With the rapidly aging human population,age-related cognitive decline and dementia are becoming increasingly prevalent worldwide.Aging is considered the main risk factor for cognitive decline and acts through alterati...With the rapidly aging human population,age-related cognitive decline and dementia are becoming increasingly prevalent worldwide.Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota,microbial metabolites,and the functions of astrocytes.The microbiota–gut–brain axis has been the focus of multiple studies and is closely associated with cognitive function.This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases.This article also summarizes the gut microbiota components that affect astrocyte function,mainly through the vagus nerve,immune responses,circadian rhythms,and microbial metabolites.Finally,this article summarizes the mechanism by which the gut microbiota–astrocyte axis plays a role in Alzheimer’s and Parkinson’s diseases.Our findings have revealed the critical role of the microbiota–astrocyte axis in age-related cognitive decline,aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.展开更多
There is growing evidence that diabetes can induce cognitive decline and dementia.It is a slow,progressive cognitive decline that can occur in any age group,but is seen more frequently in older individuals.Symptoms re...There is growing evidence that diabetes can induce cognitive decline and dementia.It is a slow,progressive cognitive decline that can occur in any age group,but is seen more frequently in older individuals.Symptoms related to cognitive decline are worsened by chronic metabolic syndrome.Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention.This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.展开更多
BACKGROUND Blood pressure variability(BPV)has been shown to be related to mild cognitive impairment and Alzheimer's disease in a number of studies.However,the relationship between BPV and subtle cognitive decline(...BACKGROUND Blood pressure variability(BPV)has been shown to be related to mild cognitive impairment and Alzheimer's disease in a number of studies.However,the relationship between BPV and subtle cognitive decline(SCD)has received minimal attention in this field of research to date and has rarely been reported.AIM To examine whether SCD is independently associated with changes in BPV in older adults.METHODS Participants were selected based on having participated in cognitive function evaluation and ambulatory blood pressure measurement at the Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine between June 2020 and August 2022.The participants included 182 individuals with SCD as the experimental group and 237 with normal cognitive function as the control group.The basic data,laboratory examinations,scale tests,and ambulatory blood pressure test results of the two groups were analyzed retrospectively,and the relationship between SCD and BPV was subsequently evaluated.RESULTS Significant differences were observed between the two groups of participants(P<0.05)in terms of age,education level,prevalence rate of diabetes,fasting blood glucose level,24-h systolic blood pressure standard deviation and coefficient of variation,24-h diastolic blood pressure standard deviation and coefficient of variation.The scale monitoring results showed significant differences in the scores for memory,attention,and visual space between the experimental and control groups.Logistic regression analysis indicated that age,education level,blood sugar level,and BPV were factors influencing cognitive decline.Linear regression analysis showed that there was an independent correlation between blood pressure variation and SCD,even after adjusting for related factors.Each of the above differences was still significant.CONCLUSION This study suggests that increased BPV is associated with SCD.展开更多
Cognitive decline is a common complication after cardiac surgery with cardiopulmonary bypass(CPB),but as such no pharmacological therapy has been shown to be efficacious in preventing the decline.However,gastrodin h...Cognitive decline is a common complication after cardiac surgery with cardiopulmonary bypass(CPB),but as such no pharmacological therapy has been shown to be efficacious in preventing the decline.However,gastrodin has been shown to have multi-pharmacological effects on neurological functions.We undertook this study to test the hypothesis that gastrodin would potentially prevent CPB-associated neurocognitive decline.We randomly assigned 200 patients undergoing mitral valve replacement surgery to receive either gastrodin(40 mg/kg) or saline after the induction of anesthesia and subsequently evaluated cognitive function before surgery,at discharge,and at 3rd month after surgery by using a battery of five neurocognitive tests,or adverse effects of gastrodin postoperatively.Neurocognitive decline in postoperative function was defined as a drop of 1 SD or more in the scores on tests of any one of the four domains of cognitive function.Cognitive decline occurred in 9% of the patients in the gastrodin group in contrast to 42% in the control group(P〈0.01) at discharge.Cognitive outcome could be determined at 3rd month in 87 patients in the gastrodin group and 89 in the control group.Cognitive decline was detected in 6% in the gastrodin group and 31% in the control group(P〈0.01).The incidences of possible adverse effects were similar between two groups.These results indicate that gastrodin is an effective and a safe drug for the prevention of neurocognitive decline in patients undergoing mitral valve replacement surgery with CPB.展开更多
Recent emerging research on intestinal microbiota and its contribution to the central nervous system during health and disease has attra cted significant attention.Age-related intestinal microbiota changes initiate br...Recent emerging research on intestinal microbiota and its contribution to the central nervous system during health and disease has attra cted significant attention.Age-related intestinal microbiota changes initiate brain aging and age-related neurodegenerative disorders.Aging is one of the critical predisposing risk factors for the development of neurodegenerative diseases.Maintaining a healthy gut microbiota is essential for a healthy body and aging,but dys biosis could initiate many chro nic diseases.Understanding the underlying mechanisms of gut microbiota alterations/dys biosis will help identify biomarkers for aging-related chro nic conditions.This review summarizes recent advances in micro biota-neurodegenerative disease research and will enhance our unde rstanding of gut microbiota dys biosis and its effects on brain aging.展开更多
Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent ...Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease(amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.展开更多
