RESUMO
Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Proteínas Facilitadoras de Transporte de Glucose/genética , Neurocalcina/genética , Transtornos Psicóticos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Apolipoproteínas E/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 4/genética , DNA Intergênico/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Transtornos Psicóticos/complicações , Transtornos Psicóticos/diagnósticoRESUMO
Patients with muscle disorders can present a diagnostic challenge to physicians because of the different ways they can present and the large number of different underlying causes. Recognition of the 'myopathic phenotype' coupled with investigations usually including electrodiagnostic and histological investigations have been essential for diagnosing the underlying cause of a myopathy. Despite these standard investigations, some patients can remain undiagnosed. New tests including more specific antibody tests for immune-mediated myopathies and the introduction of next-generation sequencing promise to revolutionise diagnostic approaches for immune and inherited myopathies, but clinical expertise remains essential to choose the most appropriate tests and interpret the results. The aim of this review is to provide an overview of the different presentations to the neuromuscular clinic and the latest investigations that can be helpful in the diagnosis of muscle disorders.
Assuntos
Testes Diagnósticos de Rotina/tendências , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Animais , Eletromiografia/tendências , Testes Genéticos/tendências , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/genética , Miosite/diagnóstico , Miosite/genética , Miosite/metabolismoRESUMO
Alzheimer's disease (AD) is a complex disease that is likely influenced by many genetic and environmental factors. Citing evidence that iron may play a role in AD pathology, Robson et al. [Robson et al. (2004); J Med Genet 41:261-265] reported that epistatic interaction between rs1049296 (P589S) in the transferrin gene (TF) and rs1800562 (C282Y) in the hemochromatosis gene (HFE) results in significant association with risk for AD. In this study we attempted to replicate their findings in a total of 1,166 cases and 1,404 controls from three European and European American populations. Allele and genotype frequencies were consistent across the three populations. Using synergy factor analysis (SFA) and Logistic Regression analysis we tested each population and the combined sample for interactions between these two SNPs and risk for AD. We observed significant association between bi-carriers of the minor alleles of rs1049296 and rs1800562 in the combined sample using SFA (P = 0.0016, synergy factor = 2.71) and adjusted SFA adjusting for age and presence of the APOE epsilon 4 allele (P = 0.002, OR = 2.4). These results validate those of the previous report and support the hypothesis that iron transport and regulation play a role in AD pathology.
Assuntos
Doença de Alzheimer/genética , Hemocromatose/genética , Transferrina/genética , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Apolipoproteínas E/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Ferro/metabolismo , Masculino , Estudos Multicêntricos como Assunto , Polimorfismo de Nucleotídeo Único , Risco , Fatores de RiscoRESUMO
A recent scan of single nucleotide polymorphisms (SNPs) in the region 40-107 Mb on chromosome 10q in a large Japanese case-control cohort identified six SNPs in or near the dynamin-binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in individuals lacking the APOE epsilon4 allele [Kuwano et al. (2006); Hum Mol Genet 15:2170-2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the sample as a whole. When stratifying the sample by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in individuals lacking the epsilon4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD.
Assuntos
Idade de Início , Doença de Alzheimer/genética , Cromossomos Humanos Par 10 , Proteínas do Citoesqueleto/genética , População Branca , Apolipoproteína E4/genética , Humanos , Polimorfismo de Nucleotídeo Único , Reino UnidoRESUMO
Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10 , Polimorfismo de Nucleotídeo Único , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Anquirinas/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Ligação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista , Proteínas Proto-Oncogênicas/genética , alfa Catenina/genéticaRESUMO
Twelve children with severe systemic juvenile chronic arthritis, all requiring high dose corticosteroids, have been admitted to a pilot study to evaluate the effect of low-dose methotrexate (mean dose: 8.5 mg/M2) on disease activity over a 6 month period. Definite improvement occurred in 4 children, allowing reduction of the steroid dose in 2 cases. Two children showed an acute flare of disease activity during the treatment period and in three, steroids had to be increased. Overall, side effects were rare with a rise in transaminases only occurring once. MTX blood levels taken on 14 occasions in 8 children documented absorption in all cases with a mean level of 3.45 x 10(-7) mol/l on a mean dose of 9 mg/M2. Low-dose MTX appears to be a safe drug in the short term treatment of severe systemic JCA with beneficial effect in about a third of patients. Long-term controlled trials will be needed to evaluate its role in the treatment of systemic disease as well as side effects.
Assuntos
Artrite Juvenil/tratamento farmacológico , Metotrexato/administração & dosagem , Absorção , Administração Oral , Adolescente , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Juvenil/sangue , Criança , Pré-Escolar , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Humanos , Masculino , Metotrexato/sangue , Metotrexato/farmacocinéticaRESUMO
We report herein the results of the cross-cultural adaptation and validation into the British language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. A total of 440 subjects were enrolled: 219 patients with JIA (17% systemic onset, 41% polyarticular onset, 33% extended oligoarticular subtype, and 9% persistent oligoarticular subtype) and 221 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the British version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.
