Molecular biomarkers for vascular cognitive impairment and dementia:the current status and directions for the future

Dementia is a syndrome with various underlying pathologies acting independently or in concert to cause cognitive dysfunction.The development of disease-specific treatments and targeted prevention strategies requires precise clinical sub-typing via etiology and pathophysiological processes.Furthermore,recent research advances in biomarkers,especially for Alzheimer's disease(AD)diagnosis,have improved diagnostic precision for dementia.

Factors Associated with Renal Impairment in Patients on Tenofovir for Chronic Hepatitis B in Yaoundé (Cameroon)

Background: Tenofovir (TFV) is widely used to treat patients with hepatitis B virus (HBV) infection. But kidney abnormalities are the main concern using this drug. Few studies have described the renal impairment due to the TFV in chronic hepatitis B (CHB) in Sub-Saharan Africa. The objective was to evaluate factors associated with renal impairment observed in patients on TFV for CHB. Method: It was a hospital based cross sectional prospective study carried out from June 2023 to July 2023 in Yaoundé (Cameroon) and included any patient treated with TFV for CHB during at least a period of 6 months. For each participant, we collected in the medical report socio-demographic data, clinical data, baseline creatinine, treatment information (type of TFV which was Disoproxil Fumarate (TDF) or Alafenamide (TAF), duration). Then, we collected blood samples to measure serum creatinine and phosphate levels and urine dipstick analysis. Factors associated with renal impairment were assessed with the Odds Ratio. A p value of Results: A total of 60 participants were included. The median age was 44 years [36-55] and median duration of TFV therapy was 17.5 months [11.7-25.7]. The prevalence of reduced eGFR (Conclusion: Kidney function was impaired in some patients receiving TFV for CHB. It should be monitored, particularly after 36 months and for those receiving TDF prodrug.

Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment

Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function. Glyphosate-based herbicides could adversely affect cognitive function either indirectly and/or directly. Indirectly, glyphosate could affect gut microbiota, and if dysbiosis results in endotoxemia(leaky gut), infiltrated bacterial by-products such as lipopolysaccharides could activate pro-inflammatory cascades. Glyphosate can also directly trigger pro-inflammatory cascades. Indeed, we observed that acute glyphosate exposure inhibits long-term potentiation in rat hippocampal slices. Interestingly, direct inhibition of long-term potentiation by glyphosate appears to be similar to that of lipopolysaccharides. There are several possible measures to control dysbiosis and neuroinflammation caused by glyphosate. Dietary intake of polyphenols, such as quercetin, which overcome the inhibitory effect of glyphosate on long-term potentiation, could be one effective strategy. The aim of this narrative review is to discuss possible mechanisms underlying neurotoxicity following glyphosate exposure as a means to identify potential treatments.

Relationship of Retinal Nerve Fiber Layer Thickness and Retinal Vessel Calibers with Cognitive Impairment in the Asymptomatic Polyvascular Abnormalities Population

Objective Cognitive impairment(CI)in older individuals has a high morbidity rate worldwide,with poor diagnostic methods and susceptible population identification.This study aimed to investigate the relationship between different retinal metrics and CI in a particular population,emphasizing polyvascular status.Methods We collected information from the Asymptomatic Polyvascular Abnormalities Community Study on retinal vessel calibers,retinal nerve fiber layer(RNFL)thickness,and cognitive function of 3,785participants,aged 40 years or older.Logistic regression was used to analyze the relationship between retinal metrics and cognitive function.Subgroups stratified by different vascular statuses were also analyzed.Results RNFL thickness was significantly thinner in the CI group(odds ratio:0.973,95%confidence interval:0.953–0.994).In the subgroup analysis,the difference still existed in the non-intracranial arterial stenosis,non-extracranial carotid arterial stenosis,and peripheral arterial disease subgroups(P<0.05).Conclusion A thin RNFL is associated with CI,especially in people with non-large vessel stenosis.The underlying small vessel change in RNFL and CI should be investigated in the future.