Alzheimer's disease(AD)redefined:For the past century,AD has been defined as a disease of progressive cognitive decline paired with a burden of amyloid-β(Aβ)plaques and pathologic tau tangles in the hippocampu...Alzheimer's disease(AD)redefined:For the past century,AD has been defined as a disease of progressive cognitive decline paired with a burden of amyloid-β(Aβ)plaques and pathologic tau tangles in the hippocampus and forebrain.However,a recent Framework paper jointly sponsored by the National Institute on Aging and the Alzheimer's Association(Jack et al.,2018)proposes new classification guidelines for AD,which,if adopted,will have profoundconsequences for the future management of AD.展开更多
Objective:To systematically evaluate the efficacy and safety of Donepezil in treating the cognitive decline in patients with Parkinson's disease(PD).Methods:Nine literature databases in domestic and abroad were se...Objective:To systematically evaluate the efficacy and safety of Donepezil in treating the cognitive decline in patients with Parkinson's disease(PD).Methods:Nine literature databases in domestic and abroad were searched by computer,and the search deadline was November 2,2020.The randomized controlled trials(RCT)using donepezil to treat the cognitive decline in patients with PD were screened.The MMSE(Mini-Mental State Exam)scores,MoCA(Montreal Cognitive Assessment)scores and adverse events of the included RCTs were extracted.Meta-analysis was implemented with RevMan 5.3 software,and the subgroup analyses were conducted to evaluate the effects of mean age and mean course of disease on the MMSE scores.Results:14 RCTs with 1263 patients were selected,including 646 cases in the experimental group and 617 cases in the control group.There were 1209 effective patients who completed MMSE score,including 612 in the experimental group and 597 in the control group.Meta-analysis results showed that MMSE scores in the experimental group were higher than that in the control group after using donepezil intervention,and the difference was statistically significant[SMD=0.55,95%CI(0.24,0.87),P=0.0006].It was also found that the MoCA scores of experimental group were higher than that of control group after using donepezil intervention,and the difference was statistically significant[SMD=1.25,95%CI(0.79,1.72),P<0.00001].Subgroup analysis showed that donepezil improved MMSE scores in different subgroups,and the difference between each group was statistically significant.There was no heterogeneity in the subgroup of mean age lower than 65 years,and the heterogeneity existed between the subgroup of mean course of disease lower than 3 years and the subgroup of mean course of disease larger than or equal to 3 years.For adverse events,the incidence of adverse events in the experimental group was 22.18%.There was no heterogeneity between the included studies(I2=0%),and the difference was not statistically significant[RR=1.18,95%CI(0.95,1.47),P=0.14].Conclusion:The results of meta-analysis showed that donepezil can improve the cognitive decline in patients with Parkinson's disease significantly,and it has good safety.展开更多
Cardiovascular health metrics are now widely recognized as modifable risk factors for cognitive decline and dementia.Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia.Circ...Cardiovascular health metrics are now widely recognized as modifable risk factors for cognitive decline and dementia.Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia.Circulating metabolites profling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline.In a prospective community-based cohort in China(n=725),312 serum metabolic phenotypes were quantifed,and cardiovascular health score was calculated including smoking,exercise,sleep,diet,body mass index,blood pressure,and blood glucose.Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline.A better cardiovascular health was signifcantly associated with lower risk of concentration decline and orientation decline(hazard ratio(HR):0.84–0.90;p<0.05).Apolipoprotein-A1,high-density lipoprotein(HDL)cholesterol,cholesterol ester,and phospholipid concentrations were signifcantly associated with a lower risk of longitudinal memory and orientation decline(p<0.05 and adjusted-p<0.20).Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and-3(proportion of mediation:7.68–8.21%,both p<0.05).Cardiovascular risk factors were associated with greater risks of cognitive decline,which were found to be mediated by circulating lipoproteins,particularly the medium-size HDL components.These fndings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention.展开更多
Alzheimer's disease(AD)is a neurodegenerative disease that gradually impairs cognitive functions.Recently,there has been a conceptual shift toward AD to view the disease as a continuum.Since AD is currently incura...Alzheimer's disease(AD)is a neurodegenerative disease that gradually impairs cognitive functions.Recently,there has been a conceptual shift toward AD to view the disease as a continuum.Since AD is currently incurable,effective intervention to delay or prevent pathological cognitive decline may best target the early stages of symptomatic disease,such as subjective cognitive decline(SCD),in which cognitive function remains relatively intact.Diagnostic methods for identifying AD,such as cerebrospinal fluid biomarkers and positron emission tomography,are invasive and expensive.Therefore,it is imperative to develop blood biomarkers that are sensitive,less invasive,easier to access,and more cost effective for AD diagnosis.This review aimed to summarize the current data on whether individuals with SCD differ reliably and effectively in subjective and objective performances compared to cognitively normal elderly individuals,and to find one or more convenient and accessible blood biomarkers so that researchers can identify SCD patients with preclinical AD in the population as soon as possible.Owing to the heterogeneity and complicated pathogenesis of AD,it is difficult to make reliable diagnoses using only a single blood marker.This review provides an overview of the progress achieved to date with the use of SCD blood biomarkers in patients with preclinical AD,highlighting the key areas of application and current challenges.展开更多
Biological agents threats people's life through different ways,one of which lies in the impairment of cognition.It is believed cognitive decline may result from biological agents mediated neuron damage directly,or...Biological agents threats people's life through different ways,one of which lies in the impairment of cognition.It is believed cognitive decline may result from biological agents mediated neuron damage directly,or from the activation of the host immune response to eradicate the pathogen.However,direct linkage between infections and cognitive decline is very limited.Here we focus on the mechanisms of how different biological virus or they induced systemic and local inflammation link to the cognitive impairment,focusing on the roles of acti-vated microglia and several molecular pathways mediated neurotoxicity.展开更多
