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1.
J Clin Endocrinol Metab ; 96(10): E1684-93, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21795453

RESUMO

CONTEXT: Corticosteroid-binding globulin (CBG) is the binding protein for cortisol. Rare kindreds with CBG mutations reducing CBG levels or altering binding affinity have been described, along with clinical manifestations encompassing fatigue, chronic pain, and hypotension. The largest kindred, exhibiting two mutations (null and Lyon) were Australian immigrants from Italy. OBJECTIVE: Our objective was to determine the prevalence of the null/Lyon mutations in the village where the original null/Lyon family emigrated and compare subjects with and without CBG mutations, without previous knowledge of their mutation status. DESIGN, SETTING, AND PARTICIPANTS: We conducted a survey field study that included 495 adult residents. MAIN OUTCOMES: We assessed clinical history, CBG mutation analysis, plasma CBG, salivary cortisol, body mass index, waist circumference, blood pressure, and the Krupp fatigue scale. RESULTS: Eighteen of 495 participants (3.6%, seven males and 11 females) had one of two function-altering CBG mutations. All were heterozygous for the null (n = 6) or Lyon mutations (n = 12). Of 12 Lyon participants (four males and eight females), eight (two males and six females) had chronic widespread pain and five osteoarthritis with associated pain (one male and four females). Of six null participants (three males and three females), three (one male and two females) had chronic pain and four osteoarthritis with associated pain (two males and two females). CONCLUSIONS: A high combined prevalence (3.6%) of these two CBG mutations was detected. The presence of either mutation conferred a propensity to chronic pain. In other communities, individuals with the same genetic background complain more of fatigue than pain, suggesting an environmental effect on the phenotype. These findings, combined with animal CBG gene knockout and human CBG single-nucleotide polymorphism haplotype studies, suggest that CBG influences the endocrine and neurobehavioral response to stress, including the development of pain/fatigue syndromes.


Assuntos
Transcortina/genética , Adolescente , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Doença Crônica , DNA/genética , Emigração e Imigração , Feminino , Humanos , Hidrocortisona/metabolismo , Itália/epidemiologia , Itália/etnologia , Masculino , Pessoa de Meia-Idade , Fadiga Muscular/genética , Mutação , Dor/epidemiologia , Dor/genética , Linhagem , Qualidade de Vida , Saliva/metabolismo , Adulto Jovem
2.
Neurobiol Aging ; 32(4): 757.e1-757.e11, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21295377

RESUMO

Intronic MAPT mutations altering exon 10 splicing lead mainly to an increase of 4Rtau. The objective of this study is to report clinical, genetic, and neuropathological data of an apparently sporadic early onset frontotemporal dementia (FTD) case associated with 2 novel intronic MAPT gene mutations IVS10+4A > C and IVS9-15T > C that increase 3Rtau. Methods and subjects used are clinical, neuroradiological, and neuropathological examination; molecular genetics of MAPT, PGRN, and other relevant genes. Exon 10 splicing tested with minigene constructs. Tau deposits detected by immunohistochemistry. Sarkosyl-insoluble and soluble tau investigated by immunoblotting. Two novel MAPT mutations IVS10+4A > C and the IVS9-15T > C transmitted by the unaffected parents were identified. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analyses on minigenes and in brain tissue showed that both mutations cause an increase of tau mRNA (messenger ribonucleic acid) transcripts lacking exon 10 only in the patient. Immunohistochemistry and immunoblotting of the patient's brain revealed tau deposits composed mostly of 3Rtau isoforms with a predominance of the shorter 3Rtau isoforms. The compound heterozygosity of the patient increasing 3Rtau seems to be responsible for the disease and furthermore suggests that sporadic cases can be caused by genetic mutations.


