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AIMS: While certain drug-use indicators are known to be associated with clinical outcomes, the relationship is unclear for some highly prevalent conditions in in patients aged ≥65 years. We examine correlations between 3 drug-use indicators and postdischarge healthcare services use by older patients according to the presence of dementia, advanced age and frailty. METHODS: This retrospective cohort study analysed data collected from hospital electronic health records between April and December 2017. Potentially inappropriate medications (PIMs) and anticholinergic burden were assessed using the 2015 Beers Criteria and anticholinergic cognitive burden scale (ACBS) score. Minor and major polypharmacy were defined as the use of 5-9 and ≥10 drugs, respectively. Outcomes were set as emergency room revisits and readmissions at 1, 3 and 6 months postdischarge. The correlation between drug-use indicators and outcomes was analysed by multivariable logistic regression. RESULTS: The final cohort included 3061 patients for the analysis, and 2930, 2671 and 2560 patients were followed up to 1, 3 and 6 months after discharge. After controlling for confounders, all 3 drug-use indicators were significantly associated with readmission and emergency room revisits except for the relationship between PIMs and readmission within 6 months. These associations were significantly observed among patients without dementia, aged >80 years and with frailty. CONCLUSION: PIMs, polypharmacy and anticholinergic burden are common at discharge and correlate with future use of healthcare services. In older patients, the absence of dementia, advanced age and frailty should be given extra consideration with regard to medication safety.
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Demência , Fragilidade , Humanos , Idoso , Lista de Medicamentos Potencialmente Inapropriados , Alta do Paciente , Readmissão do Paciente , Prescrição Inadequada , Estudos Retrospectivos , Assistência ao Convalescente , Fragilidade/tratamento farmacológico , Polimedicação , Antagonistas Colinérgicos/uso terapêutico , Hospitais , Demência/tratamento farmacológico , Serviço Hospitalar de EmergênciaRESUMO
Large-scale 'omic' studies investigating the pathophysiological processes that lead to Alzheimer's disease (AD) dementia have identified an increasing number of susceptibility genes, many of which are poorly characterized and have not previously been implicated in AD. Here, we evaluated the utility of human induced pluripotent stem cell-derived neurons and astrocytes as tools to systematically test AD-relevant cellular phenotypes following perturbation of candidate genes identified by genome-wide studies. Lentiviral-mediated delivery of shRNAs was used to modulate expression of 66 genes in astrocytes and 52 genes in induced neurons. Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly altered extracellular amyloid-ß (Aß) levels. Knockdown of AP3M2, CNN2, GSTP1, NPC1, NPC2, PSAP and SORL1 reduced interleukin-6 levels in astrocytes. Only knockdown of FERMT2 led to a reduction in the proportion of TAU that is phosphorylated. Further, CRISPR-Cas9 targeting of FERMT2 in both familial AD (fAD) and fAD-corrected human neurons validated the findings of reduced extracellular Aß. Interestingly, FERMT2 reduction had no effect on the Aß42:40 ratio in corrected neurons and a reduction of phospho-tau, but resulted in an elevation in Aß42:40 ratio and no reduction in phospho-tau in fAD neurons. Taken together, this study has prioritized 15 genes as being involved in contributing to Aß accumulation, phosphorylation of tau and/or cytokine secretion, and, as illustrated with FERMT2, it sets the stage for further cell-type-specific dissection of the role of these genes in AD.
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Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neurônios/metabolismo , Proteostase , Proteínas tau/metabolismo , Biomarcadores , Encéfalo/metabolismo , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Técnicas de Silenciamento de Genes , Marcação de Genes , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , FenótipoRESUMO
Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aß aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aß cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that Aß, α-synuclein and tau are toxic to neurons in a manner that requires PrPC. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.