Background Subjective cognitive decline(SCD)is a preclinical stage along the Alzheimer’s disease(AD)continuum.However,little is known about the aberrant patterns of connectivity and topological alterations of the bra...Background Subjective cognitive decline(SCD)is a preclinical stage along the Alzheimer’s disease(AD)continuum.However,little is known about the aberrant patterns of connectivity and topological alterations of the brain functional connectome and their diagnostic value in SCD.Methods Resting-state functional magnetic resonance imaging and graph theory analyses were used to investigate the alterations of the functional connectome in 66 SCD individuals and 64 healthy controls(HC).Pearson correlation analysis was computed to assess the relationships among network metrics,neuropsychological performance and pathological biomarkers.Finally,we used the multiple kernel learning-support vector machine(MKL-SVM)to differentiate the SCD and HC individuals.Results SCD individuals showed higher nodal topological properties(including nodal strength,nodal global efficiency and nodal local efficiency)associated with amyloid-βlevels and memory function than the HC,and these regions were mainly located in the default mode network(DMN).Moreover,increased local and medium-range connectivity mainly between the bilateral parahippocampal gyrus(PHG)and other DMN-related regions was found in SCD individuals compared with HC individuals.These aberrant functional network measures exhibited good classification performance in the differentiation of SCD individuals from HC individuals at an accuracy up to 79.23%.Conclusion The findings of this study provide insight into the compensatory mechanism of the functional connectome underlying SCD.The proposed classification method highlights the potential of connectome-based metrics for the identification of the preclinical stage of AD.展开更多
Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy...Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy)are significantly elevated in the plasma of stressed animals,which suggests that Hcy is associated with stress and cognitive decline.To test this hypothesis,we analyzed the cognitive function,plasma concentrations of Hcy,and brain-derived neurotropic factor(BDNF)levels in rats undergoing chronic unpredicted mild stress(CUMS).The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia(HHcy)levels in stressed rats.Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS,while Hcy reduction(by means of vitamin B complex supplements)alleviated the cognitive deficits and BDNF reduction in CUMS rats.Furthermore,we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter.In contrast,control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain.These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline.We also used ten-eleven translocation(TET1),an enzyme that induces DNA demethylation,to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline.The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats.Taken together,novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits.In addition,the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter.The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.展开更多
Background: Memory complaint is common in the elderly. Recently, it was shown that self-report memory complaint was predictive of cognitive decline. This study aimed to investigate the predictive value of the source ...Background: Memory complaint is common in the elderly. Recently, it was shown that self-report memory complaint was predictive of cognitive decline. This study aimed to investigate the predictive value of the source of memory complaints on the risk of cognitive impairment and cognitive decline in a community-based cohort. Methods: Data on memory complaints and cognitive function were collected among 1840 Chinese participants (aged ≥55 years old) in an urban community at baseline interview and 5-year follow-up. Incident cognitive impairment was identified based on education-adjusted Mini-Mental State Examination score. Logistic regression model was used to estimate the association between the source of memory complaints and risk of cognitive impairment conversion and cognitive decline, after adjusting for covariates. Results: A total of 1840 participants were included into this study including 1713 normal participants and 127 cognitive impairment participants in 2009. Among 1713 normal participants in 2009, 130 participants were converted to cognitive impairment alter 5 years of follow-up. In 2014, 606 participants were identified as cognitive decline. Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment (odds ratio [OR] - 1.60, 95% confidence interval [CI]: 1.04 2.48) and cognitive decline (OR = 1.30, 95% CI: 1.01-1.68). Furthermore, this association was more significant in males (OR = 2.10, 95% CI: 1.04-4.24 for cognitive impairment and OR - 1.87, 95% CI:1.20-2.99 for cognitive decline) and in higher education level (OR - 1.79, 95% CI: 1.02-3.15 for cognitive impairment and OR = 1.40, 95% CI:1.02-1.91 for cognitive decline). Conclusions: Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment conversion and cognitive decline, especially in persons with male gender and high educational background.展开更多
Objective:This study aims to determine the relationship between education level,memory function,and hippocampus functional and structural alterations in subjective cognitive decline(SCD).Methods:Seventy-five participa...Objective:This study aims to determine the relationship between education level,memory function,and hippocampus functional and structural alterations in subjective cognitive decline(SCD).Methods:Seventy-five participants with SCD were divided into high education(HE)and low education(LE)level groups.A Wechsler Memory Scale-Chinese Revision test and functional and structural MRI were performed within 1 week after participant recruitment.The bilateral hippocampus resting-state functional connectivity(rsF C),gray matter volume(GMV)of brain regions identified by rsF C analysis,and moderating and mediating effects were assessed.Results:Compared with the LE group,HE individuals showed 1)higher memory quotient(MQ)and Digit Span subscore,2)decreased hippocampal rs FC with the right medial prefrontal cortex(mPFC)and dorsolateral prefrontal cortex(DLPFC),and 3)increased GMV in the right mP FC and DLPFC.The bilateral hippocampus-right DLPFCrs FC significantly associated with the MQ and the bilateral hippocampus-right m PFCrs FC with the Digit Span subscore in each group.The bilateral hippocampus-right DLPFCrsFC moderated the relationship between the education level and MQ.The bilateral hippocampus-right mP FC rsF C mediated the relationship between the education level and Digit Span subscore in all subjects.Conclusion:The hippocampal rsF C with the right mP FC and DLPFC contributes to the education level effect on memory function in SCD.展开更多
