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
12 resultados
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- 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.
- Neuropathological correlates of neuropsychiatric symptoms in dementia(2023) GIBSON, Lucy L.; GRINBERG, Lea T.; FFYTCHE, Dominic; LEITE, Renata E. P.; RODRIGUEZ, Roberta D.; FERRETTI-REBUSTINI, Renata E. L.; PASQUALUCCI, Carlos A.; NITRINI, Ricardo; JACOB-FILHO, Wilson; AARSLAND, Dag; SUEMOTO, Claudia K.Introduction Neuropsychiatric symptoms (NPS) are common in Lewy body disease (LBD), but their etiology is poorly understood. Methods In a population-based post mortem study neuropathological data was collected for Lewy body (LB) neuropathology, neurofibrillary tangles (NFT), amyloid beta burden, TDP-43, lacunar infarcts, cerebral amyloid angiopathy (CAA), and hyaline atherosclerosis. Post mortem interviews collected systematic information regarding NPS and cognitive status. A total of 1038 cases were included: no pathology (NP; n = 761), Alzheimer's disease (AD; n = 189), LBD (n = 60), and AD+LBD (n = 28). Results Hallucinations were associated with higher LB Braak stages, while higher NFT Braak staging was associated with depression, agitation, and greater number of symptoms in the Neuropsychiatric Inventory. Cases with dual AD+LBD pathology had the highest risk of hallucinations, agitation, apathy, and total symptoms but a multiplicative interaction between these pathologies was not significant. Discussion LB and AD pathology contribute differentially to NPS likely with an additive process contributing to the increased burden of NPS.
- 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 62 allele is associated with lower risk of carotid artery obstruction in a population-based autopsy study(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 KimieIntroduction: Apolipoprotein E (APOE) 64 allele has been associated with higher carotid atherosclerosis risk, while the APOE-62 seems to decrease this risk. Data from autopsy studies, where carotid arteries can be evaluated in their full extension, is scarce. Therefore, we investigated the association between APOE alleles and direct morphometric measurements of carotid atherosclerosis in an autopsy study with an admixed sample.Methods: We measured the intima-media thickness (IMT) and stenosis of the common (CCA) and internal carotid (ICA) arteries. The APOE polymorphisms were determined by real-time polymerase chain reaction. Participants were classified into three groups according to the APOE alleles (62, 63, and 64). We evaluated the association between APOE groups and carotid atherosclerosis using adjusted regression models and included interaction terms of APOE alleles with age, sex, and race. Results: We evaluated 1,850 carotid artery samples from 185 participants (mean age=75 & PLUSMN;12 years old, 55% female, and 71% White). The APOE-62 group (n=17) had a lower carotid obstruction and a lower number of severe stenoses (& GE; 70%). Having at least one 64 allele (n=51) was not associated with carotid atherosclerosis. APOE alleles were also not associated with carotid IMT. Age, sex, and race did not modify these relationships.Conclusion: APOE-62 carriers had a lower percentage of carotid obstruction and less severe stenosis. APOE-64 was not related to a higher risk of carotid atherosclerosis in this cross-sectional population-based autopsy study.
- Risk and protective factors for dementia: epidemiological evidence and windows of opportunity(2022) SUEMOTO, C. K.; NITRINI, R.; GRINBERG, L. T.; LEITE, R. E. P.; PASQUALLUCCI, C. A.; BERTOLA, L.; VIDAL-FERREIRA, N.; SZLEFJ, C.; CARAMELLI, P.; BENSENOR, I. M.; LOTUFO, P. A.; ALIBERTI, M. J. R.; FERRI, C. P.; JACOB-FILHO, W.Background: Most people with dementia already live in low- to middle-income countries (LMIC). However, most evidence regarding dementia prevention comes from high-income countries that have different socioeconomic status (SES) and risk factors prevalence than LMIC. In this session, we will present results on risk and protective factors for dementia from the Longitudinal Study of Adult Health (ELSA-Brasil), the Brazilian Longitudinal Study of Aging (ELSI-Brazil), and the Brazilian Biobank for Aging Studies (BAS). Method: The ELSA-Brasil follows 15,105 public servants since 2008-10. The ELSI-Brazil is a nationally representative study with 9,412 adults aged 50 years and older, who were enrolled in 2015-16. The BAS is a neuropathology study that started in 2004 and is the largest brain bank in Latin America with a collection of 1,441 brains. The focus of this presentation will be on the associations of education, SES, and cardiovascular factors with dementia using data from these three studies. Result: In the BAS, 77% of the sample has less than 5 years of education and 56% unskilled occupations. Compared to the group without education, those with formal education had better cognitive performance (1-4 years: β = -0.99, 95%CI = –1.85; –0.14, p = 0.02; ≥5 years: = –1.42, 95% CI = –2.47; –0.38, p = 0.008). On the other hand, occupation complexity and demands were unrelated to cognition. Similarly, we showed that education and early-life SES were the main contributors to cognitive performance in the ELSA-Brasil, while later SES had a lower influence on cognitive scores. Cardiovascular factors are also important contributors to brain health. Ideal vascular health was related to better cognitive function in the ELSA-Brasil. Participants with intermediate (β = 0.064, 95%CI = 0.033; 0.096) and optimal health (β = 0.108, 95%CI = 0.052; 0.164) had better cognitive z-scores. Moreover, carotid artery atherosclerosis evaluated by morphometric measurements was related to cognitive impairment in BAS and with cognitive decline in the ELSA-Brasil after 8 years of follow-up (β = -0.028, 95%CI = -0.036; -0.020, p<0.001). Finally, hypertension was related to worse cognition (β = -0.09; 95%CI = -0.15, -0.04; p = 0.001) in ELSI-Brazil, mainly in non-frail participants. Conclusion: Studies from LMIC regarding dementia risk factors are essential to implement tailored public policies for dementia primary prevention. © 2022 the Alzheimer's Association.
