Searching for new drugs to treat Alzheimer’s disease dementia through multiple pathways

Dementia is a group of diseases,including Alzheimer's disease(AD),vascular dementia,Lewy body dementia,frontotemporal dementia,Parkinson's disease dementia,metabolic dementia and toxic dementia.The treatment of dementia mainly includes symptomatic treatment by controlling the primary disease and accompanying symptoms,nutritional support therapy for repairing nerve cells,psychological auxiliary treatment,and treatment that improves cognitive function through drugs.Among them,drug therapy to improve cognitive function is important.This review focuses on introducing and commenting on some recent progress in exploring drugs to improve cognitive function,especially the new progress in drug treatment for AD.We mainly discuss the opportunities and challenges in finding and developing new therapeutic drugs from the aspects of acetylcholinesterase,N-methyl-D-aspartate glutamate receptor,amyloid protein,tau protein and chronic immune inflammation.

The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia

With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.

Jian Nao Ning for Treatment of Memory Impairment in Patients with Mild or Moderate Multi-infarct Dementia

Forty patients with multi-infarct dementia (MID) were randomly assigned to the treatment group (25 cases) treated with Jian Nao Ning (健脑宁JNN) and the duxil control group (15 cases). Memory function were assessed at baseline and endpoint using memory subscales of a battery of New Psychometric Tests (Chinese version) including mini-mental state examination (MMSE), verbal memory, and non-verbal memory, etc. After treatment, the mean scores of verbal memory in the Hopkins Verbal Learning Test (P<0.05) and total memory scores of memory items (P<0.001) in JNN group increased significantly; and improvement in episodic memory function including story recall (immediate and delayed), delayed word recall, verbal learning and verbal recognition and visual recognition in the JNN group was better than that in the duxil control group, suggesting that JNN can obviously improve memory function for the patients with mild or moderate multi-infarct dementia.

Strategies for translating proteomics discoveries into drug discovery for dementia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

Effectiveness of Music-Based Therapeutic Intervention on People with Dementia: A Rapid Review

Background: Dementia is a condition with progressive cognitive dysfunction and manifestation of both behavioral and psychosocial symptoms. Non-pharmacological measures such as music therapy are gaining importance since efficacy and safety of people with dementia have been questionable for pharmacological measures. Patient’s response to music is persistent even in the later stage of dementia. Aim: This rapid review aims to identify, analyze, evaluate, and summarize the best available evidence on the effectiveness of music-based therapeutic interventions among people with dementia. Method: CINAHL Cochrane Library, internet websites of rapid review producers, and reference lists were searched to identify articles for inclusion. Two reviewers independently screened the literature search results. Effectiveness, music-based therapeutic intervention, dementia, Alzheimer’s disease, systematic review and systematic review with meta-analysis terms were used to abstract data from included studies. Main Findings: 11 SRs and SRs with meta-analysis were reviewed which revealed positive effect of music therapy on five major outcomes with 9 studies effect on behavioral outcome, 6 studies with positive effect on psychosocial outcome reducing anxiety, 6 with improved cognition, 1 study revealed with improved quality of life and 1 study revealed effect on physiological outcomes. Conclusion: Music therapy has positive effect on treatment of dementia but further studies with larger sample size and specified to single intervention should be conducted to provide generalisable and precise results on this topic.

Human immunodeficiency virus-associated dementia complex with positive 14-3-3 protein in cerebrospinal fluid:A case report

BACKGROUND Human immunodeficiency virus(HIV)-associated dementia(HAD)is a subcortical form of dementia characterized by memory deficits and psychomotor slowing.However,HAD often presents with symptoms similar to those of Creutzfeldt-Jakob disease(CJD),particularly in patients with acquired immune deficiency syndrome(AIDS).CASE SUMMARY We report the case of a 54-year-old male who exhibited cognitive dysfunction and secondary behavioral changes following HIV infection and suspected prion exposure.The patient was diagnosed with HIV during hospitalization and his cerebrospinal fluid tested positive for 14-3-3 proteins.His electroencephalogram showed a borderline-abnormal periodic triphasic wave pattern.Contrast-enhanced magnetic resonance imaging revealed moderate encephalatrophy and demyelination.Initially,symptomatic treatment and administration of amantadine were pursued for presumed CJD,but the patient’s condition continued to deteriorate.By contrast,the patient’s condition improved following anti-HIV therapy.This individual is also the only patient with this prognosis to have survived over 4 years.Thus,the diagnosis was revised to HAD.CONCLUSION In the diagnostic process of rapidly progressive dementia,it is crucial to rule out as many potential causes as possible and to consider an autopsy to diminish diagnostic uncertainty.The 14-3-3 protein should not be regarded as the definitive marker for CJD.Comprehensive laboratory screening for infectious diseases is essential to enhance diagnostic precision,especially in AIDS patients with potential CJD.Ultimately,a trial of diagnostic treatment may be considered when additional testing is not feasible.

