RESUMO
Importance: Race differences in dementia prevalence and incidence have previously been reported, with higher dementia burden in Black decedents. However, previous neuropathological studies were conducted mostly in convenience samples with White participants; conducting clinicopathological studies across populations is crucial for understanding the underlying dementia causes in individuals from different racial backgrounds. Objective: To compare the frequencies of neuropathological lesions and cognitive abilities between Black and White Brazilian adults in an autopsy study. Design, Setting, and Participants: This cross-sectional study used samples from the Biobank for Aging Studies, a population-based autopsy study conducted in Sao Paulo, Brazil. Participants were older adults whose family members consented to the brain donations; Asian participants and those with missing data were excluded. Samples were collected from 2004 to 2023. Neuropathologists were masked to cognitive outcomes. Exposure: Race as reported by the deceased's family member. Main Outcomes and Measures: The frequencies of neurodegenerative and cerebrovascular lesions were evaluated in 13 selected cerebral areas. Cognitive and functional abilities were examined with the Clinical Dementia Rating Scale. Results: The mean (SD) age of the 1815 participants was 74.0 (12.5) years, 903 (50%) were women, 617 (34%) were Black, and 637 (35%) had cognitive impairment. Small vessel disease (SVD) and siderocalcinosis were more frequent in Black compared with White participants (SVD: odds ratio [OR], 1.74; 95% CI, 1.29-2.35; P < .001; siderocalcinosis: OR, 1.70; 95% CI, 1.23-2.34; P = .001), while neuritic plaques were more frequent in White compared with Black participants (OR, 0.61; 95% CI, 0.44-0.83; P = .002). Likewise, Alzheimer disease neuropathological diagnosis was more frequent in White participants than Black participants (198 [39%] vs 77 [33%]), while vascular dementia was more common among Black participants than White participants (76 [32%] vs 121 [24%]). Race was not associated with cognitive abilities, nor did it modify the association between neuropathology and cognition. Conclusions and Relevance: In this cross-sectional study of Brazilian older adults, Alzheimer disease pathology was more frequent in White participants while vascular pathology was more frequent in Black participants. Further neuropathological studies in diverse samples are needed to understand race disparities in dementia burden.
Assuntos
População Branca , Humanos , Brasil/epidemiologia , Feminino , Masculino , Idoso , Estudos Transversais , População Branca/estatística & dados numéricos , População Branca/psicologia , Idoso de 80 Anos ou mais , Cognição , Demência/epidemiologia , Demência/etnologia , Encéfalo/patologia , Autopsia , População Negra/estatística & dados numéricos , População Negra/psicologiaRESUMO
BACKGROUND: We aimed to analyze the trajectories of cognitive decline as a function of the presence of type 2 diabetes and glycemic control in analyzes stratified by sex in an 8-year follow-up period. METHODS: A total of 1 752 men and 2 232 women aged ≥50 years who participated in the English Longitudinal Study of Ageing (ELSA), conducted from 2004 to 2012, were analyzed. The outcomes of interest were performance on the cognitive domains of memory, executive function, and temporal orientation as well as the global cognition score. Cognitive performance was standardized in z-scores in strata based on schooling and age. The participants were classified as without diabetes, with controlled glycemia, and with uncontrolled glycemia, according to medical diagnosis, glucose-lowering medications use and HbA1c levels. Generalized linear mixed models controlled by sociodemographic, behavioral, and health-related characteristics were used for the trajectory analyses. RESULTS: No differences in z-scores were found for global cognition or cognitive domains based on diabetes classification in men and women at baseline. More than 8 years of follow up, women with uncontrolled glycemia had a greater decline in z-scores for global cognition (-0.037 SD/year [95% CI: -0.073; -0.001]) and executive function (-0.049 SD/year [95% CI: -0.092; -0.007]) compared with those without diabetes. No significant difference in trajectories of global cognition or any cognitive domain was found in men as a function of diabetes classification. CONCLUSIONS: Women with uncontrolled glycemia are at greater risk of a decline in global cognition and executive function than those without diabetes.
