The pleiotropic cytokine IL-6 regulates numerous processes in the body, including neuronal functions. IL-6 either binds to membrane-bound receptor (mIL-6R) and triggers signaling via heteromerization with the signal transducer gp130 (classical signaling), or binds to its soluble form (sIL-6R) to act on cells that do not express mIL-6R (trans-signaling). The ß-secretase BACE1 can cleave gp130 as well as IL-6R and we hypothesized that BACE1 may alter neuron activity and synaptic transmission via modulation of IL-6 signaling. We used multielectrode array (MEA) recordings to monitor electrical activity of neuronal networks in acute cerebellar slices as well as long-term potentiation (LTP) induced by high-frequency stimulation in the hippocampus and to assess how exposure to IL-6 affects these processes. A pharmacological approach was applied to elucidate the contribution of trans-signaling involving BACE1. Spontaneous neuronal activity in cerebellar slices significantly decreased upon perfusion with IL-6 but not LIF and recovered during wash out. BACE1 inhibitors verubecestat or AZD3839 abolished the inhibitory effects of IL-6. Furthermore, IL-6 and LIF reversibly inhibited LTP in hippocampal slices, and in contrast to cerebellar neurons, BACE1 inhibitors verubecestat or AZD3839 did not abolish the inhibitory effect of IL-6 on LTP. Interestingly, a dramatic rebound effect on excitatory postsynaptic potentials was observed with BACE1 inhibitor AZD3839 but not verubecestat during wash out. Our results support relevant and differential roles of IL-6, LIF and BACE1 in pathways modulating neuronal discharge activity in the cerebellum and the synaptic plasticity in the hippocampus, and a possible involvement of this interaction in deficits of memory and learning.

This study investigated the association between handgrip strength (HGS) asymmetry and weakness with cognitive function and depressive symptoms among 920 community-dwelling adults aged above 60 years in suburban Shanghai. Participants were selected using a multistage cluster-stratified sampling approach. Assessments included HGS measured with a dynamometer, the Montreal Cognitive Assessment (MoCA) for cognition, and the Geriatric Depression Scale (GDS) for depressive symptoms. Restricted cubic splines revealed a positive association between dominant HGS and MoCA scores, indicating better cognitive performance, and a negative association with GDS scores, suggesting fewer depressive symptoms. The association between the HGS ratio and MoCA scores and the HGS ratio and GDS scores varied by sex. Women with HGS weakness alone (odds ratio (OR) = 2.00, 95% confidence interval (CI) = 1.17-3.37), asymmetry alone (OR = 1.93, 95% CI = 1.14-3.29), or weakness and asymmetry together (OR = 2.57, 95% CI = 1.48-4.46) had a significantly increased risk of cognitive impairment. However, no such associations observed in men. These findings suggest that HGS weakness and asymmetrical HGS may be associated with a higher risk of cognitive decline and depressive symptoms, particularly in women. This study emphasizes the need for sex-specific assessments and prevention strategies to address cognitive and mental health issues among older adults.

This research aims to investigate the connection between systemic inflammatory response and metabolic syndrome (MetS) across different age groups, with the aim of proposing more targeted recommendations.

This study enrolled 15 959 adults from the 2001-2018 National Health and Nutrition Examination Survey of whom 6739 were diagnosed with MetS. After dividing the systemic immune-inflammation index (SII) into 4 quartiles, the Kruskal-Wallis test and weighted chi-square test were employed to assess statistical differences. Weighted multivariable logistic regression analysis, subgroup analysis, sensitivity analysis, and restricted cubic spline were employed to examine the relationship between SII and MetS.

Our study revealed that SII exhibits a quantitative association with MetS [odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.37-1.79; P < .001]. Elevated SII is an independent risk factor for the 5 components of MetS. Different age groups and alcohol consumption status could modify the connection between SII and MetS. This connection was statistically significant in the 18 to 65 age group but not in the elderly subgroup (OR = 1.08; 95% CI, .95-1.23; P = .248). Multiple imputation confirmed the robustness of our results. Moreover, the connection exhibits an inverted U-shaped curve.

