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INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.
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Doença de Alzheimer , Encéfalo , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico por imagem , Humanos , Fluordesoxiglucose F18/metabolismo , Masculino , Feminino , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Idoso , Transcriptoma , Hipocampo/metabolismo , Hipocampo/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico por imagem , Idoso de 80 Anos ou maisRESUMO
In the pursuit of novel antioxidant therapies for the prevention and treatment of neurodegenerative diseases, three new arylpiperazine derivatives (LQFM181, LQFM276, and LQFM277) were synthesized through a molecular hybridization approach involving piribedil and butylated hydroxytoluene lead compounds. To evaluate the antioxidant and neuroprotective activities of the arylpiperazine derivatives, we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (neurotoxicity induced by 3-nitropropionic acid in Swiss mice) models. In the in vitro tests, LQFM181 showed the most promising antioxidant activity at the neuronal membrane and cytoplasmic levels, and significant neuroprotective activity against the neurotoxicity induced by 3-nitropropionic acid. Hence, this compound was further subjected to in vivo evaluation, which demonstrated remarkable antioxidant capacity such as reduction of MDA and carbonyl protein levels, increased activities of succinate dehydrogenase, catalase, and superoxide dismutase. Interestingly, using the same in vivo model, LQFM181 also reduced locomotor behavior and memory dysfunction through its ability to decrease cholinesterase activity. Consequently, LQFM181 emerges as a promising candidate for further investigation into its neuroprotective potential, positioning it as a new therapeutic agent for neuroprotection.
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Antioxidantes , Fármacos Neuroprotetores , Nitrocompostos , Piperazinas , Propionatos , Animais , Propionatos/toxicidade , Nitrocompostos/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Camundongos , Piperazinas/farmacologia , Piperazinas/química , Humanos , Linhagem Celular Tumoral , Antioxidantes/farmacologia , Masculino , Succinato Desidrogenase/metabolismo , Superóxido Dismutase/metabolismo , Catalase/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVES: To evaluate whether the glycosylation of chrysin (CHR) enhances its protective effects against aluminum-induced neurotoxicity. METHODS: To compare the antioxidant, anticholinesterase, and behavioral effects of CHR with its glycosylated form (CHR bonded to ß-d-glucose tetraacetate, denoted as LQFM280), we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (aluminum-induced neurotoxicity in Swiss mice) models. KEY FINDINGS: LQFM280 demonstrated higher antioxidant activity than CHR in both models. Specifically, LQFM280 exhibited the ability to exert antioxidant effects in the cytoplasm of SH-SY5Y cells, indicating its competence in traversing neuronal membranes. Remarkably, LQFM280 proved more effective than CHR in recovering memory loss and counteracting neuronal death in the aluminum chloride mice model, suggesting its increased bioavailability at the brain level. CONCLUSIONS: The glycosylation of CHR with ß-d-glucose tetraacetate amplifies its neuroprotective effects, positioning LQFM280 as a promising lead compound for safeguarding against neurodegenerative processes involving oxidative stress.
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Flavonoides , Neuroblastoma , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Camundongos , Animais , Humanos , Alumínio/toxicidade , Glucose/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Antioxidantes/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/prevenção & controle , Linhagem Celular TumoralRESUMO
BACKGROUND: Demographic changes in the world population have resulted in an increasingly aging society, with a progressive increase in the number of people in situations of dependence, who require assistance from family members to meet their basic needs. Caring for older adults involves performing diverse activities, resulting in reduced free time and tiredness, and fulfilling the demands and expectations related to personal, family, physical, and social life, consequently compromising the quality of life of the caregiver. In this context, the informal caregiver of hospitalized older adults emerges as the focus of attention. OBJECTIVE: The aim of this study was to describe the sociodemographic profile, health conditions, and burden of informal caregivers of older adults admitted to a university hospital in Brazil during the COVID-19 pandemic period. METHODS: This is a cross-sectional, descriptive, and analytical study that was conducted with 25 informal caregivers of hospitalized older adults in a university hospital in Brazil between August and September 2022. Three instruments were applied: Caregiver Burden Inventory, sociodemographic questionnaire, and health conditions questionnaire. The data were analyzed using SPSS version 28.0. Descriptive (frequency and percentage) and inferential analyses were performed using 2-sided Student t test with 95% CIs. RESULTS: Of the 25 interviewees, 18 (72%) were females, 17 (46%) were married or in a stable union, 14 (56%) completed secondary education, and 11 (44%) lived with the older adults who needed care. The average age of the participants was 44 (SD 12.8) years. Regarding their health conditions, most caregivers self-reported it as good (12/25, 48%). They provided care to their father or mother older than 70 years (14/25, 56%). The Caregiver Burden Inventory analysis showed that the caregivers were the most negatively impacted in the domains of personal life overload (mean 10.8, SD 3.46; P=.047) and physical overload (mean 10.6, SD 2.32; P=.02). CONCLUSIONS: In recent years, there has been an increase in the burden on informal caregivers of hospitalized older adults in Brazil, thereby impacting their personal and physical lives. The findings of our study show that health care professionals should be trained to promote health guidelines and actions to improve the personal and physical lives of the caregiver population in Brazil.
