RENATA ELAINE PARAIZO LEITE
Projetos de Pesquisa
Unidades Organizacionais
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
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- Trace element concentration differences in regions of human brain by INAA(2013) SAIKI, M.; LEITE, R. E. P.; GENEZINI, F. A.; GRINBERG, L. T.; FERRETTI, R. E. L.; FARFEL, J. M.; SUEMOTO, C.; PASQUALUCCI, C. A.; JACOB-FILHO, W.Studies have shown that there is a potential relationship between the levels of trace elements in cerebral tissues and neurological disorders. However, there are few publications available on the elemental composition of these tissues as well as for different regions of the brain. The aim of this study was to investigate trace element differences in various regions of the human brain from an elderly population of normal individuals. Brain samples from 31 individuals of both genders, aged 51-95 years were provided by the Brain Bank of the Brazilian Aging Study Group of the So Paulo University, Medical School. The tissues from the regions of the hippocampus, cerebellum and frontal, parietal, temporal, occipital cortex were dissected using a titanium knife, ground, freeze-dried and then analyzed by instrumental neutron activation analysis (INAA). Samples and element standards were irradiated with a neutron flux at the IEA-R1 nuclear research reactor for Br, Fe, K, Na, Rb, Se and Zn determinations. One-way ANOVA test (p < 0.05) was used to compare the results which showed significant differences for several elements among the brain regions. Most of our brain analysis results agreed with the literature data. The results were also submitted for brain region classification by cluster analysis.
- Very low levels of education and cognitive reserve A clinicopathologic study(2013) FARFEL, Jose Marcelo; NITRINI, Ricardo; SUEMOTO, Claudia Kimie; GRINBERG, Lea Tenenholz; FERRETTI, Renata Eloah Lucena; LEITE, Renata Elaine Paraizo; TAMPELLINI, Edilaine; LIMA, Luzia; FARIAS, Daniela Souza; NEVES, Ricardo Caires; RODRIGUEZ, Roberta Diehl; MENEZES, Paulo Rossi; FREGNI, Felipe; BENNETT, David A.; PASQUALUCCI, Carlos Augusto; JACOB FILHO, WilsonObjective: We conducted a clinicopathologic study in a large population with very low levels of education to determine whether very few years of education could contribute to cognitive reserve and modify the relation of neuropathologic indices to dementia. Methods: In this cross-sectional study, we included 675 individuals 50 years of age or older from the Brazilian Aging Brain Study Group. Cognitive abilities were evaluated through a structured interview with an informant at the time of autopsy, including the Clinical Dementia Rating (CDR) scale. Neuropathologic examinations were performed using immunohistochemistry and following internationally accepted criteria. Multivariate linear regression models were conducted to determine whether the association between cognitive abilities (measured by CDR sum of boxes) and years of education was independent of sociodemographic variables and neuropathologic indices, including neuritic plaques, neurofibrillary tangles, lacunar infarctions, small-vessel disease, and Lewy bodies. In addition, interaction models were used to examine whether education modified the relation between neuropathologic indices and cognition. Results: Mean education was 3.9 +/- 3.5 years. Formal education was associated with a lower CDR sum of boxes (beta = -0.197; 95% confidence interval -0.343, -0.052; p = 0.008), after adjustment for sociodemographic variables and neuropathologic indices. Furthermore, education modified the relationship of lacunar infarcts with cognitive abilities (p = 0.04). Conclusions: Even a few years of formal education contributes to cognitive reserve.
- Depression and cardiovascular risk factors: evidence from a large postmortem sample(2013) SUEMOTO, Claudia K.; DAMICO, Marcio V.; FERRETTI, Renata E. L.; GRINBERG, Lea T.; FARFEL, Jose Marcelo; LEITE, Renata E. P.; NITRINI, Ricardo; LAFER, Beny; JACOB-FILHO, Wilson; PASQUALUCCI, Carlos A.Objectives We aimed to investigate the association of depression with cardiovascular risk factors and diseases (CVRFD) in a large population-based sample. Methods This cross-sectional study included 1012 deceased individuals greater than 50years of age from a general autopsy service located in SAo Paulo, Brazil. Demographics, socioeconomic profile, and CVRFD information were collected by caregivers from the deceased individuals from the Brain Bank of the Brazilian Aging Brain Study Group. Depression diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Mental Disorders was the main outcome. Results Depression was associated with female gender (odds ratio (OR)=1.86; 95% confidence interval (CI)=1.282.71, p=0.001), widowhood (OR=1.54; 95% CI=1.032.32, p=0.04), physical inactivity (OR=1.61; 95% CI=1.152.26, p=0.006), and smoking (OR=2.03; 95% CI=1.402.95, p<0.001) after multivariate logistic regression analysis. Other CVRFD were not associated with the presence of depression. Conclusions In our cross-sectional study, sedentary individuals and smokers showed a higher chance of depression during lifetime. Measures to control these common risk factors could decrease the incidence of depression.
