RESUMO
We aimed to assess the feasibility of three-dimensional (3D) segmentation and to investigate whether semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters are associated with traditional prognostic factors for breast cancer. In addition, we evaluated whether both intra-tumoural and peri-tumoural DCE parameters can differentiate the breast cancers that are more aggressive from those that are less aggressive. Consecutive patients with newly diagnosed invasive breast cancer and structural breast MRI (3.0 T) were included after informed consent. Fifty-six patients (mean age, 57 years) with mass lesions of > 7 mm in diameter were included. A semi-automatic image post-processing algorithm was developed to measure 3D pharmacokinetic information from the DCE-MRI images. The kinetic parameters were extracted from time-signal curves, and the absolute tissue contrast agent concentrations were calculated with a reference tissue model. Markedly, higher intra-tumoural and peri-tumoural tissue concentrations of contrast agent were found in high-grade tumours (n = 44) compared to low-grade tumours (n = 12) at every time point (P = 0.006-0.040), providing positive predictive values of 90.6-92.6% in the classification of high-grade tumours. The intra-tumoural and peri-tumoural signal enhancement ratios correlated with tumour grade, size, and Ki67 activity. The intra-observer reproducibility was excellent. We developed a model to measure the 3D intensity data of breast cancers. Low- and high-grade tumours differed in their intra-tumoural and peri-tumoural enhancement characteristics. We anticipate that pharmacokinetic parameters will be increasingly used as imaging biomarkers to model and predict tumour behavior, prognoses, and responses to treatment.
Assuntos
Neoplasias da Mama , Mama , Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Meios de Contraste , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland.
Assuntos
Anemia de Fanconi/genética , Mutação , Neoplasias da Próstata/genética , Adolescente , Adulto , Idoso , Neoplasias da Mama/genética , Criança , Pré-Escolar , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação G da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Finlândia , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.
Assuntos
Neoplasias da Mama/genética , Morte Fetal/genética , Genes Supressores de Tumor , Variação Genética , Proteínas de Neoplasias/genética , Síndromes Neoplásicas Hereditárias/genética , Razão de Masculinidade , Fatores de Transcrição/genética , Alelos , Animais , Proteína BRCA2 , Peso ao Nascer , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Reparo do DNA , Éxons/genética , Feminino , Morte Fetal/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Masculino , Camundongos , Proteínas de Neoplasias/deficiência , Síndromes Neoplásicas Hereditárias/epidemiologia , Razão de Chances , Risco , Fatores Sexuais , Método Simples-Cego , Fatores de Transcrição/deficiênciaRESUMO
BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Modelos Estatísticos , Receptor ErbB-2/biossíntese , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Adulto JovemRESUMO
AIM: A causative association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been suggested based on clinical and epidemiological studies. One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta). Thus, in diabetics, insulin and Abeta might compete for IDE and this might lead to an increase in Abeta. The objective of this study was to test the hypothesis that hyperinsulinaemia can elevate Abeta levels and thus contribute to AD pathology in humans. METHODS: Neuropathological examination was carried out employing conventional and immunohistochemical (IHC) methods of the brains obtained post mortem from 701 aged subjects. RESULTS: The loads of IHC/Abeta, silver stained neuritic plaques (NP) and neurofibrillary tangles (NFT) were significantly higher in subjects carrying the Apolipoprotein E e4 allele. In contrast, the loads of Abeta, NPs and NFT in the brains were not influenced by hyperglycaemia when comparing 134 diabetic with 567 non-diabetic subjects. CONCLUSIONS: We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus/patologia , Idoso , Alelos , Infarto Encefálico/patologia , Angiopatia Amiloide Cerebral/patologia , Demência/genética , Demência/patologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Feminino , Humanos , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Imuno-Histoquímica , Masculino , Emaranhados Neurofibrilares/patologia , Placa Amiloide/genética , Placa Amiloide/patologiaRESUMO
Polymorphisms in genes encoding amyloid beta-peptide (A beta)-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) individually affect the susceptibility to Alzheimer disease (AD) among the Finnish population. Here we show that a combination of risk genotypes for NEP and IDE genes leads to a higher susceptibility to AD. Individuals with the combination of risk genotypes for NEP and IDE conferred a threefold higher susceptibility to AD when compared with individuals not carrying these genotypes. Although no significant interaction was observed between NEP and IDE genes, these data suggest that NEP and IDE exhibit an additive risk effect in AD.
