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.

Diabetes and cognitive decline:Challenges and future direction

There is growing evidence that diabetes can induce cognitive decline and dementia.It is a slow,progressive cognitive decline that can occur in any age group,but is seen more frequently in older individuals.Symptoms related to cognitive decline are worsened by chronic metabolic syndrome.Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention.This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.

Analysis of the relationship between blood pressure variability and subtle cognitive decline in older adults

BACKGROUND Blood pressure variability(BPV)has been shown to be related to mild cognitive impairment and Alzheimer's disease in a number of studies.However,the relationship between BPV and subtle cognitive decline(SCD)has received minimal attention in this field of research to date and has rarely been reported.AIM To examine whether SCD is independently associated with changes in BPV in older adults.METHODS Participants were selected based on having participated in cognitive function evaluation and ambulatory blood pressure measurement at the Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine between June 2020 and August 2022.The participants included 182 individuals with SCD as the experimental group and 237 with normal cognitive function as the control group.The basic data,laboratory examinations,scale tests,and ambulatory blood pressure test results of the two groups were analyzed retrospectively,and the relationship between SCD and BPV was subsequently evaluated.RESULTS Significant differences were observed between the two groups of participants(P<0.05)in terms of age,education level,prevalence rate of diabetes,fasting blood glucose level,24-h systolic blood pressure standard deviation and coefficient of variation,24-h diastolic blood pressure standard deviation and coefficient of variation.The scale monitoring results showed significant differences in the scores for memory,attention,and visual space between the experimental and control groups.Logistic regression analysis indicated that age,education level,blood sugar level,and BPV were factors influencing cognitive decline.Linear regression analysis showed that there was an independent correlation between blood pressure variation and SCD,even after adjusting for related factors.Each of the above differences was still significant.CONCLUSION This study suggests that increased BPV is associated with SCD.

Preventive Effect of Gastrodin on Cognitive Decline after Cardiac Surgery with Cardiopulmonary Bypass:A Double-Blind,Randomized Controlled Study

Cognitive decline is a common complication after cardiac surgery with cardiopulmonary bypass（CPB）,but as such no pharmacological therapy has been shown to be efficacious in preventing the decline.However,gastrodin has been shown to have multi-pharmacological effects on neurological functions.We undertook this study to test the hypothesis that gastrodin would potentially prevent CPB-associated neurocognitive decline.We randomly assigned 200 patients undergoing mitral valve replacement surgery to receive either gastrodin（40 mg/kg） or saline after the induction of anesthesia and subsequently evaluated cognitive function before surgery,at discharge,and at 3rd month after surgery by using a battery of five neurocognitive tests,or adverse effects of gastrodin postoperatively.Neurocognitive decline in postoperative function was defined as a drop of 1 SD or more in the scores on tests of any one of the four domains of cognitive function.Cognitive decline occurred in 9% of the patients in the gastrodin group in contrast to 42% in the control group（P〈0.01） at discharge.Cognitive outcome could be determined at 3rd month in 87 patients in the gastrodin group and 89 in the control group.Cognitive decline was detected in 6% in the gastrodin group and 31% in the control group（P〈0.01）.The incidences of possible adverse effects were similar between two groups.These results indicate that gastrodin is an effective and a safe drug for the prevention of neurocognitive decline in patients undergoing mitral valve replacement surgery with CPB.