Garcinia Kola and Kolaviron Attenuates Bisphenol A-Induced Memory Impairment and Hippocampal Neuroinflammation in Male Wistar Rats

Bisphenol A (BPA), a toxicant which can leach into food from plastic containers, is reported to induce neurotoxicity among others via oxidative mechanisms. However, antioxidant compounds have been suggested to mitigate BPA-induced toxicities. Garcinia kola (GK) and its bioactive compound, kolaviron, are well-established natural antioxidants, which can exert protective effects against BPA-induced toxicities. This study was designed to investigate the likely mitigating effect of GK and kolaviron on BPA-induced memory impairment and hippocampal neuroinflammation in male Wistar rats. Thirty-five rats were equally grouped and treated as follows: I and II received distilled water and corn oil, respectively at 0.2 mL, while III - VII received BPA (50 mg/kg), BPA + GK (200 mg/kg), BPA + kolaviron (200 mg/kg), GK and kolaviron, respectively for 28 days p.o. Thereafter, behavioral studies were done using the Novel Object Recognition and Y maze tests. Subsequently under anaesthesia, the hippocampus in each animal was dissected out, homogenized and analysed for malondialdehyde, superoxide dismutase, catalase, reduced glutathione, glutathione transferase, nitrites, interleukin-6, tumour necrosis factor-α, acetylcholinesterase, glutamate acid decarboxylase, and arginase activity. Data were analyzed by ANOVA and Tukey Post-hoc test at p p Garcinia kola and Kolaviron mitigate bisphenol A-induced memory impairment and neuroinflammation via antioxidant potentiation and neurotransmitter balance.

Prevalence of visual impairment and estimation of refractive errors among school children in Kakamega,Kenya

AIM:To investigate the prevalence of visual impairment(VI)and provide an estimation of uncorrected refractive errors in school-aged children,conducted by optometry students as a community service.METHODS:The study was cross-sectional.Totally 3343 participants were included in the study.The initial examination involved assessing the uncorrected distance visual acuity(UDVA)and visual acuity(VA)while using a+2.00 D lens.The inclusion criteria for a subsequent comprehensive cycloplegic eye examination,performed by an optometrist,were as follows:a UDVA<0.6 decimal(0.20 logMAR)and/or a VA with+2.00 D≥0.8 decimal(0.96 logMAR).RESULTS:The sample had a mean age of 10.92±2.13y(range 4 to 17y),and 51.3%of the children were female(n=1715).The majority of the children(89.7%)fell within the age range of 8 to 14y.Among the ethnic groups,the highest representation was from the Luhya group(60.6%)followed by Luo(20.4%).Mean logMAR UDVA choosing the best eye for each student was 0.29±0.17(range 1.70 to 0.22).Out of the total,246 participants(7.4%)had a full eye examination.The estimated prevalence of myopia(defined as spherical equivalent≤-0.5 D)was found to be 1.45%of the total sample.While around 0.18%of the total sample had hyperopia value exceeding+1.75 D.Refractive astigmatism(cil<-0.75 D)was found in 0.21%(7/3343)of the children.The VI prevalence was 1.26%of the total sample.Among our cases of VI,76.2%could be attributed to uncorrected refractive error.Amblyopia was detected in 0.66%(22/3343)of the screened children.There was no statistically significant correlation observed between age or gender and refractive values.CONCLUSION:The primary cause of VI is determined to be uncorrected refractive errors,with myopia being the most prevalent refractive error observed.These findings underscore the significance of early identification and correction of refractive errors in school-aged children as a means to alleviate the impact of VI.

SIL1 improves cognitive impairment in APP23/PS45 mice by regulating amyloid precursor protein processing and Aβ generation

SIL1,an endoplasmic reticulum(ER)-resident protein,is reported to play a protective role in Alzheimer’s disease(AD).However,the effect of SIL1 on amyloid precursor protein(APP)processing remains unclear.In this study,the role of SIL1 in APP processing was explored both in vitro and in vivo.In the in vitro experiment,SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695.In the in vivo experiment,AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates.Western blotting(WB),immunohistochemistry,RNA sequencing(RNA-seq),and behavioral experiments were performed to evaluate the relevant parameters.Results indicated that SIL1 expression decreased in APP23/PS45 mice.Overexpression of SIL1 significantly decreased the protein levels of APP,presenilin-1(PS1),and C-terminal fragments(CTFs)of APP in vivo and in vitro.Conversely,knockdown of SIL1 increased the protein levels of APP,β-site APP cleavage enzyme 1(BACE1),PS1,and CTFs,as well as APP mRNA expression in 2EB2 cells.Furthermore,SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice.Importantly,Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice.These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.

