CARLOS AUGUSTO GONCALVES PASQUALUCCI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
ATCIENT-50, SVOC
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina - Líder
ATCIENT-50, SVOC
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina - Líder
31 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 31
- Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis(2018) NASCIMENTO, C.; ALHO, A. T. Di Lorenzo; AMARAL, C. Bazan Conceicao; LEITE, R. E. P.; NITRINI, R.; JACOB-FILHO, W.; PASQUALUCCI, C. A.; HOKKANEN, S. R. K.; HUNTER, S.; KEAGE, H.; KOVACS, G. G.; GRINBERG, L. T.; SUEMOTO, C. K.ObjectiveTo perform a systematic review and meta-analysis on the prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults. MethodsWe systematically reviewed and performed a meta-analysis on the prevalence of TDP-43 proteinopathy in older adults with normal cognition, evaluated by the Mini-Mental State Examination or the Clinical Dementia Rating. We estimated the overall prevalence of TDP-43 using random-effect models, and stratified by age, sex, sample size, study quality, antibody used to assess TDP-43 aggregates, analysed brain regions, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease score, hippocampal sclerosis and geographic location. ResultsA total of 505 articles were identified in the systematic review, and 7 were included in the meta-analysis with 1196 cognitively normal older adults. We found an overall prevalence of TDP-43 proteinopathy of 24%. Prevalence of TDP-43 proteinopathy varied widely across geographic location (North America: 37%, Asia: 29%, Europe: 14%, and Latin America: 11%). Estimated prevalence of TDP-43 proteinopathy also varied according to study quality (quality score >7: 22% vs. quality score <7: 42%), antibody used to assess TDP-43 proteinopathy (native: 18% vs. hyperphosphorylated: 24%) and presence of hippocampal sclerosis (without 24% vs. with hippocampal sclerosis: 48%). Other stratified analyses by age, sex, analysed brain regions, sample size and severity of AD neuropathology showed similar pooled TDP-43 prevalence. ConclusionsDifferent methodology to access TDP-43, and also differences in lifestyle and genetic factors across different populations could explain our results. Standardization of TDP-43 measurement, and future studies about the impact of genetic and lifestyle characteristics on the development of neurodegenerative diseases are needed.
- Chronic Traumatic Encephalopathy Presenting as Alzheimer's Disease in a Retired Soccer Player(2016) GRINBERG, Lea T.; ANGHINAH, Renato; NASCIMENTO, Camila Fernandes; AMARO JR., Edson; LEITE, Renata P.; MARTIN, Maria da Graca M.; NASLAVSKY, Michel S.; TAKADA, Leonel T.; JACOB FILHO, Wilson; PASQUALUCCI, Carlos A.; NITRINI, RicardoThe relationship between soccer and chronic traumatic encephalopathy (CTE) is not well established. We report clinicopathological correlations in an 83-year-old retired center-back soccer player, with no history of concussion, manifesting typical Alzheimer-type dementia. Examination revealed mixed pathology including widespread CTE, moderate Alzheimer's disease, hippocampal sclerosis, and TDP-43 proteinopathy. This case adds to a few CTE cases described in soccer players. Furthermore, it corroborates that CTE may present clinically as typical Alzheimer-type dementia. Further studies investigating the extent to which soccer is a risk for CTE are needed.
- Education, but not occupation, is associated with cognitive impairment: The role of cognitive reserve in a sample from a low-to-middle-income country(2022) SUEMOTO, Claudia K.; BERTOLA, Laiss; GRINBERG, Lea T.; LEITE, Renata E. P.; RODRIGUEZ, Roberta D.; SANTANA, Pedro H.; PASQUALUCCI, Carlos A.; JACOB-FILHO, Wilson; NITRINI, RicardoIntroduction Education, and less frequently occupation, has been associated with lower dementia risk in studies from high-income countries. We aimed to investigate the association of cognitive impairment with education and occupation in a low-middle-income country sample. Methods In this cross-sectional study, cognitive function was assessed by the Clinical Dementia Rating sum of boxes (CDR-SOB). We investigated the association of occupation complexity and education with CDR-SOB using adjusted linear regression models for age, sex, and neuropathological lesions. Results In 1023 participants, 77% had < 5 years of education, and 56% unskilled occupations. Compared to the group without education, those with formal education had lower CDR-SOB (1-4 years: beta= -0.99, 95% confidence interval [CI] = -1.85; -0.14, P = .02; >= 5 years: beta= -1.42, 95% CI = -2.47; -0.38, P = .008). Occupation complexity and demands were unrelated to cognition. Discussion Education, but not occupation, was related to better cognitive abilities independent of the presence of neuropathological insults.