- African ancestry protects against Alzheimer's disease-related neuropathology(2013) SCHLESINGER, D.; GRINBERG, L. T.; ALBA, J. G.; NASLAVSKY, M. S.; LICINIO, L.; FARFEL, J. M.; SUEMOTO, C. K.; FERRETTI, R. E. de Lucena; LEITE, R. E. P.; ANDRADE, M. P. de; SANTOS, A. C. F. dos; BRENTANI, H.; PASQUALUCCI, C. A.; NITRINI, R.; JACOB-FILHO, W.; ZATZ, M.Previous studies in dementia epidemiology have reported higher Alzheimer's disease rates in African-Americans when compared with White Americans. To determine whether genetically determined African ancestry is associated with neuropathological changes commonly associated with dementia, we analyzed a population-based brain bank in the highly admixed city of Sao Paulo, Brazil. African ancestry was estimated through the use of previously described ancestry-informative markers. Risk of presence of neuritic plaques, neurofibrillary tangles, small vessel disease, brain infarcts and Lewy bodies in subjects with significant African ancestry versus those without was determined. Results were adjusted for multiple environmental risk factors, demographic variables and apolipoprotein E genotype. African ancestry was inversely correlated with neuritic plaques (P = 0.03). Subjects with significant African ancestry (n = 112, 55.4%) showed lower prevalence of neuritic plaques in the univariate analysis (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.55-0.95, P = 0.01) and when adjusted for age, sex, APOE genotype and environmental risk factors (OR 0.43, 95% CI 0.21-0.89, P = 0.02). There were no significant differences for the presence of other neuropathological alterations. We show for the first time, using genetically determined ancestry, that African ancestry may be highly protective of Alzheimer's disease neuropathology, functioning through either genetic variants or unknown environmental factors. Epidemiological studies correlating African-American race/ethnicity with increased Alzheimer's disease rates should not be interpreted as surrogates of genetic ancestry or considered to represent African-derived populations from the developing nations such as Brazil. Molecular Psychiatry (2013) 18, 79-85; doi:10.1038/mp.2011.136; published online 8 November 2011
- The human cerebral cortex is neither one nor many: neuronal distribution reveals two quantitatively different zones in the gray matter, three in the white matter, and explains local variations in cortical folding(2013) RIBEIRO, Pedro F. M.; VENTURA-ANTUNES, Lissa; GABI, Mariana; MOTA, Bruno; GRINBERG, Lea T.; FARFEL, Jose M.; FERRETTI-REBUSTINI, Renata E. L.; LEITE, Renata E. P.; FILHO, Wilson J.; HERCULANO-HOUZEL, SuzanaThe human prefrontal cortex has been considered different in several aspects and relatively enlarged compared to the rest of the cortical areas. Here we determine whether the white and gray matter of the prefrontal portion of the human cerebral cortex have similar or different cellular compositions relative to the rest of the cortical regions by applying the Isotropic Fractionator to analyze the distribution of neurons along the entire anteroposterior axis of the cortex, and its relationship with the degree of gyrification, number of neurons under the cortical surface, and other parameters. The prefrontal region shares with the remainder of the cerebral cortex (except for occipital cortex) the same relationship between cortical volume and number of neurons. In contrast, both occipital and prefrontal areas vary from other cortical areas in their connectivity through the white matter, with a systematic reduction of cortical connectivity through the white matter and an increase of the mean axon caliber along the anteroposterior axis. These two parameters explain local differences in the distribution of neurons underneath the cortical surface. We also show that local variations in cortical folding are neither a function of local numbers of neurons nor of cortical thickness, but correlate with properties of the white matter, and are best explained by the folding of the white matter surface. Our results suggest that the human cerebral cortex is divided in two zones (occipital and non-occipital) that differ in how neurons are distributed across their gray matter volume and in three zones (prefrontal, occipital, and non-occipital) that differ in how neurons are connected through the white matter. Thus, the human prefrontal cortex has the largest fraction of neuronal connectivity through the white matter and the smallest average axonal caliber in the white matter within the cortex, although its neuronal composition fits the pattern found for other, non-occipital areas.
