DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKMζ.

Protein kinase M zeta, PKMζ, is a brain enriched kinase with a well characterized role in Long-Term Potentiation (LTP), the activity-dependent strengthening of synapses involved in long-term memory formation. However, little is known about the molecular mechanisms that maintain the tissue specificity of this kinase. Here, we characterized the epigenetic factors, mainly DNA methylation, regulating PKMζ expression in the human brain. The PRKCZ gene has an upstream promoter regulating Protein kinase C ζ (PKCζ), and an internal promoter driving PKMζ expression. A demethylated region, including a canonical CREB binding site, situated at the internal promoter was only observed in human CNS tissues. The induction of site-specific hypermethylation of this region resulted in decreased CREB1 binding and downregulation of PKMζ expression. Noteworthy, CREB binding sites were absent in the upstream promoter of PRKCZ locus, suggesting a specific mechanism for regulating PKMζ expression. These observations were validated using a system of human neuronal differentiation from induced pluripotent stem cells (iPSCs). CREB1 binding at the internal promoter was detected only in differentiated neurons, where PKMζ is expressed. The same epigenetic mechanism in the context of CREB binding site was identified in other genes involved in neuronal differentiation and LTP. Additionally, aberrant DNA hypermethylation at the internal promoter was observed in cases of Alzheimer's disease, correlating with decreased expression of PKMζ in patient brains. Altogether, we present a conserved epigenetic mechanism regulating PKMζ expression and other genes enhanced in the CNS with possible implications in neuronal differentiation and Alzheimer's disease.

Association between health literacy and glycemic control in elderly patients with type 2 diabetes and modifying effect of social support.

OBJECTIVE: To investigate the association between inadequate functional health literacy, considering the Short Assessment of Health Literacy for Portuguese-speaking Adults, and glycemic control in elderly patients with type 2 diabetes, and to examine this association in low social support settings, according to Medical Outcomes Study . METHODS: Cross-sectional study conducted at the diabetes referral center of a university hospital. Participants were recruited among type 2 diabetes patients aged 60 years or older, between May 2013 and November 2014. The primary outcome was the most recent glycated hemoglobin value measured within the last 6 months. RESULTS: A total of 398 elderly patients with type 2 diabetes were evaluated. Of these, 232 were not eligible to participate. The final sample comprised 166 participants. Hierarchical multiple linear regression was performed. The following variables were entered in three blocks: sociodemographic characteristics, clinical variables and health literacy scores. Regression analysis of the interaction between health literacy and social support as a determinant of glycemic control was also performed. Mean age of subjects was 68.0 years (standard deviation of 5.9). Mean glycated hemoglobin value was 8.5% (standard deviation of 1.4). Short assessment of health literacy for Portuguese speaking adults score was independently associated with glycated hemoglobin (B=-0.059; p=0.043). The interaction between social support and health literacy score (p=0.003) was a determinant of glycemic control. CONCLUSION: Health literacy is associated with glycemic control. Social support may modify the relation between health literacy and glycemic control.

Association between health literacy and glycemic control in elderly patients with type 2 diabetes and modifying effect of social support / Associação entre alfabetismo em saúde e controle glicêmico em idosos com diabetes tipo 2 e efeito modificador do suporte social

ABSTRACT Objective: To investigate the association between inadequate functional health literacy, considering the Short Assessment of Health Literacy for Portuguese-speaking Adults, and glycemic control in elderly patients with type 2 diabetes, and to examine this association in low social support settings, according to Medical Outcomes Study . Methods: Cross-sectional study conducted at the diabetes referral center of a university hospital. Participants were recruited among type 2 diabetes patients aged 60 years or older, between May 2013 and November 2014. The primary outcome was the most recent glycated hemoglobin value measured within the last 6 months. Results: A total of 398 elderly patients with type 2 diabetes were evaluated. Of these, 232 were not eligible to participate. The final sample comprised 166 participants. Hierarchical multiple linear regression was performed. The following variables were entered in three blocks: sociodemographic characteristics, clinical variables and health literacy scores. Regression analysis of the interaction between health literacy and social support as a determinant of glycemic control was also performed. Mean age of subjects was 68.0 years (standard deviation of 5.9). Mean glycated hemoglobin value was 8.5% (standard deviation of 1.4). Short assessment of health literacy for Portuguese speaking adults score was independently associated with glycated hemoglobin (B=-0.059; p=0.043). The interaction between social support and health literacy score (p=0.003) was a determinant of glycemic control. Conclusion: Health literacy is associated with glycemic control. Social support may modify the relation between health literacy and glycemic control.