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Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Príons/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Ligação ProteicaRESUMO
OBJECTIVES: To evaluate the roles of preoperative anemia and intraoperative blood transfusion in the development of postoperative delirium among older patients undergoing elective orthopedic surgery. METHODS: This prospective cohort study recruited subjects aged 60 years old and above who were admitted for elective orthopedic surgery in a tertiary medical center during April 2011 to December 2013. Demographic data (age, gender, body mass index [BMI], and educational level), surgery-related factors (American Society of Anesthesiology [ASA] class, type of anesthesia and surgery, and intraoperative blood transfusion), results of geriatric assessment (hearing/visual impairment, cognition, depressive mood, comorbidity, malnutrition, polypharmacy, activities of daily living [ADL], and instrumental activities of daily living [IADL]), laboratory data, length of hospital stay, and the development of postoperative delirium were collected for analysis. RESULTS: Overall, 461 patients (mean age: 73.5 ± 7.5 years, 42.1% males) were enrolled for study, and 37 (8.0%) of them developed postoperative delirium. We categorized all subjects into four groups based on anemia on admission and blood transfusion during operation or not. Multivariate logistic regression showed that subjects with anemia on admission and received intraoperative blood transfusion were at higher risk of developing postoperative delirium (adjusted odds ratio 3.090; 95% confidence interval [CI], 1.070-8.926) and those without anemia on admission but received intraoperative blood transfusion were at marginal risk (adjusted odds ratio 2.906; 95% CI, 0.912-9.259) after adjustment for covariates. CONCLUSIONS: Anemic older patients receiving intraoperative blood transfusion during operation were at the greatest risk for postoperative delirium when they underwent elective orthopedic surgery. Further intervention study is needed to reduce the risk of postoperative delirium for these patients.
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Anemia/complicações , Transfusão de Sangue/estatística & dados numéricos , Delírio/etiologia , Procedimentos Ortopédicos/estatística & dados numéricos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Delírio/epidemiologia , Procedimentos Cirúrgicos Eletivos/estatística & dados numéricos , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
Secreted factors play a central role in normal and pathological processes in every tissue in the body. The brain is composed of a highly complex milieu of different cell types and few methods exist that can identify which individual cells in a complex mixture are secreting specific analytes. By identifying which cells are responsible, we can better understand neural physiology and pathophysiology, more readily identify the underlying pathways responsible for analyte production, and ultimately use this information to guide the development of novel therapeutic strategies that target the cell types of relevance. We present here a method for detecting analytes secreted from single human induced pluripotent stem cell (iPSC)-derived neural cells and have applied the method to measure amyloid ß (Aß) and soluble amyloid precursor protein-alpha (sAPPα), analytes central to Alzheimer's disease pathogenesis. Through these studies, we have uncovered the dynamic range of secretion profiles of these analytes from single iPSC-derived neuronal and glial cells and have molecularly characterized subpopulations of these cells through immunostaining and gene expression analyses. In examining Aß and sAPPα secretion from single cells, we were able to identify previously unappreciated complexities in the biology of APP cleavage that could not otherwise have been found by studying averaged responses over pools of cells. This technique can be readily adapted to the detection of other analytes secreted by neural cells, which would have the potential to open new perspectives into human CNS development and dysfunction. SIGNIFICANCE STATEMENT: We have established a technology that, for the first time, detects secreted analytes from single human neurons and astrocytes. We examine secretion of the Alzheimer's disease-relevant factors amyloid ß (Aß) and soluble amyloid precursor protein-alpha (sAPPα) and present novel findings that could not have been observed without a single-cell analytical platform. First, we identify a previously unappreciated subpopulation that secretes high levels of Aß in the absence of detectable sAPPα. Further, we show that multiple cell types secrete high levels of Aß and sAPPα, but cells expressing GABAergic neuronal markers are overrepresented. Finally, we show that astrocytes are competent to secrete high levels of Aß and therefore may be a significant contributor to Aß accumulation in the brain.
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Precursor de Proteína beta-Amiloide/metabolismo , Astrócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Análise de Célula Única/métodos , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/análise , Animais , Astrócitos/química , Células CHO , Cricetinae , Cricetulus , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/química , Masculino , Neurônios/químicaRESUMO
BACKGROUND: Early identification of different stages of cognitive impairment is important to provide available intervention and timely care for the elderly. OBJECTIVE: This study aimed to examine the ability of the artificial intelligence (AI) technology to distinguish participants with mild cognitive impairment (MCI) from those with mild to moderate dementia based on automated video analysis. METHODS: A total of 95 participants were recruited (MCI, 41; mild to moderate dementia, 54). The videos were captured during the Short Portable Mental Status Questionnaire process; the visual and aural features were extracted using these videos. Deep learning models were subsequently constructed for the binary differentiation of MCI and mild to moderate dementia. Correlation analysis of the predicted Mini-Mental State Examination, Cognitive Abilities Screening Instrument scores, and ground truth was also performed. RESULTS: Deep learning models combining both the visual and aural features discriminated MCI from mild to moderate dementia with an area under the curve (AUC) of 77.0% and accuracy of 76.0%. The AUC and accuracy increased to 93.0% and 88.0%, respectively, when depression and anxiety were excluded. Significant moderate correlations were observed between the predicted cognitive function and ground truth, and the correlation was strong excluding depression and anxiety. Interestingly, female, but not male, exhibited a correlation. CONCLUSION: The study showed that video-based deep learning models can differentiate participants with MCI from those with mild to moderate dementia and can predict cognitive function. This approach may offer a cost-effective and easily applicable method for early detection of cognitive impairment.