Recently, cognitive impairments(CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis(ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current s...Recently, cognitive impairments(CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis(ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current study, we explored the role of gut microbiota in CI of ALS patients. We collected fecal samples from 35ALS patients and 35 healthy controls. The cognitive function of the ALS patients was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen. We analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted(bile acids) metabolite mapping between patients with CI and patients with normal cognition(CN). We found altered gut microbial communities and a lower ratio of Firmicutes/Bacteroidetes in the CI group, compared with the CN group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the CI group, compared with the CN group. These metabolites were mapped to the metabolic pathways associated with bile acids. We further found that cholic acid and chenodeoxycholic acid were significantly lower in the CI group than in the CN group. In conclusion, we found that the gut microbiota and its metabolome profile differed between ALS patients with and without CI and that the altered bile acid profile in fecal samples was significantly associated with CI in ALS patients. These results need to be replicated in larger studies in the future.展开更多
Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
A severe impairment of cognitive function characterizes dementia.Mild cognitive impairment represents a transition between normal cognition and dementia.The frequency of cognitive changes is higher in women than in me...A severe impairment of cognitive function characterizes dementia.Mild cognitive impairment represents a transition between normal cognition and dementia.The frequency of cognitive changes is higher in women than in men.Based on this fact,hormonal factors likely contribute to cognitive decline.In this sense,cognitive complaints are more common near menopause,a phase marked by a decrease in hormone levels,especially estrogen.Additionally,a tendency toward worsened cognitive performance has been reported in women during menopause.Vasomotor symptoms(hot flashes,sweating,and dizziness),vaginal dryness,irritability and forgetfulness are common and associated with a progressive decrease in ovarian function and a subsequent reduction in the serum estrogen concentration.Hormone therapy(HT),based on estrogen with or without progestogen,is the treatment of choice to relieve menopausal symptoms.The studies conducted to date have reported conflicting results regarding the effects of HT on cognition.This article reviews the main aspects of menopause and cognition,including the neuroprotective role of estrogen and the relationship between menopausal symptoms and cognitive function.We present and discuss the findings of the central observational and interventional studies on HT and cognition.展开更多
Insulin,a key pleiotropic hormone,regulates metabolism through several signaling pathways in target tissues including skeletal muscle,liver,and brain.In the brain,insulin modulates learning and memory,and impaired ins...Insulin,a key pleiotropic hormone,regulates metabolism through several signaling pathways in target tissues including skeletal muscle,liver,and brain.In the brain,insulin modulates learning and memory,and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases.At the receptor level,in aging and Alzheimer’s disease(AD)models,the amount of insulin receptors and their functions are decreased.Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels.Furthermore,diabetes mellitus(DM)and insulin resistance are associated with age-related cognitive decline,increased levels ofβ-amyloid peptide,phosphorylation of tau protein;oxidative stress,pro-inflammatory cytokine production and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mildobesity and insulin resistance without influencing brain size and apoptosis development.Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size anddevelopment, and contributes to behavior changes. Insulin is synthesized locally in the brain andis released from the neurons. Here, we reviewed proposed pathophysiological hypotheses toexplain increased risk of dementia in the presence of DM. Regardless of the exact sequence ofevents leading to neurodegeneration, there is strong evidence that mitochondrial dysfunctionplays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrialdysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable tothose induced in wild-type mice treated with sucrose, which is consistent with the proposal thatmitochondrial alterations are associated with DM and contribute to AD development. Alterationsin insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidantcapacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing andsystemic metabolism, and could be a specific target for therapeutic strategies to decreasealterations associated with age-related cognitive decline.展开更多
In this editorial we comment on the article by Cahn-Hidalgo D published in a recent issue of the World Journal of Psychiatry 2020;10(1);1-11.We focus on the importance of utilizing psychometrically valid cognitive scr...In this editorial we comment on the article by Cahn-Hidalgo D published in a recent issue of the World Journal of Psychiatry 2020;10(1);1-11.We focus on the importance of utilizing psychometrically valid cognitive screening tools when assessing for cognitive decline in older adults in a psychiatric outpatient setting.We compared the use of Cognivue®to use of the montreal cognitive assessment(MoCA)as a cognitive screening tool.A total of 58 patients aged 55 and over participated in this comparison study.Patients completed cognitive screening on Cognivue®,a new Food and Drug Administration-cleared computer screening device,and the MoCA.The results of patient performance using these two instruments were analyzed.Sixteen(28%)patients screened negative for cognitive impairment on both assessments.Forty-two(72%)patients screened positive on one or both of the assessments.There was 43%agreement between Cognivue®and the MoCA in identifying patients with cognitive impairment,and individual subtests were weakly correlated.The MoCA was determined to be the preferred instrument due to its high sensitivity and specificity(100%and 87%,respectively)when screening for cognitive impairment.We propose that the use of Cognivue®cognitive screening tool be closely reviewed until more research proves that the test meets the standards for reliability and validity.It is important for clinicians to remember that screeners should not be used to diagnosis patients with neurocognitive disorders;instead,they should be used to determine whether further evaluation is warranted.Additionally,misdiagnosing of neurocognitive disorders can pose unnecessary psychological and emotional harm to patients and their families and also lead to incorrect treatment and undue healthcare costs.展开更多
基金supported by the Haihe Laboratory of Cell Ecosystem Innovation Foundation,No.22HHXBSS00047(to PL)Graduate Science and Technology Innovation Project of Tianjin,No.2022BKY173(to LZ)Tianjin Municipal Science and Technology Bureau Foundation,No.20201194(to PL).