- The influence of age and sex on the absolute cell numbers of the human brain cerebral cortex(2023) CASTRO-FONSECA, Emily; MORAIS, Viviane; SILVA, Camila G. da; WOLLNER, Juliana; FREITAS, Jaqueline; MELLO-NETO, Arthur F.; OLIVEIRA, Luiz E.; OLIVEIRA, Vilson C. de; LEITE, Renata E. P.; ALHO, Ana T.; RODRIGUEZ, Roberta D.; FERRETTI-REBUSTINI, Renata E. L.; SUEMOTO, Claudia K.; JACOB-FILHO, Wilson; NITRINI, Ricardo; PASQUALUCCI, Carlos A.; GRINBERG, Lea T.; TOVAR-MOLL, Fernanda; LENT, RobertoThe human cerebral cortex is one of the most evolved regions of the brain, responsible for most higher-order neural functions. Since nerve cells (together with synapses) are the processing units underlying cortical physiology and morphology, we studied how the human neocortex is composed regarding the number of cells as a function of sex and age. We used the isotropic fractionator for cell quantification of immunocytochemically labeled nuclei from the cerebral cortex donated by 43 cognitively healthy subjects aged 25-87 years old. In addition to previously reported sexual dimorphism in the medial temporal lobe, we found more neurons in the occipital lobe of men, higher neuronal density in women's frontal lobe, but no sex differences in the number and density of cells in the other lobes and the whole neocortex. On average, the neocortex has similar to 10.2 billion neurons, 34% in the frontal lobe and the remaining 66% uniformly distributed among the other 3 lobes. Along typical aging, there is a loss of non-neuronal cells in the frontal lobe and the preservation of the number of neurons in the cortex. Our study made possible to determine the different degrees of modulation that sex and age evoke on cortical cellularity.
- 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.
- 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.
- Direct Measurements of Abdominal Visceral Fat and Cognitive Impairment in Late Life: Findings From an Autopsy Study(2019) NISHIZAWA, Aline; CUELHO, Anderson; FARIAS-ITAO, Daniela S. de; CAMPOS, Fernanda M.; LEITE, Renata E. P.; FERRETTI-REBUSTINI, Renata E. L.; GRINBERG, Lea T.; NITRINI, Ricardo; JACOB-FILHO, Wilson; PASQUALUCCI, Carlos A.; SUEMOTO, Claudia K.Background: The relationship between cognitive impairment and abdominal visceral is controversial. Moreover, all studies so far used imaging studies to evaluate visceral fat and this association has not been described yet using autopsy material, which allows the direct quantification of abdominal fat. We aimed to investigate the association between direct measurements of abdominal visceral fat and cognitive impairment in an autopsy study. Methods: In this cross-sectional study, we collected information on sociodemographics, cardiovascular risk factors, and cognitive status from subjects aged 50 or older at time of death in a general autopsy service in Brazil. Abdominal visceral fat was obtained in natura by the dissection of perirenal, mesenteric, omental, and mesocolon fat. The associations of total abdominal visceral fat with cognitive impairment [clinical dementia rating (CDR) score >= 0.5] and CDR-sum of boxes (CDR-SB) were evaluated using logistic regression and negative binomial regression models, respectively. All analyses were adjusted for height, age, sex, education, hypertension, diabetes mellitus, stroke, smoking, alcohol use, and physical inactivity. In addition, we compared the discrimination of visceral fat, body mass index (BMI), and waist circumference (WC) measurements in predicting cognitive impairment. Results: We evaluated 234 participants (mean age = 71.2 +/- 12.9 years old, 59% male). Abdominal visceral fat was inversely associated with cognitive impairment (OR = 0.46, CI = 0.30; 0.70, p < 0.0001) and with CDR-SB scores (beta = 0.85, 95% CI = 1.28; 0.43, p < 0.0001). When we compared the area under the ROC curve (AUC), visceral fat (AUC = 0.754), BMI (AUC = 0.729), and WC (AUC = 0.720) showed similar discrimination in predicting cognitive impairment (p = 0.38). Conclusion: In an autopsy study, larger amount of directly measured abdominal visceral fat was associated with lower odds of cognitive impairment in older adults.
