Biomedical subjects
Publications and source records attributed to A Leake.
At a time when GM crops are being planted all around the globe, Europe appears to favour a more primitive and less productive agricultural system. Is the abandonment of 50 years of agricultural development the way forward or is there a rational alternative?
Several lines of evidence indicate that there may be an inflammatory component to the pathology of Alzheimer's disease (AD), the major form of degenerative dementia in the elderly. Activity of inflammatory cells, and the elaboration of toxic molecules by such cells may be a significant factor in disease progression. In peripheral inflammatory states, the increased activity of matrix metalloproteinase (MMP) enzymes are a major cause of tissue breakdown and secondary damage in diseases such as rheumatoid arthritis. The activity of such enzymes in the normal or diseased central nervous system is, however, not well characterized. We have therefore determined the levels of MMP 1 (collagenase) in the normal human brain and in AD. MMP1 levels were relatively low though were significantly elevated by approximately 50% in AD in all cortical areas examined. Given the activity towards collagen of MMP1, it is possible that enhanced MMP1 activity in AD, may contribute to the blood-brain barrier dysfunction seen in AD.
The possibility of gene interactions in Alzheimer's disease (AD) has been suggested by the finding of an association of the AA genotype of the alpha-1 antichymotrypsin (AACT) gene and the apolipoprotein E (apoE) epsilon 4/4 genotype in AD. We tested this possibility by genotyping a large series of clinically and neuropathologically confirmed cases of AD and a series of cases with dementia with Lewy bodies (DLB) with a matched control group for the AACT locus and apoE. ApoE genotyping showed the established finding of an increased frequency of the apoE epsilon 4 allele in AD and in DLB. The AD and DLB groups differed between each other with a higher epsilon 2 allele frequency and a reduced incidence of the epsilon 4/4 genotype in DLB. Differences in the apoE frequencies may account for some of the differences between the two diseases. No association was found for the AACT A allele in AD or DLB in the groups as a whole or when stratified with respect to apoE, with the exception of a trend showing an increased incidence of the apoE epsilon 4/4 AACT AA genotype combination in AD patients (chi 2 = 3.18, p = 0.07), although in DLB this was not apparent (chi 2 = 0.0, p = 1.0). The AACT A allele is not a major risk factor for late-onset AD or DLB.
The discovery of mis-sense mutations linking the presenilin-1 (PS-1) gene on chromosome 14 to Alzheimer's disease (AD) has lead to a thorough investigation of this locus. The PS-1 gene contains a polymorphism creating two alleles. The most common allele, allele 1, has been linked with late-onset AD. Given the clinical and pathological overlaps between AD and dementia with Lewy bodies we genotyped 46 pathologically confirmed cases of dementia with Lewy bodies for the PS-1 polymorphism and compared the allelic frequencies with 87 age-matched control cases and 103 age-matched AD cases. No association between dementia with Lewy bodies and PS-1 allele 1 was found either in the group as a whole, or in the group stratified according to dosage of the epsilon4 allele of the apolipoprotein E gene. We suggest that either the presenilin polymorphism has no effect on dementia with Lewy bodies or that any linkage is precluded by another, more influential, locus.
Mutations in the presenilin-1 (PS-1) gene are believed to be responsible for the majority of familial early-onset Alzheimer's disease (AD). The finding of an intronic polymorphism in the PS-1 gene prompted an investigation into its relevance in AD. An association between homozygosity for the most common allele (allele 1) in this intronic polymorphism and late-onset AD has been shown and has been confirmed by others though some studies do not support these findings. We genotyped a large series of sporadic AD cases (n = 120) and age-matched controls (n = 108) for this intronic polymorphism. We then compared both the frequency of allele 1 and allele 1 homozygosity between the AD group as a whole and in early-onset (n = 26) and late-onset (n = 94) groups with age-matched control groups (n = 29 and n = 79, respectively). No increase in the frequency or homozygosity of allele 1 in either the AD group as a whole, or when divided into late- and early-onset cases was found. Increases in the frequency of allele 1 homozygotes and in the number of non-apolipoprotein E epsilon4 carrying allele 1 homozygotes/heterozygotes was demonstrated in the early-onset AD cases although these values did not reach significance. We conclude that there is no relationship between this intronic polymorphism in the PS-1 gene and AD in the homogenous population genotyped in this study.