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Disfunção Cognitiva , Demência , Humanos , Feminino , Idoso , Demência/diagnóstico , Demência/psicologia , Inteligência Artificial , Testes Neuropsicológicos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , CogniçãoRESUMO
Introduction: Geriatric syndrome (GS) increases risk of disability and mortality in older adults. Sarcopenia is a predominant illness of GS and accelerate its progression. This study aimed to investigate associations between mortality, emergency department (ED) re-visits and GS-related illnesses among older adults who visited the ED. Method: This retrospective observational study enrolled elderly patients who visited the ED in our hospital between January 2018 and October 2020. Patients were evaluated for potential sarcopenia, which was defined by both low handgrip strength and calf circumference. Follow-up was at least 6 months. Data of age, gender, mortality, ED re-visits, and GS-related illnesses were collected and analyzed for associations. Results: A total of 273 older adults aged 74 years or older were included, of whom 194 were diagnosed with possible sarcopenia. Older adults with possible sarcopenia also had significantly lower body mass index (BMI); a higher proportion needed assistance with daily activities; more had malnutrition, frailty, and history of falls (all p < 0.001) and acute decline in activities of daily living (p = 0.027). Multivariate analysis showed that possible sarcopenia [adjusted hazard ratio, aHR): 9.89, 95% confidence interval (CI): 1.17-83.81, p = 0.036], living in residential institutions (aHR: 2.85, 95% CI: 1.08-7.50, p = 0.034), and frailty (aHR: 7.30, 95% CI: 1.20-44.62, p = 0.031) were associated with mortality. Aged over 85 years (adjusted odds ratio: 2.44, 95% CI: 1.25-4.80, p = 0.02) was associated with ED re-visits. Conclusion: Sarcopenia is associated with mortality among older adults who visit ED. Initial screening for sarcopenia and relevant risk factors among older adults in the ED may help with early intervention for those at high-risk and may improve their prognosis.
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The RNA binding protein ELAVL4/HuD regulates the translation and splicing of multiple Alzheimer's disease (AD) candidate genes. We generated ELAVL4 knockout (KO) human induced pluripotent stem cell-derived neurons to study the effect that ELAVL4 has on AD-related cellular phenotypes. ELAVL4 KO significantly increased the levels of specific APP isoforms and intracellular phosphorylated tau, molecular changes that are related to the pathological hallmarks of AD. Overexpression of ELAVL4 in wild-type neurons and rescue experiments in ELAVL4 KO cells showed opposite effects and also led to a reduction of the extracellular amyloid-beta (Aß)42/40 ratio. All these observations were made in familial AD (fAD) and fAD-corrected neurons. To gain insight into the molecular cascades involved in neuronal ELAVL4 signaling, we conducted pathway and upstream regulator analyses of transcriptomic and proteomic data from the generated neurons. These analyses revealed that ELAVL4 affects multiple biological pathways linked to AD, including those involved in synaptic function, as well as gene expression downstream of APP and tau signaling. The analyses also suggest that ELAVL4 expression is regulated by insulin receptor-FOXO1 signaling in neurons. Taken together, ELAVL4 expression ameliorates AD-related molecular changes in neurons and affects multiple synaptic pathways, making it a promising target for novel drug development.