Causal relationships between gut microbiota and dementia:A twosample,bidirectional,Mendelian randomization study

BACKGROUND Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia,including Alzheimer's dementia,vascular dementia,and dementia in other diseases classified elsewhere.However,the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear.AIM To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization(MR)analysis.METHODS A bidirectional,two-sample,MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study(GWAS)summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium.Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F-statistic.Five MR methods were employed,and the robustness of our findings was validated.To account for multiple comparisons,we applied the Bonferroni method for P-value adjustment.RESULTS We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes,potentially serving as risk or protective factors for the disease.In addition,reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes.An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy.After applying correction for multiple testing,we observed that the order Bacillales(odds ratio:0.830,95%confidence interval:0.740-0.932,P=0.00155,Padjust=0.0311)exhibited a strong association with Alzheimer’s disease-related dementia.CONCLUSION The results suggest that gut microbiota is causally associated with dementia.Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.

An Innovative Person-Centered Model for Provision of Mental, Social and Medical Care for People Living with Dementia

Globally there is an increased digitalization going on with an increasing number of people having access to the internet, having smartphones and now also in many countries being expected to access health-related information and schedule appointments through websites, apps or web-based portals. Healthcare providers have also adopted this with an increasing number of public or private organizations providing web-based portals as well as app interfaces to some of the largest electronic healthcare systems. The benefit of this is easier access, more efficient provision of services, increased transparency and improved workflows. This may increase the population’s capability to manage their conditions and reduce the contacts to, thereby burdening healthcare professionals. But not all will be able to benefit from this digital (r)evolution. Those who will not be able to include people with dementia. For people with dementia to also be able to take advantage of digital health tools and services, it will require planning and involvement of caregivers. In 2017, we presented the Epital Care Model as a framework to organize an efficient people-centered cross-disciplinary and cross-sectoral way to organize activities, roles, responsibilities and describe geographical locations and used technologies in response to individuals’ specific diagnoses and everyday changes in their condition. In 2021, an EU-funded project was initiated to investigate how living labs and scaling up could be done building upon the ECM. One of the living labs was organized around an organization providing care to PWD in Netherlands. In the period 2021 to 2024, we have tried to identify ways for how the ECM could be used to digitally enable the services provided by the organization. In 2022, the care organization tanteLouise started a project originally named Daycare Centre2.0 (now called “Van Thuis Uit” meaning “From Home”), together with healthcare insurance company CZ, and developed a model for onboarding people with dementia and introducing them to specific interventions based on their personal goals and needs. We here present how the ECM and the “Van Thuis Uit” can be mapped within each other to create synergy in creating a healthcare setting for people with dementia. This work may serve as a model for other conditions, where individuals are likely to need more intensive support from their informal caregivers due to a relatively rapid progression of the condition or development of severe impairments. Examples here can be neurologic conditions such as multiple sclerosis and amyotrophic lateral sclerosis or the final stage of conditions that require palliation.

