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Biomedical subjects

F Owen

Publications and source records attributed to F Owen.

At least 19 recordsLinked to original sources
PubMed2001

Clinical features of dementia associated with apolipoprotein epsilon4: discrimination with a neural network genetic algorithm.

BACKGROUND: It is unclear whether the APOE epsilon4 allele is associated with distinct clinical features in dementia. METHOD: 100 cases meeting ICD criteria for dementia were interviewed using standardized instruments and genotyped for APOE. The presence of the epsilon4 allele was used by a genetic algorithm neural network (GANN) to discriminate symptoms and signs. RESULTS: The GANN selected six features: gender, systolic blood pressure, absence of ankle tendon reflexes, history of weight loss, history of falls, and interviewer observed lability of mood. Using these features, a neural network discriminated cases according to epsilon4 highly accurately (area under receiver operating characteristic=0.83, sensitivity=0.78, specificity=0.78). CONCLUSIONS: A GANN is able to discriminate a clinically distinct group of features among dementia patients who express the epsilon4 allele.

Accidental Falls↗
PubMed2000

Apolipoprotein E epsilon4 allele has no effect on age at onset or duration of disease in cases of frontotemporal dementia with pick- or microvacuolar-type histology.

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. Here we have investigated the frequency of the epsilon4 allele of the Apolipoprotein (APOE) gene in FTD and in other non-Alzheimer forms of dementia related to FTD such as Motor Neurone disease dementia, semantic dementia, progressive aphasia, progressive supranuclear palsy, and corticobasal degeneration. In none of these diagnostic groups did we find a significant increase in the APOE epsilon4 allelic frequency, compared to population values. Neither did we observe any affects of the epsilon4 allele upon age at onset or duration of disease. We conclude therefore that polymorphic variations in the APOE gene do not modulate either the occurrence or progression of these non-Alzheimer forms of dementia.

Adult↗
PubMed2000

Pick's disease is associated with mutations in the tau gene.

Recently, mutations within the tau gene have been associated with some familial forms of frontotemporal dementia. To investigate whether tau gene mutations are also associated with Pick's disease, we analyzed the tau gene in 30 cases of pathologically confirmed Pick's disease. Two coding mutations were identified in separate cases of Pick's disease. A glycine-to-arginine mutation at codon 389 was detected in 1 case and a lysine-to-threonine mutation at codon 257 was identified in another. Analysis of dephosphorylated tau from the brain of the patient with the codon 389 mutation revealed a prominent band representing tau, with four microtubule-binding domains and no amino terminal inserts. This is in contrast to Pick's disease without any tau gene mutations, which consist of tau with mainly three microtubule-binding domains and only a trace of tau, with four microtubule-binding domains. Functional analysis of tau with these two mutations demonstrated a reduced ability of tau to promote microtubule assembly. Surprisingly, these mutations increased tau's susceptibility to calpain I digestion, suggesting that this feature may be related to the formation of a Pick type of histology. Moreover, these data suggest that Pick's disease is not a separate entity but part of the frontotemporal dementia disease spectrum.

Adult↗
PubMed1999

Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia.

Splice-site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non-Alzheimer's (non-AD) degenerative dementia. The groups included (1) a community-based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice-site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community-based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series.

Adult↗
PubMed1998

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Alternative Splicing↗
PubMed1998

Effect of apolipoprotein E status on clinical features of dementia.

OBJECTIVE: The aims of this study were (a) to determine the frequency of APOE genotypes in dementia, (b) to relate e4 allele frequency to clinical symptomatology of dementia and (c) to relate e4 and assess risk factors for different types of dementia. DESIGN: Prospective clinical study setting older patients with dementia known to a community-based old age psychiatry service. SAMPLE: 101 patients fulfilling ICD 10 criteria for dementia. RESULTS: Replication of previous findings of an association between APOE4 and Alzheimer's disease: younger age of onset of dementia; family history of dementia; persecutory ideation; and (retrospectively determined) rate of competent decline. No association was found between APOE4 and vascular dementia. The association between APOE4 and 'mixed dementia' was intermediate between that of pure Alzheimer's disease and pure vascular dementia. CONCLUSION: The results confirm the relationship between clinical features of dementia and APOE4 status. It may be that APOE can be used as an adjunct to clinical diagnosis.