文摘With the rapidly aging human population,age-related cognitive decline and dementia are becoming increasingly prevalent worldwide.Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota,microbial metabolites,and the functions of astrocytes.The microbiota–gut–brain axis has been the focus of multiple studies and is closely associated with cognitive function.This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases.This article also summarizes the gut microbiota components that affect astrocyte function,mainly through the vagus nerve,immune responses,circadian rhythms,and microbial metabolites.Finally,this article summarizes the mechanism by which the gut microbiota–astrocyte axis plays a role in Alzheimer’s and Parkinson’s diseases.Our findings have revealed the critical role of the microbiota–astrocyte axis in age-related cognitive decline,aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.
基金Supported by the Fundamental Research Grant Scheme(FRGS)Ministry of Higher Education Malaysia,No.FRGS/1/2020/SKK0/USM/03/5.
文摘There is growing evidence that diabetes can induce cognitive decline and dementia.It is a slow,progressive cognitive decline that can occur in any age group,but is seen more frequently in older individuals.Symptoms related to cognitive decline are worsened by chronic metabolic syndrome.Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention.This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.
基金Shanghai Municipal Commission of Science and Technology Program,No.19411960900.
文摘BACKGROUND Blood pressure variability(BPV)has been shown to be related to mild cognitive impairment and Alzheimer's disease in a number of studies.However,the relationship between BPV and subtle cognitive decline(SCD)has received minimal attention in this field of research to date and has rarely been reported.AIM To examine whether SCD is independently associated with changes in BPV in older adults.METHODS Participants were selected based on having participated in cognitive function evaluation and ambulatory blood pressure measurement at the Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine between June 2020 and August 2022.The participants included 182 individuals with SCD as the experimental group and 237 with normal cognitive function as the control group.The basic data,laboratory examinations,scale tests,and ambulatory blood pressure test results of the two groups were analyzed retrospectively,and the relationship between SCD and BPV was subsequently evaluated.RESULTS Significant differences were observed between the two groups of participants(P<0.05)in terms of age,education level,prevalence rate of diabetes,fasting blood glucose level,24-h systolic blood pressure standard deviation and coefficient of variation,24-h diastolic blood pressure standard deviation and coefficient of variation.The scale monitoring results showed significant differences in the scores for memory,attention,and visual space between the experimental and control groups.Logistic regression analysis indicated that age,education level,blood sugar level,and BPV were factors influencing cognitive decline.Linear regression analysis showed that there was an independent correlation between blood pressure variation and SCD,even after adjusting for related factors.Each of the above differences was still significant.CONCLUSION This study suggests that increased BPV is associated with SCD.
基金supported partly by grants from the National Natural Sciences Foundation of China (No. 30271255)the Natural Sciences Foundation of Hubei Province, China (No. 2006ABB023)
文摘Cognitive decline is a common complication after cardiac surgery with cardiopulmonary bypass(CPB),but as such no pharmacological therapy has been shown to be efficacious in preventing the decline.However,gastrodin has been shown to have multi-pharmacological effects on neurological functions.We undertook this study to test the hypothesis that gastrodin would potentially prevent CPB-associated neurocognitive decline.We randomly assigned 200 patients undergoing mitral valve replacement surgery to receive either gastrodin(40 mg/kg) or saline after the induction of anesthesia and subsequently evaluated cognitive function before surgery,at discharge,and at 3rd month after surgery by using a battery of five neurocognitive tests,or adverse effects of gastrodin postoperatively.Neurocognitive decline in postoperative function was defined as a drop of 1 SD or more in the scores on tests of any one of the four domains of cognitive function.Cognitive decline occurred in 9% of the patients in the gastrodin group in contrast to 42% in the control group(P〈0.01) at discharge.Cognitive outcome could be determined at 3rd month in 87 patients in the gastrodin group and 89 in the control group.Cognitive decline was detected in 6% in the gastrodin group and 31% in the control group(P〈0.01).The incidences of possible adverse effects were similar between two groups.These results indicate that gastrodin is an effective and a safe drug for the prevention of neurocognitive decline in patients undergoing mitral valve replacement surgery with CPB.
基金the College of Pharmacy,Department of Pharmaceutical Chemistry,King Saud University,Riyadh,Saudi Arabiapartly the grants from The American Heart Association,No.17AIREA33700076/ZAS/2017the National Institute of Neurological Disorders and Stroke of the National Institutes of Health,No.R01NS112642(to ZAS)。
文摘Recent emerging research on intestinal microbiota and its contribution to the central nervous system during health and disease has attra cted significant attention.Age-related intestinal microbiota changes initiate brain aging and age-related neurodegenerative disorders.Aging is one of the critical predisposing risk factors for the development of neurodegenerative diseases.Maintaining a healthy gut microbiota is essential for a healthy body and aging,but dys biosis could initiate many chro nic diseases.Understanding the underlying mechanisms of gut microbiota alterations/dys biosis will help identify biomarkers for aging-related chro nic conditions.This review summarizes recent advances in micro biota-neurodegenerative disease research and will enhance our unde rstanding of gut microbiota dys biosis and its effects on brain aging.
文摘Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease(amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.
文摘Alzheimer's disease(AD)redefined:For the past century,AD has been defined as a disease of progressive cognitive decline paired with a burden of amyloid-β(Aβ)plaques and pathologic tau tangles in the hippocampus and forebrain.However,a recent Framework paper jointly sponsored by the National Institute on Aging and the Alzheimer's Association(Jack et al.,2018)proposes new classification guidelines for AD,which,if adopted,will have profoundconsequences for the future management of AD.