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The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) < 0.001) and in the CSF (-0.41 [-0.72, -0.09], adj. p = 0.042), but not in the blood (-0.63 [-1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (-0.67 [-1.15, -0.2], adj. p = 0.006), GABAA receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.
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Shewanella algae are gram-negative bacteria commonly found in aquatic environments. Infections caused by this agent are rarely documented; however, they are increasingly reported, mainly in countries with warm to temperate climates. Herein, we present a case of a 46-year-old immunocompetent woman with acute cellulitis and S. algae bacteremia (the first isolation culture performed at our hospital). To better understand the epidemiology, clinical outcomes, and treatment possibilities for S. algae bacteremia, we searched literature for similar cases; however, we did not find any cases of infections caused by this microorganism reported in Portugal or the Azores.
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Bacteriemia , Infecções por Bactérias Gram-Negativas , Shewanella , Humanos , Pessoa de Meia-Idade , Celulite (Flegmão)/diagnóstico , Celulite (Flegmão)/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologiaRESUMO
Resumo A COVID-19 gerou impacto na sociedade com elevados índices de morbidade e mortalidade. A utilização de indicador epidemiológico que estime a carga de doença, agregando em uma medida a mortalidade precoce e os casos não fatais, tem potencial de auxiliar no planejamento de ações adequadas em diferentes níveis de atenção à saúde. O objetivo deste artigo é estimar a carga de doença por COVID-19 em Florianópolis/SC de abril de 2020 a março de 2021. Foi realizado um estudo ecológico com dados de notificação e óbitos por COVID-19 no período de 12 meses. Utilizou-se o indicador de carga denominado Anos de Vida Perdidos Ajustados por Incapacidade (DALY), obtido pela soma dos Anos de Vida Perdidos (YLL) com os Anos Vividos com Incapacidade (YLD). Foram incluídos 78.907 casos de COVID-19 confirmados. Desses, 763 evoluíram a óbito no período estudado. No total, foram estimados 4.496,6 DALYs, taxa de 883,8 DALYs/100.000 habitantes. No sexo masculino, foram 2.693,1 DALYs, taxa de 1.098,0 DALYs/100.000 homens. Em mulheres, foram 1.803,8 DALYs, taxa de 684,4 DALYs/100.000 mulheres. A faixa etária mais acometida em ambos os sexos foi de 60 a 69 anos. Foi alta a carga de COVID-19 na cidade estudada. As maiores taxas foram encontradas no sexo feminino e na faixa-etária de 60-69 anos.
Abstract COVID-19 has had a powerful impact on society with high rates of morbidity and mortality. The use of an epidemiological indicator that estimates the burden of a disease by aggregating early mortality and non-fatal cases in a single measure has the potential to assist in the planning of more appropriate actions at different levels of health care. The scope of this article is to estimate the burden of disease due to COVID-19 in Florianópolis/SC from April 2020 through March 2021. An ecological study was carried out with data from notification and deaths by COVID-19 in the period of 12 months. The burden indicator called Disability-Adjusted Life Years (DALY) was used, obtained by adding the Years of Life Lost (YLL) to the Years of healthy life lost due to disability (YLD). A total of 78,907 confirmed COVID-19 cases were included. Of these, 763 died during the period under study. Overall, 4,496.9 DALYs were estimated, namely a rate of 883.8 DALYs per 100,000 inhabitants. In males, there were 2,693.1 DALYs, a rate of 1,098.0 DALYs per 100,000 males. In women, there were 1,803.8 DALYs, a rate of 684.4 DALYs per100,000 women. The age group most affected in both sexes was 60 to 69 years. The burden of COVID-19 was high in the city studied. The highest rates were in females and in the 60-69 age group.