Assuntos
Doença de Alzheimer/genética , Insulisina/genética , Neprilisina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
We compared cognitive performance and hippocampal volumes using magnetic resonance imaging (MRI) in adult fragile-X [fra(X)] males and females with either premutation (pM) or full mutation (fM) (n = 10 in all groups). Cognitive performance of fM males in the Wechsler Adult Intelligence Scale-Revised was worse than that of pM males, and the deficits in fM females were qualitatively similar, but less severe. In a visual memory test, both fM groups were impaired. In a list learning test, fM males were impaired in the learning phase and in delayed recognition. In a logical memory test, fM males and females were not significantly different from pM subjects. Hippocampal volumes normalized for intracranial or brain area did not significantly differ between fM and pM groups. However, positive correlations between left normalized hippocampal volumes and performance in many delayed memory tests observed in pM subjects were absent in fM subjects. Furthermore, in > 50% of the fM subjects, nonspecific changes, such as enlargement of ventricles and perivascular spaces, focal hyperintensities in temporal pole white matter, and/or subjectively assessed atypical appearance of hippocampal morphology, were observed in MRI. The data suggest minor abnormalities in temporal lobe structures in adult fra(X) subjects with fM.
Assuntos
Cognição , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Hipocampo/patologia , Proteínas de Ligação a RNA , Repetições de Trinucleotídeos/genética , Adulto , DNA/análise , DNA/sangue , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Testes Neuropsicológicos , Escalas de WechslerRESUMO
The familial association of breast cancer with other tumors such as rhabdomyosarcoma that show loss of heterozygosity (LOH) for chromosome 11p15 as well as limited analyses showing LOH for chromosome 11p in breast tumors suggests the presence of a pleiotropic tumor suppressor gene in this region. In order to test this idea, we analyzed DNA samples for 50 matched normal and tumor tissues from unselected breast cancer patients for LOH at loci throughout the chromosome 11p15.5 region. We found that 12.5% of informative cases showed LOH at HRAS1, 26.8% at TH, and 33.3% at both D11S860 and HBB, providing genetic support for this hypothesis. In contrast to previous observations which excluded the involvement of 11p15.5 regions distal to the HBB cluster, our results indicate that the subregion between TH and HBB is a critical region in breast cancer. This region is identical to that identified for the clinically associated tumor, rhabdomyosarcoma, and thus warrants intensive molecular analysis.
Assuntos
Neoplasias da Mama/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Genes Supressores de Tumor , Sequência de Bases , Mama/química , Neoplasias da Mama/patologia , Mapeamento Cromossômico , DNA/análise , Primers do DNA , DNA de Neoplasias/análise , Feminino , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo Genético , Valores de Referência , Sequências Repetitivas de Ácido NucleicoRESUMO
The development of sporadic human breast cancer is associated with the accumulation of genetic alterations on several chromosomes. In the case of chromosome 11, loss of heterozygosity (LOH) at loci on the short arm has been well documented and suggests the presence of a suppressor gene(s) at 11p15.5. However, the evidence for similar events on the long arm is less compelling. Here, we determined the prevalence of LOH for chromosome 11q in 44 malignant and 3 benign cases of unselected sporadic breast tumor samples. We found that alteration of chromosome 11q is common in the pathogenesis of breast cancer as 19 of 44 (43%) malignant tumor specimens exhibited LOH. Eleven (58%) of these genetic alterations were specific to the long arm of the chromosome. The smallest region of shared LOH places the target between 11q22 and 11q23.3, the same general region frequently altered in cancers of the ovary, colon, skin, and uterine cervix, perhaps indicating the location of a tumor suppressor gene or genes of importance in each of these different tumor types.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 11 , Deleção de Genes , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Carcinoma Papilar/genética , Mapeamento Cromossômico , Feminino , HumanosRESUMO
A common feature of the malignant progression of human tumors is loss of heterozygosity (LOH) for various regions of their genomes. Such events encompassing chromosomes 11p15 and 11q23 are frequent in human breast tumors. Here, we have analyzed genetic and clinical characteristics of a series of primary breast tumors in order to determine: (a) a more finely mapped estimate of the involved regions; (b) whether there is a relationship in the presentation of LOH between the two regions; and (c) whether a correlation exists between such LOH and any of the clinical parameters pertaining to each patient. We found that LOH for 11p15.5 and 11q23 occurred in 35 and 46% of the 86 primary breast carcinomas, respectively, but in none of the 10 benign tumors examined. The minimal region of LOH for 11p15 was in the approximately 2-megabase region between loci TH and D11S988. Twenty-nine % of the tumors showed LOH simultaneously at both 11p15 and 11q23, 5% had LOH only at 11p15.5, and 15% had LOH only at 11q23. Among these genetic groups, clinical features such as tumor size, involvement of auxiliary nodes, histological subtype, tumor grade, estrogen/progesterone receptor status, and patient age were not markedly different. However, LOH of 11q23 (either alone or in conjunction with LOH of 11p15) in the primary tumor was found to be highly predictive of aggressive postmetastatic disease course with substantially reduced survival (P = 0.0004; log rank test). We also observed a slight trend toward a more rapid development of metastatic lesions, without obvious site specificity, in patients with primary tumors showing LOH for chromosome 11 in the pathogenesis of human breast cancer; we suggest that its effects are late in the progression of this disease.
