ratio of individual isoforms. It also had no quantitative or qualitative effect on APP-immunoreactive bands detected in protein extracts from conditioned medium of these cells. In total cell extracts, aluminium reduced the intensity of APP-immunoreactive bands between 120-105 kDa but had no effect on a 9 kDa band. In rat brains, aluminium had no effect on APP-immunoreactive bands from soluble or insoluble-membranous extracts. The results, in general, provide no evidence for any effect of aluminium on APP expression or processing.

Aluminum↗
PubMed1996

Apolipoprotein E genotype and Alzheimer's disease in an elderly Norwegian cohort.

Apolipoprotein E (Apo E) genotyping was performed on an autopsy cohort of neuropathologically verified non-demented controls and subjects with Alzheimer's disease (AD) resident in nursing homes in the Oslo area. AD was associated with a significantly increased frequency of the Apo E epsilon 4 allele; the frequency of the epsilon 2 and epsilon 3 alleles was lower in AD but not significantly so. Age at death in the control group and the AD group did not differ significantly; neither did age at death nor age at onset of dementia in AD vary according to Apo E genotype, though tendencies towards an earlier age at death was seen in individuals with epsilon 4/4 and earlier age at onset dementia in the presence of an epsilon 4 allele and a later age of onset the presence of an epsilon 3 allele were seen. Possession of an epsilon 2 allele had no effect on age at onset of dementia or age at death. Among the possible genotypes there was a trend towards a progression of earliest onset epsilon 4/4, epsilon 2/4, epsilon 3/4, epsilon 3/3, epsilon 2/3 latest onset of dementia and longest duration epsilon 2/4, epsilon 4/4, epsilon 3/4, epsilon 3/3, epsilon 2/3 to shortest duration of dementia.

Age of Onset↗
PubMed1996

Molecular biology of APO E alleles in Alzheimer's and non-Alzheimer's dementias.

Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the epsilon 4 allele has been shown to be a risk factor for late onset Alzheimer's disease (AD) where there is an increased frequency of the epsilon 4 allele. The epsilon 4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependent manner, with the epsilon 2 allele having an opposing effect. We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein epsilon 4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased epsilon 4 frequency is also found though a normal epsilon 2 frequency exists, unlike in AD where the epsilon 2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinson's disease with or without dementia, or in Down's syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype. Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the epsilon 2 allele frequency may indicate a genetic difference between AD and LBD. The epsilon 4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.

Alleles↗
PubMed1996

Content of brain aluminum is not elevated in Alzheimer disease.

Several studies have reported that the bulk aluminum (Al) concentration is increased in the brain in Alzheimer disease (AD), while other studies have failed to demonstrate an increase. Most of these investigations have had one or more methodological deficiencies, including lack of adequate neuropathological assessment; failure to age-match the control samples; small sample sizes, lacking statistical power; and geographical heterogeneity in the AD and control populations. The present population-based study of 92 clinically and histopathologically diagnosed AD patients and normal elderly nursing home residents was designed to avoid these potential biases. When a subsample of AD cases with the most severe brain pathology was compared with controls having no or minimal pathology, no statistically significant differences were found in the bulk aluminum concentration measured by graphite furnace atomic absorption spectrometry in frontal cortex (1.8 +/- 0.7 vs. 1.7 +/- 0.7 micrograms/g dry wt), temporal cortex (1.4 +/- 0.3 vs. 1.5 +/- 0.5 micrograms/g dry wt), liver (2.0 +/- 1.3 vs. 2.0 +/- 1.2 micrograms/g dry wt), or head of femur (2.4 +/- 1.6 vs. 2.2 +/- 1.0 micrograms/g ash wt). Within the whole series of 92 cases, there was no difference in the bulk aluminum concentration of the frontal cortex between individuals diagnosed as definite, probable, and possible cases of AD using the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria. The density of senile plaques and neurofibrillary tangles in frontal and temporal cortex showed no correlation with the bulk aluminum concentration. Logistic regression analyses, which controlled for age and sex, did not influence outcome for any of the comparisons. The data show conclusively that in AD, bulk aluminum concentration is not increased in two cortical brain regions that are selectively vulnerable to the neuropathological changes associated with this disorder.

Aged↗
PubMed1996

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

Dementia↗
PubMed1995

Effect of apolipoprotein E genotype on Alzheimer's disease neuropathology in a cohort of elderly Norwegians.

A cohort of elderly Norwegians dying in nursing homes in the Oslo region have been genotyped for the Apolipoprotein E (ApoE) gene. Alzheimer's disease (AD) cortical neuropathology and clinical evidence of dementia were used to assign cases without evidence of other confounding neuropathology. Senile plaque (SP) and neurofibrillary tangle (NFT) densities in frontal, temporal and parietal cortex were then correlated with ApoE genotype to determine any relationship between ApoE genotype and AD pathology. Comparisons with ApoE epsilon 3, epsilon 4 and epsilon 2 allele dosage failed to show any significant effect on cortical SP densities in any cortical area. NFT densities were increased by epsilon 4 allele dosage in the frontal cortex but not in other cortical regions. A reduction was seen in cortical NFT densities with epsilon 2 allele, though again this was not consistently significant in any of the groups. The epsilon 3 allele failed to show any consistent effect on cortical NFT densities. Assessment by individual genotypes showed epsilon 2/3 < epsilon 2/4 < epsilon 3/3 < epsilon 3/4 < epsilon 4/4 which had highest cortical NFT densities in all areas. By genotype, SP densities were generally of the order epsilon 2/4 < epsilon 2/3 < epsilon 3/3 < epsilon 4/4 < epsilon 3/4 though in none of the groups was this significant. Duration of disease showed no consistent effect on neuropathological burden. ApoE genotype may have an effect on determining whether individuals suffer from AD and the age at onset of disease but may only have a minimal effect on pathology burden.

Aged↗
PubMed1995

Effects of apolipoprotein E genotype on cortical neuropathology in senile dementia of the Lewy body and Alzheimer's disease.

Apolipoprotein E (APO E) genotypes were determined in a UK population of neuropathologically confirmed control cases, and in cases of Lewy body dementia (SDLT) and late onset Alzheimer's disease (AD). APO E epsilon 4 allele frequency was significantly elevated in both SDLT and AD groups with a concomitant reduction in the APO E epsilon 3 allele frequency. The epsilon 2 allele frequency in the AD group was only 25% of the control population, though because of the relatively small sample size this reduction was not significant; the epsilon 2 allele frequency in the SDLT group was normal. No significant association was found between senile plaque density and neurofibrillary tangle density in the neocortex and APO E allele dose in either SDLT or AD. Although the possession of APO E epsilon 4 is associated with an increased risk of developing SDLT and AD, actual APO E genotype does not appear to affect the burden of pathology.

Alleles↗
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↗