基金National Natural Science Foundation of China(No.81760237)National Natural Science Foundation of China(No.81860243)Hainan province key R&D plan science and technology cooperation project in 2017(No.ZDYF2017170)。
文摘Objective:To systematically evaluate the efficacy and safety of Donepezil in treating the cognitive decline in patients with Parkinson's disease(PD).Methods:Nine literature databases in domestic and abroad were searched by computer,and the search deadline was November 2,2020.The randomized controlled trials(RCT)using donepezil to treat the cognitive decline in patients with PD were screened.The MMSE(Mini-Mental State Exam)scores,MoCA(Montreal Cognitive Assessment)scores and adverse events of the included RCTs were extracted.Meta-analysis was implemented with RevMan 5.3 software,and the subgroup analyses were conducted to evaluate the effects of mean age and mean course of disease on the MMSE scores.Results:14 RCTs with 1263 patients were selected,including 646 cases in the experimental group and 617 cases in the control group.There were 1209 effective patients who completed MMSE score,including 612 in the experimental group and 597 in the control group.Meta-analysis results showed that MMSE scores in the experimental group were higher than that in the control group after using donepezil intervention,and the difference was statistically significant[SMD=0.55,95%CI(0.24,0.87),P=0.0006].It was also found that the MoCA scores of experimental group were higher than that of control group after using donepezil intervention,and the difference was statistically significant[SMD=1.25,95%CI(0.79,1.72),P<0.00001].Subgroup analysis showed that donepezil improved MMSE scores in different subgroups,and the difference between each group was statistically significant.There was no heterogeneity in the subgroup of mean age lower than 65 years,and the heterogeneity existed between the subgroup of mean course of disease lower than 3 years and the subgroup of mean course of disease larger than or equal to 3 years.For adverse events,the incidence of adverse events in the experimental group was 22.18%.There was no heterogeneity between the included studies(I2=0%),and the difference was not statistically significant[RR=1.18,95%CI(0.95,1.47),P=0.14].Conclusion:The results of meta-analysis showed that donepezil can improve the cognitive decline in patients with Parkinson's disease significantly,and it has good safety.
基金the National Key Research and Development program of China(2022YFC3400700,2022YFA0806400,2021YFC2500100,2020YFE0201600)the Science and Technology Innovation 2030 Major Projects(2022ZD0211600)+5 种基金the Shanghai Rising-Star Program(22QA1404000)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Natural Science Foundation of Shanghai,China(22ZR1405300)the National Natural Science Foundation of China(31821002)the Key Research and Development Plans of Jiangsu Province,China(BE2021696)the Greater Bay Area Institute of Precision Medicine(Guangzhou).
文摘Cardiovascular health metrics are now widely recognized as modifable risk factors for cognitive decline and dementia.Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia.Circulating metabolites profling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline.In a prospective community-based cohort in China(n=725),312 serum metabolic phenotypes were quantifed,and cardiovascular health score was calculated including smoking,exercise,sleep,diet,body mass index,blood pressure,and blood glucose.Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline.A better cardiovascular health was signifcantly associated with lower risk of concentration decline and orientation decline(hazard ratio(HR):0.84–0.90;p<0.05).Apolipoprotein-A1,high-density lipoprotein(HDL)cholesterol,cholesterol ester,and phospholipid concentrations were signifcantly associated with a lower risk of longitudinal memory and orientation decline(p<0.05 and adjusted-p<0.20).Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and-3(proportion of mediation:7.68–8.21%,both p<0.05).Cardiovascular risk factors were associated with greater risks of cognitive decline,which were found to be mediated by circulating lipoproteins,particularly the medium-size HDL components.These fndings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention.
基金National Natural Science Foundation of China(Nos.61633018,82020108013,and 82001773)
文摘Alzheimer's disease(AD)is a neurodegenerative disease that gradually impairs cognitive functions.Recently,there has been a conceptual shift toward AD to view the disease as a continuum.Since AD is currently incurable,effective intervention to delay or prevent pathological cognitive decline may best target the early stages of symptomatic disease,such as subjective cognitive decline(SCD),in which cognitive function remains relatively intact.Diagnostic methods for identifying AD,such as cerebrospinal fluid biomarkers and positron emission tomography,are invasive and expensive.Therefore,it is imperative to develop blood biomarkers that are sensitive,less invasive,easier to access,and more cost effective for AD diagnosis.This review aimed to summarize the current data on whether individuals with SCD differ reliably and effectively in subjective and objective performances compared to cognitively normal elderly individuals,and to find one or more convenient and accessible blood biomarkers so that researchers can identify SCD patients with preclinical AD in the population as soon as possible.Owing to the heterogeneity and complicated pathogenesis of AD,it is difficult to make reliable diagnoses using only a single blood marker.This review provides an overview of the progress achieved to date with the use of SCD blood biomarkers in patients with preclinical AD,highlighting the key areas of application and current challenges.
基金supported by the National Natural Sciences Foundation of China(81971473,82171753).
文摘Biological agents threats people's life through different ways,one of which lies in the impairment of cognition.It is believed cognitive decline may result from biological agents mediated neuron damage directly,or from the activation of the host immune response to eradicate the pathogen.However,direct linkage between infections and cognitive decline is very limited.Here we focus on the mechanisms of how different biological virus or they induced systemic and local inflammation link to the cognitive impairment,focusing on the roles of acti-vated microglia and several molecular pathways mediated neurotoxicity.