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Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteína Semelhante a ELAV 4/metabolismo , Neurônios/metabolismo , Proteômica , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/farmacologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Accumulation of amyloid ß-protein (Aß) into brain parenchymal plaques and the cerebral vasculature is a pathological feature of Alzheimer disease and related disorders. Aß peptides readily form ß-sheet-containing oligomers and fibrils. Previously, we reported a strong interaction between myelin basic protein (MBP) and Aß peptides that resulted in potent inhibition of fibril assembly (Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2007) J. Biol. Chem. 282, 9952-9961; Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2009) Biochemistry 48, 4720-4727). MBP is recognized as a highly post-translationally modified protein. In the present study, we demonstrate that human MBP purified from either brain or a bacterial recombinant expression system comparably bound to Aß and inhibited Aß fibril assembly indicating that post-translational modifications are not required for this activity. We also show that purified mouse brain MBP and recombinantly expressed mouse MBP similarly inhibited Aß fibril formation. Through a combination of biochemical and ultrastructural techniques, we demonstrate that the binding site for Aß is located in the N-terminal 64 amino acids of MBP and that a stable peptide (MBP1) comprising these residues was sufficient to inhibit Aß fibrillogenesis. Under conditions comparable with those used for Aß, the fibrillar assembly of amylin, another amyloidogenic peptide, was not inhibited by MBP1, although MBP1 still bound to it. This observation suggests that the potent inhibitory effect of MBP on fibril formation is not general to amyloidogenic peptides. Finally, MBP1 could prevent the cytotoxic effects of Aß in primary cortical neurons. Our findings suggest that inhibition of Aß fibril assembly by MBP, mediated through its N-terminal domain, could play a role in influencing amyloid formation in Alzheimer disease brain and corresponding mouse models.
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Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Proteína Básica da Mielina/metabolismo , Fragmentos de Peptídeos/metabolismo , Sequência de Aminoácidos , Amiloide/química , Amiloide/ultraestrutura , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Escherichia coli/genética , Humanos , Camundongos , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Dados de Sequência Molecular , Proteína Básica da Mielina/química , Proteína Básica da Mielina/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/genética , Ligação Proteica , Ratos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Ressonância de Plasmônio de SuperfícieRESUMO
INTRODUCTION: As populations age, sarcopenia becomes a major health problem among adults aged 65 years and older. However, little information is available about the relationship between sarcopenia and brain structure abnormalities. The objective of this study was to investigate associations between sarcopenia and brain atrophy in older adults and relationships with regional brain areas. METHODS: This prospective cohort study recruited 102 retirement community residents aged 65 years and older. All participants underwent gait speed measurement, handgrip strength measurement and muscle mass measurement by dual X-ray absorptiometry. Diagnosis of sarcopenia was made according to criteria of the Asian Working Group for Sarcopenia (AWGSOP). All patients underwent magnetic resonance imaging (MRI), and images were analysed for global cortical atrophy (GCA) (range 0-3), parietal atrophy (PA) (range 0-3) and medial temporal atrophy (MTA) (range 0-4). RESULTS: Among 102 older adult participants (81.4 ± 8.2 years), 47 (46.1%) were diagnosed with sarcopenia according to AWGSOP criteria. The sarcopenia group had more moderate to severe PA (Grade 2: 19.1% vs. 5.5%; grade 3:6.4% vs. 0%, P = 0.016) and GCA (Grade 2: 40.4% vs. 18.2%, P = 0.003) and a trend of more moderate to severe MTA (Grade 2: 46.8% vs. 30.9%; grade 3: 8.5% vs. 1.8%, P = 0.098) than the non-sarcopenia group. In univariate logistic regression, sarcopenia was significantly associated with PA (OR 5.94, 95% CI 1.56-22.60, P = 0.009), GCA (OR 3.05, 95% CI 1.24-7.51, P = 0.015), and MTA (OR 2.55, 95% CI 1.14-5.69, P = 0.023). In multivariable logistic regression analysis, sarcopenia was an independent risk factor for PA (adjusted OR 6.90, 95% CI 1.30-36.47, P = 0.023). After adjusting for all covariates, only age had a significant relationship with GCA (Adjusted OR 1.09, 95% CI 1.00-1.19, P = 0.044) and MTA (Adjusted OR 1.09, 95% CI 1.01-1.17, P = 0.022). CONCLUSIONS: This is the first study to explore associations between sarcopenia and global as well as regional brain atrophy in older adults. The sarcopenia group had higher rates of moderate to severe PA, GCA and MTA than the non-sarcopenia group. PA was significantly associated with sarcopenia in older adults. Further longitudinal studies are needed to address the mechanism and pathogenesis of brain atrophy and sarcopenia.