Our research highlights the predictive significance of SII in forecasting the incidence of MetS in young and middle-aged populations. The differences in inflammatory mechanisms across various age groups necessitate further research for exploration.

Hand grip strength (HGS) is crucial for the performance of daily activities and has been linked to various clinical parameters, including morbidity, mortality, and both physical and cognitive functions. While HGS has been shown to decline in numerous diseases, it has not been previously examined in patients diagnosed with temporal lobe epilepsy. This study aims to investigate the differences in hand grip strength between individuals with temporal lobe epilepsy and healthy volunteers.

A total of forty-four patients diagnosed with temporal lobe epilepsy (22 with controlled epilepsy and 22 with drug-resistant epilepsy) and 22 healthy volunteers were followed up at the Epilepsy and Sleep Center. Maximum and mean hand grip strength measurements were obtained for both the dominant and non-dominant hands using a digital hand dynamometer. Based on the assumption of normality, data from healthy volunteers and all epilepsy patients were analyzed using independent samples t-tests or Mann-Whitney U tests. Comparisons among the resistant epilepsy group, controlled epilepsy group, and healthy volunteer group were conducted using one-way analysis of variance (ANOVA) or Kruskal-Wallis tests. Pairwise comparisons were performed using independent samples t-tests or Mann-Whitney U tests. Correlations were assessed using Spearman's rank correlation tests.

The mean age of the sample was 32.56 years (SD = ±1.29). The sample comprised 24 male and 42 female participants. The average duration of education was 11.68 ± 3.20 years, while the average age of onset of epilepsy among patients was 16.39 ± 10.95 years, with a disease duration of 16.45 ± 10.97 years. Significant differences were observed in all hand grip strength variables between healthy volunteers and individuals diagnosed with temporal lobe epilepsy. Notably, there were significant differences in hand grip strength between healthy volunteers and the patient group; however, no differences were found between subgroups with controlled seizures and those with drug-resistant epilepsy.

A significant reduction in hand grip strength has been observed in patients diagnosed with temporal lobe epilepsy, regardless of treatment resistance and disease severity. This decline may be attributed to several factors, including impaired motor coordination resulting from seizures, side effects of medications, and mood disturbances. Further comprehensive studies are necessary to explore the relationship between these underlying factors and hand grip strength, as well as its association with other clinical variables such as functionality and mortality.

While the impact of chronic, low-grade inflammation on cognitive functioning is documented in the context of neurodegenerative disease, less is known about the association between acute increases in inflammation and cognitive functioning in daily life. This study investigated how changes in interleukin-6 (IL-6) levels were associated with performance on an inhibitory control task, the go/no-go task. We further examined whether the opportunity to earn different incentive types (social or monetary) and magnitudes (high or low) was associated with differential performance on the task, depending on IL-6 levels. Using a within-participant design, individuals completed an incentivized go/no-go task before and after receiving the annual influenza vaccine. Multilevel logistic regressions were performed on the trial-level data (Nobs = 30,528). For no-go trials, we did not find significant associations in IL-6 reactivity and changes in trial accuracy between sessions. For go trials, we found significant differences in the associations between IL-6 reactivity and changes in accuracy as a function of the incentive condition. Notably, greater IL-6 reactivity was consistently associated with fewer omission errors (i.e., greater accuracy on go trials) on high-magnitude social incentives (i.e., viewing a picture of a close-other) when compared to both low-magnitude social and high-magnitude monetary incentives. Together, these results suggest that mild fluctuations in inflammation might alter the valuation of an incentive, and possibly a shift toward devoting greater attentional resources when a large social incentive is on the line. Overall, this study sheds light on how everyday, low-grade fluctuations in inflammation may influence cognitive abilities essential for daily life and effective inhibitory control.

