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.

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.

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.

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.

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.

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.

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.

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.

Efficacy and Safety of Guilingji Capsules(龟龄集胶囊)for Treating Mild-to-Moderate Cognitive Impairment:Study Protocol for A Randomized,Double-Blind,Positive-Controlled,Multicenter and Noninferiority Trial

Background:The incidence of cognitive impairment(CI)is gradually increasing,which has attracted more attention from medical researchers worldwide.Definitive mechanisms of pathogenesis remain elusive,and there are few medications that have been proven effective for CI.The utilization of Chinese herbal medicine has shown positive therapeutic effects for a broad spectrum of diseases,including CI.Objective:The purpose of this study is to evaluate the safety and efficacy of Guilingji Capsules(GLJC,龟龄集胶囊)in treating mild-to-moderate CI with Shen(Kidney)and marrow deficiency syndrome.Methods:This is a randomized,double-blind,positive-controlled,multicenter clinical trial with a noninferiority design that included 348 participants randomly divided into an experimental arm and an active comparator arm.Individuals in the experimental arm(174 cases)took 0.6 g of GLJC once a day and 19.2 mg of Gingko biloba extract mimetic 3 times a day.Individuals in the active comparator arm(174 cases)took 0.6 g of GLJC mimetic once a day and 19.2 mg of Gingko biloba extract in tablet form 3 times a day.The intervention period included two sessions over 24 weeks.The primary outcome be the effectiveness of GLJC on cognitive improvement after 24 weeks of treatment,which was defined as an increase in the Mini Mental State Examination(MMSE)and Montreal Cognitive Assessment(MoCA)Scale.The secondary outcomes were improvement in independence,daily living ability,and Chinese medicine(CM)syndrome,which were measured with the Alzheimer’s disease Rating Scale-Cognitive Project(ADAS-Cog),Clinical Dementia Rating(CDR)Total Score,Activities of Daily Living(ADL)Total Score and the Chinese Medicine Symptom Scale(CM-SS),respectively.Serum acetylcholine,acetylcholinesterase,bax and bcl-2 were monitored to explore the mechanism of GLJC on CI.In addition,safety measures,including vital signs,electrocardiography,laboratory indicators(full blood count,kidney and liver function tests,routine urine test and routine stool test)and adverse events,were also recorded.Discussion:The purpose of this trial is to evaluate the efficacy and safety of GLJC in patients with mild-to-moderate CI with kidney and marrow deficiency syndrome.If successful,the results would provide a viable treatment for patients with mild-to-moderate CI.

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.

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.

Proteomics of serum exosomes identified fibulin-1 as a novel biomarker for mild cognitive impairment

Mild cognitive impairment(MCI)is a prodrome of Alzheimer’s disease pathology.Cognitive impairment patients often have a delayed diagnosis because there are no early symptoms or conventional diagnostic methods.Exosomes play a vital role in cell-to-cell communications and can act as promising biomarkers in diagnosing diseases.This study was designed to identify serum exosomal candidate proteins that may play roles in diagnosing MCI.Mass spectrometry coupled with tandem mass tag approach-based non-targeted proteomics was used to show the differentially expressed proteins in exosomes between MCI patients and healthy controls,and these differential proteins were validated using immunoblot and enzyme-linked immunosorbent assays.Correlation of cognitive performance with the serum exosomal protein level was determined.Nanoparticle tracking analysis suggested that there was a higher serum exosome concentration and smaller exosome diameter in individuals with MCI compared with healthy controls.We identified 69 exosomal proteins that were differentially expressed between MCI patients and healthy controls using mass spectrometry analysis.Thirty-nine exosomal proteins were upregulated in MCI patients compared with those in control patients.Exosomal fibulin-1,with an area under the curve value of 0.81,may be a biomarker for an MCI diagnosis.The exosomal protein signature from MCI patients reflected the cell adhesion molecule category.In particular,higher exosomal fibulin-1 levels correlated with lower cognitive performance.Thus,this study revealed that exosomal fibulin-1 is a promising biomarker for diagnosing MCI.

