WILSON JACOB FILHO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/66, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/66, Hospital das Clínicas, Faculdade de Medicina - Líder
8 resultados
Resultados de Busca
Agora exibindo 1 - 8 de 8
- Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease(2017) EHRENBERG, A. J.; NGUY, A. K.; THEOFILAS, P.; DUNLOP, S.; SUEMOTO, C. K.; ALHO, A. T. Di Lorenzo; LEITE, R. P.; RODRIGUEZ, R. Diehl; MEJIA, M. B.; RUEB, U.; FARFEL, J. M.; FERRETTI-REBUSTINI, R. E. de Lucena; NASCIMENTO, C. F.; NITRINI, R.; PASQUALLUCCI, C. A.; JACOB-FILHO, W.; MILLER, B.; SEELEY, W. W.; HEINSEN, H.; GRINBERG, L. T.AimsHyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.MethodsWe utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-m-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases.ResultsIn Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9x between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN.ConclusionsLC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.
- Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery(2017) THEOFILAS, Panos; EHRENBERG, Alexander J.; DUNLOP, Sara; ALHO, Ana T. Di Lorenzo; NGUY, Austin; LEITE, Renata Elaine Paraizo; RODRIGUEZ, Roberta Diehl; MEJIA, Maria B.; SUEMOTO, Claudia K.; FERRETTI-REBUSTINI, Renata Eloah De Lucena; POLICHISO, Livia; NASCIMENTO, Camila F.; SEELEY, William W.; NITRINI, Ricardo; PASQUALUCCI, Carlos Augusto; JACOB FILHO, Wilson; RUEB, Udo; NEUHAUS, John; HEINSEN, Helmut; GRINBERG, Lea T.Introduction: Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). Methods: The methods include unbiased stereologiCal analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages. Results: As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC. Discussion: The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage-wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages.
- A novel approach for integrative studies on neurodegenerative diseases in human brains(2014) THEOFILAS, Panos; POLICHISO, Livia; WANG, Xuehua; LIMA, Luzia C.; ALHO, Ana T. L.; LEITE, Renata E. P.; SUEMOTO, Claudia K.; PASQUALUCCI, Carlos A.; JACOB-FILHO, Wilson; HEINSEN, Helmut; GRINBERG, Lea T.Despite a massive research effort to elucidate Alzheimer's disease (AD) in recent decades, effective treatment remains elusive. This failure may relate to an oversimplification of the pathogenic processes underlying AD and also lack of understanding of AD progression during its long latent stages. Although evidence shows that the two specific neuropathological hallmarks in AD (neuronal loss and protein accumulation), which are opposite in nature, do not progress in parallel, the great majority of studies have focused on only one of these aspects. Furthermore, research focusing on single structures is likely to render an incomplete picture of AD pathogenesis because as AD involves complete brain networks, potential compensatory mechanisms within the network may ameliorate impairment of the system to a certain extent. Here, we describe an approach for enabling integrative analysis of the dual-nature lesions, simultaneously, in all components of one of the brain networks most vulnerable to AD. This approach is based on significant development of methods previously described mainly by our group that were optimized and complemented for this study. It combines unbiased stereology with immunohistochemistry and immunofluorescence, making use of advanced graphics computing for three-dimensional (3D) volume reconstructions. Although this study was performed in human brainstem and focused in AD, it may be applied to the study of any neurological disease characterized by dual-nature lesions, in humans and animal models. This approach does not require a high level of investment in new equipment and a significant number of specimens can be processed and analyzed within a funding cycle.
- Chemical Composition of Quasi-ultrafine Particles and their Sources in Elderly Residences of Sao Paulo Megacity(2020) SEGALIN, Bruna; FORNARO, Adalgiza; KUMAR, Prashant; KLEMM, Otto; ANDRADE, Maria F.; TREZZA, Beatriz Maria; BUSSE, Alexandre; FILHO, Wilson J.; GONCALVES, Fabio L. T.Atmospheric quasi-ultrafine particles (qUFP; PM<0.25) can cause harmful effects to human health, mainly to elderly people. Although not always considered, these effects can be mostly due to its chemical composition. The scope of this work is (i) to quantify the abundance of ions and trace elements in qUFP in elderly residences, (ii) to identify the sources of these qUFP and (iii) to estimate the respiratory deposition doses (RDD) of qUFP and black carbon (rBC), which is an important component of qUFP, to various parts of the respiratory tract. In order to evaluate the qUFP chemical composition in elderly residences in the Metropolitan Area of Sao Paulo (MASP), we collected qUFP by using a Personal Cascade Impactor Sampler (PCIS). We analysed ions by chromatography and trace elements by Energy Dispersive X-Ray Fluorescence. We identified the sources of qUFP by applying Positive Matrix Factorization. We calculated the RDD through an equation, which use the tidal volume of lung, the typical breath frequency, the deposition fraction and the mass concentration of different size fractions of a PM. We collected 60 samples from 59 residences between May 2014 and July 2015. The major of ions concentrations in qUFP were found to be SO42- and NH4+, and the major trace elements were Si and Fe. Some residences have a high concentration of the toxic heavy metals Cu, Ni, Pb and Cr. We found six dominant sources of the indoor qUFP: vehicular emission (57%), secondary inorganic aerosol (21%), soil and construction (7%), wall painting (7%), cooking (5%) and industry (3%). The maximum RDD of qUFP and rBC are in the tracheobronchial part. Our results show that vehicular emissions dominate the indoor qUFP concentrations and uptake in elderly residences in the MASP.
- Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans(2018) THEOFILAS, Panos; EHRENBERG, Alexander J.; NGUY, Austin; THACKREY, Julia M.; DUNLOP, Sara; MEJIA, Maria B.; ALHO, Ana T.; LEITE, Renata Elaine Paraizo; RODRIGUEZ, Roberta Diehl; SUEMOTO, Cclaudia K.; NASCIMENTO, Camila F.; CHIN, Marcus; MEDINA-CLEGHORN, Daniel; CUERVO, Ana Maria; ARKIN, Michelle; SEELEY, William W.; MILLER, Bruce L.; NITRINI, Ricardo; PASQUALUCCI, Carlos Augusto; JACOB FILHO, Wilson; RUEB, Udo; NEUHAUS, John; HEINSEN, Helmut; GRINBERG, Lea T.Clarifying the mechanisms connecting neurofibrillary tangle (NFT) neurotoxicity to neuronal dysfunction in humans is likely to be pivotal for developing effective treatments for Alzheimer's disease (AD). To model the temporal progression of AD in humans, we used a collection of brains with controls and individuals from each Braak stage to quantitatively investigate the correlation between intraneuronal caspase activation or macroautophagy markers, NFT burden, and neuronal loss, in the dorsal raphe nucleus and locus coeruleus, the earliest vulnerable areas to NFT accumulation. We fit linear regressions with each count as outcomes, with Braak score and age as the predictors. In progressive Braak stages, intraneuronal active caspase-6 positivity increases both alone and overlapping with NETs. Likewise, the proportion of NFT-bearing neurons showing autophagosomes increases. Overall, caspases may be involved in upstream cascades in AD and are associated with higher NFTs. Macroautophagy changes correlate with increasing NFT burden from early AD stages.
- Brazilian psychiatric brain bank: a new contribution tool to network studies(2012) OLIVEIRA, K. C. de; NERY, F. G.; FERRETI, R. E. L.; LIMA, M. C.; CAPPI, C.; MACHADO-LIMA, A.; POLICHISO, L.; CARREIRA, L. L.; AVILA, C.; ALHO, A. T. D. L.; BRENTANI, H. P.; MIGUEL, E. C.; HEINSEN, H.; JACOB-FILHO, W.; PASQUALUCCI, C. A.; LAFER, B.; GRINBERG, L. T.There is an urgent need for expanding the number of brain banks serving psychiatric research. We describe here the Psychiatric Disorders arm of the Brain Bank of the Brazilian Aging Brain Study Group (Psy-BBBABSG), which is focused in bipolar disorder (BD) and obsessive compulsive disorder (OCD). Our protocol was designed to minimize limitations faced by previous initiatives, and to enable design-based neurostereological analyses. The Psy-BBBABSG first milestone is the collection of 10 brains each of BD and OCD patients, and matched controls. The brains are sourced from a population-based autopsy service. The clinical and psychiatric assessments were done by an expert team including psychiatrists, through an informant. One hemisphere was perfused-fixed to render an optimal fixation for conducting neurostereological studies. The other hemisphere was comprehensively dissected and frozen for molecular studies. In 20 months, we collected 36 brains. A final report was completed for 14 cases: 3 BDs, 4 major depressive disorders, 1 substance use disorder, 1 mood disorder NOS, 3 obsessive compulsive spectrum symptoms, 1 OCD and 1 schizophrenia. The majority were male (64%), and the average age at death was 67.2 +/- 9.0 years. The average postmortem interval was 16 h. Three matched controls were collected. The pilot stage confirmed that the protocols are well fitted to reach our goals. Our unique autopsy source makes possible to collect a fairly number of high quality cases in a short time. Such a collection offers an additional to the international research community to advance the understanding on neuropsychiatric diseases.
conferenceObject Argyrophilic grain disease may delay cognitive decline in AD: an autopsy study(2015) GRINBERG, Lea; RODRIGUEZ, Roberta; SUEMOTO, Claudia; MOLINA, Mariana; NASCIMENTO, Camila; LEITE, Renata; FERRETTI-REBUSTINI, Renata; FARFEL, Jose; HEINSEN, Helmut; NITRINI, Ricardo; PASQUALLUCCI, Carlos; JACOB-FILHO, Wilson; YAFFE, Kristine- 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.