RESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Endofenótipos/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Transtornos Cognitivos/genética , Colômbia , Etnicidade/genética , Feminino , Estudos de Associação Genética/métodos , Ligação Genética/genética , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/psicologia , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Linhagem , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (ß=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10(-8), PFDR=2.48 × 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (ß=8.24, 95% CI: 4.45-12.01, P=3.84 × 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.
Assuntos
Apolipoproteína E2/genética , Presenilina-1/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E2/metabolismo , Apolipoproteínas E/genética , Feminino , Genótipo , Haplótipos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Presenilina-1/metabolismoRESUMO
We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.
Assuntos
Doença de Alzheimer/genética , Quimiocina CCL11/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idade de Início , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Quimiocina CCL11/sangue , Cromossomos Humanos Par 17/genética , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 × 10⻹²; NPHP1, rs10173717, P=1.74 × 10⻹²; CADPS2, rs3757536, P=1.54 × 10⻹°; GREM2, rs12129547, P=1.69 × 10⻹³, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions.
Assuntos
Alanina/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença , Ácido Glutâmico/genética , Presenilina-1/genética , Idade de Início , Doença de Alzheimer/epidemiologia , Estudos de Coortes , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Efeito Fundador , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Mutação/genética , Polimorfismo de Nucleotídeo Único , Locos de Características QuantitativasRESUMO
In this study, we address three key challenges in photonic crystals: modeling of isolated flat bands, electric field prediction, and band separation in dispersion relations. Using twisted square Bravais lattices at specific angles, we create Bravais-Moiré photonic crystals exhibiting unique characteristics. These include band pairing and parallelism in certain Brillouin zones, enabling predictable electric field behavior and identification of isolated, flat band pairs within extensive band gaps. We apply advanced Shape theory-based classification methods for precise band separation, offering significant contributions to photonics research and light manipulation applications.
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Contextual memory, the ability to remember spatial or temporal features related to an event, is affected in Alzheimer's disease (AD). There is a shortfall of tests that measure contextual memory. To evaluate visuospatial contextual memory, we developed a computerized cognitive test, the MAPP Room Memory Test, which requires participants to identify in which visual scene target items were previously presented. We hypothesized that cognitively-unimpaired carriers of an autosomal dominant AD mutation (Presenilin-1 E280A, n=15) would perform more poorly on this test than non-carrier family members (n=31). Compared to non-carriers, the carriers had significantly worse delayed room recognition. The results indicate that the MAPP Room Memory Test may be sensitive to subtle cognitive changes associated with risk of AD. Future studies with larger samples using the MAPP Room Memory Test and biomarkers are needed to examine whether this test may also be sensitive to the earliest pathological changes in preclinical AD.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Mutação , Testes NeuropsicológicosRESUMO
In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Cromossomos Humanos Par 11/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Encéfalo/metabolismo , Estudos de Casos e Controles , Colina/metabolismo , Glutamina/metabolismo , Humanos , Inositol/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Metilfenidato/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , PrótonsRESUMO
Early cognitive changes due to Alzheimer's disease (AD) include difficulties in semantic access and working memory. Using a computerized cognitive test developed by our group, called the Memory for Semantically Related Objects test (MESERO), we evaluated if cognitively unimpaired carriers of an autosomal dominant AD (ADAD) mutation performed worse on this test than non-carrier family members. 35 cognitively unimpaired ADAD mutation carriers and 26 non-carrier family members from a Colombian ADAD cohort took the MESERO on a laptop computer. Cognitively unimpaired ADAD carriers had significantly worse MESERO total scores than non-carrier family members, driven by worse performance in semantically-related object sets; group performances did not differ on semantically unrelated object sets. Findings suggest that MESERO performance may be sensitive to subtle cognitive changes associated with AD. Future MESERO research should examine performances between healthy older adults and people at risk for sporadic AD.