article 0 Citação(ões) na Scopus Cause of Death Determined by Full-body Autopsy in Neuropathologically Diagnosed Dementias The Biobank for Aging Studies of the University of Sao Paulo (BAS-USP), Brazil(2022) NEVES, Beatriz Astolfi; NUNES, Paula Villela; RODRIGUEZ, Roberta Diehl; HAIDAR, Atmis Medeiros; LEITE, Renata Elaine Paraizo; NASCIMENTO, Camila; PASQUALUCCI, Carlos Augusto; NITRINI, Ricardo; JACOB-FILHO, Wilson; LAFER, Beny; GRINBERG, Lea TenenholzObjective: This study aimed to compare causes of death in the most prevalent neuropathologically diagnosed dementias. Methods: We analyzed causes of death in a community-based cohort of participants aged 50 or older, submitted to full-body autopsy and a comprehensive neuropathologic examination of the brain. Individuals with Alzheimer disease (AD), vascular dementia (VaD), mixed dementia (AD+VaD), or dementia with Lewy bodies (DLBs) were compared with individuals with no dementia. Results: In a sample of 920 individuals, 456 had no dementia, 147 had AD, 120 had VaD, 53 had DLB, and 37 had AD+VaD. Pneumonia as the cause of death was more frequent in the AD (P= 0.023), AD+VaD (P= 0.046), and DLB (P= 0.043) groups. In addition, VaD (P= 0.041) and AD+VaD (P= 0.028) groups had a higher frequency of atherosclerosis as detected by full-body autopsy. Conclusion: Our findings highlight the importance of preventive measures regarding atherosclerosis and pneumonia in patients with dementia. Moreover, because of cognitive impairment, these patients may not fully account for symptoms to make early detection and diagnosis possible. These results confirm findings from previous studies that were based on clinical data, with added accuracy provided by neuropathologic diagnosis and full-body autopsy reports.- Resilience of Neural Cellularity to the Influence of Low Educational Level(2023) MORAIS, Viviane A. Carvalho de; OLIVEIRA-PINTO, Ana V. de; MELLO NETO, Arthur F.; FREITAS, Jaqueline S.; SILVA, Magnolia M. da; SUEMOTO, Claudia Kimie; LEITE, Renata P.; GRINBERG, Lea T.; JACOB-FILHO, Wilson; PASQUALUCCI, Carlos; NITRINI, Ricardo; CARAMELLI, Paulo; LENT, RobertoBackground: Education is believed to contribute positively to brain structure and function, as well as to cognitive reserve. One of the brain regions most impacted by education is the medial temporal lobe (MTL), a region that houses the hippocampus, which has an important role in learning processes and in consolidation of memories, and is also known to undergo neurogenesis in adulthood. We aimed to investigate the influence of education on the absolute cell numbers of the MTL (comprised by the hippocampal formation, amygdala, and parahippocampal gyrus) of men without cognitive impairment. Methods: The Isotropic Fractionator technique was used to allow the anisotropic brain tissue to be transformed into an isotropic suspension of nuclei, and therefore assess the absolute cell composition of the MTL. We dissected twenty-six brains from men aged 47 to 64 years, with either low or high education. Results: A significant difference between groups was observed in brain mass, but not in MTL mass. No significant difference was found between groups in the number of total cells, number of neurons, and number of non-neuronal cells. Regression analysis showed that the total number of cells, number of neurons, and number of non-neuronal cells in MTL were not affected by education. Conclusions: The results indicate a resilience of the absolute cellular composition of the MTL of typical men to low schooling, suggesting that the cellularity of brain regions is not affected by formal education.