Factors influencing the employed caregiver burden for patients with dementia residing in nursing homes:A cross-sectional study from China

Objective:The institutionalization of care for patients with dementia is becoming a trend.Understanding the burden on employed caregivers and exploring associated factors are of great importance in practice.Therefore,this study aimed to examine the relationship between basic attributes,caring ability,and caregiver burden in employed caregivers practicing in nursing homes.Methods:This cross-sectional study included 541 employed caregivers in 11 four-star nursing homes in Zhejiang Province from April to December 2022.Caregiver burden was assessed using the Zarit Burden Interview(ZBI).Demographic characteristics of participants,characteristics of the older patients with dementia,caring characteristics,training in dementia care,and caring abilities were collected for analysis of influencing factors.A hierarchical multiple regression analysis was conducted to explore the factors influencing the burden on employed caregivers in nursing homes.Results:The ZBI score of employed caregivers in nursing homes was 40.42±10.18,representing a moderate caregiver burden.Factors such as age(U=27.82,P<0.001),residence(U=7.89,P<0.001),educational level(H=55.81,P<0.001),self-care of older patients with dementia(H=85.21,P<0.001),daily care hours(H=73.25,P<0.001),number of older people with dementia cared for(H=14.56,P<0.012)and training in dementia care(U=-9.43,P<0.001)were significantly associated with caregiver burden.Caring ability was negatively associated with caregiver burden(r=-0.22,P<0.01).Furthermore,after controlling for demographic characteristics,the characteristics of older people with dementia,caring characteristics,training in dementia care,and caring ability explained 8.5%,5.8%,and 4.8%of the caregiver burden,respectively.Conclusion:The burden of employed caregivers on patients with dementia in nursing homes can be attributed to various factors.We recommend tailored interventions,such as dementia care training and reviewing the number and duration of hours worked to reduce the burden experienced by caregivers.

The Alzheimer’s Dementia Patients’ Observed Illness Course and Experience in Ghana and Care Lessons to Be Learnt: A Mental Health Professional’s Perspective

Alzheimer’s disease (AD) and associated dementia patient numbers continue to increase globally with associated economic costs to healthcare systems. Of note is the increase in numbers in lower and middle-income countries (LMICs) including Sub-Saharan African (SSA) countries, which already face challenges with their health budgets from communicable and non-communicable diseases. Ghana, an SSA country, faces the problem of healthcare budgetary difficulties and the additional impact of AD as a consequence of increasing population strata of old aged persons (OAPs) due to the demographic transition effect. This article uses examples of known patients’ illness courses to give a perspective on the lived experience of patients with dementia (PWD) in Ghana, living amongst a populace with a culture of stigmatization of PWD, and a relatively fragile public mental health system (PMHS) for those with mental illness, including AD. The lived experience of AD patients is characterised by stigmatisation, discrimination, non-inclusiveness, diminished dignity and human rights abuses in the face of their mental disability, and eventually death. This article is an advocacy article giving voice to the voiceless and all persons suffering from AD and other dementias in Ghana, whilst pleading for a call to action from healthcare professionals and responsible state agencies.

Assessment of sensory impairment in older adults with dementia

Background:Over 55 million people worldwide are living with dementia.The rate of cognitive decline increases with age,and loss of senses may be a contributing factor.Objectives:This study aimed to analyze hearing,olfactory function,and color vision in patients with dementia.Materials and methods:The sample comprised 40 patients with dementia and 37 cognitively normal controls aged 41–85 years.All participants underwent conventional pure-tone audiometry and a screening version of the Hearing Handicap Inventory for Adults,the Odorized Markers Test of olfactory function and the Ishihara color vision test.The effects of comorbidities and lifestyle factors were also assessed.Results:Patients with dementia had significantly worse hearing at almost all frequencies tested and significantly greater olfactory impairment than cognitively normal controls.Color vision impairment was found in less than 8%of the sample,with no significant difference between the groups.Impairment of two senses(hearing and olfaction)was significantly more common in patients with dementia than in controls.Conclusion:Individuals with dementia were found to have sensory decline,namely hearing and olfactory impairment.Color vision was rarely impaired in the sample.Participants with dementia tended to have more multisensory impairments than controls.