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Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/psicologia , Mutação/genética , Testes Neuropsicológicos , ColômbiaRESUMO
Alzheimer's disease (AD) is the most common cause of dementia among older adults. APOE3 Christchurch (R136S, APOE3Ch ) variant homozygosity was reported in an individual with extreme resistance to autosomal dominant AD due to the PSEN1 E280A mutation. This subject had a delayed clinical age at onset and resistance to tauopathy and neurodegeneration despite extremely high amyloid plaque burden. We established induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and from a non-protected kindred control (with PSEN1 E280A and APOE3/3 ). We used CRISPR/Cas9 gene editing to successfully remove the APOE3Ch to wild type in iPS cells from the protected case and to introduce the APOE3Ch as homozygote in iPS cells from the non-protected case to examine causality. We found significant reduction of tau phosphorylation (pTau 202/205 and pTau396) in cerebral organoids with the APOE3Ch variant, consistent with the strikingly reduced tau pathology found in the resistant case. We identified Cadherin and Wnt pathways as signaling mechanisms regulated by the APOE3Ch variant through single cell RNA sequencing in cerebral organoids. We also identified elevated ß-catenin protein, a regulator of tau phosphorylation, as a candidate mediator of APOE3Ch resistance to tauopathy. Our findings show that APOE3Ch is necessary and sufficient to confer resistance to tauopathy in an experimental ex-vivo model establishing a foundation for the development of novel, protected case-inspired therapeutics for tauopathies, including Alzheimer's.
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Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Predisposição Genética para Doença , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Adolescente , Adulto , Encéfalo/metabolismo , Sobrevivência Celular/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Ligação Genética , Genótipo , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Polimorfismo Genético , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismoRESUMO
Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Cerebelo/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Mutação Puntual , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Química Encefálica , Cerebelo/patologia , Códon/genética , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Proteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/fisiologia , Emaranhados Neurofibrilares/química , Emaranhados Neurofibrilares/patologia , Presenilina-1RESUMO
Background: Weight loss and malnutrition are frequent findings in late-onset and sporadic presentations of Alzheimer's Disease (AD). However, less is known about nutritional status in Early-Onset Autosomal Dominant AD (EO-ADAD). Objective: To analyze the association between nutritional status and other clinical and sociodemographic characteristics in individuals with a genetic form of EO-ADAD. Design settings and participants: Cross-sectional study with 75 non-institutionalized participants from a cohort of Autosomal Dominant AD (13 with mild cognitive impairment and 61 with dementia, ages from 38 to 67 years) underwent a structured clinical assessment with emphasis on nutritional status. Measurements: Primary outcome was nutritional status and it was measured using the Mini Nutritional Assessment (MNA). Patients were categorized according to MNA total score, as undernourished (MNA ≤23.5) and well-nourished (MNA ≥ 24). Sociodemographic and clinical variables identified as potential predictors or confounders of nutritional status were also collected. Results: Undernourishment by MNA was present in 57.3% of the sample. Forty-two percent of participants had abnormal BMI values considered lower than 18.5 or higher than 24.9 kg/m2. Total BMI values were similar in well and undernourished patients (median 24.2 IQR 3.59 and median 23.9 IQR 4.42, respectively, p=0.476). When comparing well and undernourished groups, we found statistically significant differences for variables: severity of dementia (p=0.034), frailty (p=0.001), multimorbidity (p=0.035) and, polymedication (p=0.045). Neither adjusted logistic regression nor the Poisson regression showed that any clinical or sociodemographic variables explained undernourishment. Conclusions: Undernourishment was a frequent finding in our sample of EO-ADAD, especially in later stages of the disease. Patients with polymedication, multimorbidity, frailty and severe dementia show differences in their nutritional status with a tendency to be more frequently undernourished. Further studies with larger sample sizes are needed to establish this association.
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BACKGROUND AND OBJECTIVES: Parkinson's disease is a neurological disorder that affects the motor system producing lack of coordination, resting tremor, and rigidity. Impairments in handwriting are among the main symptoms of the disease. Handwriting analysis can help in supporting the diagnosis and in monitoring the progress of the disease. This paper aims to evaluate the importance of different groups of features to model handwriting deficits that appear due to Parkinson's disease; and how those features are able to discriminate between Parkinson's disease patients and healthy subjects. METHODS: Features based on kinematic, geometrical and non-linear dynamics analyses were evaluated to classify Parkinson's disease and healthy subjects. Classifiers based on K-nearest neighbors, support vector machines, and random forest were considered. RESULTS: Accuracies of up to 93.1% were obtained in the classification of patients and healthy control subjects. A relevance analysis of the features indicated that those related to speed, acceleration, and pressure are the most discriminant. The automatic classification of patients in different stages of the disease shows κ indexes between 0.36 and 0.44. Accuracies of up to 83.3% were obtained in a different dataset used only for validation purposes. CONCLUSIONS: The results confirmed the negative impact of aging in the classification process when we considered different groups of healthy subjects. In addition, the results reported with the separate validation set comprise a step towards the development of automated tools to support the diagnosis process in clinical practice.
