RESUMO
Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.
Assuntos
Senescência Celular , Quitinases , Microglia , Neurônios Motores , Primatas , Medula Espinal , Animais , Humanos , Biomarcadores/metabolismo , Quitinases/metabolismo , Microglia/enzimologia , Microglia/metabolismo , Microglia/patologia , Neurônios Motores/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Primatas/metabolismo , Reprodutibilidade dos Testes , Análise da Expressão Gênica de Célula Única , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-ß (Aß) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aß clearance have fueled a debate as to whether Aß is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aß clearance trials provide critical evidence to support the role of Aß in AD pathogenesis and suggest that targeting Aß clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aß targeting therapies, and provide perspectives on early intervention, adequate Aß removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.
RESUMO
Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between the brain and bone, but the interaction between bone and brain in AD remains unclear. In this review, we summarize human studies of the association between bone and brain and provide an overview of their interactions and the underlying mechanisms in AD. We review the effects of AD on bone from the aspects of AD pathogenic proteins, AD risk genes, neurohormones, neuropeptides, neurotransmitters, brain-derived extracellular vesicles (EVs), and the autonomic nervous system. Correspondingly, we elucidate the underlying mechanisms of the involvement of bone in the pathogenesis of AD, including bone-derived hormones, bone marrow-derived cells, bone-derived EVs, and inflammation. On the basis of the crosstalk between bone and the brain, we propose potential strategies for the management of AD with the hope of offering novel perspectives on its prevention and treatment. HIGHLIGHTS: The pathogenesis of AD, along with its consequent changes in the brain, may involve disturbing bone homeostasis. Degenerative bone disorders may influence the progression of AD through a series of pathophysiological mechanisms. Therefore, relevant bone intervention strategies may be beneficial for the comprehensive management of AD.
Assuntos
Doença de Alzheimer , Osso e Ossos , Encéfalo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Encéfalo/metabolismo , Encéfalo/patologia , Osso e Ossos/metabolismo , Vesículas Extracelulares/metabolismo , AnimaisRESUMO
INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.
RESUMO
Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Fígado/metabolismo , Fígado/patologia , Camundongos Transgênicos , Modelos Animais de DoençasRESUMO
BACKGROUND AND PURPOSE: This study was undertaken to investigate the longitudinal impact of type 2 diabetes mellitus (T2DM) on the prodromal and dementia stages of Alzheimer disease (AD), focusing on diabetes duration and other comorbidities. METHODS: A total of 1395 dementia-free individuals aged 55-90 years with maximum 15-year follow-up data were enrolled from the Alzheimer's Disease Neuroimaging Initiative database. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of the incidence of prodromal or dementia stages of AD. RESULTS: Longer T2DM duration (≥5 years; multiadjusted HR = 2.19, 95% confidence interval [CI] = 1.05-4.58), but not shorter T2DM duration (<5 years), was associated with a significantly increased risk of incident prodromal AD over a mean follow-up of 4.8 years. APOE ε4 allele (HR = 3.32, 95% CI = 1.41-7.79) and comorbid coronary artery disease (CAD; HR = 3.20, 95% CI = 1.29-7.95) further increased the risk of incident prodromal AD in patients with T2DM. No significant association was observed between T2DM and the risk of progression from prodromal AD to AD dementia. CONCLUSIONS: T2DM, which is characterized by a longer duration, increases the incidence risk of prodromal AD but not AD dementia. APOE ε4 allele and comorbid CAD strengthen the relationship between T2DM and prodromal AD. These findings highlight T2DM characteristics and its comorbidities as predictors for accurate prediction of AD and screening of at-risk populations.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Humanos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Estudos Longitudinais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Apolipoproteína E4/genética , Genótipo , Fatores de RiscoRESUMO
Early and accurate diagnosis of Alzheimer's disease (AD) in clinical practice is urgent with advances in AD treatment. Blood biomarker assays are preferential diagnostic tools for widespread clinical use with the advantages of being less invasive, cost effective, and easily accessible, and they have shown good performance in research cohorts. However, in community-based populations with maximum heterogeneity, great challenges are still faced in diagnosing AD based on blood biomarkers in terms of accuracy and robustness. Here, we analyze these challenges, including the confounding impact of systemic and biological factors, small changes in blood biomarkers, and difficulty in detecting early changes. Furthermore, we provide perspectives on several potential strategies to overcome these challenges for blood biomarkers to bridge the gap from research to clinical practice.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , BiomarcadoresRESUMO
The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (α1-ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or an equal volume of saline for 6 months. SH-SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1-ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aß species, compact and total Aß plaques, than control mice. α1-ARs inhibitor terazosin substantially reduced Aß deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3ß, thus reducing Aß production. This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Transgênicos , Receptores Adrenérgicos/uso terapêutico , Transdução de SinaisRESUMO
Genome-wide association studies (GWASs) have discovered numerous risk genes for Alzheimer's disease (AD), but how these genes confer AD risk is challenging to decipher. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteomes in the brain and blood by systematically applying proteome-wide association study (PWAS), Mendelian randomization (MR) and Bayesian colocalization. Collectively, we identified the brain protein abundance of 7 genes (ACE, ICA1L, TOM1L2, SNX32, EPHX2, CTSH, and RTFDC1) are causal in AD (P < 0.05/proteins identified for PWAS and MR; PPH4 >80% for Bayesian colocalization). The proteins encoded by these genes were mainly expressed on the surface of glutamatergic neurons and astrocytes. Of them, ACE with its protein abundance was also identified in significant association with AD on the blood-based studies and showed significance at the transcriptomic level. SNX32 was also found to be associated with AD at the blood transcriptomic level. Collectively, our current study results on genetic, proteomic, and transcriptomic approaches has identified compelling genes, which may provide important leads to design future functional studies and potential drug targets for AD.
