RESUMO
Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14 , Idoso , Alelos , Precursor de Proteína beta-Amiloide/genética , Sequência de Bases , Mapeamento Cromossômico , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , LinhagemRESUMO
AIM: To compare ultrasound gradings of steatosis with fat fraction (FF) on magnetic resonance spectroscopy (MRS; the non-invasive reference standard for quantification of hepatic steatosis), and evaluate inter- and intraobserver variability in the ultrasound gradings. MATERIALS AND METHODS: Triple grading of hepatic ultrasound examination was performed by three independent graders on 131 people with type 2 diabetes. The stored images of 60 of these individuals were assessed twice by each grader on separate occasions. Fifty-eight patients were pre-selected on the basis of ultrasound grading (normal, indeterminate/mild steatosis, or severe steatosis) to undergo (1)H-MRS. The sensitivity and specificity of the ultrasound gradings were determined with reference to MRS data, using two cut-offs of FF to define steatosis, ≥9% and ≥6.1%. RESULTS: Median (intraquartile range) MRS FF (%) in the participants graded on ultrasound as normal, indeterminate/mild steatosis, and severe steatosis were 4.2 (1.2-5.7), 4.1 (3.1-8.5) and 19.4 (12.9-27.5), respectively. Using a liver FF of ≥6.1% on MRS to denote hepatic steatosis, the unadjusted sensitivity and specificity of ultrasound gradings (severe versus other grades of steatosis) were 71 and 100%, respectively. Interobserver agreement within one grade was observed in 79% of cases. Exact intraobserver agreement ranged from 62 to 87%. CONCLUSION: Hepatic ultrasound provided a good measure of the presence of significant hepatic steatosis with good intra- and interobserver agreement. The grading of a mildly steatotic liver was less secure and, in particular, there was considerable overlap in hepatic FF with those who had a normal liver on ultrasound.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Fígado Gorduroso/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Idoso , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Progressão da Doença , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Sensibilidade e Especificidade , Ultrassonografia , Reino UnidoRESUMO
Presenilin 1 (PS1) is the causative gene for an autosomal dominant familial Alzheimer's disease (AD) mapped to chromosome 14. Here we show that QM/Jun-interacting factor (Jif)-1, a negative regulator of c-Jun, is a candidate to mediate the function of PS1 in the cell. We screened for proteins that bind to PS1 from a human embryonic brain cDNA library using the two-hybrid method and isolated one clone encoding the QM/Jif-1 gene. The binding of QM/Jif-1 to full-length PS1 was confirmed in vitro by pull-down assay, and in vivo by immunoprecipitation assays with human samples, including AD brains. Immunoelectronmicroscopic analysis showed that QM/Jif-1 and PS1 are colocalized at the endoplasmic reticulum, and the nuclear matrix in human brain neurons. Chloramphenicol acetyltransferase assays in F9 cells showed that PS1 suppresses transactivation by c-Jun/c-Jun but not by c-Jun/c-Fos heterodimers, consistent with the reported function of QM/Jif-1. By monitoring fluorescent recombinant protein and by gel mobility shift assays, PS1 was shown to accelerate the translocation of QM from the cytoplasm to the nucleus and to thereby suppress the binding of c-Jun homodimer to 12-O-tetradecanoylphorbol-13- acetate (TPA)-responsive element (TRE). PS1 suppressed c-jun-associated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas this suppression of apoptosis is attenuated by mutation in PS1. Collectively, the novel function of PS1 via QM/Jif-1 influences c-jun-mediated transcription and apoptosis.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Ribossômicas , Adulto , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Apoptose , Transporte Biológico , Encéfalo/citologia , Encéfalo/embriologia , Encéfalo/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/genética , Núcleo Celular/metabolismo , Dimerização , Feminino , Humanos , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Mutação , Presenilina-1 , Proteínas Proto-Oncogênicas c-jun/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-jun/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Proteína Ribossômica L10 , Ativação Transcricional , Células Tumorais Cultivadas , Técnicas do Sistema de Duplo-Híbrido , Dedos de ZincoRESUMO
Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 21 , Mapeamento Cromossômico , Ligação Genética , Humanos , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
The possibility that Alzheimer's disease (AD) is caused by overexpression or duplication of one or more genes on chromosome 21 has been raised by the observation of AD-like neuropathologic changes in individuals with Down syndrome and by the mapping of both the defect for familial AD and the amyloid beta protein gene to this autosome. Possible duplication on chromosome 21 was investigated in both familial and sporadic AD by means of restriction fragment length polymorphisms for the amyloid and SODI loci, as well as for DNA markers in the vicinity of the familial AD defect and in the critical Down syndrome region of chromosome 21. No evidence of increased DNA dosage was observed in either brain or leukocytes of patients with inherited or sporadic forms of AD. Duplication of these regions is therefore not a frequent event in either form of AD. Furthermore, no significant allelic association was detected between AD and any of the loci, including the amyloid and SODI genes, providing no support for the hypothesis that defects in these specific genes are the primary cause of AD.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 21 , Alelos , Amiloide/genética , Genes , Ligação Genética , Humanos , Polimorfismo de Fragmento de RestriçãoRESUMO
This paper builds a method to detect the apparent restrictiveness or permissiveness of communities towards drunk-driving. A framework of three mutually interacting community domains is used to motivate a minimum set of DUI patterns to be expected from an appropriately deterrent environment. Based on the (simplified) system dynamics model, an empirical estimation strategy and scoring methodology is outlined. This "macroscopic" approach is demonstrated using results from time-series panel analyses of California's 58 counties for the years 1990 to 2010 (Van Vleck et al., 2017). The process successfully classified three-quarters of California counties, encompassing almost 90% of the state population. The paper demonstrates a potential tool to classify communities' systemic behavior toward drinking-and-driving and other enforcement-sensitive subjects.