Cognitive frailty (CF), characterized by the coexistence of physical frailty and cognitive impairment, is linked to increased morbidity and mortality in older adults. While CF has been linked to multiple physiological and lifestyle factors, the underlying biological mechanisms remain poorly understood. This study investigated the risk factors for CF and explored the relationship between mitochondrial function and CF in hospitalized patients.

A total of 279 hospitalized individuals were recruited from December 2020 to August 2022, conducted comprehensive clinical assessments, and collected peripheral blood samples. CF was evaluated using the Physical Frailty Phenotype and Montreal Cognitive Assessment scales. Nutritional status was assessed with the Mini Nutritional Assessment, and depression was measured using the Geriatric Depression Scale. DNA was obtained from the peripheral blood and interrogated for mitochondrial DNA copy number (mtDNAcn). Peripheral blood mononuclear cells isolated from peripheral blood were examined for respiratory function and reactive oxygen species (ROS) levels. Additionally, plasma samples were analyzed for inflammatory markers and Carnitine Palmitoyltransferase II (CPT2).

Among the participants, 90 were classified as CF and 46 as non-CF. Logistic regression analysis revealed that increased age (OR 1.156, 95% CI 1.064-1.255), lower educational attainment (OR 0.115, 95% CI 0.024-0.550), malnutrition (OR 0.713, 95% CI 0.522-0.973), and higher depression scores (OR 1.345, 95% CI 1.065-1.699) were significantly associated with CF. The independent t tests and Mann-Whitney U tests showed the CF group exhibited impaired mitochondrial function, characterized by reduced mtDNAcn and respiratory activity, coupled with elevated ROS, interleukin-6, and CPT2 levels compared with the non-CF group. After adjusted for age, sex, and BMI, compared with non-CF group, the OR values for the CF group of mtDNAcn and ROS were 0.234 (95% CI = 0.065-0.849) (p = 0.027) and 1.203 (95% CI = 1.075-1.347) (p = 0.001), respectively. The Sensitive analysis showed that the area under curve values for mtDNAcn and ROS were 0.653 and 0.925.

Age, lower educational attainment, malnutrition, and depression are significant risk factors for CF. Moreover, mitochondrial dysfunction, characterized by decreased mtDNAcn, impaired respiratory function and increased ROS levels appears to be a critical phenotype of CF.

Intellectually disabled individuals have been observed to lead sedentary lifestyles resulting in poor health. Physical fitness has been positively correlated to better health outcomes with small changes in fitness translating to major health changes among unfit older adults with intellectual disability. However, there is currently no literature on safe exercise regimens for the intellectually disabled population.

In this article, a retrospective review was conducted using the Special Olympics Athlete database and analyzed the mean differences of various performance metrics based on self-reported exercise frequency.

These results demonstrated that those who exercised daily performed significantly better in flexibility, static balance and functional strength as compared to those who did not exercise. No statistically significant differences were found among athletes and self-reported exercise frequency for aerobic fitness.

Overall, these findings suggest that 3-6 days-a-week of moderate exercise would be a recommended exercise dose to see significant improvement in performance and physiological adaptations.

A significant quantity of substance P (SP) and its receptor, the neurokinin 1 (NK1) receptors are found in the brain. SP is a neuropeptide distributed in the central nervous system and functions as a neurotransmitter, neuromodulator, and neurotrophic factor. The concentrations of SP in the brain and cerebrospinal fluid fluctuate in individuals with Alzheimer's disease (AD). SP is an endogenous ligand for NK1 receptor, enhancing the expression of toll-like receptors (TLR) and vice versa. So, both pathways are interconnected, where activation of one pathway activates the second pathway. Researchers have observed the interaction of TLR with SP in the pathophysiology of AD. Thus, this review discusses various TLRs involved in regulating amyloid processing and its interaction with SP in AD. Further, in AD pathology, SP can regulate the non-amyloidogenic pathway. Recent studies have also demonstrated the capacity of SP in regulating voltage-gated potassium channel currents, emphasizing SP's neuroprotective ability. Therefore, we corroborate the findings linking the SP, NK1R, and TLRs in AD.