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Sarcopenia , Idoso , Atrofia , Força da Mão , Humanos , Imageamento por Ressonância Magnética , Estudos Prospectivos , Sarcopenia/epidemiologiaRESUMO
PURPOSE: To develop a predictive model to identify hospitalized older patients at risk of functional decline. METHODS: This retrospective cohort study recruited participants aged 65 years and over admitted to internal medicine wards of a tertiary medical center in Taiwan during May to October 2017 for developing predictive model (n = 1698) and those admitted during November to December 2017 for validation study (n = 530) of the model. Demographic data, geriatric assessments and hospital conditions (admission route and length of hospital stay) were collected for analysis. RESULTS: Overall, of the 1698 participants (mean age 75.8 ± 7.9 years, 60.9% male) enrolled in the development study, 20.1% had functional decline. Results of multivariate logistic regression showed that older age, hearing impairment, history of falls within one year, risk of malnutrition, physical restraint, admission via emergency department and hospital stay ≥ 5 days were independent predictive factors for decline. A scoring system, HAD-FREE Score, constructed from the above predictive factors ranged from 0 to 18 points and ≥ 6 points was chosen as the cut-off point. The area under the receiver operating characteristic analysis was 0.748 (95% confidence interval: 0.720-0.776), the sensitivity was 65.3% and the specificity was 71.3%. Validation of the HAD-FREE Score showed moderate discriminative ability in the validation study. CONCLUSION: A HAD-FREE Score developed from seven independent factors could predict functional decline with moderate discriminative ability and good validation. This scoring system can be the basis of an automatic dynamic tracking within the electronic medical record to identify those older patients at risk of functional decline during hospitalization.
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Avaliação Geriátrica , Hospitalização , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitais , Humanos , Masculino , Estudos RetrospectivosRESUMO
The progressive accumulation of beta-amyloid (Abeta) in senile plaques and in the cerebral vasculature is the hallmark of Alzheimer's disease and related disorders. Degradation of Abeta by specific proteolytic enzymes is an important process that regulates its levels in brain. Matrix metalloproteinase 2 (MMP2) was shown to be expressed in reactive astrocytes surrounding amyloid plaques and may contribute to Abeta degradation. Membrane type 1 (MT1) MMP is the physiological activator for the zymogen pro-MMP2. Here, we show that, in addition to MMP2, its activator MT1-MMP is also expressed in reactive astrocytes in regions with amyloid deposits in transgenic mice. Using a Cos-1 cell expression system, we demonstrated that MT1-MMP can degrade exogenous Abeta40 and Abeta42. A purified soluble form of MT1-MMP degraded both soluble and fibrillar Abeta peptides in a time-dependent manner, yielding specific degradation products. Mass spectrometry analysis identified multiple MT1-MMP cleavage sites on soluble Abeta40 and Abeta42. MT1-MMP-mediated Abeta degradation was inhibited with the general MMP inhibitor GM6001 or the specific MT1-MMP inhibitor tissue inhibitor of metalloproteinases 2. Furthermore, in situ experiments showed that purified MT1-MMP degraded parenchymal fibrillar amyloid plaques that form in the brains of Abeta precursor protein transgenic mice. Together, these findings indicate that MT1-MMP possesses Abeta degrading activity in vitro.