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

BACKGROUND Type 2 diabetes mellitus(T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia.The mechanisms of diabetes-associated cognitive dysfunction(DACD) have not been fully elucidated to date.Some studies proved lower cerebral blood flow(CBF) in the hippocampus was associated with poor executive function and memory in T2DM.Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor(VEGF) expression and CBF changes in humans and animal models.In this study,we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional(3D) arterial spin labeling(3D-ASL) and VEGF expression in the hippocampus.AIM To assess the correlation between CBF(measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM.METHODS Forty Sprague-Dawley male rats were divided into control and T2DM groups.The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM.Cognitive function was assessed using the Morris water maze experiment.The CBF changes were measured by 3D-ASL magnetic resonance imaging.VEGF expression was determined using immunofluorescence.RESULTS The escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group.The total distance traveled was longer in the T2DM group;also,the platform was crossed fewer times.The percentage of distance in the target zone significantly decreased.CBF decreased in the bilateral hippocampus in the T2DM group.No difference was found between the right CBF value and the left CBF value in the T2DM group.The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value.The escape latency negatively correlated with the CBF value.The number of rats crossing the platform positively correlated with the CBF value.CONCLUSION Low CBF in the hippocampus and decreased VEGF expression might be crucial in DACD.CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.

The influence of gut microbiota alteration on age-related neuroinflammation and cognitive decline

Recent emerging research on intestinal microbiota and its contribution to the central nervous system during health and disease has attra cted significant attention.Age-related intestinal microbiota changes initiate brain aging and age-related neurodegenerative disorders.Aging is one of the critical predisposing risk factors for the development of neurodegenerative diseases.Maintaining a healthy gut microbiota is essential for a healthy body and aging,but dys biosis could initiate many chro nic diseases.Understanding the underlying mechanisms of gut microbiota alterations/dys biosis will help identify biomarkers for aging-related chro nic conditions.This review summarizes recent advances in micro biota-neurodegenerative disease research and will enhance our unde rstanding of gut microbiota dys biosis and its effects on brain aging.

Chemotherapy-Induced Cognitive Decline: Moving from the Mechanistic Debate towards Prevention and Treatment—A Clinical Review

Patients receiving chemotherapy have reported cognitive challenges including short-term memory loss and reduced executive functioning. While cognitive decline can be multifactorial and related to aging, depression, surgery, and other medications, there has been a steadily increasing body of knowledge showing a significant association between cognitive decline and chemotherapy administration. This clinical review summarizes patient-reported cognitive changes, support from neuroimaging and neuropsychological testing. The mechanism of action of and patient susceptibilities to cognitive decline are reviewed. Current behavioral and pharmacologic interventions are discussed. There is a need to identify patients at risk for developing chemotherapy induced cognitive decline and?to?screen for early signs of cognitive deterioration. The risk of cognitive dysfunction and possible interventions should be included in the informed consent discussion with patients who are undergoing cytotoxic treatments.

Hashimoto's encephalopathy presenting as acute cognitive decline in an elderly male

Hashimoto’s encephalopathy(HE)is a rare form of reversible encephalopathy characterized by the presence of anti-thyroid antibodies in serum and/or cerebrospinal fl uid.The syndrome is more common in women and the presentation varies considerably.Here,we report a case of an elderly male with a history of Hashimoto’s thyroiditis,presenting with acute cognitive decline.A diagnosis of HE was established based on the presence of antithyroid antibodies in the serum,diffuse electroencephalography changes and lack of an alternative explanation.The patient promptly responded to steroids and was discharged on the 8th day of admission.We suggest that an assessment of thyroid antibodies should be included in anyone presenting with acute cognitive decline in the absence of alternative explanation.

The Effects of Standardized Ginkgo Biloba Extracts (GBE) on Subjective Cognitive Decline (SCD) in Middle-Aged Adults: A Review