Assuntos
Doença de Alzheimer , Proteoma , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Teorema de Bayes , Encéfalo , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Proteoma/genética , ProteômicaRESUMO
It is traditionally believed that cerebral amyloid-beta (Aß) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aß. The role of peripherally produced Aß in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aß to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aß in the blood, and caused AD phenotypes including Aß plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aß levels, and alleviated brain Aß burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aß plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aß can decrease brain Aß deposition and represents a novel therapeutic approach for AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Sanguíneas/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos TransgênicosRESUMO
Amyloid-ß (Aß) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aß produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aß clearance remain largely unknown. The kidney is thought to be responsible for Aß clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aß in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aß clearance via the kidney were assessed. We detected Aß in the kidneys and urine of both humans and animals and found that the Aß level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aß deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aß levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aß from the blood, suggesting that facilitation of Aß clearance via the kidney represents a novel potential therapeutic approach for AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Rim/metabolismo , Camundongos , Camundongos Transgênicos , Presenilina-1/metabolismoRESUMO
INTRODUCTION: Ablation index (AI)-guided radiofrequency ablation has been increasingly used for the treatment of drug-resistant paroxysmal atrial fibrillation (AF)ï¼but the optimal AI targets remain to be determined. We aimed to examine the efficacy and safety of catheter ablation guided by moderate AI values but more strict procedural endpoints in patients with paroxysmal AF. METHODS: We conducted a retrospective review of a consecutive series of patients who received their first AI-guided ablation for paroxysmal AF from 2017 to 2018. The standard procedural protocol recommends AI targets as follows: anterior: 400-450; posterior: 280-330; and roof/inferior wall: 380-430. After circumferential pulmonary vein isolation (PVI), we performed bipolar pacing along the ablation line, adenosine triphosphate (ATP)-provocation, and waited for 30 min to verify PVI. The primary clinical outcome was the rate of freedom from AF recurrence at 12 months. RESULTS: A total of 140 consecutive patients were included. The mean procedure and ablation times were 132.2 ± 30.2 min and 24.2 ± 7.9 min, respectively. The first-pass isolation and final isolation rates were documented in 49.3% and in 100% of the patients, respectively. At 12 months, single-procedure freedom from atrial tachyarrhythmias was observed in 92.1% of patients. No major procedure-related complications were encountered. CONCLUSIONS: Moderate AI-guided catheter ablation is highly effective for the treatment of drug-refractory paroxysmal AF in real-world settings. Over 90% of patients achieved single-procedure arrhythmia-free survival at 1 year. The outcome was obtained without major complications and the procedure involved relatively short procedure and ablation times.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Humanos , Veias Pulmonares/cirurgia , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. METHODS: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. RESULTS: A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). INTERPRETATION: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.