Assuntos
Escrita Manual , Doença de Parkinson/fisiopatologia , Máquina de Vetores de Suporte , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Fenômenos Biomecânicos , Aprendizado Profundo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Dinâmica não Linear , Reconhecimento Automatizado de Padrão , Reprodutibilidade dos Testes , TremorRESUMO
The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.
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Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Adolescente , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Doenças Assintomáticas , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Criança , Colômbia , Imagem de Tensor de Difusão , Progressão da Doença , Eletroencefalografia , Etilenoglicóis , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único , Adulto JovemRESUMO
The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) trial evaluates the anti-amyloid-ß antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed pre-screening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.
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Doença de Alzheimer/diagnóstico , Doença de Alzheimer/prevenção & controle , Anticorpos Monoclonais/uso terapêutico , Predisposição Genética para Doença , Seleção de Pacientes , Adulto , Doença de Alzheimer/genética , Anticorpos Monoclonais Humanizados , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-1/genética , Sistema de Registros , Inquéritos e Questionários , Cooperação e Adesão ao TratamentoRESUMO
INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease that affects small vessels and presents with vascular episodes, neuropsychiatric disorders, migraine and cognitive impairment. The cognitive disorder varies according to the time elapsed since onset. It is a condition with a subcortical origin related to executive dysfunction, slowing, attention-related disorders and memory disorders. AIM: To define the cognitive characteristics in two neuropsychological evaluations of carriers of Notch3 gene mutations as compared to non-carriers belonging to Colombian families with CADASIL. SUBJECTS AND METHODS: The study followed a longitudinal, retrospective design with 140 participants, including both carriers and non-carriers of the mutation. Cognitive performance was analysed by comparing the first and the last neuropsychological evaluation carried out on each subject at a four-year interval. RESULTS: There were statistically significant differences (p < 0.05) between the two groups in the last evaluation, but only in some tests. Carriers and non-carriers did not display any significant changes between the first and the last evaluation. CONCLUSIONS: No differences were found between both groups in the two evaluations. Cognitive impairment is not observed with the passage of time in carriers, probably owing to the fact that most of them were young, asymptomatic subjects. We believe that four years' follow-up is not enough time to observe a significant progression in the alterations affecting the cognitive functions in carriers of mutations in the Notch3 gene, which causes CADASIL. We also consider that more sensitive cognitive tools are needed to perform the neuropsychological evaluation.
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CADASIL/psicologia , Transtornos Cognitivos/etiologia , Adulto , CADASIL/epidemiologia , CADASIL/genética , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Colômbia/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Exame Neurológico , Testes Neuropsicológicos , Mutação Puntual , Receptor Notch3 , Receptores Notch/genética , Estudos RetrospectivosRESUMO
INTRODUCTION: Alzheimer's disease (AD) is an important public health problem due to its disabling character and high individual, familial and social costs. The CERAD neuropsychological battery has been widely used for evaluation and diagnosis of the cognitive deficit associated with AD. This instrument has been adapted to the Colombian culture (CERAD-Col) for the Neurosciences Group. SUBJECTS AND METHODS: A study was carried out to establish the validity and reliability of the CERAD-Col in Colombian, Spanish-speaking individuals aged 50 years or more. It included 151 controls and 151 AD patients. Controls were selected from a convenience sample of 848 adults aged 50 years or more. The construct validity was determined in three ways: 1) factorial analysis; 2) correlation with the functional scales FAST and GDS (convergent-type validity) and, 3) comparison between the two groups. Internal consistency was determined by means of Cronbach's alpha coefficient. RESULTS: Three factors -memory, language and praxis- explained 88% of the total variance. Moderate but statistically significant correlations were found between neuropsychological tests and functional scales. Internal consistency and test-retest reproducibility were high. The AD group exhibited significantly lower scores (p < 0.05) than the control one. CONCLUSION: CERAD-Col is valid and reliable for the diagnosis of AD in Colombian Spanish-speaking population aged 50 years or more.