Assuntos
Encéfalo/patologia , Demência Frontotemporal/genética , Proteínas tau/genética , Western Blotting , Encéfalo/metabolismo , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/metabolismo , Humanos , Imuno-Histoquímica , Íntrons , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Testes Neuropsicológicos , Proteínas tau/metabolismo
3.
Alzheimer Dis Assoc Disord ; 25(1): 96-9, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21343707

RESUMO

The V363I mutation of the microtubule-associated protein tau gene has previously been associated with a case of primary progressive nonfluent aphasia with variable penetrance. Herein, we report the finding of the V363I variation in a sporadic early onset frontotemporal dementia patient and in several members of her family. The V363I variation was associated with frontotemporal dementia only in the proband which was also homozygous for the A allele of the progranulin single-nucleotide polymorphism rs9897526 and for methionine at codon 129 of the prion protein gene. The microtubule-associated protein tau V363I variation could be considered either an incomplete penetrant mutation or a rare polymorphism; although its pathogenicity has yet to be clearly demonstrated, modifier genetic factors seem to contribute to the pathogenic effects observed in the patient underlining the great complexity existing in neurodegenerative diseases and questioning so-called sporadic cases that can potentially be caused by gene mutation.


Assuntos
Demência Frontotemporal/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas tau/genética , Feminino , Demência Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
4.
Neurol Sci ; 31(1): 65-70, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19768372

RESUMO

A clinical and molecular overlap between Alzheimer's disease (AD) and frontotemporal dementia (FTD) has been reported. Presenilins have been associated with FTD or with FTD-like phenotype, while mutations in the MAPT gene have been linked to a clinical phenotype of AD. We performed a clinical and genetic examination in two FTD siblings and their family tree has been reconstructed. We identified a novel Val75Ala MAPT mutation in one patient and in the other the Arg62His Presenilin2 mutation. The DNA variations identified, defined mutations by frequency, per se are not causative of the disease. These mutations, possibly in association with other unknown environmental and genetic factors, may contribute to neurodegeneration. In this family, the disease might result from a genetically interconnected spectrum of altered pathways that could link most neurodegenerative disorders. Moreover, the novel mutation identified merits further functional studies that would contribute to the unravelling of such a complex field.


Assuntos
Demência Frontotemporal/genética , Mutação de Sentido Incorreto , Presenilina-2/genética , Proteínas tau/genética , Adulto , Idade de Início , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Análise de Sequência de DNA , Irmãos
5.
J Alzheimers Dis ; 17(2): 383-9, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19363265

RESUMO

Mutations in the amyloid-beta protein precursor (AbetaPP) gene can cause autosomal dominant early-onset Alzheimer's disease, or Alzheimer's disease (AD) associated with cerebral amyloid angiopathy (CAA), cerebral hemorrhage, or both. We have previously reported that the AbetaPP A713T mutation is associated with AD and subcortical ischemic lesions at magnetic resonance imaging in a large family which neuropathology confirmed CAA, stroke, and AD lesions. The objective of this clinical and molecular study was to investigate AbetaPP gene mutations in 59 patients affected by AD with cerebrovascular lesions (CVLs) and a family history of dementia. We identified three affected subjects with the AbetaPP A713T mutation. Since the prevalence of this mutation worldwide is very low, a common founder could exist in southern Italy. The pathogenicity of this mutation was confirmed and the clinical AD phenotype with CVLs seems to be a distinctive feature in the southern Italian population. The identification of these patients suggests that genetic epidemiology in large cohorts of familial late onset AD with CVLs would increase the probability of identifying AbetaPP mutations.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/genética , Mutação/genética , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Transtornos Cerebrovasculares/patologia , Análise Mutacional de DNA/métodos , Éxons/genética , Saúde da Família , Feminino , Humanos , Itália , Imageamento por Ressonância Magnética/métodos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco , Tomografia Computadorizada por Raios X/métodos
6.
Neurobiol Aging ; 30(11): 1825-33, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18314228