Novel insights into immune-related genes associated with type 2 diabetes mellitus-related cognitive impairment

BACKGROUND The cognitive impairment in type 2 diabetes mellitus(T2DM)is a multifaceted and advancing state that requires further exploration to fully comprehend.Neu-roinflammation is considered to be one of the main mechanisms and the immune system has played a vital role in the progression of the disease.AIM To identify and validate the immune-related genes in the hippocampus associated with T2DM-related cognitive impairment.METHODS To identify differentially expressed genes(DEGs)between T2DM and controls,we used data from the Gene Expression Omnibus database GSE125387.To identify T2DM module genes,we used Weighted Gene Co-Expression Network Analysis.All the genes were subject to Gene Set Enrichment Analysis.Protein-protein interaction network construction and machine learning were utilized to identify three hub genes.Immune cell infiltration analysis was performed.The three hub genes were validated in GSE152539 via receiver operating characteristic curve analysis.Validation experiments including reverse transcription quantitative real-time PCR,Western blotting and immunohistochemistry were conducted both in vivo and in vitro.To identify potential drugs associated with hub genes,we used the Comparative Toxicogenomics Database(CTD).RESULTS A total of 576 DEGs were identified using GSE125387.By taking the intersection of DEGs,T2DM module genes,and immune-related genes,a total of 59 genes associated with the immune system were identified.Afterward,machine learning was utilized to identify three hub genes(H2-T24,Rac3,and Tfrc).The hub genes were associated with a variety of immune cells.The three hub genes were validated in GSE152539.Validation experiments were conducted at the mRNA and protein levels both in vivo and in vitro,consistent with the bioinformatics analysis.Additionally,11 potential drugs associated with RAC3 and TFRC were identified based on the CTD.CONCLUSION Immune-related genes that differ in expression in the hippocampus are closely linked to microglia.We validated the expression of three hub genes both in vivo and in vitro,consistent with our bioinformatics results.We discovered 11 compounds associated with RAC3 and TFRC.These findings suggest that they are co-regulatory molecules of immunometabolism in diabetic cognitive impairment.

Risk factors for cognitive impairment in patients with chronic kidney disease

BACKGROUND Chronic kidney disease(CKD)patients have been found to be at risk of concurrent cognitive dysfunction in previous studies,which has now become an important public health issue of widespread concern.AIM To investigate the risk factors for concurrent cognitive dysfunction in patients with CKD.METHODS This is a prospective cohort study conducted among patients with CKD between October 2021 and March 2023.A questionnaire was formulated by literature review and expert consultation and included questions about age,sex,education level,per capita monthly household income,marital status,living condition,payment method,and hypertension.RESULTS Logistic regression analysis showed that patients aged 60-79 years[odds ratio(OR)=1.561,P=0.015]and≥80 years(OR=1.760,P=0.013),participants with middle to high school education(OR=0.820,P=0.027),divorced or widowed individuals(OR=1.37,P=0.032),self-funded patients(OR=2.368,P=0.008),and patients with hypertension(OR=2.011,P=0.041)had a higher risk of cognitive impairment.The risk of cognitive impairment was lower for those with a college degree(OR=0.435,P=0.034)and married individuals.CONCLUSION The risk factors affecting cognitive dysfunction are age,60-79 years and≥80 years;education,primary school education or less;marital status,divorced or widowed;payment method,selffunded;hypertension;and CKD.

Enhancing Mild Cognitive Impairment Detection through Efficient Magnetic Resonance Image Analysis

Neuroimaging has emerged over the last few decades as a crucial tool in diagnosing Alzheimer’s disease(AD).Mild cognitive impairment(MCI)is a condition that falls between the spectrum of normal cognitive function and AD.However,previous studies have mainly used handcrafted features to classify MCI,AD,and normal control(NC)individuals.This paper focuses on using gray matter(GM)scans obtained through magnetic resonance imaging(MRI)for the diagnosis of individuals with MCI,AD,and NC.To improve classification performance,we developed two transfer learning strategies with data augmentation(i.e.,shear range,rotation,zoom range,channel shift).The first approach is a deep Siamese network(DSN),and the second approach involves using a cross-domain strategy with customized VGG-16.We performed experiments on the Alzheimer’s Disease Neuroimaging Initiative(ADNI)dataset to evaluate the performance of our proposed models.Our experimental results demonstrate superior performance in classifying the three binary classification tasks:NC vs.AD,NC vs.MCI,and MCI vs.AD.Specifically,we achieved a classification accuracy of 97.68%,94.25%,and 92.18%for the three cases,respectively.Our study proposes two transfer learning strategies with data augmentation to accurately diagnose MCI,AD,and normal control individuals using GM scans.Our findings provide promising results for future research and clinical applications in the early detection and diagnosis of AD.