Mendelian Randomization Study of Causal Relationship between Inflammatory Factors and Vascular Dementia and Chinese Herbal Medicines Screening for Prevention and Treatment

Objective: This study aims to examine the causal relationship between inflammatory factors and the probability of developing vascular dementia (VD) using Mendelian Randomization (MR) and Chinese herbal medicine prediction method, and to screen potential Chinese herbal medicines for the prevention and treatment of VD. Methods: Single nucleotide polymorphisms (SNPs) that exhibit a strong association with vascular dementia (VD) were identified as instrumental variables from the summary statistics of genome-wide association studies (GWAS). The primary analytical method employed was inverse variance weighting (IVW), while auxiliary analyses included the MR-Egger method, weighted median method, simple model, and weighted model. A two-way Mendelian randomization analysis was conducted to assess the causal relationship between inflammatory factors and the risk of VD, thereby identifying the key inflammatory factors involved. The MR-Egger intercept test and Cochran’s Q test were employed to assess the horizontal polymorphism and heterogeneity of instrumental variables. A sensitivity analysis was conducted by excluding one method at a time. Ultimately, based on key inflammatory factors, predictions for the prevention and treatment using traditional Chinese medicine were made, along with the screening of homologous herbal remedies. Results: Based on the results of the forward MR, the probability of developing VD was elevated when the inflammatory factors CXCL10 and CXCL5 were expressed at higher levels, whereas the probability of developing VD decreased as the expression levels of IL-13 and IL-20RA increased. These findings were supported by the assessment of pleiotropy, heterogeneity, and sensitivity. The results of the reverse MR analysis showed that there was no causal relationship between VD, as an exposure dataset, and these four inflammatory factors. According to the key inflammatory factors, 37 Chinese herbal medicines such as Siraitia grosvenorii were selected. Their characteristics including four natures, five flavors, channel tropism and treatment efficiency were cold, warm, neutral, pungent, sweet, bitter, lung meridian, spleen meridian, liver meridian, kidney meridian and clearing heat. Among them, Siraitia grosvenorii, Poria with hostwood, Perilla frutescens, and Radix Platycodi were all medicine and food homologous Chinese herbal medicines. Conclusions: The increase of CXCL10 and CXCL5 expression levels can increase the risk of VD, and the increase of IL-13 and IL-20 RA expression levels can reduce the risk of VD. Siraitia grosvenorii and other Chinese herbal medicines might be potential sources of therapeutic drugs for the treatment of VD. Medicine and food homologous Chinese herbal medicines, such as Siraitia grosvenorii, Poria with hostwood, Perilla frutescens, and Radix Platycodi, may help the elderly population with corresponding Traditional Chinese Medicine (TCM) constitutions to prevent VD.

Association between inflammatory bowel disease and all-cause dementia:A two-sample Mendelian randomization study

BACKGROUND Numerous observational studies have documented a correlation between inflammatory bowel disease(IBD)and an increased risk of dementia.However,the causality of their associations remains elusive.AIM To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization(MR)method.METHODS Genetic variants extracted from the large genome-wide association study(GWAS)for IBD(the International IBD Genetics Consortium,n=34652)were used to identify the causal link between IBD and dementia(FinnGen,n=306102).The results of the study were validated via another IBD GWAS(United Kingdom Biobank,n=463372).Moreover,MR egger intercept,MR pleiotropy residual sum and outlier,and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity.Finally,multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia,with the inverse variance weighted approach adopted as the primary analysis.RESULTS The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS.No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted[odds ratio(OR)=0.980,95%CI:0.942-1.020,P value=0.325],weighted median(OR=0.964,95%CI:0.914-1.017,P value=0.180),and MR-Egger(OR=0.963,95%CI:0.867-1.070,P value=0.492)approaches.Consistent results were observed in validation analyses.Reverse MR analysis also showed no effect of dementia on the development of IBD.Furthermore,MR analysis suggested that IBD and its subtypes did not causally affect allcause dementia and its four subtypes,including dementia in Alzheimer's disease,vascular dementia,dementia in other diseases classified elsewhere,and unspecified dementia.CONCLUSION Taken together,our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes.Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.

Coping review of dementia fear studies among middle-aged and elderly people in the community