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COVID-19 has had a powerful impact on society with high rates of morbidity and mortality. The use of an epidemiological indicator that estimates the burden of a disease by aggregating early mortality and non-fatal cases in a single measure has the potential to assist in the planning of more appropriate actions at different levels of health care. The scope of this article is to estimate the burden of disease due to COVID-19 in Florianópolis/SC from April 2020 through March 2021. An ecological study was carried out with data from notification and deaths by COVID-19 in the period of 12 months. The burden indicator called Disability-Adjusted Life Years (DALY) was used, obtained by adding the Years of Life Lost (YLL) to the Years of healthy life lost due to disability (YLD). A total of 78,907 confirmed COVID-19 cases were included. Of these, 763 died during the period under study. Overall, 4,496.9 DALYs were estimated, namely a rate of 883.8 DALYs per 100,000 inhabitants. In males, there were 2,693.1 DALYs, a rate of 1,098.0 DALYs per 100,000 males. In women, there were 1,803.8 DALYs, a rate of 684.4 DALYs per100,000 women. The age group most affected in both sexes was 60 to 69 years. The burden of COVID-19 was high in the city studied. The highest rates were in females and in the 60-69 age group.
A COVID-19 gerou impacto na sociedade com elevados índices de morbidade e mortalidade. A utilização de indicador epidemiológico que estime a carga de doença, agregando em uma medida a mortalidade precoce e os casos não fatais, tem potencial de auxiliar no planejamento de ações adequadas em diferentes níveis de atenção à saúde. O objetivo deste artigo é estimar a carga de doença por COVID-19 em Florianópolis/SC de abril de 2020 a março de 2021. Foi realizado um estudo ecológico com dados de notificação e óbitos por COVID-19 no período de 12 meses. Utilizou-se o indicador de carga denominado Anos de Vida Perdidos Ajustados por Incapacidade (DALY), obtido pela soma dos Anos de Vida Perdidos (YLL) com os Anos Vividos com Incapacidade (YLD). Foram incluídos 78.907 casos de COVID-19 confirmados. Desses, 763 evoluíram a óbito no período estudado. No total, foram estimados 4.496,6 DALYs, taxa de 883,8 DALYs/100.000 habitantes. No sexo masculino, foram 2.693,1 DALYs, taxa de 1.098,0 DALYs/100.000 homens. Em mulheres, foram 1.803,8 DALYs, taxa de 684,4 DALYs/100.000 mulheres. A faixa etária mais acometida em ambos os sexos foi de 60 a 69 anos. Foi alta a carga de COVID-19 na cidade estudada. As maiores taxas foram encontradas no sexo feminino e na faixa-etária de 60-69 anos.
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COVID-19 , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , COVID-19/epidemiologia , Brasil/epidemiologia , Morbidade , Nível de Saúde , Efeitos Psicossociais da Doença , Anos de Vida Ajustados por Qualidade de VidaRESUMO
INTRODUCTION: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released/leaked into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-ß (Aß) or tau pathologies. The molecular underpinnings behind this specificity are little explored. Here we investigated biomarker and transcriptomic associations of hippocampal GFAP-positive astrocytes with Aß and tau pathologies in humans and mouse models. METHODS: We studied 90 individuals with plasma GFAP, Aß- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aß (PS2APP) or tau (P301S) pathologies was conducted to explore differentially expressed genes (DEGs), Gene Ontology terms, and protein-protein interaction networks associated with each phenotype. RESULTS: In humans, we found that plasma GFAP associates with Aß but not tau pathology. Unveiling the unique nature of hippocampal GFAP-positive astrocytic responses to Aß or tau pathologies, mouse transcriptomics showed scarce overlap of DEGs between the Aß. and tau mouse models. While Aß GFAP-positive astrocytes were overrepresented with DEGs associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics. CONCLUSION: Our results offer insights into Aß- and tau-driven specific signatures in hippocampal GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte biomarkers and suggests the need to develop context-specific astrocyte targets to study AD. FUNDING: This study was supported by Instituto Serrapilheira, Alzheimer's Association, CAPES, CNPq and FAPERGS.
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Doença de Alzheimer , Astrócitos , Humanos , Camundongos , Animais , Astrócitos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Hipocampo/metabolismo , Proteínas tau/metabolismoRESUMO
Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-ß (Aß) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aß deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aß-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aß-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aß pathology.