RESUMO Objetivo: Verificar a associação entre alfabetismo em saúde inadequado, segundo o Short Assessment of Health Literacy for Portuguese-speaking Adults , e controle glicêmico, em pacientes idosos com diabetes tipo 2, bem como avaliar tal associação no contexto de baixo suporte social, segundo o Medical Outcomes Study . Métodos: Estudo transversal conduzido no centro de referência de diabetes de um hospital universitário. Os participantes foram recrutados entre pacientes com diabetes tipo 2 com idade de 60 anos ou mais, entre maio de 2013 e novembro de 2014. O desfecho primário foi o valor mais recente de hemoglobina glicada obtido nos últimos 6 meses. Resultados: Foram avaliados 398 pacientes idosos com diabetes tipo 2. Destes, 232 não foram considerados elegíveis para participar da pesquisa. A amostra final incluiu 166 participantes. Foi realizada análise de regressão linear múltipla hierárquica com as seguintes variáveis inseridas em três blocos: características sociodemográficas, variáveis clínicas e escore de alfabetismo em saúde. Realizou-se também uma análise de regressão adicional da interação entre alfabetismo em saúde e apoio social como determinante do controle glicêmico. A média de idade dos indivíduos foi 68,0 anos (desvio-padrão de 5,9). O valor médio de hemoglobina glicada foi de 8,5% (desvio-padrão de 1,4). O Short Assessment of Health Literacy for Portuguese-speaking Adults mostrou-se independentemente associado à hemoglobina glicada (B=-0,059; p=0,043). A interação entre suporte social e escore de alfabetismo em saúde (p=0,003) foi determinante para o controle glicêmico. Conclusão: O alfabetismo em saúde está associado ao controle glicêmico. O suporte social pode modificar a relação entre o escore de alfabetismo em saúde e o controle glicêmico.

Initial findings of striatum tripartite model in OCD brain samples based on transcriptome analysis.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions. Different striatal subregions belonging to the cortico-striato-thalamic circuitry (CSTC) play an important role in the pathophysiology of OCD. The transcriptomes of 3 separate striatal areas (putamen (PT), caudate nucleus (CN) and accumbens nucleus (NAC)) from postmortem brain tissue were compared between 6 OCD and 8 control cases. In addition to network connectivity deregulation, different biological processes are specific to each striatum region according to the tripartite model of the striatum and contribute in various ways to OCD pathophysiology. Specifically, regulation of neurotransmitter levels and presynaptic processes involved in chemical synaptic transmission were shared between NAC and PT. The Gene Ontology terms cellular response to chemical stimulus, response to external stimulus, response to organic substance, regulation of synaptic plasticity, and modulation of synaptic transmission were shared between CN and PT. Most genes harboring common and/or rare variants previously associated with OCD that were differentially expressed or part of a least preserved coexpression module in our study also suggest striatum subregion specificity. At the transcriptional level, our study supports differences in the 3 circuit CSTC model associated with OCD.

Is Olfactory Epithelium Biopsy Useful for Confirming Alzheimer's Disease?

OBJECTIVES: The clinical symptoms of Alzheimer's disease (AD) are preceded by a long asymptomatic period associated with "silent" deposition of aberrant paired helical filament (PHF)-tau and amyloid-beta proteins in brain tissue. Similar depositions have been reported within the olfactory epithelium (OE), a tissue that can be biopsied in vivo. The degree to which such biopsies are useful in identifying AD is controversial. This postmortem study had 3 main goals: first, to quantify the relative densities of AD-related proteins in 3 regions of the olfactory neuroepithelium, namely, the nasal septum, middle turbinate, and superior turbinate; second, to establish whether such densities are correlated among these epithelial regions as well as with semi-quantitative ratings of general brain cortex pathology; and third, to evaluate correlations between the protein densities and measures of antemortem cognitive function. METHODS: Postmortem blocks of olfactory mucosa were obtained from 12 AD cadavers and 24 controls and subjected to amyloid-beta and PHF-tau immunohistochemistry. RESULTS: We observed marked heterogeneity in the presence of the biomarkers of tau and amyloid-beta among the targeted olfactory epithelial regions. No significant difference was observed between the cadavers with AD and the controls regarding the concentration of these proteins in any of these epithelial regions. Only one correlation significant was evident, namely, that between the tau protein densities of the middle and the upper turbinate (r = .58, P = .002). CONCLUSION: AD-related biomarker heterogeneity, which has not been previously demonstrated, makes comparisons across studies difficult and throws into question the usefulness of OE amyloid-beta and PHF-tau biopsies in detecting AD.

Layer-specific reduced neuronal density in the orbitofrontal cortex of older adults with obsessive-compulsive disorder.

Neurobiological models have provided consistent evidence of the involvement of cortical-subcortical circuitry in obsessive-compulsive disorder (OCD). The orbitofrontal cortex (OFC), involved in motivation and emotional responses, is an important regulatory node within this circuitry. However, OFC abnormalities at the cellular level have so far not been studied. To address this question, we have recruited a total of seven senior individuals from the Sao Paulo Autopsy Services who were diagnosed with OCD after an extensive post-mortem clinical evaluation with their next of kin. Patients with cognitive impairment were excluded. The OCD cases were age- and sex-matched with 7 control cases and a total of 14 formalin-fixed, serially cut, and gallocyanin-stained hemispheres (7 subjects with OCD and 7 controls) were analyzed stereologically. We estimated laminar neuronal density, volume of the anteromedial (AM), medial orbitofrontal (MO), and anterolateral (AL) areas of the OFC. We found statistically significant layer- and region-specific lower neuron densities in our OCD cases that added to a deficit of 25% in AM and AL and to a deficit of 21% in MO, respectively. The volumes of the OFC areas were similar between the OCD and control groups. These results provide evidence of complex layer and region-specific neuronal deficits/loss in old OCD cases which could have a considerable impact on information processing within orbitofrontal regions and with afferent and efferent targets.

APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults.

INTRODUCTION: Apolipoprotein E (APOE) is a susceptibility gene for late-onset Alzheimer's disease neuropathology; less is known about the relationship between APOE and cerebrovascular disease (CVD) neuropathology. METHODS: We investigated associations of APOE status with arteriolosclerosis, macroinfarcts and microinfarcts, and atherosclerosis in 1383 adults (65.9-108.2 years at death) with and without dementia. Excluding ε2/ε4 carriers, multivariable regressions for each CVD-related neuropathology compared ε4 and ε2 carriers to ε3/ε3 carriers adjusting for confounders including age and Alzheimer's neuropathology. RESULTS: Three hundred forty-two individuals (24.7%; ∼87.7 years at death; 39.9% nondemented) were ε3/ε4 or ε4/ε4, and 180 (13.0%; ∼89.9 years at death; 66.6% nondemented) were ε2/ε3 or ε2/ε2. ε4 carriers had higher odds of macroinfarcts (odds ratio = 1.41, 95% confidence interval: 1.02-1.94, P = .03), whereas ε2 carriers had higher odds of moderate-to-severe arteriolosclerosis (odds ratio = 1.68, 95% confidence interval: 1.15-2.45, P = .006) compared to ε3/ε3 carriers. Age-stratified analyses suggested that these relationships were driven by ε4 carriers <90 years at death and ε2 carriers ≥90 years at death, respectively. DISCUSSION: APOE differentially affects type and timing of CVD-related neuropathology.

Factors associated with brain volume in major depression in older adults without dementia: results from a large autopsy study.

OBJECTIVE: We examined brain volume and atrophy in individuals with major depressive disorder (MDD) without dementia that were referred to a large autopsy service. We also examined potential risk factors for brain atrophy, including demographics and clinical variables. METHODS: In this study, 1373 participants (787 male) aged 50 years or older who died from natural causes were included. Participants with no reliable informant, with cognitive impairment or dementia, with a medical history of severe chronic disease, or with prolonged agonal state were excluded. Presence of MDD at least once in their lifetime was defined according to the Structured Clinical Interview for DSM. Brain volume was measured immediately after removal from the skull. RESULTS: Mean age at death was 68.6 ± 11.6, and MDD was present in 185 (14%) individuals. Smaller brain volume was associated with older age (p < 0.001), lower education (years; p < 0.001), hypertension (p = 0.001), diabetes (p = 0.006), and female gender (p < 0.001). In the multivariate analysis adjusted for sociodemographics and cardiovascular risk factors, smaller brain volume was not associated with major depression (ß = -0.86, 95% CI = -26.50 to 24.77, p = 0.95). CONCLUSIONS: In this large autopsy study of older adults, MDD was not associated with smaller brain volumes. Regardless of the presence of MDD, in this sample of older adults without dementia, we found that smaller brain volumes were associated with risk factors for brain neurodegeneration such as older age, diabetes, hypertension, and lower education. Copyright © 2017 John Wiley & Sons, Ltd.

Diabetes is Not Associated with Alzheimer's Disease Neuropathology.

BACKGROUND: Previous evidence linking diabetes to Alzheimer's disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries. OBJECTIVE: To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults. METHODS: In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. A standardized neuropathological examination was performed using immunohistochemistry. The associations of diabetes with Consortium to Establish and Registry for Alzheimer Disease (CERAD) scores for neuritic plaques and Braak-Braak (BB) scores for neurofibrillary tangles were investigated using multivariable ordinal logistic regression. We investigated effect modification of education, race, and APOE on these associations. RESULTS: Among 1,037 subjects (mean age = 74.4±11.5 y; mean education = 4.0±3.7 y; 48% male, 61% White), diabetes was present in 279 subjects. Diabetes was not associated with BB (OR = 1.12, 95% CI = 0.81-1.54, p = 0.48) or with CERAD (OR = 0.97, 95% CI = 0.68-1.38, p = 0.86) scores on analyses adjusted for sociodemographic and clinical variables. We observed effect modification by the APOE allele ɛ4 on the association between diabetes mellitus and BB scores. CONCLUSION: No evidence of an association between diabetes and AD neuropathology was found in a large sample of Brazilians; however, certain subgroups, such as APOE allele ɛ4 carriers, had higher odds of accumulation of neurofibrillary tangles.

