JOSE MARCELO FARFEL
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Ortopediae Traumatologia, Faculdade de Medicina - Docente
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
5 resultados
Resultados de Busca
Agora exibindo 1 - 5 de 5
- Sex differences in Alzheimer's disease and common neuropathologies of aging(2018) OVEISGHARAN, Shahram; ARVANITAKIS, Zoe; YU, Lei; FARFEL, Jose; SCHNEIDER, Julie A.; BENNETT, David A.Alzheimer's dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer's disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (n=971; 67%), with a mean age at death of 89.8 (SD=6.6) years in women and 87.3 (SD=6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate=0.102, SE=0.022, p<0.001), and tau tangle density in particular (estimate=0.334, SE=0.074, p<0.001), and there was a borderline difference between women and men in amyloid- load (estimate=0.124, SE=0.065, p=0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR=1.28, 95% CI:1.04-1.58, p=0.018), and less likely to have gross infarcts (OR=0.78, 95% CI:0.61-0.98, p=0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.
- Association of APOE with tau-tangle pathology with and without beta-amyloid(2016) FARFEL, Jose M.; YU, Lei; JAGER, Philip L. De; SCHNEIDER, Julie A.; BENNETT, David A.This study tested the hypothesis that the association of apolipoprotein E (APOE) with paired helical filament tau (PHF-tau) tangle pathology differs in brains with and without beta-amyloid. Participants were 1056 autopsied individuals from 2 clinical-pathologic cohort studies of aging and Alzheimer's disease (AD), the Religious Orders Study, and the Rush Memory and Aging Project. Neuropathologic measures were obtained using immunohistochemistry targeting beta-amyloid and PHF-tau tangles in 8 brain regions. Linear regression was used to compare the relation of APOE epsilon 4 and epsilon 2 to PHF-tau-tangle density in persons with beta-amyloid relative to persons without beta-amyloid. We found an interaction between APOE epsilon 4 carriers and presence of beta-amyloid (beta = -0.968, p = 0.013) such that the association of APOE epsilon 4 with PHF-tau tangles was much stronger in brains with beta-amyloid. Stratified analysis shows that the association of APOE epsilon 4 with PHF-tau tangles was considerably stronger among those with beta-amyloid (beta = 0.757, p = 1.1 x 10(-15)) compared to those without beta-amyloid which was not significant (beta = -0.201, p = 0.424). Separately, APOE epsilon 2 was associated with fewer tangles in brains with beta-amyloid (beta = -0.425, p = 7.6 x 10(-4)) compared to those without beta-amyloid which was not significant (beta = -0.102, p = 0.506). Thus, the presence of APOE epsilon 4 and epsilon 2 alleles was not associated with PHF-tau tangles in the absence of beta-amyloid. The data provide additional evidence that PHF-tau tangles in the absence of beta-amyloid may reflect a pathologic process distinct from Alzheimer's disease.
- Alzheimer's disease frequency peaks in the tenth decade and is lower afterwards(2019) FARFEL, Jose M.; YU, Lei; BOYLE, Patricia A.; LEURGANS, Sue; SHAH, Raj C.; SCHNEIDER, Julie A.; BENNETT, David A.Age is the most robust risk factor for Alzheimer's dementia, however there is little data on the relation of age to Alzheimer's disease (AD) and other common neuropathologies that contribute to Alzheimer's dementia. We use data from two community-based, clinical-pathologic cohorts to examine the association of age with AD and other common pathologies. Participants were 1420 autopsied individuals from the Religious Orders Study or Rush Memory and Aging Project who underwent annual clinical evaluations for diagnosis of Alzheimer's dementia, mild cognitive impairment (MCI), and level of cognition. The neuropathologic traits of interest were pathologic AD according to modified NIA-Reagan criteria, three quantitative measures of AD pathology (global AD pathology score, beta-amyloid load and PHFtau tangle density), macro- and micro-scopic infarcts, neocortical Lewy bodies, TDP-43 and hippocampal sclerosis. Semiparametric generalized additive models examined the nonlinear relationship between age and the clinical and pathological outcomes. The probability of Alzheimer's dementia at death increased with age such that for every additional year of age, the log odds of Alzheimer's dementia was 0.067 higher, corresponding to an odds ratio of 1.070 (p<0.001). Results were similar for cognitive impairment and level of cognition. By contrast, a nonlinear relationship of age with multiple indices of AD pathology was observed (all ps<0.05), such that pathologic AD reached a peak around 95years of age and leveled off afterwards; the quantitative measures of AD pathology were significantly lower at ages above 95. The association of age with other neuropathologies was quite distinct from that of AD in that most increased with advancing age. AD pathology appears to peak around 95years of age while other common pathologies continue to increase with age.
- APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults(2019) LAMAR, Melissa; YU, Lei; RUBIN, Leah H.; JAMES, Bryan D.; BARNES, Lisa L.; FARFEL, Jose Marcelo; GAITERI, Chris; BUCHMAN, Aron S.; BENNETT, David A.; SCHNEIDER, Julie A.Introduction: Apolipoprotein E (APOE) is a susceptibility gene for late-onset Alzheimer's disease neuropathology; less is known about the relationship between APOE and cerebrovascular disease (CVD) neuropathology. Methods: We investigated associations of APOE status with arteriolosclerosis, macroinfarcts and microinfarcts, and atherosclerosis in 1383 adults (65.9-108.2 years at death) with and without dementia. Excluding epsilon 2/epsilon 4 carriers, multivariable regressions for each CVD-related neuropathology compared epsilon 4 and epsilon 2 carriers to epsilon 3/epsilon 3 carriers adjusting for confounders including age and Alzheimer's neuropathology. Results: Three hundred forty-two individuals (24.7%; similar to 87.7 years at death; 39.9% nondemented) were epsilon 3/epsilon 4 or epsilon 4/epsilon 4, and 180 (13.0%; similar to 89.9 years at death; 66.6% nondemented) were epsilon 2/epsilon 3 or epsilon 2/epsilon 2. epsilon 4 carriers had higher odds of macroinfarcts (odds ratio = 1.41, 95% confidence interval: 1.02-1.94, P = .03), whereas epsilon 2 carriers had higher odds of moderate-to-severe arteriolosclerosis (odds ratio = 1.68, 95% confidence interval: 1.15-2.45, P = .006) compared to e3/e3 carriers. Age-stratified analyses suggested that these relationships were driven by epsilon 4 carriers <90 years at death and epsilon 2 carriers >= 90 years at death, respectively. Discussion: APOE differentially affects type and timing of CVD-related neuropathology.
- APOE epsilon 2 epsilon 4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults(2018) OVEISGHARAN, Shahram; BUCHMAN, Aron S.; YU, Lei; FARFEL, Jose; HACHINSKI, Vladimir; GAITERI, Chris; JAGER, Philip L. De; SCHNEIDER, Julie A.; BENNETT, David A.Objective To examine the association of the APOE epsilon 2 epsilon 4 genotype with incident Alzheimer disease (AD), mild cognitive impairment (MCI), cognitive decline, and AD pathology in older adults. Methods We used data from 2,151 older adults of European ancestry who were free of dementia at baseline and underwent structured annual clinical evaluation in a longitudinal study for incident AD and MCI, and cognitive decline. Postmortem examination in decedents documented pathologic AD and quantified ss-amyloid and neurofibrillary tangles. Participants were stratified into 4 groups based on APOE genotyping: epsilon 2 epsilon 4, epsilon 4 (epsilon 4 epsilon 4, epsilon 4 epsilon 3), epsilon 2 (epsilon 2 epsilon 2, epsilon 2 epsilon 3), with epsilon 3 epsilon 3 carriers serving as the reference group. We used Cox proportional hazards models to examine the association of APOE genotype with incident AD and MCI. Linear mixed-effect models were used to examine the association with cognitive decline. Logistic and linear regression models were used to examine AD pathology. All the models controlled for age, sex, and education. Results Of the 2,151 participants included in this study, epsilon 2 epsilon 4 accounted for 2.1%, epsilon 3/4 and 4/4 21.8%, epsilon 2/3 and 2/2 14.0%, and epsilon 3 epsilon 3 62.1%. We did not observe a difference in the risk of AD for epsilon 2 epsilon 4 compared to epsilon 3 epsilon 3. In cases without cognitive impairment at baseline, epsilon 2 epsilon 4 carriers had an increased risk of incident MCI (hazard ratio 2.13, 95% confidence interval 1.34-3.39, p = 0.002) and a faster rate of cognitive decline (estimate -0.047, SE 0.018, p = 0.008) compared to epsilon 3 epsilon 3 carriers. In decedents (n = 1,100), epsilon 2 epsilon 4 showed a 3-fold increased odds of pathologic AD and a higher ss-amyloid load than epsilon 3 epsilon 3. Conclusion APOE epsilon 2 epsilon 4 genotype in older adults is associated with risk of MCI, cognitive decline, and a greater burden of AD pathology, especially ss-amyloid.