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Doença de Alzheimer , Transtorno do Deficit de Atenção com Hiperatividade , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Tomografia por Emissão de Pósitrons/métodos , Fatores de Risco , Proteínas tau , Biomarcadores/líquido cefalorraquidianoRESUMO
BACKGROUND: The aim of this study was whether the Food Intake Visual Scale (FIVS) can be used in clinical practice to measure food intake in patients with decompensated cirrhosis. METHODS: A cross-sectional study was performed with patients with cirrhosis between April 2017 and July 2019. The food intake was assessed through the 1-day diet record (DR) and according to FIVS, which consists of pictures of four plates of food at different levels of consumption: "about all," "half," "a quarter," or "nothing." The analysis of variance test with Bonferroni multiple comparison analysis was used to compare the mean energy intake through the DR according to the FIVS categories. RESULTS: This study included 94 patients with a mean age of 60.29 ± 9.33 years. Patients with lower food intake according to the FIVS categories also had lower mean energy and macronutrient intake according to the DR: patients eating "about all" (n = 49, 52.1%) consumed a mean of 1526.58 ± 428.27 kcal/day, patients eating "half" (n = 16, 17%) consumed a mean of 1282.08 ± 302.83 kcal/day, patients eating "a quarter" (n = 25, 26.6%) consumed a mean of 978.96 ± 468.81 kcal/day, and patients eating "nothing" (n = 4, 4.3%) consumed a mean of 353.59 ± 113.16 kcal/day (P < .001). CONCLUSION: The results of this study demonstrate that FIVS can be implemented in clinical practice to measure food intake in patients with decompensated cirrhosis as a substitute for the DR because it is a noninvasive, low-cost, quick, reliable, and easy bedside method for obtaining data.
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Ingestão de Alimentos , Avaliação Nutricional , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Ingestão de Energia , DietaRESUMO
Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Endocanabinoides , Receptores de Canabinoides , Tomografia por Emissão de Pósitrons , Biomarcadores , Progressão da DoençaRESUMO
ABSTRACT Shewanella algae are gram-negative bacteria commonly found in aquatic environments. Infections caused by this agent are rarely documented; however, they are increasingly reported, mainly in countries with warm to temperate climates. Herein, we present a case of a 46-year-old immunocompetent woman with acute cellulitis and S. algae bacteremia (the first isolation culture performed at our hospital). To better understand the epidemiology, clinical outcomes, and treatment possibilities for S. algae bacteremia, we searched literature for similar cases; however, we did not find any cases of infections caused by this microorganism reported in Portugal or the Azores.
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Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood-brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.
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Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais , Transplante de Células-Tronco/métodos , Acidente Vascular Cerebral/terapia , Administração Intranasal , Adulto , Animais , Barreira Hematoencefálica , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Teste de Labirinto em Cruz Elevado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Fisiológica , Ratos Wistar , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/patologiaRESUMO
BACKGROUND: Changes in soluble amyloid-beta (Aß) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer's disease (AD). However, whether Aß levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aß isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. METHODS: We used CSF measurements of three soluble Aß peptides (Aß1-38, Aß1-40 and Aß1-42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. RESULTS: Our findings indicate that Aß isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML model. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. CONCLUSIONS: Our results demonstrate that, by applying a refined ML analysis, a combination of Aß isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.
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Amyloid-ß (Aß) dysmetabolism is thought to be the main trigger for neurodegenerative events in Alzheimer's disease (AD). In particular, soluble Aß oligomers (AßOs) are proposed as key mediators of synaptic and cognitive dysfunction in AD. Over the past few decades, AßOs prepared from synthetic Aß have been widely applied in vitro and in vivo, the so-called chemical models of AD, uncovering their multiple neurotoxic mechanisms. However, the lack of a reliable quality control (QC) for synthetic AßOs may reflect poor experimental reproducibility. In keeping with this, we optimized and validated a rapid and reproducible SECHPLC method using fluorescence detection for the QC of synthetic AßOs. Our analytical method offers an unprecedent alternative to improve the reproducibility of AD chemical models.
