Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neur...Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the pho...Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.展开更多
在双通道信号检测领域,肯德尔秩相关系数(Kendall’s Tau, KT)作为一种检测器,对含脉冲噪声的信号具有显著的鲁棒性。然而,当通道间的噪声存在相关性时,KT的检测性能仍有待提升。为此,本文提出一种改进的肯德尔秩相关系数(Improved Kend...在双通道信号检测领域,肯德尔秩相关系数(Kendall’s Tau, KT)作为一种检测器,对含脉冲噪声的信号具有显著的鲁棒性。然而,当通道间的噪声存在相关性时,KT的检测性能仍有待提升。为此,本文提出一种改进的肯德尔秩相关系数(Improved Kendall’s Tau, IKT)检测器,在KT的基础上引入了阈值可调节的硬限幅函数。同时采用二元高斯混合模型(Gaussian Mixture Model, GMM)模拟两通道间噪声的相关性及脉冲特性,深入探讨了IKT在该模型下的统计性质,并建立了针对双通道高斯随机信号检测问题的虚警率和检测概率的解析式。通过蒙特卡罗实验与高斯噪声下性能最优的匹配滤波器(Matched Filter Detector, MFD)、脉冲噪声下具有鲁棒性的极性重合相关器(Polarity Coincidence Correlator, PCC)、KT的接收机工作特性(Receiver Operating Characteristic, ROC)曲线下面积(Area Under the Curve, AUC)进行比较,表明IKT在含相关性高斯噪声的信号检测中相较于PCC在AUC上表现出12.9%左右的提升,相较于KT的提升约为4.8%。在含相关性脉冲噪声的信号检测中相较于PCC的AUC提升约为8.3%,相较于KT的提升约为1.6%,从而验证了其优越性。In dual-channel signal detection, the Kendall’s Tau (KT) correlation coefficient is well-regarded for its robustness in handling signals affected by impulsive noise. However, its detection performance declines when there is noise correlation between channels. To address this limitation, this paper presents an Improved Kendall’s Tau (IKT) detector, which enhances the traditional KT by incorporating a threshold-adjustable hard limiting function. Furthermore, a bivariate Gaussian Mixture Model (GMM) is used to simulate the noise correlation and impulsive characteristics between the two channels. The statistical properties of IKT under this model are thoroughly analyzed, and analytical expressions for the false alarm rate and detection probability in dual-channel Gaussian random signal detection are derived. Monte Carlo simulations and comparisons with the matched filter detector (MFD), which is optimal for Gaussian noise, the polarity coincidence correlator (PCC), known for its robustness against impulsive noise, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for KT, are performed. The results show that in the presence of correlated Gaussian noise, IKT achieves approximately a 12.9% improvement in AUC over PCC and a 4.8 % improvement over KT. In the presence of correlated impulsive noise, IKT shows about an 8.3% improvement in AUC over PCC and a 1.6% improvement over KT, thereby validating its superiority.展开更多
Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is k...Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.展开更多
Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofib...Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.展开更多
基金supported by the National Natural Science Foundation of China,No.82101493(to JY)。
文摘Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.
基金supported by the European Regional Development Funds-European Union(ERDF-EU),FATZHEIMER project(EU-LAC HEALTH 2020,16/T010131 to FRdF),“Una manera de hacer Europa”Ministerio de Economía,Industria y Competitividad,Gobierno de Espa?a,Programa Estatal de Investigación,Desarrollo e Innovación Orientada a los Retos de la Sociedad(RTC2019-007329-1 to FRdF)+2 种基金Consejería de Economía,Conocimiento y Universidad,Junta de Andalucía,Plan Andaluz de Investigación,Desarrollo e Innovación(P18TP-5194 to FRdF)Instituto de Salud CarlosⅢ(DTS22/00021 to FRdF)DMV(FI20/00227)holds a“PFIS’’predoctoral contract from the National System of Health,EU-ERDF-Instituto de Salud CarlosⅢ。
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.
文摘在双通道信号检测领域,肯德尔秩相关系数(Kendall’s Tau, KT)作为一种检测器,对含脉冲噪声的信号具有显著的鲁棒性。然而,当通道间的噪声存在相关性时,KT的检测性能仍有待提升。为此,本文提出一种改进的肯德尔秩相关系数(Improved Kendall’s Tau, IKT)检测器,在KT的基础上引入了阈值可调节的硬限幅函数。同时采用二元高斯混合模型(Gaussian Mixture Model, GMM)模拟两通道间噪声的相关性及脉冲特性,深入探讨了IKT在该模型下的统计性质,并建立了针对双通道高斯随机信号检测问题的虚警率和检测概率的解析式。通过蒙特卡罗实验与高斯噪声下性能最优的匹配滤波器(Matched Filter Detector, MFD)、脉冲噪声下具有鲁棒性的极性重合相关器(Polarity Coincidence Correlator, PCC)、KT的接收机工作特性(Receiver Operating Characteristic, ROC)曲线下面积(Area Under the Curve, AUC)进行比较,表明IKT在含相关性高斯噪声的信号检测中相较于PCC在AUC上表现出12.9%左右的提升,相较于KT的提升约为4.8%。在含相关性脉冲噪声的信号检测中相较于PCC的AUC提升约为8.3%,相较于KT的提升约为1.6%,从而验证了其优越性。In dual-channel signal detection, the Kendall’s Tau (KT) correlation coefficient is well-regarded for its robustness in handling signals affected by impulsive noise. However, its detection performance declines when there is noise correlation between channels. To address this limitation, this paper presents an Improved Kendall’s Tau (IKT) detector, which enhances the traditional KT by incorporating a threshold-adjustable hard limiting function. Furthermore, a bivariate Gaussian Mixture Model (GMM) is used to simulate the noise correlation and impulsive characteristics between the two channels. The statistical properties of IKT under this model are thoroughly analyzed, and analytical expressions for the false alarm rate and detection probability in dual-channel Gaussian random signal detection are derived. Monte Carlo simulations and comparisons with the matched filter detector (MFD), which is optimal for Gaussian noise, the polarity coincidence correlator (PCC), known for its robustness against impulsive noise, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for KT, are performed. The results show that in the presence of correlated Gaussian noise, IKT achieves approximately a 12.9% improvement in AUC over PCC and a 4.8 % improvement over KT. In the presence of correlated impulsive noise, IKT shows about an 8.3% improvement in AUC over PCC and a 1.6% improvement over KT, thereby validating its superiority.
基金supported by the National Key Research&Development Program of China,Nos.2021YFC2501205(to YC),2022YFC24069004(to JL)the STI2030-Major Project,Nos.2021ZD0201101(to YC),2022ZD0211800(to YH)+2 种基金the National Natural Science Foundation of China(Major International Joint Research Project),No.82020108013(to YH)the Sino-German Center for Research Promotion,No.M-0759(to YH)a grant from Beijing Municipal Science&Technology Commission(Beijing Brain Initiative),No.Z201100005520018(to JL)。
文摘Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.
基金the support by the Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
文摘Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.