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Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Humanos , Feminino , Masculino , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/sangue , Pessoa de Meia-Idade , Idoso , Estudos Longitudinais , Fatores Sexuais , Função Executiva/fisiologia , Controle Glicêmico , Glicemia/análise , Glicemia/metabolismo , Hemoglobinas Glicadas/análiseRESUMO
INTRODUCTION: Twelve modifiable risk factors (RFs) account for 40% of dementia cases worldwide. However, limited data exist on such factors in middle- and low-income countries. We aimed to estimate the population-attributable fractions (PAFs) for the 12 RFs in Argentina, assessing changes over a decade and exploring socioeconomic and sex influences. METHODS: We conducted cross-sectional analyses of the 12 RFs from Argentinian surveys conducted in 2009, 2015, and 2018, including 96,321 people. We calculated PAFs and stratified estimates based on sex and income. RESULTS: We estimated an overall PAF of 59.6% (95% CI = 58.9-60.3%). The largest PAFs were hypertension = 9.3% (8.7-9.9%), physical inactivity = 7.4% (6.8-8.2%), and obesity = 7.4% (6.8-7.9%). Men were more impacted by excessive alcohol, while women by isolation and smoking. Lower income linked to higher PAFs in education, hypertension, and obesity. DISCUSSION: Argentina has a higher PAF for dementia than the world population, with distinct RF distribution. PAF varied by sex and economic status, advocating tailored prevention strategies.
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Demência , Fatores Socioeconômicos , Humanos , Argentina/epidemiologia , Feminino , Masculino , Demência/epidemiologia , Estudos Transversais , Idoso , Fatores de Risco , Pessoa de Meia-Idade , Fatores Sexuais , Idoso de 80 Anos ou mais , Adulto , Obesidade/epidemiologia , Hipertensão/epidemiologia , Disparidades nos Níveis de Saúde , Disparidades Socioeconômicas em SaúdeRESUMO
The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models. We found a marked increase in ubiquitinylated proteins in post-mortem AD hippocampi compared to controls. Using several experimental models, we show that amyloid-ß oligomers (AßOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1ΔE9 mice. Reduced synaptic proteasome activity instigated by AßOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AßO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.
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Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Complexo de Endopeptidases do Proteassoma , Plasticidade Neuronal , Transtornos da Memória/tratamento farmacológicoRESUMO
BACKGROUND: The association between social isolation and cognitive performance has been less investigated in low-to-middle-income countries (LMIC) and the presence of depression as a moderator on this association has not been examined. The authors examined the associations of social isolation and perceived loneliness with cognitive performance in the Brazilian Longitudinal Study of Aging. METHODS: In this cross-sectional analysis, social isolation was evaluated by a composite score including marital status, social contact, and social support. The dependent variable was global cognitive performance, which considered memory, verbal fluency, and temporal orientation tests. Linear and logistic regressions were adjusted for sociodemographic and clinical variables. The authors added interaction terms of depressive symptoms with social isolation and loneliness to examine whether depression, measured through the Center for Epidemiologic Studies-Depression Scale, modified these associations. RESULTS: Among 6,986 participants (mean age = 62.1 ± 9.2 years), higher levels of social connections were associated with better global cognitive performance (B = 0.02, 95%CI: 0.02; 0.04). Perceived loneliness was associated with worse cognition (B = -0.26, 95%CI = -0.34; -0.18). Interactions of depressive symptoms with social connections scores were found on memory z-score and with loneliness on global and memory z-scores, suggesting a weaker association between social isolation or loneliness and cognition among those with depressive symptoms. CONCLUSION: In a large sample from an LMIC, social isolation and loneliness were associated with worse cognitive performance. Surprisingly, depressive symptoms decrease the strength of these associations. Future longitudinal studies are important to assess the direction of the association between social isolation and cognitive performance.
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Solidão , Isolamento Social , Humanos , Idoso , Solidão/psicologia , Brasil/epidemiologia , Estudos Longitudinais , Estudos Transversais , Isolamento Social/psicologia , CogniçãoRESUMO
The 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 ~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.