This study used Arksey and O’Malley’s scoping review methodology as a framework and searched the following databases:PubMed,Embase,EBSCO,CINAHL,Web of Science,Cochrane Library,Scopus,CNKI,Wanfang,VIP,and the Chinese Biomedical Literature Database.The database is open to December 20,2023,and documents related to the fear of dementia among the elderly in the community are described and analyzed to provide a reference for future research in this field.At the same time,we screened,extracted,and summarized relevant information from 21 included documents(16 in English and 5 in Chinese),which consisted of 16 cross-sectional studies,2 quasi-experimental studies,2 randomized controlled studies,and 1 longitudinal study.Sixteen of the included documents mentioned the incidence or level of dementia fear among the elderly in the community,2 addressed the adverse effects of dementia fear,and 4 reported prevention and intervention measures for dementia fear.In total,there are 8 assessment tools,and the influencing factors are categorized into sociodemographic characteristics,psychological and behavioral characteristics,sociocultural background factors,and health and dementia-related factors.The final conclusion is that the fear of dementia is common among the elderly in the community.In the future,the application of research tools should be expanded among middle-aged individuals,with considerations for other types of dementia in mind.It is recommended to conduct large-scale,multi-center randomized controlled trials while confirming the intervention’s effect on different types of middle-aged and elderly individuals,focusing on the long-term impact of these intervention measures to promote healthy aging.

Clinical Study on the Treatment of Senile Alzheimer’s Dementia with Sodium Oligomannate Combined with Memantine Hydrochloride

Objective:To analyze the clinical effects of sodium oligomannate combined with memantine hydrochloride in the treatment of senile Alzheimer’s dementia.Methods:Sixty-eight cases of Alzheimer’s dementia treated at the Second People’s Hospital of Fujian University of Traditional Chinese Medicine from March 2020 to March 2022 were selected as the study subjects.The patients were divided into two groups based on different treatment methods:the control group(treated with memantine hydrochloride,34 cases)and the treatment group(treated with sodium oligomannate+memantine hydrochloride,34 cases).Cognitive function,activities of daily living,neurotransmitters,serum intestinal flora metabolic markers,inflammatory factors,neurotrophic factors,and adverse reactions were compared between the two groups.Results:The treatment group showed better cognitive function,quality of life scores,and levels of relevant metabolic markers in the body compared to the control group,with statistically significant differences(P<0.05).The incidence of adverse reactions between the two groups(treatment group:2%;control group:4%)was not statistically significant(χ^(2)=0.731,P=0.393).Conclusion:Sodium oligomannate combined with memantine hydrochloride has better efficacy than the control group for treating senile Alzheimer’s dementia.It significantly improves and restores cognitive function and daily living abilities,benefits neurotransmitter secretion and internal regulation,upregulates the expression of neurotrophic factors,and has fewer adverse reactions,making it a treatment worthy of further clinical promotion and application.

CLINICAL RESEARCH OF IMPACTS ON PLASMA ENDOTHELIN AND INTELLIGENCE IN MULTI-INFARCT DEMATIA TREATED WITH CLUSTER PRICKING ON HEAD POINTS

Objective To probe into the impacts on the therapeutic effects and endothelin （ET） in multi-infarct dementia （MID） treated with cluster pricking on head points.Methods 60 cases of MID were randomized into acupuncture group and western medicine group,treated with cluster pricking on head points and huperzien A tablet respectively.Plasma ET lever,HDS,ADL and CNFDS （clinical neurological functional defect scoring） were determined before treatment,and the statistical analysis showed that there were no significant difference （P〉0.05）.Results In 8-week treatment,ET level in both groups were decreased,but it was decreased much more obviously in acupuncture group,indicating significant difference in the statistical comparison （P〈0.05）.The scores of HDS and ADL were all up in acupuncture and western medicine groups,but the significant statistical difference was obtained in the comparison between acupuncture group and western medicine group （P〈0.05）.In acupuncture group,the result of CNFDS was much down comparing with that before the treatment,indicating significant difference （P〈0.05）;but in western medicine group,there was no significant difference in CNFDS before and after treatment （P〉0.05）,suggesting that acupuncture reduces CNFDS of MID patient,neither for western medicine.Conclusion Cluster pricking on head points improves the intelligence of MID patient,reduces ET level and grades up HDS and ADL,moreover,it reduces CNFDS of MID patients and releases the symptoms.

Decoding molecular mechanisms:brain aging and Alzheimer's disease

The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.