Assuntos
Artrite Juvenil/diagnóstico , Comparação Transcultural , Nível de Saúde , Inquéritos e Questionários , Adolescente , Criança , Características Culturais , Avaliação da Deficiência , Feminino , Humanos , Idioma , Masculino , Psicometria , Qualidade de Vida , Reprodutibilidade dos Testes , Reino UnidoRESUMO
Thirteen patients with isolated pain and swelling of a sterno-clavicular clavicular joint have been reviewed. Three groups were identified. Group 1 comprised four patients, all of whom had a short history of less than six weeks and suffered a pyarthrosis or malignant disease; group 2, four patients who were shown to have features of condensing osteitis of the clavicle (Cone et al, 1983); and group 3, five patients, had degenerative arthritis of a sterno-clavicular joint. The only difference between groups 2 and 3 were that patients in group 3 had a rather longer history, both articular surfaces were involved and showed a possible increase in the incidence of degenerative joint disease elsewhere. It is suggested that condensing osteitis is but a part of a spectrum of degenerative disease of the sterno-clavicular joints, akin to discogenic vertebral body sclerosis (McCarthy & Dorfman, 1982).
Assuntos
Articulação Esternoclavicular/diagnóstico por imagem , Adulto , Idoso , Artrite/diagnóstico por imagem , Feminino , Radioisótopos de Gálio , Humanos , Masculino , Pessoa de Meia-Idade , Osteíte/diagnóstico por imagem , Dor , Radiografia , Cintilografia , Esclerose/diagnóstico por imagem , Articulação Esternoclavicular/patologia , Medronato de Tecnécio Tc 99mRESUMO
PIP: The Australian Royal Commission on Human Relationships summarized the problems of adolescents and family planning by declaring there is a level of teenage sexual activity that cannot be ignored. Young single people have a low rate of effective contraception. Teenagers suffer a very high proportion of unwanted pregnancies and abortions. Placing the ethical questions in a contemporary social context enables society to face the issues in a practical, realistic fashion. Historically preserved traditions, like the taboo against premarital sex, are and will continue to be important in the bonding of families, individuals, and societies. A situational ethic applies to changes in the social fabric and addresses them. Society has changed from rural to urban, from agrarian to technological, from literacy to mass media, from superstitious knowledge of reproduction to scientific methods of birth control. The realities of change should be faced with a sense of ethics that is grounded in tradition and adjusted to the needs of the actual situation which is that too many teenagers have too many unwanted pregnancies. They can be helped.^ieng
Assuntos
Adolescente , Anticoncepção , Ética , Sexualidade , Valores Sociais , Austrália , Aconselhamento , Humanos , Disseminação de Informação , Serviços de Informação , Meios de Comunicação de Massa , Relações Pais-Filho , ReligiãoRESUMO
OBJECTIVE: Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain. METHODS: We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis. RESULTS: In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD. CONCLUSION: The current evidence linking common mtDNA variations with AD is not compelling.
Assuntos
Doença de Alzheimer/genética , DNA Mitocondrial/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Doença de Alzheimer/diagnóstico , Estudos de Coortes , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
INTRODUCTION: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated. METHODS: We have analysed a sample of 1850 probable AD patients from the UK and Greece with 10 item Neuropsychiatric Inventory (NPI) data. We applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of MMSE, disease duration, gender, age and age of onset on the structure of a four-factor model consisting of "psychosis", "moods", "agitation" and "behavioural dyscontrol". RESULTS: Specific clinical variables predicted the expression of individual factors. When the inter-relationship of factors is modelled, some previously significant associations are lost. For example, lower MMSE scores predict psychosis, agitation and behavioural dyscontrol factors, but psychosis and mood predict the agitation factor. Taking these associations into account MMSE scores did not predict agitation. CONCLUSIONS: The complexity of the inter-relations between symptoms, factors and clinical variables is efficiently captured by this MIMIC model.