Assuntos
Doença de Alzheimer/prevenção & controle , Medicina Baseada em Evidências , Anti-Hipertensivos/uso terapêutico , Cognição , Traumatismos Craniocerebrais/prevenção & controle , Depressão/terapia , Diabetes Mellitus/terapia , Educação , Exercício Físico , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipotensão Ortostática/terapia , Estilo de Vida , Obesidade/terapia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento de Redução do Risco , Estresse Psicológico/terapiaRESUMO
AIMS: Circumferential pulmonary vein isolation can be effective as sole treatment for persistent atrial fibrillation. However, identifying those patients who will respond to this therapy remains a challenge. We investigated the clinical value of the sequential low-dose ibutilide test for identifying patients with persistent atrial fibrillation in whom pulmonary vein isolation is effective as sole therapy. METHODS AND RESULTS: In a prospective cohort of 180 consecutive patients with persistent atrial fibrillation, intravenous low-dose (0.004 mg/kg) ibutilide was administered 3 days before ablation and after the completion of circumferential pulmonary vein isolation. In patients in whom ibutilide did not terminate atrial fibrillation pre-procedurally, but successfully terminated it intraprocedurally, no further atrial substrate modification was performed. Pre-procedural low-dose ibutilide failed to terminate the arrhythmia in all patients with persistent atrial fibrillation, while pulmonary vein isolation ± low-dose ibutilide terminated persistent atrial fibrillation in 55 (30.6%) of them (PsAF group 1). The remaining 125 (69.4%) patients underwent electrogram-based ablation (PsAF Group 2). The control group comprised 379 consecutive patients with paroxysmal atrial fibrillation who underwent pulmonary vein isolation over the same period. At 24 months follow-up, 39 (70.9%) patients in PsAF Group 1 and 276 (72.8%) patients in the control group were free from atrial tachyarrhythmias (P = NS); the arrhythmia-free rates in both groups were higher than that in PsAF group 2 (58.4%, P = 0.005). CONCLUSION: The sequential low-dose ibutilide test is a simple method for identifying patients with persistent atrial fibrillation in whom pulmonary vein isolation alone is an appropriate treatment strategy.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Humanos , Estudos Prospectivos , Veias Pulmonares/cirurgia , Recidiva , Sulfonamidas , Resultado do TratamentoRESUMO
MMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer's disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (ß-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5' untranslated region (5'UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5'UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer's disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-ß precursor protein processing, amyloid-ß load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer's disease, via the translational regulation of BACE1.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Benzofuranos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Morfolinas/uso terapêutico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Células Cultivadas , Fatores de Iniciação em Eucariotos/genética , Técnicas de Silenciamento de Genes , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Oligopeptídeos/genética , Fosfatidilinositol 3-Quinases/metabolismo , RatosRESUMO
INTRODUCTION: Combined catheter ablation (CA) and left atrial appendage closure (LAAC) have proven to be a feasible and safe strategy in treating patients with nonvalvular atrial fibrillation (AF). However, the interactions between CA and LAAC have not been systematically explored. We analyzed the impact of CA on long-term outcomes of LAAC in patients with AF treated with the hybrid procedure. METHODS: A total of 107 consecutive patients with AF who underwent LAAC were divided into two groups: group A (n = 61) included patients who underwent CA followed by LAAC during the same procedure and group B (n = 46) included patients who underwent LAAC only. All patients underwent systematic transesophageal echocardiography (TEE) follow-up. RESULTS: In group A, CA resulted in severe edema of the left atrial ridge (LAR), which manifested as an increase in LAR thickness from 4.6 ± 0.4 mm before CA to 6.8 ± 0.6 mm (P < .01) after CA. TEE at 45 days showed that the incidence of peri-device leakage was significantly higher in group A than in group B (45.9% vs 4.3%, P < .001). At the 12-month follow-up, the peri-device leakage rate remained higher in group A than in group B (14.8% vs 2.2%, P < .01). Three (4.9%) patients in group A experienced transient ischemia attacks; no events were reported in group B during the 1-year follow-up. CONCLUSION: Edema of LAR with the single-stage procedure that consists of CA followed by LAAC could result in increased peri-device leakage and decreased compression rate over time, which may be also associated with elevated risk profiles when compared with an LAAC-only procedure.