Cognitive and Functional Profiles in Mild-to-Moderate Alzheimer’s Disease and Mild Cognitive Impairment Compared to Healthy Elderly

Background: Amnestic mild cognitive impairment (aMCI) and mild-to-moderate Alzheimer’s disease (AD) are clinically distinct but impact cognitive and functional ability similarly. Comprehensive assessment of cognitive and functional deficits may prove useful in informing differential diagnosis in early stages of dementia and in informing endpoint selection in therapeutic AD trials. Objective: The objective of this study was to characterize patterns of cognitive and functional impairment in aMCI and mild-to-moderate AD subjects compared to cognitively intact healthy elderly (HE). Methods: Thirty-one healthy elderly, 20 aMCI and 19 AD participants were administered a cognitive test battery that included the ADAS-Cog and functional assessments. Z-scores were calculated for all endpoints based on the HE reference group. Results: Cognitive deficits were observed in AD and aMCI participants relative to the referent group. On average, aMCI participants performed 1 - 2 standard deviations below HE on cognitive tests, and AD participants performed 2 - 3 standard deviations below HE. Domain-specific functional deficits among AD participants (z- score -0.4 to -6.4) were consistently greater than those of aMCI participants (z-score 0 to -1.7). Conclusion: This study provides further support for comprehensive assessment and monitoring of cognitive and functional domain scores in the diagnosis and treatment of aMCI and mild AD. Domain-specific cognitive scores may be more useful than composite scores in characterizing impairment and decline. Measuring domains such as attention, processing speed and executive function may increase the sensitivity of detecting disease progression and therapeutic effects, particularly in mild-moderate AD where memory decline may be too slow to detect drug effects during a typical clinical trial.

Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function

Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.

Blunt dopamine transmission due to decreased GDNF in the PFC evokes cognitive impairment in Parkinson’s disease

Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.

The Effect of Sleep and Cognition Enhancement Multimodal Intervention for Mild Cognitive Impairment with Sleep Disturbance in the Community-Dwelling Elderly

Dementia prevalence has soared due to population aging. In Mild Cognitive Impairment (MCI) as a pre-dementia stage, sleepdisturbances have raised much interest as a factor in a bidirectional relationship with cognitive decline. Thus, this studydeveloped the Sleep and Cognition Enhancement Multimodal Intervention (SCEMI) based on Lazarus’ multimodal approachand conducted a randomized controlled experiment to investigate the effects of the novel program on sleep and cognition inMCI elderly. The participants were 55 MCI elderly with sleep disturbances at two dementia care centers located in S-city,Gyeonggi-do, South Korea (n = 25 in the experimental group and n = 30 in the control group). The study period was fromNovember 01 to December 27, 2022. The experimental group received 8 sessions of SCEMI, 60 min per session once a week.The control group received general education and guidance using a simplified booklet on the sleep and cognitive improvement.For data collection, a self-reported questionnaire was used to investigate sleep quality, presleep arousal, cognitive function,stress, and depression. The results showed that, compared to the control group, the experimental group had significantlyimproved across all variables: sleep quality (U = 109.50, p < 0.001), presleep arousal (U = 11.50, p < 0.001), cognitive function(U = 72.00, p < 0.001), stress (U = 139.00, p < 0.001), and depression (U = 231.50, p = 0.015). Thus, the SCEMI appears topositively affect symptomatic improvement and delays the progression to dementia as an integrated intervention to enhancesleep and cognition in community-dwelling MCI elderly with sleep disturbances.

Receded near point of convergence as a predictor of mild cognitive impairment in the general geriatric population:results from a population-based study

AIM:To investigate the relationship between near point of convergence(NPC)and mild cognitive impairment(MCI)in the general elderly population.METHODS:The present report is a part of the Tehran Geriatric Eye Study(TGES):a population-based crosssectional study conducted on individuals 60 years of age and above living in Tehran,Iran using the multi-stage stratified random cluster sampling method.Cognitive status was assessed using the Persian version of the Mini-Mental State Examination(MMSE).All study participants underwent complete ocular examination including measurement of uncorrected and best-corrected visual acuity,objective and subjective refraction,cover testing,NPC measurement,and slit-lamp biomicroscopy.RESULTS:The data of 1190 individuals were analyzed for this report.The mean age of the participants analyzed was 66.82±5.42(60-92y)and 728(61.2%)of them were female.Patients with MCI had a significantly more receded NPC compared to subjects with normal cognitive status(10.89±3.58 vs 7.76±2.71 cm,P<0.001).In the multivariable logistic regression model and in the presence of confounding variables,a receded NPC was statistically significantly associated with an increased risk of MCI(odds ratio:1.334,95%confidence interval:1.263 to 1.410,P<0.001).According to receiver operating characteristic(ROC)analysis,a cut point NPC>8.5 cm(area under the curve:0.764,P<0.001)could predict the presence of MCI with a sensitivity and specificity of 70.9%and 69.5%,respectively.CONCLUSION:A receded NPC can be clinically proposed as a predictor of MCI in older adults.It is recommended that elderly with a receded NPC>8.50 cm undergo detailed cognitive screening for a definite diagnosis of MCI.In this case,the necessary interventions can be carried out to slow down MCI progression to dementia.