Subjective cognitive decline (SCD) is defined as the presence of self-reported cognitive complaints with unimpaired performance in neuropsychological cognitive tests. SCD has been identified as a precursor of mild cognitive impairment (MCI) and potentially represents the earliest clinical sign of Alzheimer’s disease (AD). Standardized extracts of Ginkgo biloba (GBE) are widely used as a treatment for cognitive impairment. Nonetheless, most of the available review articles focus on the effects of GBE in MCI and dementia but not in SCD and its specific cognitive effects. Thus, this review collects and discusses the available published clinical data for the effects of standardized GBE on the early stages of cognitive decline among an age group where SCD becomes a topic—the middle-aged adults. Randomized clinical trials (RCTs), systematic reviews and meta-analyses of standardized GBEs in cognitive decline subjects were searched using PubMed/MEDLINE, Science direct, Cochrane, and Google Scholar until January 2019. Data from relevant RCT were critically evaluated to determine the potential effects of GBE on SCD. The results showed that the number of available GBE studies on SCD is small. Eight studies were selected in which subjects reported memory impairment, in some cases with concerns (worries), and with an average age at onset SCD of 60 years. Six studies gave a proof of efficacy for GBE for the treatment of SCD in at least one cognitive parameter. One study is inconclusive, however, a post-hoc analysis demonstrates efficacy in preventing AD with intake >4 years. The most common GBE dosage used was 240 mg GBE/day over a minimum period of 8 weeks. Hence, there might be beneficial effects of GBE to prevent, improve or delay SCD in the generation of 50 years or older. However, larger, well-defined RCTs using SCD criteria are necessary to further substantiate this effect in SCD subjects.

The neuroimaging of neurodegenerative and vascular disease in the secondary prevention of cognitive decline

Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease(amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.

Consequences of redefining Alzheimer＇s disease in terms of amyloid burden without regard to cognitive decline

Alzheimer＇s disease（AD）redefined：For the past century,AD has been defined as a disease of progressive cognitive decline paired with a burden of amyloid-β（Aβ）plaques and pathologic tau tangles in the hippocampus and forebrain.However,a recent Framework paper jointly sponsored by the National Institute on Aging and the Alzheimer＇s Association（Jack et al.,2018）proposes new classification guidelines for AD,which,if adopted,will have profoundconsequences for the future management of AD.

Aging gracefully: social engagement joins exercise and enrichment as a key lifestyle factor in resistance to age-related cognitive decline

Cognitive impairment is a consequence of the normal aging process that effects many species, including humans and rodent models. Decline in hippocampal memory function is especially prominent with age and often reduces quality of life. As the aging population expands, the need for interventional strategies to prevent cognitive decline has become more pressing. Fortunately, several major lifestyle factors have proven effective at combating hippocampal aging, the most well-known of which are environmental enrichment and exercise. While the evidence supporting the beneficial nature of these factors is substantial, a less well-understood factor may also contribute to healthy cognitive aging: social engagement. We review the evidence supporting the role of social engagement in preserving hippocampal function in old age. In elderly humans, high levels of social engagement correlate with better hippocampal function, yet there is a dearth of work to indicate a causative role. Existing rodent literature is also limited but has begun to provide causative evidence and establish candidate mechanisms. Summed together, while many unanswered questions remain, it is clear that social engagement is a viable lifestyle factor for preserving cognitive function in old age. Social integration across the lifespan warrants more investigation and more appreciation when designing living circumstances for the elderly.

“Teaching old dogs new tricks”:targeting neural extracellular matrix for normal and pathological aging-related cognitive decline

Cognitive decline is a feature of normal and pathological aging. As the proportion of the global aged population continues to grow, it is imperative to understand the molecular and cellular substrates of cognitive aging for therapeutic discovery. This review focuses on the critical role of neural extracellular matrix in the regulation of neuroplasticity underlying learning and memory in another under-investigated "critical period": the aging process. The fascinating ideas of neural extracellular matrix forming a synaptic cradle in the tetrapartite synapse and possibly serving as a substrate for storage of very long-term memories will be introduced. We emphasize the distinct functional roles of diffusive neural extracellular matrix and perineuronal nets and the advantage of the coexistence of two structures for the adaptation to the ever-changing external and internal environments. Our study of striatal neural extracellular matrix supports the idea that chondroitin sulfate proteoglycan-associated extracellular matrix is restrictive on synaptic neuroplasticity, which plays important functional and pathogenic roles in early postnatal synaptic consolidation and aging-related cognitive decline. Therefore, the chondroitin sulfate proteoglycan-associated neural extracellular matrix can be targeted for normal and pathological aging. Future studies should focus on the cell-type specificity of neural extracellular matrix to identify the endogenous, druggable targets to restore juvenile neuroplasticity and confer a therapeutic benefit to neural circuits affected by aging.