Inflammation has been associated with cognitive decline, whether in the peripheral or central nervous systems. The primary mechanism involves the response of microglia, an immune cell in the brain, which generates pro-inflammatory mediators such as cytokines, chemokines, and adhesion molecules. The excessive production of pro-inflammatory mediators may accelerate the damage to neurons, contributing to the development of neurodegenerative diseases such as Alzheimer's disease, mild cognitive impairment, and vascular dementia, as well as a general decline in cognitive function. Various studies have supported the correlation between elevated pro-inflammatory mediators and a decline in cognitive function, particularly in aging and age-related neurodegenerative diseases. Moreover, this association has also been observed in other inflammatory-related conditions, including post-operative cognitive impairment, diabetes, stroke, obesity, and cancer. However, the interaction between inflammatory processes and cognitive function in humans remains unclear and varies according to different health conditions. Therefore, this review aims to consolidate and evaluate the available evidence from original studies as well as meta-analyses in order to provide a greater understanding of the inflammatory process in connection with cognitive function in humans. Furthermore, relevant biological cellular processes, putative inflammatory biomarkers, and the role of nutraceuticals on the interaction between cognitive performance and inflammatory status are outlined.

The term "Activities of Daily Living" (ADLs) refers to a set of fundamental tasks (i.e., toileting, bathing, personal care, eating, grooming, and getting dressed) considered necessary for living and being autonomous in everyday life. Although in the clinical setting ADLs efficiency is a marker to diagnose dementia, limited evidence on the mechanism implicating muscular function and cognitive alterations in ADLs skills in late adulthood exists. This study primarily intended to determine the extent to which executive functions mediate between muscular strength, as assessed through handgrip strength (HGS) measurement, and ADLs skills of older community-dwellers. A further goal was to explore the impact of gender and cognitive status on ADLs and HGS scores, using education as a covariate. Three hundred and thirty-four older participants, 199 females and 135 males (Mage = 77.5 years, SD = 5.6 years, age range = 63-93 years) completed a battery of tests assessing ADLs, HGS, and executive functions. The results showed that 34-56% of the variance in the ADLs condition was explained by HGS and executive functioning. Furthermore, cognitively healthy participants exhibited better ADLs skills, whereas cognitively impaired individuals, both males and females, exhibited poorer HGS efficiency. In conclusion, in clinical settings, the concurrent evaluation of ADLs skills, motor, and higher-order cognitive processes should be encouraged to detect individuals needing a person-tailored intervention to boost their quality of life.

Recent research has revolutionized our understanding of memory consolidation by emphasizing the critical role of astrocytes, microglia, and immune cells in through cytokine signaling. Cytokines, compact proteins, play pivotal roles in neuronal development, synaptic transmission, and normal aging. This review explores the cellular mechanisms contributing to cognitive decline in inflammaging and Alzheimer's disease, highlighting the paradoxical effects of most studied cytokines (IL-1, IL-6, TNF-α) in brain function, which act as a double-edged sword in brain physiology, acting both as facilitators of healthy cognitive function and as a potential contributor to cognitive decline.

Aging represents a natural and unavoidable phenomenon in organisms. With the acceleration of population aging, investigations into aging have garnered widespread global interest. One of the most striking aspects of human aging is the decline in brain function, a phenomenon intricately tied to the onset of neurodegenerative conditions. This study aimed to assess the impact of a fish hydrolysate, rich in low-molecular-weight peptides and n-3 LC-PUFAs, on cognitive function, inflammatory response, and oxidative stress via the AGE-RAGE axis in a mouse model of accelerated aging. This model induces cognitive decline and biochemical alterations akin to those observed during natural aging. The findings revealed that fish hydrolysate exhibited a protective effect against cognitive impairment induced by D-galactose. This effect was associated with increased protein expression of SOD1 and decreased genetic expression of IL-6 and advanced glycation end products (AGE). Consequently, within the realm of preventive and personalized nutrition, fish hydrolysate emerges as a promising avenue for mitigating age-related declines in memory function.

