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
10 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 10
- 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.
- Low brain-derived neurotrophic factor levels in post-mortem brains of older adults with depression and dementia in a large clinicopathological sample(2018) NUNES, Paula Villela; NASCIMENTO, Camila Fernandes; KIM, Helena Kyunghee; ANDREAZZA, Ana Cristina; BRENTANI, Helena Paula; SUEMOTO, Claudia Kimie; LEITE, Renata Elaine Paraizo; FERRETTI-REBUSTINI, Renata Eloah de Lucena; PASQUALUCCI, Carlos Augusto; NITRINI, Ricardo; GRINBERG, Lea Tenenholz; YONG, Lionel Trevor; JACOB-FILHO, Wilson; LAFER, BenyBackground: Disturbances in peripheral brain-derived neurotrophic factor (BDNF) have been reported in major depressive disorder (MDD). However, there are no studies measuring BDNF levels directly in post-mortem brains of older subjects with MDD and dementia. We aimed to verify if brain BDNF levels were lower in older adults with lifetime history of MDD with and without dementia. Methods: BDNF levels of post-mortem brains from 80 community-dwelling older individuals with lifetime MDD with and without dementia were compared with levels from 80 controls without lifetime MDD. Participants with no reliable close informant, or with prolonged agonal state were excluded. Lifetime MDD was defined as at least one previous episode according to the Structured Clinical Interview for DSM (SCID). Results: BDNF levels were lower in the MDD group with dementia than in participants with dementia and without MDD as confirmed by multivariate analysis adjusted for clinical and cardiovascular risk factors (beta = - 0.106, 95%CI = - 0.204; - 0.009, p = 0.034). No difference was found in the group with MDD without dementia compared with their controls. Limitations: The retrospective assessment of a lifetime history of depression may be subject to information bias and this study only establishes a cross-sectional association between lifetime history of MDD and lower levels of BDNF in patients with dementia. Conclusions: In this community sample of older individuals, lower brain BDNF levels were found in cases with both lifetime MDD and dementia. Low BDNF levels could be a moderator to accelerated brain aging observed in MDD with dementia.
- Factors associated with brain volume in major depression in older adults without dementia: results from a large autopsy study(2018) NUNES, Paula Villela; SUEMOTO, Claudia Kimie; LEITE, Renata Elaine Paraizo; FERRETTI-REBUSTINI, Renata Eloah de Lucena; PASQUALUCCI, Carlos Augusto; NITRINI, Ricardo; FARFEL, Jose Marcelo; OLIVEIRA, Katia Cristina de; GRINBERG, Lea Tenenholz; COSTA, Nicole Rezende da; NASCIMENTO, Camila Fernandes; SALMASI, Faraz; KIM, Helena Kyunghee; YOUNG, Lionel Trevor; JACOB-FILHO, Wilson; LAFER, BenyObjectiveWe examined brain volume and atrophy in individuals with major depressive disorder (MDD) without dementia that were referred to a large autopsy service. We also examined potential risk factors for brain atrophy, including demographics and clinical variables. MethodsIn this study, 1373 participants (787 male) aged 50years or older who died from natural causes were included. Participants with no reliable informant, with cognitive impairment or dementia, with a medical history of severe chronic disease, or with prolonged agonal state were excluded. Presence of MDD at least once in their lifetime was defined according to the Structured Clinical Interview for DSM. Brain volume was measured immediately after removal from the skull. ResultsMean age at death was 68.611.6, and MDD was present in 185 (14%) individuals. Smaller brain volume was associated with older age (p<0.001), lower education (years; p<0.001), hypertension (p=0.001), diabetes (p=0.006), and female gender (p<0.001). In the multivariate analysis adjusted for sociodemographics and cardiovascular risk factors, smaller brain volume was not associated with major depression (=-0.86, 95% CI=-26.50 to 24.77, p=0.95). ConclusionsIn this large autopsy study of older adults, MDD was not associated with smaller brain volumes. Regardless of the presence of MDD, in this sample of older adults without dementia, we found that smaller brain volumes were associated with risk factors for brain neurodegeneration such as older age, diabetes, hypertension, and lower education.
- Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease(2018) EHRENBERG, Alexander J.; SUEMOTO, Claudia K.; RESENDE, Elisa de Paula Franca; PETERSEN, Cathrine; LEITE, Renata Elaine Paraizo; RODRIGUEZ, Roberta Diehl; FERRETTI-REBUSTINI, Renata Eloah de Lucena; YOU, Michelle; OH, Jun; NITRINI, Ricardo; PASQUALUCCI, Carlos Augusto; JACOB-FILHO, Wilson; KRAMER, Joel H.; GATCHEL, Jennifer R.; GRINBERG, Lea T.Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-beta pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of Sao Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-beta burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-beta pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.
conferenceObject Increased Transactive Response DNA-Binding Protein (TDP-43) Levels in Bipolar Disorder: A Postmortem Study(2018) NASCIMENTO, Camila; NUNES, Paula Villela; KIM, Helena K.; OLIVEIRA, Katia C.; LEITE, Renata P.; FERRETTI-REBUSTINI, Renata E.; GRINBERG, Lea T.; SUEMOTO, Claudia K.; PASQUALUCCI, Carlos A.; NITRINI, Ricardo; ACOB-FILHO, Wilson J.; BRENTANI, Helena P.; LAFER, BenyconferenceObject Transactive response DNA-binding protein 43 as a neuromarker of bipolar disorder(2018) NASCIMENTO, C.; VILLELA, P. Nunes; OLIVEIRA, K. C. De; BARBOSA, A.; KIM, H. Kyunghee; MORETTO, A. C.; LEITE, R. E. Paraizo; FERRETTI-REBUSTINI, R. Eloah de Lucena; GRINBERG, L. Tenenholz; SUEMOTO, C. Kimie; FARFEL, J. M.; PASQUALUCCI, C. A.; BRENTANI, H. P.; NITRINI, R.; JACOB-FILHO, W.; LAFER, B.- 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.