Applicability of the Spoken Knowledge in Low Literacy Patients with Diabetes in Brazilian elderly / Aplicabilidade do Spoken Knowledge in Low Literacy Patients with Diabetes em idosos brasileiros

ABSTRACT Objective To translate, adapt and evaluate the properties of a Brazilian Portuguese version of the Spoken Knowledge in Low Literacy Patients with Diabetes, which is a questionnaire that evaluate diabetes knowledge. Methods A cross-sectional study with type 2 diabetes patients aged ≥60 years, seen at a public healthcare organization in the city of Sao Paulo (SP). After the development of the Portuguese version, we evaluated the psychometrics properties and the association with sociodemographic and clinical variables. The regression models were adjusted for sociodemographic data, functional health literacy, duration of disease, use of insulin, and glycemic control. Results We evaluated 129 type 2 diabetic patients, with mean age of 75.9 (±6.2) years, mean scholling of 5.2 (±4.4) years, mean glycosylated hemoglobin of 7.2% (±1.4), and mean score on Spoken Knowledge in Low Literacy Patients with Diabetes of 42.1% (±25.8). In the regression model, the variables independently associated to Spoken Knowledge in Low Literacy Patients with Diabetes were schooling (B=0.193; p=0.003), use of insulin (B=1.326; p=0.004), duration of diabetes (B=0.053; p=0.022) and health literacy (B=0.108; p=0.021). The determination coefficient was 0.273. The Cronbach a was 0.75, demonstrating appropriate internal consistency. Conclusion This translated version of the Spoken Knowledge in Low Literacy Patients with Diabetes showed to be adequate to evaluate diabetes knowledge in elderly patients with low schooling levels. It presented normal distribution, adequate internal consistency, with no ceiling or floor effect. The tool is easy to be used, can be quickly applied and does not depend on reading skills.

RESUMO Objetivo Traduzir, adaptar e avaliar as propriedades de uma versão, em português do Brasil, do Spoken Knowledge in Low Literacy Patients with Diabetes, um questionário que avalia conhecimento em diabetes. Métodos Estudo transversal, em diabéticos tipo 2, com idade ≥60 anos de uma instituição pública de saúde, em São Paulo (SP). Após o desenvolvimento da versão na língua portuguesa, foram avaliadas suas propriedades psicométricas e associação com variáveis sociodemográficas e clínicas. Os modelos de regressão foram ajustados para dados sociodemográficos, alfabetismo funcional em saúde, tempo de doença, uso de insulina e controle glicêmico. Resultados Foram avaliados 129 diabéticos, com média de idade de 75,9 (±6,2) anos, escolaridade média de 5,2 (±4,4) anos, hemoglobina glicada média de 7,2% (±1,4) e valor médio do Spoken Knowledge in Low Literacy Patients with Diabetes de 42,1% (±25,8). No modelo de regressão, as variáveis associadas de forma independente ao Spoken Knowledge in Low Literacy Patients with Diabetes foram escolaridade (B=0,193; p=0,003), uso de insulina (B=1,326; p=0,004), tempo de doença (B=0,053; p=0,022) e alfabetismo em saúde (B=0,108; p=0,021). O coeficiente de determinação foi de 0,273. O a de Cronbach apresentou valor de 0,75, revelando consistência interna adequada. Conclusão Esta versão traduzida do Spoken Knowledge in Low LiteraFcy Patients with Diabetes mostrou-se adequada para avaliar conhecimentos em diabetes em idosos de baixa escolaridade, apresentando distribuição normal, consistência interna adequada, sem a presença de efeito teto ou chão. O instrumento teve boa aplicabilidade, já que pôde ser administrado de maneira rápida e não depende da capacidade de leitura.

Association between adiposity and systemic atherosclerosis: a protocol of a cross-sectional autopsy study.

INTRODUCTION: Adiposity has been associated with atherosclerosis in clinical studies. However, few autopsy studies have investigated this association, and they had only examined the coronary artery disease. Moreover, most studies had small sample sizes and were limited to middle-aged or young adults. Our aim is to investigate the association between adiposity and systemic atherosclerosis in an autopsy study. METHODS AND ANALYSIS: A sample of 240 deceased with 30 years or more will be evaluated. The sample size was calculated using the lowest correlation coefficient found in previous studies (r=0.109), assuming a power of 90% and α=0.05. We will collect information about sociodemographics, frequency of previous contact of the deceased's next of kin and cardiovascular risk factors. We will measure neck, waist and hip circumferences, weight, height and abdominal subcutaneous tissue thickness, and then we will calculate the body mass index, waist-to-hip ratio, waist-to-height ratio and body shape index. We will also weigh the pericardial and abdominal visceral fat, the heart, and we will measure the left ventricular wall thickness. We will evaluate the presence of myocardial infarction, the degree of atherosclerosis in the aorta, carotid, coronary and cerebral arteries and plaque composition in carotid, coronary and cerebral arteries. For each individual, we will fix arterial and adipose tissue samples in 10% formalin and freeze another adipose tissue sample at -80°C for future studies. ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee of University of Sao Paulo Medical School, Brazil. Results will be submitted for publication in a peer-reviewed journal.

Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study.