- Gene expression alterations in the postmortem hippocampus from older patients with bipolar disorder-A hypothesis generating study(2023) NASCIMENTO, Camila; KIM, Helena Kyunghee; NUNES, Paula Villela; LEITE, Renata Elaine Paraiso; CRISTINA, De Oliveira Katia; BARBOSA, Andre; BERTONHA, Fernanda Bernardi; MOREIRA-FILHO, Carlos Alberto; JACOB-FILHO, Wilson; NITRINI, Ricardo; PASQUALUCCI, Carlos A.; GRINBERG, Lea Tenenholz; SUEMOTO, Claudia Kimie; BRENTANI, Helena Paula; LAFER, BenyBipolar disorder (BD) presents with a progressive course in a subset of patients. However, our knowledge of molecular changes in older BD is limited. In this study, we examined gene expression changes in the hippocampus of BD from the Biobank of Aging Studies to identify genes of interest that warrant further exploration. RNA was extracted from the hippocampus from 11 subjects with BD and 11 age and sex-matched controls. Gene expression data was generated using the SurePrint G3 Human Gene Expression v3 microarray. Rank feature selection was performed to identify a subset of features that can optimally differentiate BD and controls. Genes ranked in the top 0.1% with log2 fold change >1.2 were identified as genes of interest. Average age of the subjects was 64 years old; duration of disease was 21 years and 82% were female. Twenty-five genes were identified, of which all but one was downregulated in BD. Of these, CNTNAP4, MAP4, SLC4A1, COBL, and NEURL4 had been associated with BD and other psychiatric conditions in previous studies. We believe our findings have identified promising targets to inform future studies aiming to understand the pathophysiology of BD in later life.
- The Potential Role of Selection Bias in the Association Between Coronary Atherosclerosis and Cognitive Impairment(2023) YAHAGI-ESTEVAM, Maristella; FARIAS-ITAO, Daniela Souza; LEIT, Renata Elaine Paraizo; RODRIGUEZ, Roberta Diehl; PASQUALUCCI, Carlos Augusto; NITRINI, Ricardo; JACOB-FILHO, Wilson; POWER, Melinda C.; SUEMOTO, Claudia KimieBackground: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples. Objective: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study. Methods: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias. Results: In 253 participants (mean age = 78.0 +/- 8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR = 0.85, 95%CI = 0.69; 1.06, p = 0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR = 4.02, 95%CI = 1.39; 11.6, p = 0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR = 0.83, 95%CI = 0.60; 1.16, p = 0.28). Conclusion: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples.
- Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample(2022) NASLAVSKY, Michel Satya; SUEMOTO, Claudia K.; BRITO, Luciano Abreu; SCLIAR, Marilia Oliveira; FERRETTI-REBUSTINI, Renata Eloah; RODRIGUEZ, Roberta Diehl; LEITE, Renata E. P.; ARAUJO, Nathalia Matta; BORDA, Victor; TARAZONA-SANTOS, Eduardo; JACOB-FILHO, Wilson; PASQUALUCCI, Carlos; NITRINI, Ricardo; YAFFE, Kristine; ZATZ, Mayana; GRINBERG, Lea T.Dementia is more prevalent in Blacks than in Whites, likely due to a combination of environmental and biological factors. Paradoxically, clinical studies suggest an attenuation of APOE epsilon 4 risk of dementia in African ancestry (AFR), but a dearth of neuropathological data preclude the interpretation of the biological factors underlying these findings, including the association between APOE epsilon 4 risk and Alzheimer's disease (AD) pathology, the most frequent cause of dementia. We investigated the interaction between African ancestry, AD-related neuropathology, APOE genotype, and functional cognition in a postmortem sample of 400 individuals with a range of AD pathology severity and lack of comorbid neuropathology from a cohort of community-dwelling, admixed Brazilians. Increasing proportions of African ancestry (AFR) correlated with a lower burden of neuritic plaques (NP). However, for individuals with a severe burden of NP and neurofibrillary tangles (NFT), AFR proportion was associated with worse Clinical Dementia Rating sum of boxes (CDR-SOB). Among APOE epsilon 4 carriers, the association between AFR proportion and CDR-SOB disappeared. APOE local ancestry inference of a subset of 309 individuals revealed that, in APOE epsilon 4 noncarriers, non-European APOE background correlated with lower NP burden and, also, worse cognitive outcomes than European APOE when adjusting by NP burden. Finally, APOE epsilon 4 was associated with worse AD neuropathological burden only in a European APOE background. APOE genotype and its association with AD neuropathology and clinical pattern are highly influenced by ancestry, with AFR associated with lower NP burden and attenuated APOE epsilon 4 risk compared to European ancestry.