基金This work was supported partly by grants from the National Natural Science Foundation of China(No.81822013,81671665)Jiangsu Provincial Key Medical Talents(No.ZDRCA2016085)+2 种基金the Key Research and Development Program of Jiangsu Province of China(BE2016610)the National Key Research and Development Program of China(2016YFC1300500–504)Jiangsu Province Key Medical Discipline(ZDXKA2016020).
文摘Background Subjective cognitive decline(SCD)is a preclinical stage along the Alzheimer’s disease(AD)continuum.However,little is known about the aberrant patterns of connectivity and topological alterations of the brain functional connectome and their diagnostic value in SCD.Methods Resting-state functional magnetic resonance imaging and graph theory analyses were used to investigate the alterations of the functional connectome in 66 SCD individuals and 64 healthy controls(HC).Pearson correlation analysis was computed to assess the relationships among network metrics,neuropsychological performance and pathological biomarkers.Finally,we used the multiple kernel learning-support vector machine(MKL-SVM)to differentiate the SCD and HC individuals.Results SCD individuals showed higher nodal topological properties(including nodal strength,nodal global efficiency and nodal local efficiency)associated with amyloid-βlevels and memory function than the HC,and these regions were mainly located in the default mode network(DMN).Moreover,increased local and medium-range connectivity mainly between the bilateral parahippocampal gyrus(PHG)and other DMN-related regions was found in SCD individuals compared with HC individuals.These aberrant functional network measures exhibited good classification performance in the differentiation of SCD individuals from HC individuals at an accuracy up to 79.23%.Conclusion The findings of this study provide insight into the compensatory mechanism of the functional connectome underlying SCD.The proposed classification method highlights the potential of connectome-based metrics for the identification of the preclinical stage of AD.
基金This work was supported by Grants from the National Natural Science Foundation of China(31771290 and 81702454)the Beijing National Science Foundation(5222033)+1 种基金the Military Logistics Scientific Research Foundation of China(BWS17J027)the National Basic Scientific Research Program of China(JCKY2019548B001).
文摘Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy)are significantly elevated in the plasma of stressed animals,which suggests that Hcy is associated with stress and cognitive decline.To test this hypothesis,we analyzed the cognitive function,plasma concentrations of Hcy,and brain-derived neurotropic factor(BDNF)levels in rats undergoing chronic unpredicted mild stress(CUMS).The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia(HHcy)levels in stressed rats.Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS,while Hcy reduction(by means of vitamin B complex supplements)alleviated the cognitive deficits and BDNF reduction in CUMS rats.Furthermore,we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter.In contrast,control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain.These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline.We also used ten-eleven translocation(TET1),an enzyme that induces DNA demethylation,to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline.The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats.Taken together,novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits.In addition,the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter.The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
文摘Background: Memory complaint is common in the elderly. Recently, it was shown that self-report memory complaint was predictive of cognitive decline. This study aimed to investigate the predictive value of the source of memory complaints on the risk of cognitive impairment and cognitive decline in a community-based cohort. Methods: Data on memory complaints and cognitive function were collected among 1840 Chinese participants (aged ≥55 years old) in an urban community at baseline interview and 5-year follow-up. Incident cognitive impairment was identified based on education-adjusted Mini-Mental State Examination score. Logistic regression model was used to estimate the association between the source of memory complaints and risk of cognitive impairment conversion and cognitive decline, after adjusting for covariates. Results: A total of 1840 participants were included into this study including 1713 normal participants and 127 cognitive impairment participants in 2009. Among 1713 normal participants in 2009, 130 participants were converted to cognitive impairment alter 5 years of follow-up. In 2014, 606 participants were identified as cognitive decline. Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment (odds ratio [OR] - 1.60, 95% confidence interval [CI]: 1.04 2.48) and cognitive decline (OR = 1.30, 95% CI: 1.01-1.68). Furthermore, this association was more significant in males (OR = 2.10, 95% CI: 1.04-4.24 for cognitive impairment and OR - 1.87, 95% CI:1.20-2.99 for cognitive decline) and in higher education level (OR - 1.79, 95% CI: 1.02-3.15 for cognitive impairment and OR = 1.40, 95% CI:1.02-1.91 for cognitive decline). Conclusions: Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment conversion and cognitive decline, especially in persons with male gender and high educational background.
基金supported by the National Natural Science Foundation of China(Grant No.81904270)Natural Science Foundation of Fujian Province(Grant No.2019J01362)+1 种基金Science and Technology Platform Construction Project of Fujian Science and Technology Department(Grant No.2015Y2001)Educational Department of Fujian Province Outstanding Youth Scientific Research Talent Cultivation Program(Grant No.Min Jiao Ke[2018]47)
文摘Objective:This study aims to determine the relationship between education level,memory function,and hippocampus functional and structural alterations in subjective cognitive decline(SCD).Methods:Seventy-five participants with SCD were divided into high education(HE)and low education(LE)level groups.A Wechsler Memory Scale-Chinese Revision test and functional and structural MRI were performed within 1 week after participant recruitment.The bilateral hippocampus resting-state functional connectivity(rsF C),gray matter volume(GMV)of brain regions identified by rsF C analysis,and moderating and mediating effects were assessed.Results:Compared with the LE group,HE individuals showed 1)higher memory quotient(MQ)and Digit Span subscore,2)decreased hippocampal rs FC with the right medial prefrontal cortex(mPFC)and dorsolateral prefrontal cortex(DLPFC),and 3)increased GMV in the right mP FC and DLPFC.The bilateral hippocampus-right DLPFCrs FC significantly associated with the MQ and the bilateral hippocampus-right m PFCrs FC with the Digit Span subscore in each group.The bilateral hippocampus-right DLPFCrsFC moderated the relationship between the education level and MQ.The bilateral hippocampus-right mP FC rsF C mediated the relationship between the education level and Digit Span subscore in all subjects.Conclusion:The hippocampal rsF C with the right mP FC and DLPFC contributes to the education level effect on memory function in SCD.