Assuntos
Neoplasias da Mama/genética , Deleção Cromossômica , Cromossomos Humanos Par 11 , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Mapeamento Cromossômico , DNA Satélite/genética , Feminino , Doença da Mama Fibrocística/genética , Doença da Mama Fibrocística/patologia , Seguimentos , Marcadores Genéticos , Humanos , Metástase Neoplásica , Polimorfismo Genético , Valor Preditivo dos Testes , Prognóstico , Distribuição Aleatória , Sequências Repetitivas de Ácido Nucleico , Análise de Sobrevida , Fatores de TempoRESUMO
Fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Most women carriers of the fragile X mutation are unaware of their condition. We critically evaluated whether screening pregnant women at low risk for FMR1 mutation would be feasible as a routine part of antenatal care in general practice. We also studied acceptance and attitudes to gene testing. From July 1995 until December 1996, a carrier test was offered at the Kuopio City Health Centre free of charge to all pregnant women in the first trimester following counselling given by midwives on fragile X syndrome. All women found to be carriers of FMR1 gene mutations underwent detailed genetic counselling and were offered prenatal testing. Attitudes towards the gene test were elicited by questionnaire. Most pregnant women (85%) elected to undertake the gene test. Six women were found to be carriers (a rate of 1 in 246), and all subsequently accepted prenatal testing. Three foetuses had a normal FMR1 gene, one had a large premutation, one a 'size mosaic' mutation pattern, and another a full mutation. This observational and interventional study demonstrates that antenatal screening provides an effective way of identifying carriers and incorporating prenatal testing into this process.
Assuntos
Síndrome do Cromossomo X Frágil/genética , Testes Genéticos , Deficiência Intelectual/genética , Mutação , Proteínas do Tecido Nervoso/genética , Diagnóstico Pré-Natal , Proteínas de Ligação a RNA , Estudos de Viabilidade , Feminino , Proteína do X Frágil da Deficiência Intelectual , Conhecimentos, Atitudes e Prática em Saúde , Humanos , GravidezRESUMO
Mutations in the presenilin-1 (PS-1) gene have been shown to cause early onset Alzheimer's disease (EOAD) in an autosomal dominant manner. We have identified a novel 4.6-kb genomic deletion in the PS-1 gene in a Finnish EOAD family, which leads to an inframe exclusion of exon9 (delta9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the delta9 splice-site mutations. In this present EOAD family, the clinical and neuropathological phenotype of patients are those of the typical AD without indications of spastic paraparesis or 'cotton wool' plaques, which are the hallmarks of the variant AD. A sequence analysis of the deletion crossover site of the mutant and corresponding wild type regions revealed complete homology with the recombigenic 26 bp Alu core sequence at intron 8. In addition, a segment at the intron 9 breakpoint displayed homology with the core sequence, but comparison of the 5' and 3' breakpoint sequences did not reveal significant identity favouring involvement of Alu core sequence-stimulated non-homologous recombination rather than Alu-mediated homologous pairing of the fragments. This study shows that large genomic rearrangements can affect the EOAD gene PS-1 through a mechanism, which may involve Alu core sequence-stimulated recombination.