Assuntos
Córtex Cerebral , Neocórtex , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Lobo Temporal , Neurônios , Lobo Occipital/anatomia & histologia , Lobo Frontal/anatomia & histologia , Contagem de CélulasRESUMO
Aging is marked by complex and progressive physiological changes, including in the glutamatergic system, that lead to a decline of brain function. Increased content of senescent cells in the brain, such as glial cells, has been reported to impact cognition both in animal models and human tissue during normal aging and in the context of neurodegenerative disease. Changes in the glutamatergic synaptic activity rely on the glutamate-glutamine cycle, in which astrocytes handle glutamate taken up from synapses and provide glutamine for neurons, thus maintaining excitatory neurotransmission. However, the mechanisms of glutamate homeostasis in brain aging are still poorly understood. Herein, we showed that mouse senescent astrocytes in vitro undergo upregulation of GLT-1, GLAST, and glutamine synthetase (GS), along with the increased enzymatic activity of GS and [3H]-D-aspartate uptake. Furthermore, we observed higher levels of GS and increased [3H]-D-aspartate uptake in the hippocampus of aged mice, although the activity of GS was similar between young and old mice. Analysis of a previously available RNAseq dataset of mice at different ages revealed upregulation of GLAST and GS mRNA levels in hippocampal astrocytes during aging. Corroborating these rodent data, we showed an increased number of GS + cells, and GS and GLT-1 levels/intensity in the hippocampus of elderly humans. Our data suggest that aged astrocytes undergo molecular and functional changes that control glutamate-glutamine homeostasis upon brain aging.
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Astrócitos , Doenças Neurodegenerativas , Animais , Humanos , Camundongos , Idoso , Astrócitos/metabolismo , Glutamina/genética , Glutamina/metabolismo , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Regulação para Cima , Sistema X-AG de Transporte de Aminoácidos/genética , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Ácido D-Aspártico/genética , Ácido Glutâmico/metabolismo , Hipocampo/metabolismoRESUMO
Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid ß (Aß), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aß deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE.
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Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Adulto , Humanos , Pessoa de Meia-Idade , Epilepsia do Lobo Temporal/patologia , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Convulsões/metabolismo , Epilepsia Resistente a Medicamentos/patologia , CogniçãoRESUMO
Sleep disturbances often co-exist, which challenges our understanding of their potential impact on cognition. We explored the cross-sectional associations of insomnia and objective measures of sleep with cognitive performance in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) study stratified by middle-aged and older adults. Participants aged ≥55 years underwent cognitive evaluations, polygraphy for 1 night, and actigraphy for 7 days. Insomnia was evaluated using the Clinical Interview Scheduled Revised. Obstructive sleep apnea (OSA) and short sleep duration (SSD) were defined by an apnea-hypopnea index (AHI) of ≥15 events/h and <6 h/ night, respectively. In 703 participants (mean [SD] age 62 [6] years, 44% men), cognition was evaluated using a 10-word list, verbal fluency, and trail-making tests. The frequencies of insomnia, SSD, and OSA were 11%, 24%, and 33%, respectively. In all, 4% had comorbid OSA and insomnia, and 11% had both OSA and SSD. Higher wake after sleep onset (ß = -0.004, 95% confidence interval [CI] -0.008, -0.001) and the number of awakenings (ß = -0.006, 95% CI -0.012, -0.001) were associated with worse verbal fluency performance. Compared to those without insomnia, older participants with insomnia had worse global performance (ß = -0.354, 95% CI -0.671, -0.038). Insomnia was an effect modifier in the associations between AHI and executive function performance (p for the interaction between insomnia and AHI = 0.004) and between oxygen saturation <90% and memory performance (p for the interaction between insomnia and oxygen saturation = 0.02). Although some associations between sleep measures and cognition were significant, they should be considered with caution due to the large sample size and multiple testing performed in this study.
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Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Masculino , Pessoa de Meia-Idade , Humanos , Idoso , Feminino , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/complicações , Estudos Transversais , Estudos Longitudinais , Brasil/epidemiologia , Sono , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , CogniçãoRESUMO
INTRODUCTION: Twelve risk factors (RFs) account for 40% of dementia cases worldwide. However, most data for population attributable fractions (PAFs) are from high-income countries (HIC). We estimated how much these RFs account for dementia cases in Brazil, stratifying estimates by race and socioeconomic level. METHODS: We calculated the prevalence and communalities of 12 RFs using 9412 Brazilian Longitudinal Study of Aging participants, then stratified according to self-reported race and country macro-regions. RESULTS: The overall weighted PAF was 48.2%. Less education had the largest PAF (7.7%), followed by hypertension (7.6%), and hearing loss (6.8%). PAF was 49.0% and 54.0% in the richest and poorest regions, respectively. PAFs were similar among White and Black individuals (47.8% and 47.2%, respectively) but the importance of the main RF varied by race. DISCUSSION: Brazil's potential for dementia prevention is higher than in HIC. Education, hypertension, and hearing loss should be priority targets.