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Peptídeos beta-Amiloides/análise , Cromatografia em Gel/métodos , Multimerização Proteica , Doença de Alzheimer/patologia , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Concentração de Íons de Hidrogênio , Controle de Qualidade , Reprodutibilidade dos Testes , TemperaturaRESUMO
BACKGROUND: This study aimed to evaluate the nutrition status through phase angle (PA) and its association with mortality in patients with decompensated cirrhosis. METHODS: A prospective cohort study was performed with hospitalized decompensated cirrhotic patients. Nutrition status was assessed by PA, bioelectrical impedance vector analysis (BIVA), and Subjective Global Assessment (SGA) within 72 hours of hospital admission. The best PA cutoff point for malnutrition diagnosis was determined by ROC curve analysis, considering the SGA as the reference standard. Predictors of 6-month mortality were identified using Cox proportional hazards models, adjusted for Child-Pugh and MELD scores, and hepatocellular carcinoma. RESULTS: This study included 97 patients, 63% male (n = 61), with a mean age of 60.1 ± 10.3 years. The median follow-up time of patients was 11.2 months (IQR, 2.4-21). Overall mortality was 58.8% (n = 57) and 6-month mortality was 35.1% (n = 34). Nutrition assessment according to BIVA indicated a risk for cachexia and normal hydration. Patients with values of PA ≤5.52° were considered malnourished. Malnourished patients according to PA (58.8%, n = 57) had a higher risk of 6-month mortality (HR = 3.44; 95% CI, 1.51-7.84; P = .003), and each increase of 1° in PA values was associated with a reduction of 53% in 6-month mortality risk. CONCLUSIONS: The PA is an independent predictor of 6-month mortality in patients with decompensated cirrhosis. Therefore, PA may be useful to assess the nutrition status and identify patients at the highest risk of mortality in clinical practice.
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Cirrose Hepática , Desnutrição , Avaliação Nutricional , Idoso , Impedância Elétrica , Feminino , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Desnutrição/complicações , Pessoa de Meia-Idade , Estado Nutricional , Estudos ProspectivosRESUMO
Amyloid-ß oligomers (AßOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer's disease (AD). Considering presynaptic high energy demand and tight Ca2+ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AßOs was used to investigate the toxicity of AßOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AßOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AßOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca2+ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca2+ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.
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Peptídeos beta-Amiloides/toxicidade , Cálcio/metabolismo , Guanosina/farmacologia , Homeostase , Mitocôndrias/metabolismo , Neuroproteção/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Guanosina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/ultraestruturaRESUMO
Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non-competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric-coated mycophenolate sodium salt (EC-MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post-transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects.
Assuntos
Transplante de Rim , Ácido Micofenólico , Ciclosporina , Humanos , Imunossupressores , TacrolimoRESUMO
Sepsis is characterized by a severe and disseminated inflammation. In the central nervous system, sepsis promotes synaptic dysfunction and permanent cognitive impairment. Besides sepsis-induced neuronal dysfunction, glial cell response has been gaining considerable attention with microglial activation as a key player. By contrast, astrocytes' role during acute sepsis is still underexplored. Astrocytes are specialized immunocompetent cells involved in brain surveillance. In this context, the potential communication between the peripheral immune system and astrocytes during acute sepsis still remains unclear. We hypothesized that peripheral blood mononuclear cell (PBMC) mediators are able to affect the brain during an episode of acute sepsis. With this in mind, we first performed a data-driven transcriptome analysis of blood from septic patients to identify common features among independent clinical studies. Our findings evidenced pronounced impairment in energy-related signaling pathways in the blood of septic patients. Since astrocytes are key for brain energy homeostasis, we decided to investigate the communication between PBMC mediators and astrocytes in a rat model of acute sepsis, induced by cecal ligation and perforation (CLP). In the CLP animals, we identified widespread in vivo brain glucose hypometabolism. Ex vivo analyses demonstrated astrocyte reactivity along with reduced glutamate uptake capacity during sepsis. Also, by exposing cultured astrocytes to mediators released by PBMCs from CLP animals, we reproduced the energetic failure observed in vivo. Finally, by pharmacologically inhibiting phosphoinositide 3-kinase (PI3K), a central metabolic pathway downregulated in the blood of septic patients and reduced in the CLP rat brain, we mimicked the PBMC mediators effect on glutamate uptake but not on glucose metabolism. These results suggest that PBMC mediators are capable of directly mediating astrocyte reactivity and contribute to the brain energetic failure observed in acute sepsis. Moreover, the evidence of PI3K participation in this process indicates a potential target for therapeutic modulation.