Argyrophilic grain disease (AGD) is a frequent late-onset, 4-repeat tauopathy reported in Caucasians with high educational attainment. Little is known about AGD in non-Caucasians or in those with low educational attainment. We describe AGD demographics, clinical, and neuropathological features in a multiethnic cohort of 983 subjects ≥50 years of age from São Paulo, Brazil. Clinical data were collected through semistructured interviews with an informant and included in the Informant Questionnaire on Cognitive Decline in the Elderly, the Clinical Dementia Rating, and the Neuropsychiatric Inventory. Neuropathologic assessment relied on internationally accepted criteria. AGD was frequent (15.2%) and was the only neuropathological diagnosis in 8.9% of all cases (mean, 78.9 ± 9.4 years); it rarely occurred as an isolated neuropathological finding. AGD was associated with older age, lower socioeconomic status (SES), and appetite disorders. This is the first study of demographic, clinical, and neuropathological aspects of AGD in different ethnicities and subjects from all socioeconomic strata. The results suggest that prospective studies of AGD patients include levels of hormones related to appetite control as possible antemortem markers. Moreover, understanding the mechanisms behind higher susceptibility to AGD of low SES subjects may disclose novel environmental risk factors for AGD and other neurodegenerative diseases.

Applicability of the Spoken Knowledge in Low Literacy Patients with Diabetes in Brazilian elderly.

OBJECTIVE: To translate, adapt and evaluate the properties of a Brazilian Portuguese version of the Spoken Knowledge in Low Literacy Patients with Diabetes, which is a questionnaire that evaluate diabetes knowledge. METHODS: A cross-sectional study with type 2 diabetes patients aged ≥60 years, seen at a public healthcare organization in the city of Sao Paulo (SP). After the development of the Portuguese version, we evaluated the psychometrics properties and the association with sociodemographic and clinical variables. The regression models were adjusted for sociodemographic data, functional health literacy, duration of disease, use of insulin, and glycemic control. RESULTS: We evaluated 129 type 2 diabetic patients, with mean age of 75.9 (±6.2) years, mean scholling of 5.2 (±4.4) years, mean glycosylated hemoglobin of 7.2% (±1.4), and mean score on Spoken Knowledge in Low Literacy Patients with Diabetes of 42.1% (±25.8). In the regression model, the variables independently associated to Spoken Knowledge in Low Literacy Patients with Diabetes were schooling (B=0.193; p=0.003), use of insulin (B=1.326; p=0.004), duration of diabetes (B=0.053; p=0.022) and health literacy (B=0.108; p=0.021). The determination coefficient was 0.273. The Cronbach a was 0.75, demonstrating appropriate internal consistency. CONCLUSION: This translated version of the Spoken Knowledge in Low Literacy Patients with Diabetes showed to be adequate to evaluate diabetes knowledge in elderly patients with low schooling levels. It presented normal distribution, adequate internal consistency, with no ceiling or floor effect. The tool is easy to be used, can be quickly applied and does not depend on reading skills. OBJETIVO: Traduzir, adaptar e avaliar as propriedades de uma versão, em português do Brasil, do Spoken Knowledge in Low Literacy Patients with Diabetes, um questionário que avalia conhecimento em diabetes. MÉTODOS: Estudo transversal, em diabéticos tipo 2, com idade ≥60 anos de uma instituição pública de saúde, em São Paulo (SP). Após o desenvolvimento da versão na língua portuguesa, foram avaliadas suas propriedades psicométricas e associação com variáveis sociodemográficas e clínicas. Os modelos de regressão foram ajustados para dados sociodemográficos, alfabetismo funcional em saúde, tempo de doença, uso de insulina e controle glicêmico. RESULTADOS: Foram avaliados 129 diabéticos, com média de idade de 75,9 (±6,2) anos, escolaridade média de 5,2 (±4,4) anos, hemoglobina glicada média de 7,2% (±1,4) e valor médio do Spoken Knowledge in Low Literacy Patients with Diabetes de 42,1% (±25,8). No modelo de regressão, as variáveis associadas de forma independente ao Spoken Knowledge in Low Literacy Patients with Diabetes foram escolaridade (B=0,193; p=0,003), uso de insulina (B=1,326; p=0,004), tempo de doença (B=0,053; p=0,022) e alfabetismo em saúde (B=0,108; p=0,021). O coeficiente de determinação foi de 0,273. O a de Cronbach apresentou valor de 0,75, revelando consistência interna adequada. CONCLUSÃO: Esta versão traduzida do Spoken Knowledge in Low LiteraFcy Patients with Diabetes mostrou-se adequada para avaliar conhecimentos em diabetes em idosos de baixa escolaridade, apresentando distribuição normal, consistência interna adequada, sem a presença de efeito teto ou chão. O instrumento teve boa aplicabilidade, já que pôde ser administrado de maneira rápida e não depende da capacidade de leitura.

Higher Prevalence of TDP-43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample.