RESUMO

BACKGROUND: Frontotemporal dementia is a clinically and genetically heterogeneous syndrome. Mutations in two genes, Microtubule Associated Protein Tau (MAPT) and Progranulin (PGRN), and rarely Presenilin mutations, have been causally linked to this disorder. OBJECTIVE: To investigate the presence of PGRN, PSEN1, PSEN2 and APP mutations in a group of familial early-onset frontotemporal dementia (f-EOFTD) patients negative for MAPT gene mutations. SUBJECTS AND METHODS: We prospectively studied 17 unrelated subjects diagnosed with f-EOFTD (one case neuropathologically confirmed as FTD-Ub+). Among these subjects eight belonged to eight autosomal dominant families unrelated to each other, and nine had at least one first degree relative affected by dementia. RESULTS: We identified two novel heterozygous mutations in two unrelated patients, Cys139Arg in the PGRN gene and Val412Ile in the PSEN1 gene. CONCLUSIONS: Early-onset f-FTD remains a heterogeneous disorder from a genetic point of view. PGRN mutation frequency was low in our sample. The presence of a novel PSEN1 mutation suggests that presenilin molecular studies should be performed when screening for MAPT and PGRN genes is negative.


Assuntos
Saúde da Família , Demência Frontotemporal/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Presenilina-1/genética , Adulto , Arginina/genética , Cisteína/genética , Análise Mutacional de DNA , Feminino , Fluordesoxiglucose F18 , Demência Frontotemporal/diagnóstico por imagem , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Progranulinas , Cintilografia
9.
Arch Neurol ; 62(11): 1734-6, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16286548

RESUMO

BACKGROUND: The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model. OBJECTIVE: To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. DESIGN: Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. MAIN OUTCOME MEASURE: Plasma levels of sRAGE. RESULTS: Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001). CONCLUSIONS: Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.


Assuntos
Doença de Alzheimer/sangue , Demência Vascular/sangue , Receptores Imunológicos/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor para Produtos Finais de Glicação Avançada
10.
Dement Geriatr Cogn Disord ; 18(2): 189-96, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15211075

RESUMO

Lipoprotein(a) [Lp(a)] level is a newly established vascular risk factor which has been suggested to play a role in dementia. However, the majority of Lp(a) cell-to-cell interactions are mediated by its specific apolipoprotein(a) [apo(a)] moiety. This suggests that the size polymorphism of apo(a) may be of importance in conveying the Lp(a)-related risk. Specifically, we postulated that variation in apo(a) isoform size may lead to increased risk of vascular dementia (VaD), Alzheimer's disease (AD), stroke, or all three of them. Under a case-control design we compared Lp(a) plasma levels and the distribution of apo(a) phenotypes in groups of subjects consisting of 50 VaD patients, 162 sporadic AD patients, 95 non-demented stroke patients (NDS), and 105 normal controls. The prevalence of small-sized apo(a) isoforms in the VaD group was significantly higher than that in the stroke and normal control groups, with an odds ratio of 5.29 (95% CI 2.24-12.49, p = 0.0001) for the development of VaD for individuals with at least one apo(a) isoform of low molecular weight (LMW). Furthermore, the possession of at least one small-sized apo(a) isoform significantly increased the risk of AD to 1.92 (95% CI 1.02-3.61, p = 0.0434). Our results demonstrate that possession of at least one LMW apo(a) isoform is significantly associated with dementia and specifically offer new evidence of a strong association between the lipoprotein system and post-stroke dementia.


Assuntos
Doença de Alzheimer/diagnóstico , Demência Vascular/diagnóstico , Lipoproteína(a)/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Apolipoproteínas A/sangue , Apolipoproteínas A/genética , Infarto Cerebral/sangue , Infarto Cerebral/complicações , Infarto Cerebral/genética , Demência Vascular/sangue , Demência Vascular/genética , Feminino , Frequência do Gene/genética , Humanos , Embolia Intracraniana/sangue , Embolia Intracraniana/complicações , Embolia Intracraniana/genética , Itália , Lipoproteína(a)/genética , Masculino , Peso Molecular , Fenótipo , Polimorfismo Genético/genética , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genética , Valores de Referência , Fatores de Risco
11.
Neurosci Lett ; 357(1): 45-8, 2004 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-15036610