Assuntos
Doença de Alzheimer/genética , Éxons/genética , Proteínas de Membrana/genética , Idade de Início , Elementos Alu/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Sequência de Bases , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Finlândia , Lobo Frontal/química , Lobo Frontal/patologia , Haplótipos , Humanos , Imuno-Histoquímica , Masculino , Dados de Sequência Molecular , Linhagem , Presenilina-1 , Recombinação Genética , Deleção de Sequência , Homologia de Sequência do Ácido NucleicoRESUMO
Alzheimer's disease (AD) is a complex neurodegenerative disorder, for which several disease-associated loci have been located on different chromosomes. We have used a population-based linkage disequilibrium mapping approach in order to find potential AD-associated loci on chromosome 13. To avoid population stratification, late onset AD patients and age-matched controls were carefully chosen from the same geographical area in Eastern Finland, where the population is mainly descended from a small group of original founders. During the initial screening with chromosome 13-specific microsatellite markers, tetranucleotide marker D13S787 was found to be in linkage disequilibrium in the 13q12 region. Screening this region with additional microsatellite markers revealed that marker D13S292 was also significantly associated with AD. Stratification of the AD patients and controls into groups according to apolipoprotein E, sex, and familial/sporadic status indicated that the 13q12 locus was associated with female familial AD patients regardless of ApoE genotype. Based on the physical data from the region 13q12, markers D13S292 and D13S787 were estimated to reside in a 810kb long YAC clone 754h7 together with two infant brain-derived ESTs and the H,K-ATPase alpha-subunit protein gene (ATP1AL1). The localisation of these sequences at the linkage disequilibrium region suggests that they may be candidate genes involved in a sex-specific effect during development of AD.
Assuntos
Idade de Início , Doença de Alzheimer/genética , Cromossomos Humanos Par 13 , Desequilíbrio de Ligação , Idoso , Alelos , Apolipoproteínas E/genética , Feminino , Finlândia/epidemiologia , Testes Genéticos , Genótipo , Haplótipos , Humanos , Masculino , Repetições de MicrossatélitesRESUMO
In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.
Assuntos
Neoplasias da Mama/genética , Efeito Fundador , Genes BRCA1/genética , Mutação/genética , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Proteína BRCA2 , Neoplasias da Mama/patologia , Família , Feminino , Finlândia/epidemiologia , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Fatores de Tempo , Fatores de Transcrição/metabolismoRESUMO
Apolipoprotein E (ApoE) epsilon 4 allele is a risk factor for late-onset Alzheimer's disease (AD) and proposed to have a direct impact on cholinergic function in AD. Slowing of the EEG is characteristic in AD and the cholinergic system has an important role in modulating EEG. Fifty-eight AD patients at the early stage of the disease and 34 age- and sex-matched controls were studied using the quantitative EEG recorded from T6-O2 derivation. AD patients were divided into two subgroups: a) according to the ApoE allele (2 epsilon, 1 epsilon 4, and 0 epsilon 4) and b) according to familial aggregation. AD subgroups did not differ in clinical severity or duration of dementia. The AD patients with the epsilon 4 allele had higher relative theta amplitude and lower relative beta amplitude than controls and patients without the epsilon 4 allele. The peak frequencies were lower in all AD subgroups compared to controls. In conclusion, we found a tendency towards more pronounced EEG slowing in AD patients carrying the epsilon 4 allele. The minor differences in EEG may suggest differences in the degree of the cholinergic deficit in these subgroups.