Easy detecting signal of cognitive decline in healthy community-dwelling elderly people

The relationship between changes of elderly people’s participation in social activities and their cognitive functions was examined. Healthy, middle and upper-middle aged people (n = 407) responded to the Nagoya University Cognitive Assessment Battery and to a questionnaire inquiring about their participation in social activities. The results suggested that those whose participation in social activities increased in the last 6 months showed better verbal functioning than those whose participation was unchanged or decreased. Moreover, those whose social participation decreased showed inferior memory function compared to those whose social participation was unchanged, or increased. Furthermore, those whose social participation increased had better information processing speed than those whose social participation decreased. These results suggest that changes in social activities might act as an important signal that is indicative of the cognitive decline in elderly people, which would be useful to local health care managers in the elderly people’s community.

Long-Term Impact of Caregiving and Metabolic Syndrome with Perceived Decline in Cognitive Function 8 Years Later: A Pilot Study Suggesting Important Avenues for Future Research

The chronic stress of caregiving has been associated with increased risk for cognitive decline and dementia. One theoretical model suggests that a group of risk factors known as the metabolic syndrome MET_SYN (e.g., hypertension, poor glucose regulation, central obesity, and high triglyceride levels) that have demonstrated associations with both stress and cognitive decline, may mediate the association between caregiver stress and cognitive decline. It is also possible that caregiving may moderate the association between MET_SYN and cognitive decline. The present study examined these two potential models. The study sample consisted of 53 caregivers for a relative with dementia and 24 participants who did not have caregiving responsibilities at baseline. We examined associations among caregiving history (yes/no), self-reported decline in cognitive function (the AD8) at follow-up, and a MET_SYN factor comprised of increased systolic blood pressure (SBP), glycosylated hemoglobin concentration (HbA1c), waist circumference, and triglyceride levels at baseline when caregiving was assessed. MET_SYN was associated with AD8 (p = 0.010). Caregiving history was not directly associated with AD8 ratings, however, caregiving did moderate the association between MET_SYN and AD8 (p = 0.043) assessed 8 years later. In caregivers MET_SYN scores reflecting higher risk were associated with scores on the AD8 indicting decline, whereas, in controls MET_SYN was unrelated to AD8 assessment. Thus, it can be concluded that caregiver stress may increase the association between metabolic risk factors and decline in cognitive functioning up to 8 years later.

Meta-analysis of efficacy and safety of Donepezil in treating cognitive decline of Parkinson's disease

Objective:To systematically evaluate the efficacy and safety of Donepezil in treating the cognitive decline in patients with Parkinson's disease(PD).Methods:Nine literature databases in domestic and abroad were searched by computer,and the search deadline was November 2,2020.The randomized controlled trials(RCT)using donepezil to treat the cognitive decline in patients with PD were screened.The MMSE(Mini-Mental State Exam)scores,MoCA(Montreal Cognitive Assessment)scores and adverse events of the included RCTs were extracted.Meta-analysis was implemented with RevMan 5.3 software,and the subgroup analyses were conducted to evaluate the effects of mean age and mean course of disease on the MMSE scores.Results:14 RCTs with 1263 patients were selected,including 646 cases in the experimental group and 617 cases in the control group.There were 1209 effective patients who completed MMSE score,including 612 in the experimental group and 597 in the control group.Meta-analysis results showed that MMSE scores in the experimental group were higher than that in the control group after using donepezil intervention,and the difference was statistically significant[SMD=0.55,95%CI(0.24,0.87),P=0.0006].It was also found that the MoCA scores of experimental group were higher than that of control group after using donepezil intervention,and the difference was statistically significant[SMD=1.25,95%CI(0.79,1.72),P<0.00001].Subgroup analysis showed that donepezil improved MMSE scores in different subgroups,and the difference between each group was statistically significant.There was no heterogeneity in the subgroup of mean age lower than 65 years,and the heterogeneity existed between the subgroup of mean course of disease lower than 3 years and the subgroup of mean course of disease larger than or equal to 3 years.For adverse events,the incidence of adverse events in the experimental group was 22.18%.There was no heterogeneity between the included studies(I2=0%),and the difference was not statistically significant[RR=1.18,95%CI(0.95,1.47),P=0.14].Conclusion:The results of meta-analysis showed that donepezil can improve the cognitive decline in patients with Parkinson's disease significantly,and it has good safety.

