Increased DNA Copy Number Variation Mosaicism in Elderly Human Brain.

Aging is a complex process strongly determined by genetics. Previous reports have shown that the genome of neuronal cells displays somatic genomic mosaicism including DNA copy number variations (CNVs). CNVs represent a significant source of genetic variation in the human genome and have been implicated in several disorders and complex traits, representing a potential mechanism that contributes to neuronal diversity and the etiology of several neurological diseases and provides new insights into the normal, complex functions of the brain. Nonetheless, the features of somatic CNV mosaicism in nondiseased elderly brains have not been investigated. In the present study, we demonstrate a highly significant increase in the number of CNVs in nondiseased elderly brains compared to the blood. In two neural tissues isolated from paired postmortem samples (same individuals), we found a significant increase in the frequency of deletions in both brain areas, namely, the frontal cortex and cerebellum. Also, deletions were found to be significantly larger when present only in the cerebellum. The sizes of the variants described here were in the 150-760 kb range, and importantly, nearly all of them were present in the Database of Genomic Variants (common variants). Nearly all evidence of genome structural variation in human brains comes from studies detecting changes in single cells which were interpreted as derived from independent, isolated mutational events. The observations based on array-CGH analysis indicate the existence of an extensive clonal mosaicism of CNVs within and between the human brains revealing a different type of variation that had not been previously characterized

Morphometric brain changes during aging: Results from a Brazilian necropsy sample.

The present study aimed to establish the morphometric brain changes during aging in a necropsy series from Brazil and determine whether sexual dimorphisms interfere in these changes. Methods:A cross-sectional study was conducted at the São Paulo Autopsy Service in Brazil where, after informed consent, data was gathered from next of kin interview with reference to clinical status prior to death. Brain weight, volume and density measurements were taken and then adjusted for head circumference. Descriptive statistics and tests of hypothesis and correlations were applied, considering a p-value of 0.05. Results:414 subjects, mostly men (60.4%), with a mean age of 67.1 years, were included. The mean brain weight of the sample was 1219.2g±140.9and mean volume was 1217mL±152.3. The mean brain density of the sample was 1.0g/mL±0.09. Values differed between males and females in terms of weight and volume. Brain weight decreased during aging by about 45g per decade (r= -0.300; p<0.01) and volume by about 43mL (r= -0.278; p<0.00). Mean density of the sample was 1.0 g/mL in both genders. Conclusions:Brain weight and volume (with or without corrections) decreased during aging, and these reductions were more pronounced in women. Density remained unchanged for both genders. Further studies are needed to investigate factors associated to these reductions

Dont die like me: Which proteins are responsible for the selective neuronal vulnerability within the substantia nigra?

A hallmark of Parkinsons disease is the specific degeneration of dopaminergic neurons in the substantia nigra pars compacta. Interestingly, not all of these neurons are affected to the same extent. Studies revealed that neurons located more ventrally within the substantia nigra pars compacta have a higher prevalence to degenerate than those located in the dorsal tier. The underlying reasons for this selective neuronal vulnerability are still unknown. The aim of the present study was to gain a better understanding of molecular differences between these two neuronal subpopulations that may explain the selective neuronal vulnerability within the human substantia nigra. For this purpose, the neurons from the ventral as well as dorsal tier of the substantia nigra were specifically isolated out of neuropathologically unremarkable human substantia nigra sections with laser microdissection. Following, their proteome was analyzed by data independent acquisition mass spectrometry. The samples were analysed donor-specifically and not pooled for this purpose. A total of 5,391 proteins were identified in the substantia nigra. Of these, 2,453 proteins could be quantified in 100% of the dorsal tier samples. 1,629 could be quantified in 100% of the ventral tier samples. Nine proteins were differentially regulated with a log2 value ≥0.5 and a Qvalue ≤0.05. Of these 7 were higher abundant in the dorsal tier and 2 higher in the ventral tier. These proteins are associated with the cytoskeleton, neuronal plasticity, or calcium homeostasis. With these findings a deeper understanding can be gained of the selective neuronal vulnerability within the substantia nigra and of protective mechanisms against neurodegeneration in specific neuronal subpopulations

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

IntroductionAdiposity 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 analysisA 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 disseminationEthical 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

Post-Mortem diagnosis of dementia by informant interview.