- Increased DNA Copy Number Variation Mosaicism in Elderly Human Brain(2018) VILLELA, Darine; SUEMOTO, Claudia K.; LEITE, Renata; PASQUALUCCI, Carlos Augusto; GRINBERG, Lea T.; PEARSON, Peter; ROSENBERG, CarlaAging is a complex process strongly determined by genetics. Previous reports have shown that the genome of neuronal cells displays somatic genomic mosaicism including DNA copy number variations (CNVs). CNVs represent a significant source of genetic variation in the human genome and have been implicated in several disorders and complex traits, representing a potential mechanism that contributes to neuronal diversity and the etiology of several neurological diseases and provides new insights into the normal, complex functions of the brain. Nonetheless, the features of somatic CNV mosaicism in nondiseased elderly brains have not been investigated. In the present study, we demonstrate a highly significant increase in the number of CNVs in nondiseased elderly brains compared to the blood. In two neural tissues isolated from paired postmortem samples (same individuals), we found a significant increase in the frequency of deletions in both brain areas, namely, the frontal cortex and cerebellum. Also, deletions were found to be significantly larger when present only in the cerebellum. The sizes of the variants described here were in the 150-760 kb range, and importantly, nearly all of them were present in the Database of Genomic Variants (common variants). Nearly all evidence of genome structural variation in human brains comes from studies detecting changes in single cells which were interpreted as derived from independent, isolated mutational events. The observations based on array-CGH analysis indicate the existence of an extensive clonal mosaicism of CNVs within and between the human brains revealing a different type of variation that had not been previously characterized.
- Morphometric measurements of extracranial and intracranial atherosclerotic disease: A population-based autopsy study(2018) SUEMOTO, Claudia K.; GRINBERG, Lea T.; LEITE, Renata E. P.; FERRETTI-REBUSTINI, Renata E. L.; JACOB-FILHO, Wilson; YAFFE, Kristine; NITRINI, Ricardo; PASQUALUCCI, Carlos A.Background and aims: Intracranial (IAD) and extracranial atherosclerotic diseases (EAD) have been mostly investigated using imaging methods. Autopsy studies allow for a direct and complete evaluation of the atherosclerotic disease. We aimed to investigate the frequency of IAD and EAD, their association, and related risk profiles in a large cross-sectional autopsy study. Methods: We measured the intima-media thickness and stenosis of the common (CCA) and internal carotid arteries (ICA), using morphometric measurements. The main outcome was stenosis (>= 50%) in the artery with the largest obstruction among the 12 cerebral arteries. We used multivariable logistic regression models to investigate the association between EAD and IAD. Results: In 661 participants (mean age = 71.3 +/- 11.7 y, 51% male), stenosis was more common in IAD than in EAD (59% vs. 51%). EAD was associated with Caucasian race, hypertension, and smoking, while IAD was associated with older age, less years of education, hypertension, diabetes, and a previous history of stroke. Stenosis in CCA and ICA was associated with more than two times the odds of having stenosis in the intracranial arteries (CCA: OR = 2.32, 95% CI = 1.64; 3.28; ICA: OR = 2.51, 95% CI = 1.76; 3.57). Conclusions: In this population-based autopsy study, IAD was common, even more common than EAD, but correlated with EAD.
- Subcortical neurodegeneration in chorea: Similarities and differences between chorea-acanthocytosis and Huntington's disease(2018) LIU, Jia; HEINSEN, Helmut; GRINBERG, Lea T.; ALHO, Eduardo; AMARO JR., Edson; PASQUALUCCI, Carlos A.; RUEB, Udo; DUNNEN, Wilfred den; ARZBERGER, Thomas; SCHMITZ, Christoph; KIESSLING, Maren; BADER, Benedikt; DANEK, AdrianIntroduction: Chorea-acanthocytosis (ChAc) and Huntington's disease (HD) are neurodegenerative conditions that share clinical and neuropathological features, despite their distinct genetic etiologies. Methods: In order to compare these neuropathologies, serial gallocyanin-stained brain sections from three subjects with ChAc were analyzed and compared with our previous studies of eight HD cases, in addition to three hemispheres from two male controls. Results: Astrogliosis was much greater in the ChAc striatum, as compared to that found in HD, with dramatic increase in total striatal glia numbers and the number of glia per striatal neuron. Striatal astrocytes are most likely derived from the striatal subependymal layer in ChAc, which showed massive proliferation. The thalamic centromedian-parafascicular complex is reciprocally connected to the striatum and is more heavily affected in HD than in ChAc. Conclusion: The distinct patterns of selective vulnerability and gliosis observed in HD and ChAc challenge simplistic views on the pathogenesis of these two diseases with rather similar clinical signs. The particular roles played by astroglia in ChAc and in HD clearly need to be elucidated in more detail.