Aged↗
PubMed1998

Amyloid beta protein (A beta) deposition in dementia with Lewy bodies: predominance of A beta 42(43) and paucity of A beta 40 compared with sporadic Alzheimer's disease.

Amyloid beta protein (A-beta) deposition was investigated by quantitative immunohistochemistry in 13 cases of dementia with Lewy bodies (DLB) and compared with that in a series of age, gender and ApoE genotype matched cases of Alzheimer's disease (AD). In DLB the predominant A-beta peptide species deposited was A-beta-42(43) and this was similar in amount to that in AD. By contrast, A-beta(40) deposition was sparse in DLB and was lower than that in AD as was the total A-beta (A-beta-40 + A-beta-42(43) deposition. These data reinforce the viewpoint that in all disorders in which A-beta deposition is characteristics, the initial and predominant peptide species deposited is the longer form, A-beta-42(43). The density of Lewy bodies (LB) in DLB was unrelated to the extent of A-beta deposition, although those cases possessing one or more copies of the apolipoprotein E E4 allele had a higher LB density than those without an E4 allele. This suggests that the apolipoprotein E E4 isoform might facilitate, though not necessarily trigger, the formation of LB in susceptible individuals.

Aged↗
PubMed1997

An intronic polymorphism in the presenilin-1 gene does not influence the amount or molecular form of the amyloid beta protein deposited in Alzheimer's disease.

The frequency of the allele-1 polymorphism in intron 8 of the presenilin-1 (PS-1) gene, and the proportion of individuals homozygous in this respect, was investigated in 57 patients with autopsy verified Alzheimer's disease (AD). In 33 of these patients the amount of amyloid beta protein (A beta) was compared across the three PS-1 genotype groups (1/1, 1/2, 2/2). No excess of the allele-1 was detected in these patients with confirmed AD and no variations in the extent of A beta deposition, as either A beta 40 or A beta 42, in terms of plaque number or percentage area of tissue occupied, were found. We conclude that this intronic PS-1 polymorphism does not influence the pathological phenotype of AD, at least as far as A beta deposition is concerned.

Aged↗
PubMed1997

Preferential deposition of amyloid beta protein (Abeta) in the form Abeta40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele.

The effect of apolipoprotein E (ApoE) genotype on the deposition of amyloid beta protein (Abeta) was examined in 54 patients with Alzheimer's disease. No difference in the amount of Abeta deposited as Abeta42(43) was seen between genotype groups with no, one or two E4 alleles. However, the amount of Abeta40 deposited increased according to the copy number of E4 alleles with patients possessing one E4 allele containing more than twice, and those with two E4 alleles, four times, the amount of Abeta40 in their brains compared to patients without an E4 allele. The increase in total Abeta deposited within the tissue (i.e. Abeta40 plus Abeta42(43) loads) in the presence of an E4 allele is therefore due entirely to an enhanced deposition of Abeta40. These data are consistent with the suggestion that the presence of E4 within pre-existing Abeta42(43) containing plaques may lower the threshold to fibrilization of Abeta40 thereby promoting its subsequent deposition. Thus, although the total amount of Abeta initially deposited in the brain as Abeta42(43) is not affected by the binding of any one particular ApoE isoform this does influence the subsequent maturation of plaques with a greater proportion transforming into Abeta40 containing cored plaques when the E4 isoform is present.

Age of Onset↗
PubMed1996

Debrisoquine hydroxylase gene polymorphism frequencies in patients with amyotrophic lateral sclerosis.

Using PCR and restriction digest analysis, the frequencies of the variant cytochrome P450 debrisoquine hydroxylase CYP2D6 alleles CYP2D6(A) and CYP2D6(B) were investigated in 50 patients with amyotrophic lateral sclerosis (ALS) and 13 patients with ALS and frontotemporal dementia (FTD) and compared to those frequencies in patients with FTD alone and Alzheimer's disease (AD). The CYP2D6(T) allelic frequency was also assessed in ALS and ALS + FTD. Although the frequency of a poor metabolizer genotype was not increased in any disease group, there was a significant increase in the frequency of the CYP2D6(B) allele in the ALS patient group. This suggests that possession of a CYP2D6(B) allele may be a risk factor for the development of ALS, possibly conferring a 'gain of function' imposed by the mutation or reflecting linkage disequilibrium to a nearby susceptibility gene.

Alleles↗
PubMed1996

ApoE2 allele, Down's syndrome, and dementia.