Clinical efficacy of Baijin pills in the treatment of generalized tonicclonic seizure epilepsy with cognitive impairment

BACKGROUND The generalized tonic-clonic seizure(GTCS)is the most usual variety of epileptic seizure.It is mainly characterized by strong body muscle rigidity,loss of consciousness,a disorder of plant neurofunction,and significant damage to cognitive function.The effect of antiepileptic drugs on cognition should also be considered.At present,there is no effective treatment for patients with epilepsy,but traditional Chinese medicine has shown a significant effect on chronic disease with fewer harmful side effects and should,therefore,be considered for the therapy means of epilepsy with cognitive dysfunction.AIM To investigate the clinical efficacy of Baijin pills for treating GTCS patients with cognitive impairment.METHODS This prospective study enrolled patients diagnosed with GTCS between January 2020 and December 2023 and separate them into two groups(experimental and control)using random number table method.The control group was treated with sodium valproate,and the experimental group was Baijin pills and sodium valproate for three months.The frequency and duration of each seizure,the Montreal Cognitive Assessment Scale(MoCA),and the Quality of Life Rating Scale(QOLIE-31)were recorded before and after treatment.RESULTS There were 85 patients included(42 in the control group and 43 in the experimental group).After treatment,the seizure frequency in the experimental group was significantly reduced(P<0.05),and seizure duration was shortened(P<0.01).The total MoCA score in the experimental group significantly increased compared to before treatment(P<0.01),and the sub-item scores,except naming and abstract generalization ability,significantly increased(P<0.05),whereas the total MoCA score in the control group significantly decreased after treatment(P<0.05).The QOLIE-31 score of the experimental group increased significantly after treatment compared to before treatment(P<0.01).CONCLUSION Baijin pills have a good clinical effect on epilepsy with cognitive dysfunction.

Exploring the therapeutic potential of Qi Teng Mai Ning recipe in ischemic stroke and vascular cognitive impairment

Background:This study aims to explore the therapeutic effects of the Qi Teng Mai Ning recipe on ischemic stroke and vascular cognitive impairment through its potential to modulate cellular autophagy,with a focus on identifying its active ingredients and their target proteins.Methods:The study began with the identification of active ingredients in the Qi Teng Mai Ning recipe.It proceeded to screen the gene expression omnibus database for ischemic stroke and vascular cognitive impairment-associated differentially expressed mRNAs and to identify cellular autophagy-related proteins via the Human Autophagy Database.These proteins were annotated with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions and subjected to molecular docking with the recipe’s core active ingredients.In vitro cell experiments were conducted on hypoxic HT22 cells,involving CCK8 assay,lentiviral transfection to silence autophagy related 9B(ATG9B),immunofluorescence staining,and qPCR validation to investigate the effects of the recipe on autophagy.Results:The analysis identified 104 active ingredients targeting 408 proteins and forming a complex ingredient-target network.Intersecting 55 ischemic stroke-related and 909 vascular cognitive impairment-related differentially expressed mRNAs revealed 14 co-expressed mRNAs.Molecular docking showed quercetin,kaempferol,myrcene,and conferone as key ingredients targeting autophagy-related proteins.Cellular experiments indicated that the recipe significantly enhanced cell viability under hypoxic conditions,reduced apoptosis,and modulated the expression of autophagy-related factors,thereby decreasing apoptosis rates in HT22 cells.Conclusion:The Qi Teng Mai Ning recipe offers protective effects against ischemic stroke and vascular cognitive impairment by modulating autophagy-related proteins.Its efficacy highlights the potential of traditional Chinese medicine in treating these conditions,though further research is needed to fully understand its mechanisms and clinical applications.

