A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad

Selecting the most relevant brain regions to discriminate Alzheimer's disease patients from healthy controls using multiple kernel learning: A comparison across functional and structural imaging modalities and atlases

BACKGROUND: Machine learning techniques such as support vector machine (SVM) have been applied recently in order to accurately classify individuals with neuropsychiatric disorders such as Alzheimer's disease (AD) based on neuroimaging data. However, the multivariate nature of the SVM approach often precludes the identification of the brain regions that contribute most to classification accuracy. Multiple kernel learning (MKL) is a sparse machine learning method that allows the identification of the most relevant sources for the classification. By parcelating the brain into regions of interest (ROI) it is possible to use each ROI as a source to MKL (ROI-MKL). METHODS: We applied MKL to multimodal neuroimaging data in order to: 1) compare the diagnostic performance of ROI-MKL and whole-brain SVM in discriminating patients with AD from demographically matched healthy controls and 2) identify the most relevant brain regions to the classification. We used two atlases (AAL and Brodmann's) to parcelate the brain into ROIs and applied ROI-MKL to structural (T1) MRI, 18F-FDG-PET and regional cerebral blood flow SPECT (rCBF-SPECT) data acquired from the same subjects (20 patients with early AD and 18 controls). In ROI-MKL, each ROI received a weight (ROI-weight) that indicated the region's relevance to the classification. For each ROI, we also calculated whether there was a predominance of voxels indicating decreased or increased regional activity (for 18F-FDG-PET and rCBF-SPECT) or volume (for T1-MRI) in AD patients. RESULTS: Compared to whole-brain SVM, the ROI-MKL approach resulted in better accuracies (with either atlas) for classification using 18F-FDG-PET (92.5% accuracy for ROI-MKL versus 84% for whole-brain), but not when using rCBF-SPECT or T1-MRI. Although several cortical and subcortical regions contributed to discrimination, high ROI-weights and predominance of hypometabolism and atrophy were identified specially in medial parietal and temporo-limbic cortical regions. Also, the weight of discrimination due to a pattern of increased voxel-weight values in AD individuals was surprisingly high (ranging from approximately 20% to 40% depending on the imaging modality), located mainly in primary sensorimotor and visual cortices and subcortical nuclei. CONCLUSION: The MKL-ROI approach highlights the high discriminative weight of a subset of brain regions of known relevance to AD, the selection of which contributes to increased classification accuracy when applied to 18F-FDG-PET data. Moreover, the MKL-ROI approach demonstrates that brain regions typically spared in mild stages of AD also contribute substantially in the individual discrimination of AD patients from controls

A síndrome de tremor e ataxia associada ao X frágil (FXTAS)

FXTAS (Fragile X-associated tremor and ataxia syndrome) is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS), the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.A FXTAS (síndrome de tremor e ataxia associada ao X frágil) é uma doença neurodegenerativa de início tardio que afeta principalmente homens acima dos 50 anos de idade, portadores de pré-mutação do gene FMR1. A mutação completa desse gene é responsável pela síndrome do cromossomo X frágil (SXF), a causa mais comum de deficiência mental herdada. Indivíduos afetados pela FXTAS geralmente apresentam tremor de intenção e ataxia de marcha que podem estar associados a sinais radiológicos ou neuropatológicos específicos. Outras características comumente observadas são parkinsonismo, declínio cognitivo, neuropatia periférica e disfunções autonômicas. Quase uma década após sua caracterização clínica, a FXTAS é mal conhecida por médicos no Brasil. Esta revisão apresenta o conhecimento atual sobre os aspectos clínicos, genéticos e diagnósticos da síndrome.FAPESP - Center for the Study of Human Genom

Cross-cultural adaptation of the disability assessment for dementia (DAD)