Gut microbiota links with cognitive impairment in amyotrophic lateral sclerosis: A multi-omics study

Recently, cognitive impairments(CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis(ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current study, we explored the role of gut microbiota in CI of ALS patients. We collected fecal samples from 35ALS patients and 35 healthy controls. The cognitive function of the ALS patients was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen. We analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted(bile acids) metabolite mapping between patients with CI and patients with normal cognition(CN). We found altered gut microbial communities and a lower ratio of Firmicutes/Bacteroidetes in the CI group, compared with the CN group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the CI group, compared with the CN group. These metabolites were mapped to the metabolic pathways associated with bile acids. We further found that cholic acid and chenodeoxycholic acid were significantly lower in the CI group than in the CN group. In conclusion, we found that the gut microbiota and its metabolome profile differed between ALS patients with and without CI and that the altered bile acid profile in fecal samples was significantly associated with CI in ALS patients. These results need to be replicated in larger studies in the future.

Circulating Lipoproteins Mediate the Association Between Cardiovascular Risk Factors and Cognitive Decline:A Community‑Based Cohort Study

Cardiovascular health metrics are now widely recognized as modifable risk factors for cognitive decline and dementia.Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia.Circulating metabolites profling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline.In a prospective community-based cohort in China(n=725),312 serum metabolic phenotypes were quantifed,and cardiovascular health score was calculated including smoking,exercise,sleep,diet,body mass index,blood pressure,and blood glucose.Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline.A better cardiovascular health was signifcantly associated with lower risk of concentration decline and orientation decline(hazard ratio(HR):0.84–0.90;p<0.05).Apolipoprotein-A1,high-density lipoprotein(HDL)cholesterol,cholesterol ester,and phospholipid concentrations were signifcantly associated with a lower risk of longitudinal memory and orientation decline(p<0.05 and adjusted-p<0.20).Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and-3(proportion of mediation:7.68–8.21%,both p<0.05).Cardiovascular risk factors were associated with greater risks of cognitive decline,which were found to be mediated by circulating lipoproteins,particularly the medium-size HDL components.These fndings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention.

Menopause and cognitive impairment:A narrative review of current knowledge

A severe impairment of cognitive function characterizes dementia.Mild cognitive impairment represents a transition between normal cognition and dementia.The frequency of cognitive changes is higher in women than in men.Based on this fact,hormonal factors likely contribute to cognitive decline.In this sense,cognitive complaints are more common near menopause,a phase marked by a decrease in hormone levels,especially estrogen.Additionally,a tendency toward worsened cognitive performance has been reported in women during menopause.Vasomotor symptoms(hot flashes,sweating,and dizziness),vaginal dryness,irritability and forgetfulness are common and associated with a progressive decrease in ovarian function and a subsequent reduction in the serum estrogen concentration.Hormone therapy(HT),based on estrogen with or without progestogen,is the treatment of choice to relieve menopausal symptoms.The studies conducted to date have reported conflicting results regarding the effects of HT on cognition.This article reviews the main aspects of menopause and cognition,including the neuroprotective role of estrogen and the relationship between menopausal symptoms and cognitive function.We present and discuss the findings of the central observational and interventional studies on HT and cognition.