通脉开窍丸治疗血管性痴呆模型大鼠海马区神经元的铁死亡变化

背景:研究表明铁死亡与血管性痴呆存在密切联系,通脉开窍丸对于改善血管性痴呆患者的认知功能有一定疗效,但其作用机制不明确。目的:基于核因子E2相关因子2(nuclear factor erythroid-2 related factor 2,Nrf2)/血红素氧合酶1(heme oxygenase-1,HO-1)/谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)信号通路调控铁死亡探讨通脉开窍丸对血管性痴呆干预作用以及分子机制。方法:84只雄性SD大鼠,其中12只大鼠用作假手术组,其余大鼠用改良2-VO法制备成血管性痴呆的模型,成模后随机分为模型组、通脉开窍丸高、中、低剂量(27.6,13.8,6.9 g/kg)组、联合组[通脉开窍丸高剂量+ML385(20 mg/kg)]、盐酸多奈哌齐组(0.45 mg/kg),灌胃给药1次/d,联合组同时腹腔注射Nrf2抑制剂ML385,1次/d,连续4周。采用Morris水迷宫检测大鼠的学习记忆能力;苏木精-伊红染色观察各组大鼠海马组织中神经元病理学变化;比色法试剂盒检测大鼠血清中还原型谷胱甘肽、Fe^(2+)、丙二醛的浓度;普鲁士蓝染色法检测大鼠海马组织中铁沉积情况;透射电镜观察大鼠海马组织中神经元线粒体超微结构变化;蛋白免疫印迹法检测大鼠海马神经元Nrf2、HO-1、GPX4、XCT、铁蛋白重链1(ferritin heavy chain 1,FTH1)蛋白的表达。结果与结论:(1)与假手术相比,模型组大鼠逃避潜伏期时间明显延长(P<0.05),穿越平台次数明显减少(P<0.05);海马组织松散,神经元细胞核深染,染色质固缩甚至裂解;CA1区铁离子聚集;线粒体萎缩变小,线粒体嵴溶解消失,线粒体膜密度增厚;血清中Fe^(2+)、丙二醛水平上升,还原型谷胱甘肽水平下降(P<0.05);海马组织GPX4、HO-1、XCT、Nrf2、FTH1蛋白表达显著降低(P<0.05)。(2)与模型组相比,通脉开窍丸各剂量组和盐酸多奈哌齐组大鼠平均逃避潜伏期均明显缩短(P<0.05),穿越平台次数增加(P<0.05);海马神经元恢复明显,CA1区神经元铁离子聚集明显减少,线粒体结构和功能好转;血清Fe^(2+)、丙二醛水平显著降低(P<0.05),血清还原型谷胱甘肽浓度及海马组织中GPX4,HO-1,XCT,Nrf2,FTH1蛋白表达显著升高(P<0.05)。(3)与通脉开窍丸高剂量组相比,盐酸多奈哌齐组治疗效果差异无显著性意义(P>0.05),联合组大鼠水迷宫逃避潜伏期时间延长(P<0.05),穿越平台次数减少(P<0.05),大鼠CA1区神经元病理改变情况不明显,铁沉淀增加,血清中丙二醛、Fe^(2+)浓度增加(P<0.05),还原型谷胱甘肽浓度减少(P<0.05),海马组织神经元线粒体萎缩变小,且Nrf2、XCT、HO-1、GPX4、FTH1蛋白的表达减少(P<0.05)。在一定范围内,通脉开窍丸剂量越高效果越好,且高剂量治疗效果不亚于盐酸多奈哌齐。(4)结果说明,通脉开窍丸可以减轻大鼠海马组织神经元病理改变,改善血管性痴呆大鼠的认知功能,其作用机制可能与Nrf2/HO-1/GPX4信号通路的激活抑制铁死亡有关。

Gut microbiota-astrocyte axis: new insights into age-related cognitive decline

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.

认知症污名的研究新进展

认知障碍又称认知症。随着人口老龄化进程的加快,受认知症和阿尔茨海默病影响的人群在不断增多。有关认知症的污名在国际社会被公认为普遍存在,但相关的研究却十分有限。本文通过梳理既往有关认知症污名的研究成果,发现有关认知症污名的定义和测量方式有待统一,有关经济欠发达地区的研究十分欠缺,能够进行因果推断的证据缺乏,干预研究的数量和质量均有很大的提升空间。对于认知症污名的研究,为打破传统污名研究领域中二元主体视角提供了难得的契机。同时,对认知症污名形成机制的讨论,也可以深化学界对标签理论和归因理论的探讨。