Assuntos
Demência/complicações , Demência/psicologia , Transtornos Mentais/etiologia , Agitação Psicomotora/etiologia , Transtornos Psicóticos/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Análise Fatorial , Feminino , Grécia , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Modelos EstatísticosAssuntos
Osso e Ossos/diagnóstico por imagem , Doenças do Colágeno/diagnóstico por imagem , Osteomalacia/diagnóstico por imagem , Adolescente , Adulto , Idoso , Biópsia , Osso e Ossos/patologia , Criança , Doenças do Colágeno/complicações , Doenças do Colágeno/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteomalacia/etiologia , Osteomalacia/patologia , RadiografiaAssuntos
Pobreza , Adulto , Idoso , Austrália , Criança , Emprego , Feminino , Educação em Saúde , Serviços de Saúde , Habitação , Humanos , Renda , Masculino , Política Pública , Alienação Social , Fatores Socioeconômicos , Estatística como AssuntoAssuntos
Adolescente , Comportamento Contraceptivo , Ética , Adulto , Austrália , Criança , Feminino , Humanos , Masculino , Comportamento SexualRESUMO
Psychotic symptoms are common in individuals with Alzheimer's disease (AD), and define a phenotype associated with more rapid cognitive and functional decline. Evidence suggests that psychotic symptoms may be influenced by genetic factors, and recent studies in schizophrenia, bipolar affective disorder (BPAD) and Alzheimer's disease with psychosis (AD+P) suggest that psychosis susceptibility or modifier genes may act across diseases. We hypothesised that oligodendrocyte lineage transcription factor 2 (OLIG2), a regulator of white matter development and a candidate gene for schizophrenia, may also be associated with psychotic symptoms in AD. We genotyped 11 SNPs in OLIG2 previously tested for association with schizophrenia [L. Georgieva, V. Moskvina, T. Peirce, N. Norton, N.J. Bray, L. Jones, P. Holmans, S. Macgregor, S. Zammit, J. Wilkinson, H. Williams, I. Nikolov, N. Williams, D. Ivanov, K.L. Davis, V. Haroutunian, J.D. Buxbaum, N. Craddock, G. Kirov, M.J. Owen, M.C. O'Donovan, Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia, Proc. Natl. Acad. Sci. U.S.A. 103 (33) (2006) 12469-12474] and tested these for association with AD and AD+P. Significant evidence for association of psychotic symptoms within cases was identified for two SNPs, rs762237 (allelic P=0.002, OR=1.42, corrected P=0.019) and rs2834072 (allelic P=0.004, OR=1.41, corrected P=0.05).
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas do Tecido Nervoso/genética , Transtornos Psicóticos/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Transcrição 2 de Oligodendrócitos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Psychotic symptoms are common in Alzheimer's disease (AD) and are associated with increased cognitive impairment and earlier institutionalization. One study has suggested that they are genetically modified and two genome screens have been performed to search for susceptibility loci for AD with psychosis (AD + P). The aim of this study was to further investigate the familial aggregation of AD + P and perform a genome screen for AD, conditioning on the presence or absence of psychotic symptoms. Samples from the UK and US were combined, providing data from 374 families in which at least two members met criteria for AD and had complete data regarding psychotic symptoms. Generalized estimating equations (GEE) were used to assess the relationship of psychotic symptoms between siblings. A total of 321 affected relative pairs (ARPs) were genotyped for linkage. There was a significant association between proband psychosis status and the occurrence of AD + P in siblings in the UK (OR = 4.17, P = 0.002) and US (OR = 3.2, P < 0.001) samples. Chromosomewide and genomewide significant linkage peaks were observed on chromosomes 7 (LOD = 2.84) and 15 (LOD = 3.16), respectively, with the strongest evidence coming from pairs concordant for AD without psychosis. A LOD score of 2.98 was observed close to a previously reported AD + P linkage region on chromosome 6, however the increase in LOD attributable to psychosis was not significant. These findings support the hypothesis that psychotic symptoms in AD are genetically modified and that a gene/s implicated in their aetiology may be located on chromosome 7 and 15.
Assuntos
Doença de Alzheimer/genética , Ligação Genética , Genoma Humano , Transtornos Psicóticos/genética , Doença de Alzheimer/psicologia , Cromossomos Humanos , Análise Mutacional de DNA , Saúde da Família , Humanos , Escore Lod , Linhagem , Transtornos Psicóticos/psicologia , Fatores de RiscoRESUMO
The neuropathology of Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles and the extracellular deposition of beta-amyloid (Abeta) in senile plaques. Abeta has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, although the pathological mechanism of Abeta remains largely unknown. Recent evidence suggests that the FISH adapter protein binds to, and potentially regulates, ADAM12 (a disintegrin and metalloprotease 12) to mediate a neurotoxic effect of Abeta. The ADAM12 gene lies on chromosome 10q26.3, and the gene encoding FISH, SH3MD1, lies within a region of linkage to late-onset AD (LOAD) on 10q25.1. This study investigates whether there is a relationship between variation in ADAM12 and SH3MD1 and susceptibility to LOAD in a sample of 1,051 AD cases and 1,269 matched controls. We observe significant interactions between variants in the two genes that may influence susceptibility to LOAD. The most significant statistical interaction is between rs3740473, a synonymous single nucleotide polymorphism (SNP) in SH3MD1 and rs11244787, an intronic SNP in ADAM12 (effect size = 2.1 for interaction term, P = 0.006).