The diagnosis of normal cognition or dementia in the Brazilian Brain Bank of the Aging Brain Study Group (BBBABSG) has relied on postmortem interview with an informant. Objectives:To ascertain the sensitivity and specificity of postmortem diagnosis based on informant interview compared against the diagnosis established at a memory clinic. Methods:A prospective study was conducted at the BBBABSG and at the Reference Center for Cognitive Disorders (RCCD), a specialized memory clinic of the Hospital das Clínicas, University of São Paulo Medical School. Control subjects and cognitively impaired subjects were referred from the Hospital das Clínicas to the RCCD where subjects and their informants were assessed. The same informant was then interviewed at the BBBABSG. Specialists' panel consensus, in each group, determined the final diagnosis of the case, blind to other center's diagnosis. Data was compared for frequency of diagnostic equivalence. For this study, the diagnosis established at the RCCD was accepted as the gold standard. Sensitivity and specificity were computed. Results:Ninety individuals were included, 45 with dementia and 45 without dementia (26 cognitively normal and 19 cognitively impaired but non-demented). The informant interview at the BBBABSG had a sensitivity of 86.6% and specificity of 84.4% for the diagnosis of dementia, and a sensitivity of 65.3% and specificity of 93.7% for the diagnosis of normal cognition. Conclusions:The informant interview used at the BBBABSG has a high specificity and sensitivity for the diagnosis of dementia as well as a high specificity for the diagnosis of normal cognition

Validez del índice de katz para evaluar las actividades básicas de vida diaria por informantes en estudios neuropatológicos

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.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.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

Hyperphosphorylated Tau in Mesial Temporal Lobe Epilepsy: a Neuropathological and Cognitive Study

Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid β (Aβ), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aβ deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE

Microcephaly measurement in adults and its association with clinical variables

OBJECTIVE: To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with microcephaly via data mining. METHODS: In autopsy studies, head circumference was measured with an inelastic tape placed around the skull. Total brain volume was also directly measured. A linear regression was used to determine the association of head circumference with brain volume and clinical variables. Microcephaly was defined as head circumference that were two standard deviations below the mean of significant clinical variables. We further applied an association rule mining to find rules associating microcephaly with several sociodemographic and clinical variables. RESULTS: In our sample of 2,508 adults, the mean head circumference was 55.3 ± 2.7cm. Head circumference was related to height, cerebral volume, and sex (p < 0.001 for all). Microcephaly was present in 4.7% of the sample (n = 119). Out of 34,355 association rules, we found significant relationships between microcephaly and a clinical dementia rating (CDR) > 0.5 with an informant questionnaire on cognitive decline in the elderly (IQCODE) ≥ 3.4 (confidence: 100% and lift: 5.6), between microcephaly and a CDR > 0.5 with age over 70 years (confidence: 42% and lift: 2.4), and microcephaly and males (confidence: 68.1% and lift: 1.3). CONCLUSION: Head circumference was related to cerebral volume. Due to its low cost and easy use, head circumference can be used as a screening test for microcephaly, adjusting it for gender and height. Microcephaly was associated with dementia at old age

RELATO DE CASO: RISCO CIRÚRGICO ODONTOLÓGICO DE UM PACIENTE CARDIOPATA

Cardiopatas devem receber tratamento odontológico diferenciado, com atenção ao protocolo de atendimento, à abordagem do paciente e à interação medicamentosa, assim, pacientes portadores de válvula cardíaca protética (VCP) precisam de atenção especial quando forem submetidos a intervenções odontológicas. Este relato de caso clínico de um paciente cardiopata, que necessitava de extração de uma raiz residual, teve o intuito de demonstrar a importância da profilaxia antibiótica na prevenção de endocardite bacteriana e os exames necessários para a extração dentária em um paciente portador de VCP em terapia anticoagulante. Esses pacientes necessitam de cuidados pré, trans e pós-operatórios, evitando eventuais complicações. Os exames pré-operatórios foram hemograma, glicemia em jejum, tempo de protrombina, tempo de sangramento e a razão normalizada internacional (RNI), que se encontravam com valores normais. Como medicação pré-operatória utilizou-se a profilaxia antibiótica 2g de amoxicilina por via oral uma hora antes da cirurgia e bochecho com solução de digluconato de clorexidina 0,2% previamente ao início da cirurgia. A anestesia foi infiltrativa regional com anestésico Lidocaína 2% com adrenalina 1:100.000, para promover hemostasia local. A técnica cirúrgica de escolha foi a técnica segunda e o fio de sutura utilizado foi o de seda 4.0; como medicação pós-operatória foi receitado Paracetamol 750mg por via oral durante três dias, se houver dor. Em cardiopatas, a prevenção da endocardite bacteriana, por meio da profilaxia antibiótica, torna-se necessária, pois é possível ocorrer a migração de bactérias para a corrente sanguínea. Esse protocolo é necessário para pacientes de risco, no entanto, devem ser observados os valores de RNI, que em níveis aceitáveis, não é preconizada a interrupção do uso do anticoagulante, pois o risco de formação de um trombo é bem maior que de uma hemorragia.Palavras-chave: Anticoagulante. Endocardite bacteriana. Antibioticoprofilaxia