- Prevalence of dementia subtypes in a developing country: a clinicopathological study(2013) GRINBERG, Lea T.; NITRINI, Ricardo; SUEMOTO, Claudia K.; FERRETTI-REBUSTINI, Renata Eloah de Lucena; LEITE, Renata E. P.; FARFEL, Jose Marcelo; SANTOS, Erika; ANDRADE, Mara Patricia Guilhermino de; ALHO, Ana Tereza Di Lorenzo; LIMA, Maria do Carmo; OLIVEIRA, Katia C.; TAMPELLINI, Edilaine; POLICHISO, Livia; SANTOS, Glaucia B.; RODRIGUEZ, Roberta Diehl; UEDA, Kenji; PASQUALUCCI, Carlos A.; JACOB-FILHO, WilsonOBJECTIVES: To assess the distribution of dementia subtypes in Brazil using a population-based clinicopathological study. METHOD: Brains from deceased individuals aged >= 50 years old were collected after the next of kin signed an informed consent form and provided information through standardized questionnaires. Post-mortem clinical diagnoses were established in consensus meetings, and only cases with moderate or severe dementia or without cognitive impairment were included in the analysis. Immunohistochemical neuropathological examinations were performed following the universally accepted guidelines. A diagnosis of Alzheimer's disease was made when there were at least both a moderate density of neuritic plaques (Consortium to Establish a Register for Alzheimer's disease B or C) and Braak stage III for neurofibrillary tangle distribution. For the diagnosis of vascular dementia, at least three zones or strategic areas had to be affected by infarcts, lacunae, or microinfarcts. RESULTS: From 1,291 subjects, 113 cases were classified as having moderate or severe dementia, and 972 cases were free of cognitive impairment. The neuropathological diagnoses of the dementia sub-group were Alzheimer's disease (35.4%), vascular dementia (21.2%), Alzheimer's disease plus vascular dementia (13.3%), and other causes of dementia (30.1%). Small-vessel disease, which alone was not considered sufficient for a vascular dementia diagnosis, was present in 38.9% of all of the dementia cases and in 16.8% of the group without cognitive impairment (odds ratio = 2.91; 95% confidence interval, 1.53-5.51), adjusted for age, sex, and education. CONCLUSIONS: The relatively high frequencies of vascular dementia and small-vessel disease in the dementia sub-group constitute relevant findings for public health initiatives because control of vascular risk factors could decrease the prevalence of dementia in developing countries.
- Combined enrichment of neuromelanin granules and synaptosomes from human substantia nigra pars compacta tissue for proteomic analysis(2013) PLUM, S.; HELLING, S.; THEISS, C.; LEITE, R. E. P.; MAY, C.; JACOB-FILHO, W.; EISENACHER, M.; KUHLMANN, K.; MEYER, H. E.; RIEDERER, P.; GRINBERG, L. T.; GERLACH, M.; MARCUS, K.This article gives a detailed description of a protocol using density gradient centrifugation for the enrichment of neuromelanin granules and synaptosomes from low amounts (>= 0.15 g) of human substantia nigra pars compacta tissue. This has a great advantage compared to already existing methods as it allows for the first time (i) a combined enrichment of neuromelanin granules and synaptosomes and (ii) just minimal amounts of tissue necessary to enable donor specific analysis. Individual specimens were classified as control or diseased according to clinical evaluation and neuropathological examination. For the enrichment of synaptosomes and neuromelanin granules from the same tissue sample density gradient centrifugations using Percoll and Iodixanol were performed. The purity of resulting fractions was checked by transmission electron microscopy. We were able to establish a reproducible and easy to handle protocol combining two different density gradient centrifugations: using an Iodixanol gradient neuromelanin granules were enriched and in parallel, from the same sample, a fraction of synaptosomes with high purity using a Percoll (R) gradient was obtained. Our subfractionation strategy will enable a subsequent in depth proteomic characterization of neurodegenerative processes in the substantia nigra pars compacta in patients with Parkinson's disease and dementia with Lewy bodies compared to appropriate controls. Biological significance Key features of Parkinson's disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta, an associated loss of the brain pigment neuromelanin and a resulting impairment of the neuronal network. The accumulation of iron binding neuromelanin granules is age- and disease-dependent and disease specific alterations could affect the neuronal iron homeostasis leading to oxidative stress induced cell death. The focus of the described method is the analysis of neuromelanin granules as well as axonal cell-endings of nerve cells (synaptosomes) of individual donors (control and diseased). It is the basis for the identification of disease-relevant changes in the iron homeostasis and the generation of new insight into altered protein compositions or regulations which might lead to disturbed communications between nerve cells resulting in pathogenic processes.
- Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles(2013) ANDRADE-MORAES, Carlos Humberto; OLIVEIRA-PINTO, Ana V.; CASTRO-FONSECA, Emily; SILVA, Camila G. da; GUIMARAES, Daniel M.; SZCZUPAK, Diego; PARENTE-BRUNO, Danielle R.; CARVALHO, Ludmila R. B.; POLICHISO, Livia; GOMES, Bruna V.; OLIVEIRA, Lays M.; RODRIGUEZ, Roberta D.; LEITE, Renata E. P.; FERRETTI-REBUSTINI, Renata E. L.; JACOB-FILHO, Wilson; PASQUALUCCI, Carlos A.; GRINBERG, Lea T.; LENT, RobertoAlzheimer's disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-beta plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-beta oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimer's disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals-both groups histopathologically diagnosed as Alzheimer's-and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimer's disease, but not in asymptomatic subjects with Alzheimer's disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimer's disease can be asymptomatic; and exclude amyloid-beta deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimer's disease when compared with asymptomatic subjects with Alzheimer's disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present.