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Peptídeos beta-Amiloides/metabolismo , Metaloproteinase 14 da Matriz/fisiologia , Emaranhados Neurofibrilares/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/ultraestrutura , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/ultraestrutura , Animais , Astrócitos/enzimologia , Astrócitos/patologia , Astrócitos/ultraestrutura , Células COS , Chlorocebus aethiops , Modelos Animais de Doenças , Humanos , Hidrólise , Metaloproteinase 14 da Matriz/biossíntese , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/isolamento & purificação , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Emaranhados Neurofibrilares/ultraestrutura , Fragmentos de Peptídeos/ultraestrutura , SolubilidadeRESUMO
The progressive accumulation of beta-amyloid (Abeta) in senile plaques and in the cerebral vasculature is the hallmark of Alzheimer disease and related disorders. Impaired clearance of Abeta from the brain likely contributes to the prevalent sporadic form of Alzheimer disease. Several major pathways for Abeta clearance include receptor-mediated cellular uptake, blood-brain barrier transport, and direct proteolytic degradation. Myelin basic protein (MBP) is the major structural protein component of myelin and plays a functional role in the formation and maintenance of the myelin sheath. MBP possesses endogenous serine proteinase activity and can undergo autocatalytic cleavage liberating distinct fragments. Recently, we showed that MBP binds Abeta and inhibits Abeta fibril formation (Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2007) J. Biol. Chem. 282, 9952-9961; Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2009) Biochemistry 48, 4720-4727). Here we show that Abeta40 and Abeta42 peptides are degraded by purified human brain MBP and recombinant human MBP, but not an MBP fragment that lacks autolytic activity. MBP-mediated Abeta degradation is inhibited by serine proteinase inhibitors. Similarly, Cos-1 cells expressing MBP degrade exogenous Abeta40 and Abeta42. In addition, we demonstrate that purified MBP also degrades assembled fibrillar Abeta in vitro. Mass spectrometry analysis identified distinct degradation products generated from Abeta digestion by MBP. Lastly, we demonstrate in situ that purified MBP can degrade parenchymal amyloid plaques as well as cerebral vascular amyloid that form in brain tissue of Abeta precursor protein transgenic mice. Together, these findings indicate that purified MBP possesses Abeta degrading activity in vitro.
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Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/fisiologia , Proteína Básica da Mielina/química , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Animais , Encéfalo/metabolismo , Células COS , Chlorocebus aethiops , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/química , Isoformas de Proteínas , Proteínas Recombinantes/químicaRESUMO
BACKGROUND: No studies have yet examined the interrelationship of malnutrition and low handgrip strength in terms of mortality. The aim of the present study was to evaluate the potential synergistic effects of malnutrition and low handgrip strength on mortality among older adults living in a retirement community. METHODS: This prospective longitudinal cohort study recruited subjects aged 65 years and over from a veterans care home in Taiwan in 2013. Nutritional status was assessed using the Mini-Nutritional Assessment-Short Form (MNA-SF, malnutrition was MNA-SF<12); muscle strength was measured by handgrip strength (low handgrip strength was handgrip strength <26 kg). The Kaplan-Meier method with the log-rank test was used to estimate survival differences between groups and Cox proportional regression model was used to estimate the adjusted difference in 4-year all-cause mortality between groups. RESULTS: Recruited for the present study were 333 male participants (mean age 85.4 ± 5.7 years). Of these, 50.2% had malnutrition and 54.7% had low handgrip strength. Compared with subjects with no malnutrition and low handgrip strength, those with malnutrition had significantly greater risk of 4-year all-cause mortality (adjusted hazards ratio: 2.05, 95% confident interval [CI]: 1.04-4.01); hazard ratio increased to 3.41 (95% CI 1.93-6.04) for those with both malnutrition and low handgrip strength. CONCLUSIONS: Malnutrition was an independent risk factor for 4-year all-cause mortality and low handgrip strength with malnutrition synergistically increased the mortality risk. Further study is needed to confirm the effectiveness of integrated programs to assist those at risk.
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Força da Mão/fisiologia , Desnutrição/mortalidade , Idoso , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.
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Proteínas do Tecido Nervoso/genética , Receptores de Netrina/metabolismo , Neuritos , Neurônios , Receptores de Superfície Celular/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Linhagem , Análise de Sequência de RNA , TranscriptomaRESUMO
AIM: Slow gait speed has been associated with mortality, poor physical function and disability in older people. Our aim was to evaluate the association between slow gait speed and rapid cognitive decline among oldest-old men in Taiwan. METHODS: We carried out a longitudinal cohort study in a veterans' retirement community, and enrolled 249 male residents aged 80 years and older. Slow gait speed was defined as <1 m/s, and rapid cognitive decline was defined as a Mini-Mental State Examination (MMSE) decline of ≥3 points over 1 year. Body mass index, Charlson's Comorbidity Index, handgrip strength, gait speed and Mini-Mental State Examination datasets were collected, and a logistic regression model was built to evaluate the association between fast cognitive decline and slow gait speed. RESULTS: In all, 249 residents (mean age 86.4 ± 4.01 years) were recruited, including 58 (23.3%) with rapid cognitive decline. Univariate analysis showed that slow gait speed could predict rapid cognitive decline (OR 4.10, 95% CI 1.20-14.00, P = 0.024). After adjusting for age, Charlson's Comorbidity Index, polypharmacy, psychiatric drug usage, cigarette smoking experience, baseline cognitive function, depressive mood, handgrip strength, nutritional status and history of fall, slow gait speed was still independently associated with rapid cognitive decline (adjusted OR 4.58, 95% CI 1.22-17.2, P = 0.024). CONCLUSIONS: Slow gait speed was thus an independent predictor of rapid cognitive decline in oldest-old men in a veterans' retirement community in Taiwan. Geriatr Gerontol Int 2017: 17 (Suppl. 1): 14-19.