All individuals with Down's syndrome (trisomy 21-DS) develop the pathogenic hallmarks of Alzheimer's disease in old age (+40 years). The extent of pathology is variable, but it has been shown that the amount of beta-amyloid pathology is variable and related to age and the degree of dementia. Thus, in DS, growing old is associated with a progressive pathological process which results in cognitive decline. However, neuropsychological studies of older DS subjects have identified a clinical dementia in only a proportion of cases. These contradictory observations could be reconciled if some factor existed which modulated the rate and amount of beta-amyloid pathology. Recent studies demonstrate an association between the apolipoprotein E4 (ApoE4) allele and the earlier age of onset in both sporadic and familial AD. Increased amounts of beta-amyloid pathology can also be related to the E4 allele. However, at present there are no data documenting the effects of ApoE genotype on the expression or degree of clinical symptoms of the disease. We have examined the ApoE genotype in a cohort of clinically evaluated elderly patients with DS in order to examine the effects of ApoE genotype on the clinical symptoms of dementia. We report here that, despite the presence of an active disease process, the ApoE E2 allele is associated with longevity and preservation of cognitive functioning.

Aged↗
PubMed1996

The relative abundance of dopamine D4 receptor mRNA in post mortem brains of schizophrenics and controls.

An increase in dopamine D4 receptors has recently been reported in post mortem brain samples from schizophrenics. We have attempted to complement this finding by assessing the levels of the specific messenger RNA (mRNA) for the D4 receptor, using the technique of quantitative RNA-PCR. No significant differences in the levels of expression of mRNA for the D4 receptor were found in the brains from schizophrenics compared to controls. The relationship between D4 receptors and schizophrenia, therefore, remains unclear.

Adult↗
PubMed1995

Apolipoprotein E allelic frequencies in patients with lobar atrophy.

Apolipoprotein E (ApoE) genotype was determined by polymerase chain reaction amplification and restriction digestion of DNA extracted from brain tissues of 26 patients with clinically diagnosed and pathologically verified lobar atrophy (LA) and from blood of a further 22 patients with clinical LA. Brain tissue from 50 patients with pathologically confirmed Alzheimer's disease (AD) was also examined. As has been previously reported, the ApoE E4 allele frequency was significantly increased in AD. However, no change in the frequency of ApoE alleles was found in two of the clinical and pathological forms of LA (dementia of frontal type and dementia of frontal type with motor neurone disease) although the ApoE E4 allele frequency was elevated in cases of non-fluent progressive aphasia in accordance with the presence of coincidental Alzheimer-type pathological changes.

Aged↗
PubMed1995

Allelic variations in apolipoprotein E and prion protein genotype related to plaque formation and age of onset in sporadic Creutzfeldt-Jakob disease.

Prion gene sequence is thought to affect the phenotypic expression of prion disease and the E2 variant of apolipoprotein E (Apo E) can be neuroprotective in dementia. We determined codon 129 of the prion gene and the Apo E variants in Creutzfeldt-Jakob disease (CJD) using PCR and restriction digest. We found a significant correlation between valine at codon 129 of the prion protein gene and the presence of plaque in CJD and a later age of onset in CJD cases possessing the Apo E2 allele. This study provides further evidence that sequence variations in the prion gene can modify disease pathology and the neuroprotection afforded by Apo E2 is not confined to Alzheimer's disease.

Age of Onset↗
PubMed1994

Apolipoprotein E epsilon 2 allele promotes longevity and protects patients with Down's syndrome from dementia.

Although individuals with Down's syndrome nearly always develop the clinical and pathological features of Alzheimer's disease, some clearly do not become demented despite living into their sixth and seventh decades. Genetic variation at the apolipoprotein E locus has recently been shown to be an important determinant of Alzheimer's disease, with the epsilon 4 allele having been shown to be associated with the disease and, at least in some cases, the epsilon 2 allele being negatively associated with the disease. Here we show, in a series of clinically assessed individuals with Down's syndrome, that the epsilon 2 allele of ApoE is associated with both longevity and the absence of clinical evidence of dementia. These data show that the clinical phenotype of Down's syndrome can be modulated by genes on chromosomes other than chromosome 21. The importance of this observation to the pathogenesis of Alzheimer's disease, both in Down's syndrome and in general, is discussed.

Age of Onset↗