Assuntos
Dirigir sob a Influência/legislação & jurisprudência , Aplicação da Lei , Permissividade , Consumo de Bebidas Alcoólicas/legislação & jurisprudência , Condução de Veículo/legislação & jurisprudência , California , Feminino , Humanos , Projetos de PesquisaRESUMO
The efficacy of treatment with imipramine hydrochloride, desipramine hydrochloride, methscopolamine bromide, and placebo was compared in a study with 40 severely enuretic boys. Both tricyclic antidepressants were superior to placebo and methscopolamine, but they did not differ from each other. Psychiatric disturbance, sleep measures, and other clinical parameters did not predict antienuretic response to tricyclics nor was there a psychotropic response. Plasma concentrations of imipramine and desipramine showed a significant correlation with clinical effect. However, true nonresponders were found, and tolerance to the antienuretic drugs developed in some boys.
Assuntos
Desipramina/uso terapêutico , Enurese/tratamento farmacológico , Imipramina/uso terapêutico , Derivados da Escopolamina/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Desipramina/sangue , Método Duplo-Cego , Enurese/psicologia , Humanos , Imipramina/sangue , Masculino , Transtornos Mentais/tratamento farmacológico , N-Metilescopolamina , PlacebosRESUMO
Forty severely enuretic boys (mean age, 10.8 years) were selected; 20 had associated psychiatric disturbance and 20 had enuresis as an isolated symptom. Psychiatrically disturbed enuretics had both slightly higher scores on a neurological examination for "soft signs" and more "stressful" background events. Enuretic events were not associated with a particular sleep stage; disturbed and nondisturbed enuretics did not differ from each other with respect to the distribution of enuretic events by sleep stage. The results do not support the concepts of enuresis as an arousal disorder or of there being different sleep profiles of enuresis in relation to behavioral pathology.
Assuntos
Enurese/psicologia , Transtornos Mentais/complicações , Fases do Sono , Adolescente , Criança , Enurese/complicações , Família , Humanos , Masculino , Transtornos Mentais/psicologia , Exame Neurológico , Estresse PsicológicoRESUMO
We compared hippocampal lesions in three pedigrees of Familial Alzheimer's Disease (FAD). In these pedigrees, the disease is inherited as an autosomal dominant disorder and has been linked to DNA markers on chromosome 21. In eight cases of FAD (four from one pedigree and two each from two others) we quantified neurofibrillary tangles (NFT) and senile plaques (SP) in hippocampal subdivision CA1-4, subiculum, presubiculum, and dentate gyrus. We observed consistent patterns of the distribution of lesions: The highest density of NFT and SP was present in CA1-2; virtually no SP or NFT were present in presubiculum; SP diameter was consistently greatest in CA4. We found no overall differences among pedigrees in total densities of NFT and SP, but statistical analyses disclosed that an uncommon type of SP was disproportionately present in two pedigrees. This type of SP was usually restricted to CA4, had a marked amyloid core devoid of argyrophilic neurites. These studies also disclosed inter- and intrafamilial heterogeneity of lesion distribution (including congophilic angiopathy and cerebellar plaques) in these three pedigrees.