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Disfunção Cognitiva/fisiopatologia , Progressão da Doença , Avaliação Geriátrica/métodos , Velocidade de Caminhada/fisiologia , Idoso de 80 Anos ou mais , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Idoso Fragilizado , Habitação para Idosos , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Medição de Risco , Taiwan , Fatores de Tempo , Veteranos/psicologiaRESUMO
The impact of dynapenia on the complexity of care for residents of long-term care facilities (LTCF) remains unclear. The present study evaluated associations between dynapenia, care problems and care complexity in 504 residents of Veterans Care Homes (VCHs) in Taiwan. Subjects with dynapenia, defined as low muscle strength (handgrip strength <26 kg), were older adults with lower body mass index (BMI), slow gait speed, and higher numbers of Resident Assessment Protocol (RAP) triggers. After adjusting for age, education, BMI, and Charlson's comorbidity index (CCI), only age, education, BMI and gait speed were independently associated with higher numbers of RAP triggers, but not dynapenia or handgrip strength (kg). Dividing subjects into groups based on quartiles of gait speed, those with gait speed ≤0.803 m/s were significantly associated with higher complexity of care needs (defined as ≥4 RAP triggers) compared to the reference group (gait speed >1 m/s). Significantly slow gait speed was associated with RAP triggers, including cognitive loss, poor communication ability, rehabilitation needs, urinary incontinence, depressed mood, falls, pressure ulcers, and use of psychotropic drugs. In conclusion, slow gait speed rather than dynapenia is a simple indicator for higher complexity of care needs of older male LTCF residents.
Assuntos
Força da Mão , Velocidade de Caminhada , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos Transversais , Humanos , Assistência de Longa Duração , Masculino , Força Muscular , Sarcopenia , Taiwan , VeteranosRESUMO
Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aß, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aß plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aß and the responsiveness of TAU to Aß are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Proteínas tau/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Camundongos , Neurônios/patologia , Fenótipo , Proteínas tau/metabolismoRESUMO
BACKGROUND: Postgraduate year training programs play an important role in the development of a comprehensive medical education. The goal of these training programs is to inculcate in physicians the expected level of skill in patient care. After the initiation of such programs in the USA, Europe, and Japan, studies were conducted in Taiwan to investigate relevant training methods, and a training system was established in 2003. Beginning with 3-month programs, followed by 6-month programs, the programs were constantly modified and enhanced by the establishment of the 1-year training program in 2011. This year was the transition period from the 6-month programs to the 1-year programs. METHODS: We used a 50-item multiple choice question (MCQ) test and six 10-min stations for objective structured clinical examination (OSCE), which was composed of four stations relating to standardized patients and two stations concerning the clinical skill evaluation, to evaluate the learning results of the trainees. The trainees were divided into four groups according to the training program. RESULTS: There was no significant difference between the performance of the 6 months and 1-year groups. The p values were 0.424 in the MCQ test and 0.082 in the OSCE evaluation. CONCLUSION: A well-designed postgraduate training program should develop trainees' competencies. The results of this study may provide useful insight for ways to improve the design of training programs. Further investigation to better understand the impact of different programs is warranted.
Assuntos
Educação de Pós-Graduação em Medicina , Adulto , Humanos , TaiwanRESUMO
Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid-ß (Aß) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Aß fibril formation, and this inhibitory activity was localized to the N-terminal residues 1-64, a fragment designated MBP1. Here, we show that the modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Aß accumulation in brain. The levels of insoluble Aß and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg-MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was because of a reduction in the size of fibrillar plaques rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Aß fibril formation in vitro and demonstrate the ability of MBP1 to reduce Aß pathology and improve behavioral performance.