Estimating High-Order Functional Connectivity Networks for Mild Cognitive Impairment Identification Based on Topological Structure

Functional connectivity networks (FCNs) are important in the diagnosis of neurological diseases and the understanding of brain tissue patterns. Recently, many methods, such as Pearson’s correlation (PC), Sparse representation (SR), and Sparse low-rank representation have been proposed to estimate FCNs. Despite their popularity, they only capture the low-order connections of the brain regions, failing to encode more complex relationships (i.e. , high-order relationships). Although researchers have proposed high-order methods, like PC + PC and SR + SR, aiming to build FCNs that can reflect more real state of the brain. However, such methods only consider the relationships between brain regions during the FCN construction process, neglecting the potential shared topological structure information between FCNs of different subjects. In addition, the low-order relationships are always neglected during the construction of high-order FCNs. To address these issues, in this paper we proposed a novel method, namely Ho-FCNTops, towards estimating high-order FCNs based on brain topological structure. Specifically, inspired by the Group-constrained sparse representation (GSR), we first introduced a prior assumption that all subjects share the same topological structure in the construction of the low-order FCNs. Subsequently, we employed the Correlation-reserved embedding (COPE) to eliminate noise and redundancy from the low-order FCNs. Meanwhile, we retained the original low-order relationships during the embedding process to obtain new node representations. Finally, we utilized the SR method on the obtained new node representations to construct the Ho-FCNTops required for disease identification. To validate the effectiveness of the proposed method, experiments were conducted on 137 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to identify Mild Cognitive Impairment (MCI) patients from the normal controls. The experimental results demonstrate superior performance compared to baseline methods.

Cognitive impairment in cerebral small vessel disease induced by hypertension

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension and cerebral small vessel disease remains unclear.Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease.Chronic hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and stroke.Hypertension is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of hypertension.This review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive ability.We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

Cognitive impairment in patients with bipolar disorder alone versus those with bipolar disorder comorbid with borderline personality disorder

BACKGROUND Bipolar disorder(BD)is a severe mental illness.BD often coexists with borderline personality disorders,making the condition more complex.AIM To explore the differences in cognitive impairment between patients with BD and those with BD comorbid with borderline personality disorder.METHODS Eighty patients with BD and comorbid borderline personality disorder and 80 patients with BD alone were included in groups A and B,respectively,and 80 healthy volunteers were included as controls.Cognitive function in each group was evaluated using the Chinese version of the repeatable battery for the assess-ment of neuropsychological status(RBANS),the Stroop color-word test,and the Wechsler intelligence scale-revised(WAIS-RC).RESULTS The indices of the RBANS,Stroop color-word test,and WAIS-RC in groups A and B were significantly lower than those of the control group(P<0.05).Group A had significantly longer Stroop color-word test times for single-character,single-color,double-character,and double-color,lower scores of immediate memory,visual breadth,verbal function dimensions and total score of the RBANS,as well as lower scores of verbal IQ,performance IQ,and overall IQ of the WAIS-RC compared with group B(P<0.05).Compared to group B,group A exhibited significantly longer single-character time,single-color time,double-character time,and double-color time in the Stroop color-word test(P<0.05).CONCLUSION The cognitive function of patients with BD complicated with borderline personality disorder is lower than that of patients with BD.

Correlation between serum lipid profiles and cognitive impairment in old age:a cross-sectional study

Background The correlation between cognitive function and lipid profiles,including total cholesterol,low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C)and triglycerides,is inconsistent.Aims This cross-sectional study investigated the association between serum lipid levels and the prevalence of cognitive impairment among community-dwelling older adults and explored this difference in association by gender and urban-rural residency.Methods Participants aged 65 and above in urban and rural areas were recruited between 2018 and 2020,selected from the Hubei Memory and Aging Cohort Study.Detailed neuropsychological evaluations,clinical examinations and laboratory tests were conducted in community health service centres.Multivariate logistic regression was used to analyse the correlation between serum lipid profiles and the prevalence of cognitive impairment.Results We identified 1336 cognitively impaired adults(≥65 years)-1066 with mild cognitive impairment and 270 with dementia-from 4746 participants.Triglycerides level was correlated with cognitive impairment in the total sample(χ2=6.420,p=0.011).In gender-stratified multivariate analysis,high triglycerides in males reduced the risk of cognitive impairment(OR:0.785,95%CI:0.623 to 0.989,p=0.040),and high LDL-C in females increased the risk of cognitive impairment(OR:1.282,95%CI:1.040 to 1.581,p=0.020).In both gender-stratified and urban-rural stratified multivariate analyses,high triglycerides reduced the risk of cognitive impairment in older urban men(OR:0.734,95%CI:0.551 to 0.977,p=0.034),and high LDL-C increased the risk of cognitive impairment in older rural women(OR:1.830,95%CI:1.119 to 2.991,p=0.016).Conclusions There are gender and urban-rural differences in the correlation of serum lipids with cognitive impairment.High triglycerides levels may be a protective factor for cognitive function in older urban men,while high LDL-C levels may be a risk factor for cognitive function in older rural women.