基金supported by the National Key Research and Development Program of China(Grants No.2018YFE0118900 and 2021YFC2502200)the clinical research project of the Bethune Charitable Foundation。
文摘Recently, cognitive impairments(CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis(ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current study, we explored the role of gut microbiota in CI of ALS patients. We collected fecal samples from 35ALS patients and 35 healthy controls. The cognitive function of the ALS patients was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen. We analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted(bile acids) metabolite mapping between patients with CI and patients with normal cognition(CN). We found altered gut microbial communities and a lower ratio of Firmicutes/Bacteroidetes in the CI group, compared with the CN group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the CI group, compared with the CN group. These metabolites were mapped to the metabolic pathways associated with bile acids. We further found that cholic acid and chenodeoxycholic acid were significantly lower in the CI group than in the CN group. In conclusion, we found that the gut microbiota and its metabolome profile differed between ALS patients with and without CI and that the altered bile acid profile in fecal samples was significantly associated with CI in ALS patients. These results need to be replicated in larger studies in the future.
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
基金Supported by National Council for Scientific and Technological Development of Brazil(CNPq),No.312400/2018-7.
文摘A severe impairment of cognitive function characterizes dementia.Mild cognitive impairment represents a transition between normal cognition and dementia.The frequency of cognitive changes is higher in women than in men.Based on this fact,hormonal factors likely contribute to cognitive decline.In this sense,cognitive complaints are more common near menopause,a phase marked by a decrease in hormone levels,especially estrogen.Additionally,a tendency toward worsened cognitive performance has been reported in women during menopause.Vasomotor symptoms(hot flashes,sweating,and dizziness),vaginal dryness,irritability and forgetfulness are common and associated with a progressive decrease in ovarian function and a subsequent reduction in the serum estrogen concentration.Hormone therapy(HT),based on estrogen with or without progestogen,is the treatment of choice to relieve menopausal symptoms.The studies conducted to date have reported conflicting results regarding the effects of HT on cognition.This article reviews the main aspects of menopause and cognition,including the neuroprotective role of estrogen and the relationship between menopausal symptoms and cognitive function.We present and discuss the findings of the central observational and interventional studies on HT and cognition.
文摘Insulin,a key pleiotropic hormone,regulates metabolism through several signaling pathways in target tissues including skeletal muscle,liver,and brain.In the brain,insulin modulates learning and memory,and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases.At the receptor level,in aging and Alzheimer’s disease(AD)models,the amount of insulin receptors and their functions are decreased.Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels.Furthermore,diabetes mellitus(DM)and insulin resistance are associated with age-related cognitive decline,increased levels ofβ-amyloid peptide,phosphorylation of tau protein;oxidative stress,pro-inflammatory cytokine production and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mildobesity and insulin resistance without influencing brain size and apoptosis development.Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size anddevelopment, and contributes to behavior changes. Insulin is synthesized locally in the brain andis released from the neurons. Here, we reviewed proposed pathophysiological hypotheses toexplain increased risk of dementia in the presence of DM. Regardless of the exact sequence ofevents leading to neurodegeneration, there is strong evidence that mitochondrial dysfunctionplays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrialdysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable tothose induced in wild-type mice treated with sucrose, which is consistent with the proposal thatmitochondrial alterations are associated with DM and contribute to AD development. Alterationsin insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidantcapacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing andsystemic metabolism, and could be a specific target for therapeutic strategies to decreasealterations associated with age-related cognitive decline.
文摘In this editorial we comment on the article by Cahn-Hidalgo D published in a recent issue of the World Journal of Psychiatry 2020;10(1);1-11.We focus on the importance of utilizing psychometrically valid cognitive screening tools when assessing for cognitive decline in older adults in a psychiatric outpatient setting.We compared the use of Cognivue®to use of the montreal cognitive assessment(MoCA)as a cognitive screening tool.A total of 58 patients aged 55 and over participated in this comparison study.Patients completed cognitive screening on Cognivue®,a new Food and Drug Administration-cleared computer screening device,and the MoCA.The results of patient performance using these two instruments were analyzed.Sixteen(28%)patients screened negative for cognitive impairment on both assessments.Forty-two(72%)patients screened positive on one or both of the assessments.There was 43%agreement between Cognivue®and the MoCA in identifying patients with cognitive impairment,and individual subtests were weakly correlated.The MoCA was determined to be the preferred instrument due to its high sensitivity and specificity(100%and 87%,respectively)when screening for cognitive impairment.We propose that the use of Cognivue®cognitive screening tool be closely reviewed until more research proves that the test meets the standards for reliability and validity.It is important for clinicians to remember that screeners should not be used to diagnosis patients with neurocognitive disorders;instead,they should be used to determine whether further evaluation is warranted.Additionally,misdiagnosing of neurocognitive disorders can pose unnecessary psychological and emotional harm to patients and their families and also lead to incorrect treatment and undue healthcare costs.