Assuntos
Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/genética , Idoso , Alelos , Doença de Alzheimer/genética , Eletroencefalografia , Feminino , Humanos , Masculino , Polimorfismo GenéticoRESUMO
A recent report suggested that brains of Alzheimer patients homozygous for APOE epsilon 4 show increased amyloid pathology compared to APOE epsilon 3 homozygotes. We studied APOE allele frequencies in 73 AD patients and 38 controls. We also investigated relation of APOE genotypes to beta/A4 immunopositive plaques, cerebrovascular beta/A4 deposition, neurons expressing paired helical filaments (PHFs), and synaptophysin-like immunopositivity in 22 neuropathologically verified AD patients. We also correlated APOE genotypes of definite AD patients to beta/A4 immunoreactivity in dermal vessel walls detected in lifetime skin biopsy samples. APOE allele epsilon 4 frequency was increased in AD compared to nondemented controls (0.37 vs. 0.11; p = 0.006). The number of beta/A4 immunoreactive plaques, PHFs-containing neurons, the degree of cerebrovascular beta/A4 deposition or synaptophysin-like immunoreactivity did not differ significantly in AD patients with or without epsilon 4. beta/A4 deposition in dermal vessel walls was more frequent in definite AD patients with epsilon 4 (43%) than in patients without epsilon 4 (22%). However, the difference did not reach the statistical significance.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Análise de Variância , Vasos Sanguíneos/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Emaranhados Neurofibrilares/metabolismo , Neurônios/metabolismo , Pele/irrigação sanguínea , Sinapses , Sinaptofisina/metabolismo , Proteínas tau/metabolismoRESUMO
BACKGROUND: Myeloperoxidase (MPO) is present in senile plaques and surrounding reactive microglia, but not in normal brain parenchyma. MPO in plaques is highest in APOE epsilon4 carriers, suggesting a functional interaction. An MPO promoter polymorphism (-463G/A) linked to increased MPO expression has been associated with increased risk of AD. METHODS: To further define the possible interaction of MPO and APOE epsilon4, we examined 127 patients with AD and 174 controls from a genetically homogeneous Finnish population. RESULTS: A significantly higher percentage of male patients with AD carried the MPO A and APOE epsilon4 alleles relative to men carrying neither allele (p < 0.001; OR, 11.4; 95% CI, 3.6 to 6.7). Male APOE epsilon4 carriers lacking the MPO A allele had an OR of 3.0 (p = 0.01; 95% CI, 1.3 to 6.9), indicating that MPO A enhances AD risk by 3.8-fold. Age at onset was lower in men carrying the MPO A and APOE epsilon4 alleles (Kaplan-Meier survival analysis; p = 0.01). Also, the MPO AA genotype was associated with selective mortality in men, but not in women. AA genotypes were absent from 159 male patients with AD and controls, representing the expected 5% to 6% in women and male controls younger than age 20. The -463A creates an estrogen receptor binding site that may contribute to these gender differences. CONCLUSIONS: MPO A and APOE epsilon4 alleles interact to increase the risk of AD in men but not in women in this Finnish cohort.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Fatores de Crescimento de Células Hematopoéticas/genética , Proteínas Recombinantes de Fusão , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteína E4 , Feminino , Finlândia , Genótipo , Fator Estimulador de Colônias de Granulócitos , Humanos , Interleucina-3 , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Recombinantes , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed. METHOD: Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD. RESULTS: Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus. CONCLUSIONS: These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.
Assuntos
Doença de Alzheimer/genética , Desequilíbrio de Ligação , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4 , Apolipoproteínas E/genética , Feminino , Finlândia , Efeito Fundador , Genoma Humano , Haplótipos , Humanos , Modelos Logísticos , Masculino , Repetições de Microssatélites , Polimorfismo de Fragmento de RestriçãoRESUMO
OBJECTIVE: To examine the relationship between socioeconomic factors and APOE carrier status on the development of dementia. METHODS: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1449 (73%) subjects aged 65 to 79 years were re-examined in 1998. The diagnosis of dementia among the nonparticipants was derived from patient records of the local hospitals and primary health care clinics. RESULTS: Low income level at old age was related to dementia, but low income level at midlife was not a risk factor for dementia. Dementia was also associated with decreasing income level, from midlife to old age 21 years later, when dementia was diagnosed. A sedentary occupation (office, service, or intellectual work) was associated with a decreased risk for dementia among participants; however, when the nonparticipants were included in the analysis, the associations were no longer significant. Low educational level and the APOE epsilon4 allele independently increased the risk for dementia. CONCLUSIONS: Reduction in income level during follow-up and low income level at old age might be the consequence of a dementing process rather than being associated with risk evolution of dementia.
Assuntos
Apolipoproteínas E/genética , Demência/epidemiologia , Demência/genética , Renda/estatística & dados numéricos , Ocupações/estatística & dados numéricos , Idoso , Apolipoproteína E4 , Distribuição de Qui-Quadrado , Intervalos de Confiança , Estudos Transversais , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Razão de Chances , Pobreza/psicologia , Pobreza/estatística & dados numéricos , Fatores de Risco , Fatores SocioeconômicosRESUMO
Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.