RESUMO

Apolipoprotein(a) [apo(a)] is a highly polymorphic glycoprotein which has been suggested to play a role in Alzheimer's disease (AD). Plasma lipoprotein(a) [Lp(a)] levels and the differential expression of apo(a) isoforms were analyzed in 73 sporadic AD patients compared with 73 age- and gender-matched healthy controls. The distribution of apo(a) isoforms and Lp(a) concentrations were similar in the two groups. However, we observed that AD patients with no apo(a) isoform from immunoblots (subjects with the 'null phenotype') had a mean age at onset of 76.8+/-8.8 versus 66.9+/-9.6 years of those who expressed at least one apo(a) band (P = 0.010). Multivariate analysis showed that this effect was independent of apolipoproteinE epsilon4 allele. We conclude that the expression of at least one apo(a) isoform may interact with other pathogenic mechanisms involved in controlling the age at onset of AD.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas/deficiência , Predisposição Genética para Doença/genética , Lipoproteína(a)/deficiência , Idade de Início , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Apolipoproteína E4 , Apolipoproteínas/sangue , Apolipoproteínas/genética , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Apoproteína(a) , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Masculino , Fenótipo , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genética
12.
Neurosci Lett ; 353(3): 201-4, 2003 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-14665416

RESUMO

Apolipoprotein(a) [apo(a)] is a genetically polymorphic glycoprotein that has several similarities to apolipoprotein E. However, its role as a risk factor for frontotemporal dementia (FTD) remains to be elucidated. We therefore investigated the effect of an apo(a) polymorphism on the incidence of FTD in a sample of Caucasian Italian patients. From the entire group of FTD patients (n=54), 55.6% of the subjects had at least one apo(a) low molecular weight (MW) isoform, compared to 29.9% of non-demented controls (n=77). The difference between the two groups was statistically significant (odds ratio 2.93, 95% confidence interval 1.42-6.06, P=0.003). The FTD group was further divided into sporadic (n=26) and familial (n=28) cases. Even after such dichotomization, both sporadic and familial FTD patients showed a significantly higher prevalence of low MW apo(a) isoforms than the cognitively healthy controls (P=0.011 and P=0.025, respectively). Our data suggest a role of apo(a) phenotypes of low MW in mediating susceptibility to FTD.


Assuntos
Apolipoproteínas A/sangue , Demência/sangue , Isoformas de Proteínas/sangue , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas A/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Itália/epidemiologia , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Isoformas de Proteínas/metabolismo , Distribuição Aleatória , Análise de Regressão , Estatísticas não Paramétricas
13.
Neurosci Lett ; 343(3): 210-2, 2003 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-12770698

RESUMO

Alzheimer disease (AD) is the most common neurodegenerative disorder of aging. Identifying novel AD genetic risk factors is important for understanding its pathogenesis. A recent study demonstrated that the deletion of adenosine in the promoter region of the presenilin 2 gene (PS2) is a susceptibility factor for early-onset AD. The objective of our study was to test the possibility that this variation is associated with AD in the Italian population. A case-control association study was performed, using 200 sporadic AD cases and 160 normal controls matched by age, gender and ethnicity. The current study does not support the notion that the polymorphism in the PS2 gene constitutes a risk factor for either late-onset or early-onset AD, which means that other genetic factors play a role in the development of AD in the Italian population.


Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana/genética , Polimorfismo Genético/genética , Adulto , Apolipoproteínas E/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Presenilina-2 , Regiões Promotoras Genéticas/genética , Fatores de Risco
14.
15.
Neurosci Lett ; 328(1): 65-7, 2002 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-12123860

RESUMO

Alpha-2 macroglobulin (A2M) is a component of Lewy bodies, a hallmark of Parkinson's disease (PD). In 159 PD patients and 190 normal controls, we studied two A2M polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism method: a five-nucleotide deletion at the 5' splice site of exon 18; and a valine to isoleucine exchange in amino acid position 1000 near the thiolester active site. No significant differences in allelic and genotypic distribution were found between cases and controls or between early and late-onset PD patients. The present data suggest that these polymorphisms do not represent a risk factor for PD and do not modulate the age at onset of PD.


Assuntos
Encéfalo/metabolismo , Corpos de Lewy/genética , Neurônios/metabolismo , Doença de Parkinson/genética , Polimorfismo Genético/genética , alfa-Macroglobulinas/genética , Fatores Etários , Idade de Início , Idoso , Encéfalo/patologia , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Corpos de Lewy/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Fatores Sexuais
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