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Doença de Alzheimer/psicologia , Testes Neuropsicológicos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Colômbia/epidemiologia , Feminino , Humanos , Testes de Linguagem , Masculino , Transtornos da Memória/epidemiologia , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Desempenho Psicomotor , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: Specific developmental language disorder (SDLD) is a diagnostic entity in which language is expected to be the only cognitive function that is affected. Nevertheless, difficulties in other cognitive functions may also appear, either because the language disorder is an expression of an underlying condition or because the retarded language development gives rise to cognitive deficits in general. AIM: To determine whether there are any differences in the cognitive performance of children with SDLD and that of children who have developed normally. SUBJECTS AND METHODS: The study involved a sample of 51 children with SDLD, aged between 6 and 16 years, and 49 children in a control group, who were paired by chronological age, sex and socioeconomic level. Verbal cognitive capacity, attention, memory, visual-constructional and executive functioning were all evaluated. RESULTS: Statistically and clinically significant differences were found in the verbal-type skills, such as language comprehension and verbal cognitive capacity, which showed effect sizes of -1.31 and -1.33, respectively. In the other functions that were assessed, the performance of the SDLD group was slightly lower than that of the control group, but with no clinically significant differences. CONCLUSION: These findings show that the group of children with SDLD was well selected, since the only differences between the two groups involve linguistic aspects; moreover, this evidence supports the idea that language and other cognitive functions are relatively independent and that a language disorder would only generate an unspecific general effect in the other cognitive functions.
Assuntos
Cognição/fisiologia , Transtornos do Desenvolvimento da Linguagem , Desenvolvimento da Linguagem , Adolescente , Criança , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Testes NeuropsicológicosRESUMO
INTRODUCTION: Sperry, or interhemispheric disconnection, syndrome was reported in patients who had undergone surgical section of the corpus callosum carried out in an attempt to control medication-resistant epilepsy. It has occasionally been linked to tumours of the corpus callosum and, although even more rarely, it has also been associated to an amnesic syndrome. In this paper we report the anatomical and neuropsychological findings in a patient with interhemispheric disconnection syndrome associated to a hippocampal-type amnesic syndrome, caused by a tumour in the splenius of the corpus callosum that extended into the fornix. CASE REPORT: A 52-year-old white male who visited because of loss of memory; on admission to hospital the physical examination revealed a certain degree of asomatognosia with regard to the left-hand side of the body. An axial tomography brain scan showed a dense central lesion in the brain that extended laterally and occluded the body of both lateral ventricles. A biopsy study revealed an undifferentiated astrocytoma that affected the corpus callosum and the fornix. CONCLUSIONS: Sperry, or interhemispheric disconnection, syndrome produced by a tumour in the splenius of the corpus callosum is very likely to course with an amnesic syndrome due to disconnection caused by destruction of the fornix. This association, which characterised our patient's clinical picture, has only previously been described in three cases.
Assuntos
Amnésia Anterógrada , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Córtex Cerebral/patologia , Corpo Caloso/patologia , Fórnice/patologia , Amnésia Anterógrada/etiologia , Amnésia Anterógrada/fisiopatologia , Astrocitoma/complicações , Neoplasias Encefálicas/complicações , Córtex Cerebral/anatomia & histologia , Corpo Caloso/anatomia & histologia , Corpo Caloso/fisiologia , Evolução Fatal , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiologia , Testes Neuropsicológicos , SíndromeRESUMO
INTRODUCTION: Available treatments for Alzheimer disease allow that early diagnosis become an important issue, because treatment only are useful during the earliest stage, especially during the mild cognitive impairment (MCI), when the most of the cognitive function is preserved. AIM: To observe the performance on a shortened version of a Semantic Cue Recall Memory Test (SCRMT) from a group of adult aged over 50 years old, living in Medellin city and with dementia of Alzheimer type (DAT). SUBJECTS AND METHODS: The sample was constituted by 30 patients with DAT, 30 with MCI, and 59 healthy controls, which were matched by socio economic strata and school achievement. The SCRMT was administered to the sample. For the analyses two groups of age (50-69 and over 70 years) were conformed. RESULTS: Comparisons statistically significant differences between the groups (p < 0.05). The scores were not significant affected by age. A combination of low scores with the presence of intrusions on the free, immediate cue, and delay cue recalls suggested the diagnosis of DAT, which allow recommending a complete neuropsychological assessment. Statistically significant differences were preserved when the groups were divided by age. The effect of the gender could not determine because the small size of the male sample. CONCLUSION: The shortened version of the SCMRT would appear be useful for the DAT diagnosis.