Assuntos
Apêndice Atrial/cirurgia , Fibrilação Atrial/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Ablação por Cateter/métodos , Complicações Pós-Operatórias/epidemiologia , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
AIMS: In this study, we investigated the characteristics and underlying mechanisms of the electrocardiographic (ECG) morphology during left bundle branch area pacing (LBBAP), which have not been systematically described. METHODS: Patients with indications for permanent cardiac pacing underwent LBBAP attempts. The ECGs of patients with confirmed left bundle branch (LBB) capture were compared with those of individuals with right bundle branch block (RBBB) on 12-lead ECG. Intracardiac electrograms recorded during implantation were analyzed in all patients who underwent pacing. RESULTS: LBBAP was successfully achieved in 87.5% (56/64) of patients. The QRS morphologies in lead V1 during LBBAP, which typically demonstrated Qr (60.7%), qR (19.6%), rSR' (7.1%), or QS (12.5%) patterns, differed from those of native RBBB, which featured rsR' (57.5%), M shape (23.7%), or monophasic R patterns (18.7%). The terminal R' wave duration in lead V1 was significantly shorter during LBBAP than during native RBBB (51 ± 12 ms vs 85 ± 19 ms, p < 0.001). LBB potentials were recorded in 66.1% (37/56) of the LBBAP patients. No significant differences in ECG characteristics were found between LBBAP with and without recorded LBB potentials. The presence of bundle branch block during LBBAP significantly prolonged QRS duration, R wave peak time, and terminal R' wave duration in lead V1 . CONCLUSION: LBBAP-ECG patterns are characterized by a shorter terminal R' wave duration in lead V1 compared with that of native RBBB configurations. Bundle branch conduction integrity has an impact on ECG characteristics during LBBAP.
Assuntos
Bloqueio de Ramo/fisiopatologia , Bloqueio de Ramo/terapia , Estimulação Cardíaca Artificial , Eletrocardiografia , Idoso , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aß) accumulation. However, the mechanism by which Aß induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aß and mediates Aß neurotoxicity, implying that p75NTR may mediate Aß-induced tau phosphorylation in AD. Here, we showed that Aß-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß) significantly changed Aß/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aß to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aß-induced tau pathology and is a potential druggable target for AD and other tauopathies.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Receptores de Fator de Crescimento Neural/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Distribuição Aleatória , Receptores de Fator de Crescimento Neural/administração & dosagem , Receptores de Fator de Crescimento Neural/genética , Tauopatias/tratamento farmacológico , Tauopatias/genética , Proteínas tau/antagonistas & inibidores , Proteínas tau/genéticaRESUMO
INTRODUCTION: Adenosine triphosphate (ATP)-provoked dormant conduction (DC) and pacing for unexcitability are used to identify conduction gaps along the ablation lines after circumferential pulmonary vein isolation (CPVI). We aim to determine whether ATP provocation and pacing are interchangeable as endpoints for ablation of paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS: A total of 107 patients with PAF were randomly divided into two groups after completion of CPVI. In group I (A-P group, n = 53), ATP was administered first. If DC was uncovered, additional ablation was performed until ATP tests were negative. Bipolar pacing along the ablation line was performed subsequently. In group II (P-A group, n = 54), the same protocol was used, but the pacing and the ATP tests were performed in the opposite sequence. The 12-month ablation outcomes of all patients were compared with those of a historical control group of 107 patients with PAF in whom only ATP test was performed. Regardless of which test was performed first, the other modality still identified conduction gaps. In group I, pacing maneuvers identified gaps in 49% (n = 26) of patients who had negative ATP tests. In group II, ATP tests uncovered DC in 18.5% (n = 10) of patients in whom pacing identified no gaps. After 12 months, a higher proportion of patients (91.6%) were free from atrial tachyarrhythmias compared with the historical control group (81.3%; P = 0.031). CONCLUSION: Pacing along the ablation lines and ATP provocation are complementary tests for evaluating the durability of CPVI and can lead to better long-term outcomes when used in combination.
Assuntos
Trifosfato de Adenosina/administração & dosagem , Fibrilação Atrial/cirurgia , Estimulação Cardíaca Artificial , Ablação por Cateter , Técnicas Eletrofisiológicas Cardíacas , Veias Pulmonares/cirurgia , Potenciais de Ação , Administração Intravenosa , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Ablação por Cateter/efeitos adversos , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Prospectivos , Veias Pulmonares/fisiopatologia , Recidiva , Fatores de TempoRESUMO
OBJECTIVE: Inflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively. METHODS: Studies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity. RESULTS: A total of 170 studies were included in the meta-analysis and systematic review, which demonstrated increased peripheral levels of high-sensitivity C reactive protein (Hedges's g 0.281, p<0.05), interleukin-6 (IL-6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1-antichymotrypsin (α1-ACT) (1.217, p<0.005), IL-1ß (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL-10 (0.434, p<0.05), monocyte chemoattractant protein-1 (MCP-1) (0.798, p<0.005), transforming growth factor-beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL-40 (0.849, p<0.001), α1-ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin-like protein-1 (VILIP-1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL-6 (0.129, p<0.05) and MCP-1 (0.779, p<0.05) and lower levels of IL-8 (-1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL-40 (0.373, p<0.05), VILIP-1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI. CONCLUSION: Significantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.