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.
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.
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.
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.
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.
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The inter-relationship between putative cholinergic and noradrenergic innervation of the human adrenal cortex was investigated using a technique which combined acetylcholinesterase histochemistry, choline acetyltransferase radiochemistry and dopamine beta-hydroxylase immunohistochemistry. Cholinergic and noradrenergic nerve fibres had a near-identical distribution, with varicose noradrenergic fibres located immediately alongside non-varicose cholinergic nerve bundles in all cortical zones. Choline acetyltransferase activity was consistently detected in the adrenal cortex, confirming the presence of cholinergic neurons. It is postulated that noradrenergic innervation has a role in the modulation of cortical endocrine secretion, while cholinergic nerves are mainly concerned with the control of medullary secretion.
Corticotropin releasing hormone (CRH), somatostatin (SRIF), and arginine vasopressin (AVP) concentrations were estimated using radioimmunoassay in the temporal and occipital cortices in postmortem brain from patients clinically and neuropathologically diagnosed as senile dementia of the Lewy body type (SDLT), senile dementia of the Alzheimer type (SDAT), and Parkinson's disease (PD) and from neurologically normal controls. The concentration of temporal and occipital neocortical CRH was diminished in both SDAT and SDLT compared to control values, whereas SRIF was reduced only in temporal cortex in both these conditions. In contrast, the concentrations of both CRH and SRIF were unaltered in PD. The concentrations of AVP in SDLT, SDAT, and PD were similar to those found in the control groups. The decrement in SRIF, but not CRH, was found to be correlated with some indices of severity of illness in SDAT; a similar but nonsignificant trend for SRIF was observed in SDLT.
Serotonin (5-hydroxytryptamine; 5HT) uptake sites have been measured using the selective high affinity uptake inhibitor 3H-citalopram in post-mortem frontal cortex from depressed and matched control subjects. The lateralization of these sites was assessed in neurologically normal brain. A lower concentration of 3H-citalopram binding was found in brains from depressed subjects. A nonsignificant trend toward a greater attenuation of 5HT uptake sites was observed in brains of bipolar cases in the depressed state. No effect of antidepressant treatment or of the age at onset of illness was noted. No difference in the binding capacity of the 5HT uptake site was noted between hemispheres of normal brains.
Corticotropin-releasing hormone-immunoreactivity (CRH-IR) and CRH receptors (binding capacity and affinity) were measured in postmortem cortical areas from depressed subjects, two groups of senile dementia of the Alzheimer type (SDAT), and age-, sex-, and postmortem-delay-matched controls. No difference in CRH-IR and CRH receptor status between depressed subjects and controls was noted. CRH-IR was decreased in all cortical areas in SDAT, with a corresponding increase in CRH receptor binding capacity (with no change in affinity) in occipital cortex. No effects of postmortem delay were seen. It is suggested that the increase in CRH receptor numbers in SDAT is related to the degree of distribution of pathological involvement in specific regions.
The 5HT2 receptor has been studied using quantitative tritium film autoradiography in the postmortem frontal cortex of 15 cases suffering from major depression and controls, matched for age, gender, postmortem delay, and storage time. In unmedicated depressives there was a significant increase in 5HT2 receptor binding over matched control values. Antidepressant-treated depressives dying while depressed had 5HT2 receptor densities not significantly different from control values. Depressives dying euthymic, (i.e., recovered) showed a marked reduction in 5HT2 receptor binding when compared with controls. A tentative hierarchy of 5HT2 receptors in affective states is proposed.
Studies which have examined neuropeptides in Alzheimer's disease (AD) and normal ageing are reviewed. A marked specificity and selectivity is noted: most neuropeptides are normal, and the only two peptides consistently altered are somatostatin (SRIF) and corticotropin releasing hormone (CRH). Binding sites for CRH are increased in number in a reciprocal fashion to the reduction in CRH. These findings (1) provide evidence for selective vulnerability within the cortex in AD, (2) suggest that the primary site of pathology in AD may be cortical, and (3) indicate that the pathological process of AD is distinct from that of normal ageing.