BI-D1870 Causes the Rats’ Learning and Memory Acquisition Ability Impairment

Aim: To observe the rats’ learning and memory acquisition ability disturbance induced by BI-D1870. Methods: Male SD rats were randomly divided into control group, solvent control group and BI-D1870 group. The rats in the control group were intraperitoneally injected with saline, while those in the solvent control group were intraperitoneally injected with DMSO + sulfobutyl-β-cyclodextrin solvent, and those in the BI-D1870 group were intraperitoneally injected with BI-D1870. All the rats’ appearance and behavior were daily observed, and body weight was recorded on the day 15, 30, 45, 60, 75 and 82 of BI-D1870 injected. Morris water maze was used to screen the rats’ learning and memory acquisition ability on the day 22 - 25, 52 - 55, and 82 - 85 of training by BI-D1870 treated. The successful rates of the rats’ memory impairment were respectively calculated for three times screening. Results: During the whole experiment, there was no obvious difference in appearance and fur color in all rats. The rats’ agitation began to appear on the day 10th of BI-D1870 given. The agitation rats’ number and rats’ body weight gradually increased along with BI-D1870 treated (P P Conclusion: Intraperitoneal injection of BI-D1870 can induce the rats’ learning and memory acquisition ability disorder.

The landscape of cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis

Although mutations in the superoxide dismutase 1 gene account for only a minority of total amyotrophic lateral sclerosis cases,the discovery of this gene has been crucial for amyotrophic lateral sclerosis research.Since the identification of superoxide dismutase 1 in 1993,the field of amyotrophic lateral sclerosis genetics has considerably widened,improving our understanding of the diverse pathogenic basis of amyotrophic lateral sclerosis.In this review,we focus on cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis patients.Literature has mostly reported that cognition remains intact in superoxide dismutase 1-amyotrophic lateral sclerosis patients,but recent reports highlight frontal lobe function frailty in patients carrying different superoxide dismutase 1-amyotrophic lateral sclerosis mutations.We thoroughly reviewed all the various mutations reported in the literature to contribute to a comprehensive database of superoxide dismutase 1-amyotrophic lateral sclerosis genotype-phenotype correlation.Such a resource could ultimately improve our mechanistic understanding of amyotrophic lateral sclerosis,enabling a more robust assessment of how the amyotrophic lateral sclerosis phenotype responds to different variants across genes,which is important for the therapeutic strategy targeting genetic mutations.Cognition in superoxide dismutase 1-amyotrophic lateral sclerosis deserves further longitudinal research since this peculiar frailty in patients with similar mutations can be conditioned by external factors,including environment and other unidentified agents including modifier genes.

Mechanism of Learning and Memory Impairment in Rats Exposed to Arsenic and/or Fluoride Based on Microbiome and Metabolome

Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level(microbiome and metabolome).Methods We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.Results Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome, featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic(GABAergic) synapse, and arachidonic acid(AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.Conclusion Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.

β2-Microglobulin exacerbates neuroinflammation,brain damage,and cognitive impairment after stroke in rats

β2-Microglobulin(β2M),a component of the major histocompatibility complex class I molecule,is associated with aging-related cognitive impairment and Alzheimer’s disease.Although upregulation ofβ2M is considered to be highly related to ischemic stroke,the specific role and underlying mechanistic action ofβ2M are poorly understood.In this study,we established a rat model of focal cerebral ischemia by occlusion of the middle cerebral artery.We found thatβ2M levels in the cerebral spinal fluid,serum,and brain tissue were significantly increased in the acute period but gradually decreased during the recovery period.RNA interference was used to inhibitβ2M expression in the acute period of cerebral stroke.Tissue staining with 2,3,5-triphenyltetrazolium chloride and evaluation of cognitive function using the Morris water maze test demonstrated that decreasedβ2M expression in the ischemic penumbra reduced infarct volume and alleviated cognitive deficits,respectively.Notably,glial cell,caspase-1(p20),and Nod-like receptor pyrin domain containing 3(NLRP3)inflammasome activation as well as production of the inflammatory cytokines interleukin-1β,interleukin-6,and tumor necrosis factor-αwere also effectively inhibited byβ2M silencing.These findings suggest thatβ2M participates in brain injury and cognitive impairment in a rat model of ischemic stroke through activation of neuroinflammation associated with the NLRP3 inflammasome.