- Increased levels of TAR DNA-binding protein 43 in the hippocampus of subjects with bipolar disorder: a postmortem study(2022) NASCIMENTO, Camila; V, Paula Nunes; KIM, Helena K.; LEITE, Renata E. P.; RODRIGUEZ, Roberta D.; OLIVEIRA, Katia Cristina De; BRENTANI, Helena P.; JACOB-FILHO, Wilson; NITRINI, Ricardo; PASQUALUCCI, Carlos A.; GRINBERG, Lea T.; SUEMOTO, Claudia K.; LAFER, BenyBipolar disorder shares symptoms and pathological pathways with other neurodegenerative diseases, including frontotemporal dementia (FTD). Since TAR DNA-binding protein 43 (TDP-43) is a neuropathological marker of frontotemporal dementia and it is involved in synaptic transmission, we explored the role of TDP-43 as a molecular feature of bipolar disorder (BD). Homogenates were acquired from frozen hippocampus of postmortem brains of bipolar disorder subjects. TDP-43 levels were quantified using an ELISA-sandwich method and compared between the postmortem brains of bipolar disorder subjects and age-matched control group. We found higher levels of TDP-43 protein in the hippocampus of BD (n = 15) subjects, when compared to controls (n = 15). We did not find associations of TDP-43 with age at death, postmortem interval, or age of disease onset. Our results suggest that protein TDP-43 may be potentially implicated in behavioral abnormalities seen in BD. Further investigation is needed to validate these findings and to examine the role of this protein during the disease course and mood states.
- Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation(2023) YONAMINE, Caio Yogi; PASSARELLI, Marisa; SUEMOTO, Claudia Kimie; PASQUALUCCI, Carlos Augusto; JACOB-FILHO, Wilson; ALVES, Venancio Avancini Ferreira; MARIE, Suely Kazue Nagahashi; CORREA-GIANNELLA, Maria Lucia; BRITTO, Luiz Roberto; MACHADO, Ubiratan FabresDiabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4/GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1, TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4/GLUT4 expression but also the expression of some genes related to neuronal function (SYN1, TH, SYP). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration.
- Apolipoprotein E genotypes were not associated with intracranial atherosclerosis: a population-based autopsy study br(2023) PARADELA, Regina Silva; FARIAS-ITAO, Daniela Souza; LEITE, Renata E. P.; PASQUALUCCI, Carlos A.; GRINBERG, Lea T.; NASLAVSKY, Michel Satya; ZATZ, Mayana; NITRINI, Ricardo; JACOB-FILHO, Wilson; SUEMOTO, Claudia KimieBackground: Apolipoprotein E gene (APOE) 64 allele is associated with a higher risk of carotid atherosclerosis, but less is known about the association of APOE with intracranial atherosclerotic disease (IAD). We aimed to investigate the association of APOE alleles with IAD in a cross-sectional autopsy study.Methods: We measured the stenosis in the 12 arteries of the Circle of Willis using postmortem morphometric measurements. The APOE polymorphism was determined by real-time polymerase chain reaction. We assessed the association between APOE polymorphism and IAD using regression models adjusted for sociodemographic and clinical variables. We also verified the modifier effect of age, sex, and race on this association. We stratified the analysis by age group to investigate the possibility of attrition bias.Results: In 400 participants (mean age = 73.2 +/- 12.3 years old, 51% female, and 64% White), IAD was evaluated in 4,504 artery segments. APOE- 64 was not associated with IAD nor with the number of artery stenosis compared to non-APOE- 64 carriers. Sociodemographic variables did not modify this relationship. Among participants older than 70 years, there was a trend towards an association between APOE allele 64 and a lower stenosis index in the middle cerebral artery, suggesting attrition bias related to the APOE- 64 effect on mortality.Conclusions: APOE alleles were not associated with IAD in this population-based autopsy study. Lower stenosis in older participants suggests the possibility of attrition bias.