Transactive response DNA binding protein 43 (TDP-43) proteinopathy is the major hallmark of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. It is also present in a subset of Alzheimer's disease cases. Recently, few reports showed TDP-43 changes in cognitively normal elderly. In Caucasians, TDP-43 proteinopathy independently correlate with cognitive decline. However, it is challenging to establish direct links between cognitive and/or neuropsychiatric symptoms and protein inclusions in neurodegenerative diseases because individual cognitive reserves modify the threshold for clinical disease expression. Cognitive reserve is influenced by demographic, environmental and genetic factors. We investigated the relationships between demographic, clinical and neuropathological variables and TDP-43 proteinopathy in a large multiethnic sample of cognitively normal elderly. TDP-43 proteinopathy was identified in 10.5%, independently associated with older age (P = 0.03) and Asian ethnicity (P = 0.002). Asians showed a higher prevalence of TDP-43 proteinopathy than Caucasians, even after adjustment for sex, age, Braak stage and schooling (odds ratio = 3.50, confidence interval 1.41-8.69, P = 0.007). These findings suggested that Asian older adults may be protected from the clinical manifestation of brain TDP-43 proteinopathy. Future studies are needed to identify possible race-related protective factors against clinical expression of TDP-43 proteinopathies.

Validity of the Katz Index to assess activities of daily living by informants in neuropathological studies / Validade do índice de katz para avaliar atividades básicas de vida diária por informantes em estudos neuropatológicos / Validez del índice de katz para evaluar las actividades básicas de vida diaria por informantes en estudios neuropatológicos

Abstract OBJECTIVE To analyze the evidences of construct validity of the Katz Index for the retrospective assessment of activities of daily living (ADL) by informants, to assist neuropathological studies in the elderly. METHOD A cross-sectional study analyzed the functional ability of ADL measure by the Katz Index, of 650 cases randomly selected from the Brazilian Brain Bank of the Ageing Brain Study Group (BBBABSG) database. Sample was divided in two subsamples for the analysis (N=325, each) and then stratified according to cognitive decline assessed by the Clinical Dementia Rating Scale (CDR). Factor analyses with calculations of internal consistency and invariance were performed. RESULTS Factor analysis evidenced a unidimensional instrument with optimal internal consistency, in all subgroups. Goodness of fit indices were obtained after two treatments of covariance, indicating adequacy of the scale for assessing ADL by informants. The scale is invariant to cognitive decline meaning that it can be used for subjects with or without cognitive impairment. CONCLUSION Katz Index is valid for the retrospective assessment of basic ADL by informants, with optimal reliability.

Resumo OBJETIVO Analisar as evidências de validade de constructo do Índice de Katz para a avaliação retrospectiva das Atividades Básicas de Vida Diária (AbVD) por informantes, para apoiar estudos neuropatológicos no envelhecimento. MÉTODO Por meio de estudo transversal foi analisada a capacidade funcional para as AbVD mensurada pelo Índice de Katz em 650 casos randomizados das bases de dados do Banco de Encéfalos Humanos do Grupo de Estudos em Envelhecimento Cerebral (BEHGEEC). A amostra foi particionada em duas subamostras para as análises (N=325, cada) e então estratificada de acordo com o comprometimento cognitivo determinado pelo Escore Clínico de Demência (CDR). Foram realizadas análise fatorial, de consistência interna e de invariância. RESULTADOS A análise fatorial evidenciou um instrumento unidimensional com ótima consistência interna, em todos os grupos. Ótimos índices de ajuste foram obtidos após o tratamento de duas covariâncias, indicando adequação da escala para avaliar AbVD por informantes. A escala é invariante para o comprometimento cognitivo, o que significa que pode ser usada em indivíduos com ou sem comprometimento cognitivo. CONCLUSÃO O Índice de Katz apresenta validade de constructo para a avaliação retrospectiva das AbVD por informantes, com confiabilidade.

Resumen OBJETIVO Analizar las evidencias de validez de constructo del Índice de Katz para la evaluación retrospectiva de las Actividades Básicas de Vida Diaria (AbVD) por informantes para apoyar estudios neuropatológicos en el envejecimiento. MÉTODO Por medio de estudio transversal se analizó la capacidad funcional para las AbVD mensurada por el Índice de Katz en 650 casos randomizados de las bases de datos del Banco de Encéfalos Humanos del Grupo de Estudios en Envejecimiento Cerebral (BEHGEEC). La muestra fue dividida en dos submuestras para los análisis (N=325, cada) y luego estratificada de acuerdo con el compromiso cognitivo determinado por la Escala de Clasificación de la Demencia Clínica (CDR). Se hicieron análisis factorial, de consistencia interna y de invariancia. RESULTADOS El análisis factorial evidenció un instrumento unidimensional con excelente consistencia interna, en todos los grupos. Excelentes índices de ajuste fueron obtenidos después del tratamiento de dos covariancias, indicando la adecuación de la escala para evaluar AbVD por informantes. La escala es invariante para el compromiso cognitivo, lo que significa que se puede utilizarla en individuos con o sin compromiso cognitivo. CONCLUSIÓN El Índice de Katz presenta validez de constructo para la evaluación retrospectiva de las AbVD por informantes, con confiabilidad.