Assuntos
Doença de Alzheimer/genética , Genes Dominantes , Hipocampo/patologia , Doença de Alzheimer/patologia , Cerebelo/patologia , Humanos , Neurofibrilas/patologiaRESUMO
The calcium-sensitive photoprotein, aequorin, was used to examine serum- and bradykinin-induced transient increases in free cytosolic calcium ions in skin fibroblasts from 10 individuals with early onset familial AD (FAD), including four who were biopsied before their clinical symptoms would allow a diagnosis of AD, 2 individuals with late onset FAD, 8 at-risk but nonsymptomatic individuals, and 13 controls. The data show that (a) among controls, the peaks of the calcium transients increase in height as a function of donor age; (b) transients induced by 10% serum, 10 nM bradykinin (BK) or 100 nM BK were generally lower in FAD fibroblasts, including those from donors in the early stages of the disease, than in age-matched control cells; (c) such transients are reduced in cells from a proportion of the nonsymptomatic, at-risk individuals. Thus, serum- and BK-induced calcium transients are reduced in fibroblasts from both early and more advanced stage FAD donors and perhaps even from donors who are presymptomatic carriers of the defective gene. The data also suggest that changes in calcium transients in FAD fibroblasts neither mimic nor exaggerate the effects of normal aging.
Assuntos
Doença de Alzheimer/metabolismo , Bradicinina/farmacologia , Cálcio/metabolismo , Adulto , Equorina , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Agonistas dos Canais de Cálcio/farmacologia , Criança , Pré-Escolar , Meios de Cultura Livres de Soro , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fura-2 , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Proteínas de Membrana/genética , Mutação/genética , Placa Amiloide/genética , Placa Amiloide/patologia , Adulto , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Contagem de Células , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Presenilina-1RESUMO
Previous investigations demonstrated that the cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients contains antibodies that recognize specific neuronal populations in the adult rat central nervous system (CNS). These findings suggest a pathogenic role for immunological aberrations in this disorder. To determine if antibodies may provide a means to differentially diagnose the dementias, CSF from a diversified dementia population was screened against the developing rat CNS and a cell culture system. Markings produced by AD CSF were distinctly different from those of vascular dementias (VAD) against the developing rat CNS. More importantly, some AD CSF recognized amoeboid microglia. The recognition of amoeboid microglia by antibodies in AD CSF is particularly interesting since these cells proliferate in response to nervous system disease and also engulf debris. A cell culture technique was developed to allow the rapid screening of CSF antibodies. Patient CSF produced five different types of markings in the cell culture: microglia, glioblasts, fibers, nonspecific, or negative. Correlations with these structures and the diagnosis of four different dementia populations revealed that, in comparison to the other groups, AD CSF displayed remarkable selectivity toward microglial cells. Cortical biopsies from patients suspected to have AD were incubated with the patient's own CSF and that of confirmed AD patients. Both CSF samples recognized microglial cells in the patient's cortical biopsy. The same CSF samples incubated against normal human cortical autopsy or a biopsy from a 3-mo-old child displayed negative immunoreactivity. These three approaches suggest that the presence of CSF microglial antibodies may be a means to distinguish AD patients from other dementias. The results add further support to the widely growing concept that inflammation and similar immune mechanisms may contribute to AD pathogenesis.
Assuntos
Doença de Alzheimer/imunologia , Autoanticorpos/líquido cefalorraquidiano , Microglia/imunologia , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Encéfalo/ultraestrutura , Células Cultivadas , Humanos , Imuno-Histoquímica , Microglia/patologia , Microglia/ultraestrutura , Microscopia Imunoeletrônica , Ratos , Ratos Sprague-DawleyRESUMO
Cerebral presenilin-1 protein (PS-1) is normally composed of the amino-terminal fragment (NTF) with Mr 28 kDa and the carboxy-terminal fragment (CTF) with 18 kDa. We analyzed human PS-1 in brains with early-onset familial Alzheimer's disease (FAD) with and without PS-1 mutations to study whether mutated PS-1 was abnormally metabolized. Cerebral PS-1 were found to be cleaved into two fragments of NTF and CTF independently of the occurrence of PS-1 mutation in human brains. A small portion of PS-1 was recently found to suffer another processing by caspase-3, an apoptosis-related cysteine protease. In contrast to the recent finding that the Volga-German mutation on presenilin-2 (PS-2) affects the increasing caspase-3 PS-2 fragment, the PS-1 mutation did not cause a significant change in PS-1 fragmentation. We conclude that PS-1 fragmentation and other (probably caspase-3-mediated) digestion following apoptosis occur independently of PS-1 mutations.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação Puntual , Processamento de Proteína Pós-Traducional , Sequência de Aminoácidos , Animais , Córtex Cerebral/metabolismo , Humanos , Proteínas de Membrana/química , Camundongos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Presenilina-1 , CoelhosRESUMO
We did not find a significant association between HLA antigens and pure autonomic failure or multiple system atrophy with autonomic failure. HLA-A32, specifically, did not occur with increased frequency in either group of patients. Our results do not support an HLA contribution in these disorders of the autonomic nervous system as reported by other investigators.