The original version of the Disability Assessment for Dementia (DAD) was translated into Portuguese and back translated to English. The divergences of translation were identified and discussed, resulting in a version that was used in a preliminary investigation for cross-cultural adaptation. The final version was administered to 29 patients with mild to moderate probable Alzheimer's disease. The correlation coefficients of DAD were 0.929 and 0.932 for the inter-examiner and test-retest evaluations respectively. The reliability indexes were also high (Kappa 0.72 p<0.001 inter-examiners and 0.85 p<0.001 test-retest). The Brazilian version of DAD was easy to administer and had good reliability to assess the functional status of demented patients. It will contribute to the follow-up of these patients in our population. Moreover, it can be used in transcultural studies on functional abilities in dementia.A versão original da Escala de Avaliação de Incapacidade em Demência (Disability Assessment for Dementia, DAD) foi traduzida para a língua portuguesa e retrotraduzida para o inglês. Divergências de tradução foram identificadas e discutidas, chegando-se a uma versão que foi submetida a pré-teste para adaptação sócio-cultural. A versão final foi administrada a amostra de 29 pacientes com doença de Alzheimer provável de leve a moderada. Os coeficientes de correlação da DAD foram 0,929 e 0,932 nas avaliações inter e intra-examinadores respectivamente. Os índices de confiabilidade também foram elevados (Kappa=0,72; p<0,001 inter-examinadores e Kappa=0,85; p<0,001 intra-examinadores). A versão brasileira da escala DAD mostrou-se um instrumento de fácil aplicação e boa confiabilidade para avaliação funcional de pacientes com demência e poderá contribuir para o acompanhamento desses pacientes em nosso meio. Esta versão também poderá ser utilizada em estudos transculturais sobre habilidades funcionais de pacientes com demência.Universidade de São Paulo Faculdade de Medicina Hospital das ClínicasUniversidade Federal de São Paulo (UNIFESP) Escola de Paulista de Medicina Departamento de Neurologia e NeurocirurgiaUNIFESP, Escola de Paulista de Medicina Depto. de Neurologia e NeurocirurgiaSciEL

Brazilian version of the Cornell depression scale in dementia

OBJECTIVE: Translating and adapting the Cornell scale for depression in dementia to the Portuguese language and verifying the interrater and test-retest reliability of the translated and adapted version. METHOD: The Cornell scale was translated into Portuguese and back translated into English. Divergences of translation were identified and discussed, resulting in a version which was submitted to a pre-test for cross-cultural adaptation. The final version was administered to a sample of 29 patients with probable AD and to their caregivers. RESULTS: The Cornell Scale presented good interrater (Kappa=0,77; p<0,001) and test-retest reliability (Kappa=0,76; p<0,001). The final version was easy to administer and well understood by the caregivers. CONCLUSION: The Brazilian version of the Cornell Scale is an instrument with good reliability to evaluate depression in patients with dementia. This tool will contribute to the evaluation and follow-up of depressed patients with dementia in our population and may also be used in multicentric studies with Brazilian population.OBJETIVO: Tradução e adaptação da escala Cornell de depressão em demência e verificação da confiabilidade entre e intra-examinadores da versão na língua portuguesa. MÉTODO: A versão original da Escala Cornell foi traduzida para o português por firma especializada em tradução de textos médicos e retrotraduzida para o inglês por outros dois tradutores independentes. As divergências de tradução foram identificadas e discutidas, chegando-se à versão que foi submetida à pré-teste para adaptação sócio-cultural. Após esta adaptação, obteve-se a versão final que foi administrada a amostra de 29 pacientes com doença de Alzheimer provável e aos seus cuidadores. RESULTADOS: A versão final da escala mostrou-se de fácil aplicação e obteve boa confiabilidade intra-examinador (Kappa=0,77; p<0,001) e entre-examinadores (Kappa=0,76; p<0,001). CONCLUSÃO: A versão brasileira da Escala Cornell é um instrumento que pode ser utilizado para avaliação e acompanhamento de depressão em pacientes com demência.Universidade de São Paulo Faculdade de Medicina Hospital das ClínicasUniversidade Federal de São Paulo (UNIFESP) Escola de Paulista de Medicina Departamento de Neurologia e NeurocirurgiaUNIFESP, Escola de Paulista de Medicina Depto. de Neurologia e NeurocirurgiaSciEL

Differences in prefrontal cortex activation and deactivation during strategic episodic verbal memory encoding in mild cognitive impairment

In this study we examined differences in fMRI activation and deactivation patterns during episodic verbal memory encoding between individuals with MCI (n = 18) and healthy controls (HCs) (n = 17). Participants were scanned in two different sessions during the application of self-initiated or directed instructions to apply semantic strategies at encoding of word lists. MCI participants showed reduced free recall scores when using self-initiated encoding strategies that were increased to baseline controls\u27 level after directed instructions were provided. During directed strategic encoding, greater recruitment of frontoparietal regions was observed in both MCI and control groups; group differences between sessions were observed in the ventromedial prefrontal cortex and the right superior frontal gyrus. This study provides evidence suggesting that differences of activity in these regions may be related to encoding deficits in MCI, possibly mediating executive functions during task performance

Post-Mortem diagnosis of dementia by informant interview

Abstract 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