Olfaction in Neurologic and Neurodegenerative Diseases: A Literature Review

Introduction Loss of smell is involved in various neurologic and neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. However, the olfactory test is usually neglected by physicians at large. Objective The aim of this study was to review the current literature about the relationship between olfactory dysfunction and neurologic and neurodegenerative diseases. Data Synthesis Twenty-seven studies were selected for analysis, and the olfactory system, olfaction, and the association between the olfactory dysfunction and dementias were reviewed. Furthermore, is described an up to date in olfaction. Conclusion Otolaryngologist should remember the importance of olfaction evaluation in daily practice. Furthermore, neurologists and physicians in general should include olfactory tests in the screening of those at higher risk of dementia. .

Factors associated with morphometric brain changes in cognitively normal aging / Fatores associados às alterações morfométricas encefálicas durante o envelhecimento sem comprometimento cognitivo

ABSTRACT. OBJECTIVE: Cognitive impairment is associated with reductions in brain weight and volume. The factors related to morphometric brain changes in cognitively normal aging remain unknown. We aimed to identify which clinical factors are associated with morphometric brain changes in cognitively normal aging. METHODS: A cross-sectional study of 414 subjects, ≥50 years old submitted to clinical assessment and brain autopsy, after informed consent, was carried out at the São Paulo Autopsy Service, Brazil. Data on cognitive and functional evaluations were collected through structured interview applied to the next-of-kin. Brain weight (g) and volume (mL) measurements were obtained and adjusted for head circumference (cm). Associations between brain weight/volume and related factors were obtained through univariate and multivariate analysis. RESULTS: Participants were predominantly male (60.4%), Caucasian (69%), with mean age of 67.1 ± 10.9 years. Mean brain weight was 1219.2 ± 140.9 g, and mean brain volume was 1217.1 ± 152.3 mL. Head circumference was independently associated with low brain weight (p<0.001) and volume (p<0.001). Total and adjusted brain weight and volume decreased in some conditions. Female gender (p<0.001), hypertension (p<0.009), coronary artery disease (p<0.013) and walking assistance (p<0.011) were associated with lower adjusted brain weight while schooling was associated with higher adjusted brain weight (p<0.003). Female gender (p<0.001), age (p<0.001) and hypertension (p<0.011) were associated with low adjusted brain volume. CONCLUSION: Morphometric brain changes occur despite the absence of cognitive impairment and were predominantly associated with age, female gender, mobility impairment and cardiovascular conditions. Schooling may be a protective factor.

RESUMO. OBJETIVO: O comprometimento cognitivo está associado à redução de massa e volume encefálicos. Fatores associados às alterações morfométricas crânio-encefálicas durante o envelhecimento cerebral normal são escassos. Nosso objetivo foi identificar quais os fatores clínicos associados às alterações morfométricas encefálicas em indivíduos sem comprometimento cognitivo. MÉTODOS: Estudo transversal, realizado no Serviço de Verificação de óbitos da Capital, em São Paulo - Brasil, em que 414 indivíduos, com idade ≥50 anos, foram submetidos à avaliação clínica e autópsia encefálica, após consentimento informado. A avaliação cognitiva e funcional foi obtida por meio da entrevista com familiares. Massa (g) e de volume (mL) encefálicos foram obtidos e ajustados para o perímetro cefálico (cm). A associação entre massa/volume encefálicos e os fatores relacionados (preditores) foi obtida por meio de análise univariada e multivariada. O p-valor foi fixado em 0,05. RESULTADOS: Participantes era em sua maioria homens (60,4%), com idade média de 67,1 ± 10,9 anos, e caucasianos (69%). A média de massa encefálica da amostra foi de 1219,2 ± 140,9 g, e a média do volume foi 1217,1 ± 152,3 mL. Perímetro cefálico esteve independentemente associado à redução de massa (p<0,001) e volume (p<0,001). Massa e volume (total e corrigido) reduziu em algumas condições. Gênero feminino (p<0,001), hipertensão (p<0,009), doença arterial coronariana (p<0,013) e auxílio para deambulação (p<0,011) foram fatores associados à redução da massa encefálica corrigida, enquanto a escolaridade esteve associada com seu aumento (p<0,003). A idade (p<0,001), o gênero feminino (p<0,001) e a hipertensão (p<0,011) estiveram associados à redução no volume encefálico corrigido. CONCLUSÃO: As alterações morfométricas encefálicas ocorrem apesar da inexistência de comprometimento cognitivo e são associadas à idade, ao gênero feminino, às alterações de mobilidade e às doenças cardiovasculares. A escolaridade parece ser um fator protetor.

Olfaction in neurologic and neurodegenerative diseases: a literature review.

Introduction Loss of smell is involved in various neurologic and neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. However, the olfactory test is usually neglected by physicians at large. Objective The aim of this study was to review the current literature about the relationship between olfactory dysfunction and neurologic and neurodegenerative diseases. Data Synthesis Twenty-seven studies were selected for analysis, and the olfactory system, olfaction, and the association between the olfactory dysfunction and dementias were reviewed. Furthermore, is described an up to date in olfaction. Conclusion Otolaryngologist should remember the importance of olfaction evaluation in daily practice. Furthermore, neurologists and physicians in general should include olfactory tests in the screening of those at higher risk of dementia.