Assuntos
Doenças do Sistema Nervoso Autônomo/imunologia , Antígenos HLA , Doenças do Sistema Nervoso Autônomo/genética , Feminino , Humanos , MasculinoRESUMO
A Canadian family comprising 51 members affected with Alzheimer's disease was evaluated clinically, histologically, and genetically. Ancestors were traced through eight generations, and 51 members were examined at the National Institute of Mental Health, Bethesda, Md. The pedigree is consistent with autosomal dominant inheritance. The effect of interrelatedness among some parents of affected individuals is unknown. In contrast to other studies, there was not an increased incidence of Down's syndrome, hematologic malignancy, or preponderance of affected females.
Assuntos
Doença de Alzheimer/genética , Encéfalo/patologia , Demência/genética , Doença de Alzheimer/patologia , Atrofia , Encéfalo/anatomia & histologia , Ventrículos Cerebrais/patologia , Ventriculografia Cerebral , Feminino , Hipocampo/patologia , Humanos , Masculino , Transtornos da Memória/diagnóstico , Pessoa de Meia-Idade , Tamanho do Órgão , Linhagem , Tomografia Computadorizada por Raios XRESUMO
We report an autosomal recessive form of ataxia that is not allelic to Friedreich's disease in six individuals from a large kindred with family origins traced to a common founder of German-Swiss descent. The disorder begins during early childhood with a concentric contraction of the visual fields and proprioceptive loss. Eventually blindness, a severe sensory ataxia, achalasia, scoliosis, and inanition develop by third decade. Inversion recovery MRIs of the spinal cord in affected individuals demonstrate a hyperintense signal in the posterior columns. Finding the gene responsible for this disorder may aid in our understanding of the mechanisms that cause sensory neuronal degeneration.
Assuntos
Ataxia/genética , Genes Recessivos , Retinose Pigmentar/genética , Doenças da Medula Espinal/genética , Adolescente , Adulto , Ataxia/diagnóstico , Ataxia/fisiopatologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pescoço , Linhagem , Retinose Pigmentar/fisiopatologia , Medula Espinal/patologia , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/fisiopatologiaRESUMO
Clinical and genetic observations of Gilles de la Tourette syndrome were carried out on members of 14 families from the Minneapolis area. An unusual number of the families were of Jewish and other Eastern European ancestry, and in all but one of these families multiple members were affected. These observations parallel our earlier findings based on 21 families from the New York City area. Together with recent evidence indicating relative instability of a specific enzyme in some patients, these observations suggest that there is a genetically determined form of Gilles de la Tourette syndrome.
Assuntos
Síndrome de Tourette/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Judeus , Masculino , Minnesota , LinhagemRESUMO
Linkage disequilibrium studies suggest that progressive supranuclear palsy (PSP) is an autosomal recessive condition that maps to a polymorphism in the tau gene. These results provide evidence that homozygous mutations in the tau gene may cause PSP. Recently, a missense mutation in exon 13 of one tau allele (R406W) was found in a single family with an atypical clinicopathologic form of dominantly inherited PSP. The authors report that the R406W mutation is lacking in 25 unrelated individuals with PSP and in six unrelated individuals with another tauopathy-corticobasal degeneration.
Assuntos
Doenças dos Gânglios da Base/genética , Encefalopatias/genética , Degeneração Neural/genética , Paralisia Supranuclear Progressiva/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doenças dos Gânglios da Base/patologia , Encefalopatias/patologia , Feminino , Genes Recessivos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Polimorfismo GenéticoRESUMO
We studied two candidate genes, tau (tau) and alpha-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The tau alpha1 allele and the tau alpha1alpha1 genotype were overrepresented in individuals with PSP and the tau polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinson's disease gene on chromosome 4q21-q23.
Assuntos
Cromossomos Humanos Par 4 , Ligação Genética , Proteínas do Tecido Nervoso/genética , Paralisia Supranuclear Progressiva/genética , Proteínas tau/genética , Idoso , Alelos , Haplótipos , Humanos , Pessoa de Meia-Idade , Polimorfismo Genético , Sinucleínas , alfa-SinucleínaRESUMO
We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.