Factors associated with morphometric brain changes in cognitively normal aging.

OBJECTIVE: Cognitive impairment is associated with reductions in brain weight and volume. The factors related to morphometric brain changes in cognitively normal aging remain unknown. We aimed to identify which clinical factors are associated with morphometric brain changes in cognitively normal aging. METHODS: A cross-sectional study of 414 subjects, ≥50 years old submitted to clinical assessment and brain autopsy, after informed consent, was carried out at the São Paulo Autopsy Service, Brazil. Data on cognitive and functional evaluations were collected through structured interview applied to the next-of-kin. Brain weight (g) and volume (mL) measurements were obtained and adjusted for head circumference (cm). Associations between brain weight/volume and related factors were obtained through univariate and multivariate analysis. RESULTS: Participants were predominantly male (60.4%), Caucasian (69%), with mean age of 67.1 ± 10.9 years. Mean brain weight was 1219.2 ± 140.9 g, and mean brain volume was 1217.1 ± 152.3 mL. Head circumference was independently associated with low brain weight (p<0.001) and volume (p<0.001). Total and adjusted brain weight and volume decreased in some conditions. Female gender (p<0.001), hypertension (p<0.009), coronary artery disease (p<0.013) and walking assistance (p<0.011) were associated with lower adjusted brain weight while schooling was associated with higher adjusted brain weight (p<0.003). Female gender (p<0.001), age (p<0.001) and hypertension (p<0.011) were associated with low adjusted brain volume. CONCLUSION: Morphometric brain changes occur despite the absence of cognitive impairment and were predominantly associated with age, female gender, mobility impairment and cardiovascular conditions. Schooling may be a protective factor.

OBJETIVO: O comprometimento cognitivo está associado à redução de massa e volume encefálicos. Fatores associados às alterações morfométricas crânio-encefálicas durante o envelhecimento cerebral normal são escassos. Nosso objetivo foi identificar quais os fatores clínicos associados às alterações morfométricas encefálicas em indivíduos sem comprometimento cognitivo. MÉTODOS: Estudo transversal, realizado no Serviço de Verificação de óbitos da Capital, em São Paulo ­ Brasil, em que 414 indivíduos, com idade ≥50 anos, foram submetidos à avaliação clínica e autópsia encefálica, após consentimento informado. A avaliação cognitiva e funcional foi obtida por meio da entrevista com familiares. Massa (g) e de volume (mL) encefálicos foram obtidos e ajustados para o perímetro cefálico (cm). A associação entre massa/volume encefálicos e os fatores relacionados (preditores) foi obtida por meio de análise univariada e multivariada. O p-valor foi fixado em 0,05. RESULTADOS: Participantes era em sua maioria homens (60,4%), com idade média de 67,1 ± 10,9 anos, e caucasianos (69%). A média de massa encefálica da amostra foi de 1219,2 ± 140,9 g, e a média do volume foi 1217,1 ± 152,3 mL. Perímetro cefálico esteve independentemente associado à redução de massa (p<0,001) e volume (p<0,001). Massa e volume (total e corrigido) reduziu em algumas condições. Gênero feminino (p<0,001), hipertensão (p<0,009), doença arterial coronariana (p<0,013) e auxílio para deambulação (p<0,011) foram fatores associados à redução da massa encefálica corrigida, enquanto a escolaridade esteve associada com seu aumento (p<0,003). A idade (p<0,001), o gênero feminino (p<0,001) e a hipertensão (p<0,011) estiveram associados à redução no volume encefálico corrigido. CONCLUSÃO: As alterações morfométricas encefálicas ocorrem apesar da inexistência de comprometimento cognitivo e são associadas à idade, ao gênero feminino, às alterações de mobilidade e às doenças cardiovasculares. A escolaridade parece ser um fator protetor.

Validity of the Katz Index to assess activities of daily living by informants in neuropathological studies.

OBJECTIVE: To analyze the evidences of construct validity of the Katz Index for the retrospective assessment of activities of daily living (ADL) by informants, to assist neuropathological studies in the elderly. METHOD: A cross-sectional study analyzed the functional ability of ADL measure by the Katz Index, of 650 cases randomly selected from the Brazilian Brain Bank of the Ageing Brain Study Group (BBBABSG) database. Sample was divided in two subsamples for the analysis (N=325, each) and then stratified according to cognitive decline assessed by the Clinical Dementia Rating Scale (CDR). Factor analyses with calculations of internal consistency and invariance were performed. RESULTS: Factor analysis evidenced a unidimensional instrument with optimal internal consistency, in all subgroups. Goodness of fit indices were obtained after two treatments of covariance, indicating adequacy of the scale for assessing ADL by informants. The scale is invariant to cognitive decline meaning that it can be used for subjects with or without cognitive impairment. CONCLUSION: Katz Index is valid for the retrospective assessment of basic ADL by informants, with optimal reliability.