It is unclear whether inflammation, that is, high interleukin-6 (IL-6) levels, and genetic risk, that is, apolipoprotein E (APOE) ε4 allele, have a compounding effect on cognitive decline (CD).

We analyzed a subset of participants from the longitudinal cohort study, Chicago Health and Aging Project, comprising 1120 biracial community-dwelling older adults (60% Black and 62% women), and mean follow-up = 6.4 years. We ran adjusted mixed-effects models on2 longitudinal CD.

In APOE ε4 carriers, higher serum IL-6 was not associated with the rate of CD (β = -0.0091 [standard deviation (SD) = 0.0165, p = 0.5800]). Conversely, in non-ε4 carriers, compared to the lower tertile, those with the upper tertile of serum IL-6 levels experienced significantly accelerated CD (β = -0.0257 [SD = 0.0084, p = 0.0023]).

Even without the largest genetic risk factor for late-onset Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), elevated serum IL-6 still accelerate the rate of CD in non-APOE ε4 carriers. Hence, interventions ameliorating inflammation may prevent AD/ADRD.

Interleukin-6 (IL-6) and the apolipoprotein E (APOE) ε4 allele have been separately associated with an increased risk for cognitive decline, but their interaction remains unclear.In ε4 carriers, IL-6 was not associated with cognitive decline. However, even without the biggest genetic risk factor for Alzheimer's disease (AD), that is, APOE ε4, elevated serum IL-6 still could confer accelerated rate of cognitive decline, with a detrimental effect half of that imposed by APOE ε4 alone.We found no racial differences in these associations.These findings contribute complementary evidence on non-APOE ε4-dependent and non-AD biological pathways through which cognitive decline can still be accelerated in non-APOE ε4 carriers and highlight a specific subgroup of older adults who are at a higher risk of AD and thus may benefit from anti-inflammatory interventions.

An increasing number of cross-sectional studies suggests that diet may impact memory and cognition in healthy older adults. However, randomized controlled trials investigating the effects of whole-diet interventions on memory and cognition in healthy older adults are rather rare, and conflicting results are often reported. Therefore, a systematic review was conducted to compile the current evidence regarding the potential effects of whole-diet interventions on 1) memory and 2) other cognitive outcomes in older adults. Studies that reported on randomized controlled trials with dietary interventions in healthy older adults (≥60 y) were included. Studies utilizing supplements, single food items, or trials in specific patient groups (i.e., neurodegenerative diagnoses) were excluded. For the 23 included articles, the main outcomes examined fell into 1 or more of the following categories: cognitive task-based outcomes related to memory, other cognitive task-based outcomes, and additional outcomes related to cognitive function or disease risk. Three of the studies that investigated dietary interventions alone and 2 multidomain studies showed positive effects on memory function, whereas 5 multidomain interventions and 1 intervention that focused on diet alone showed positive effects on other cognitive outcomes. The effect of randomized, controlled whole-diet interventions on memory and cognitive function in healthy older adults is modest and inconclusive, highlighting the need for more well-designed, sufficiently powered studies. Furthermore, the potential mechanisms by which diet impacts cognition in healthy aging need to be elucidated. This systematic review is registered in PROSPERO as CRD42022329759.

Repetitive transcranial magnetic stimulation (rTMS) has recently gained relevance in treating different psychiatric disorders. Limited evidence suggests that the beneficial effects of rTMS on psychopathology could be at least partly mediated through changes in inflammatory response. This systematic review summarizes the literature on whether rTMS can modulate inflammatory markers and thus positively influence the course of psychiatric illnesses.

A systematic review of rTMS and inflammatory markers in psychiatric diseases was conducted according to PRISMA guidelines. Information on the association between rTMS treatment response and changes of inflammatory markers was extracted. The quality of the studies was assessed using the National Heart, Lung, and Blood Institute for human studies and the Systematic Review Center for Laboratory Animal Experimentation for animal studies.

This review includes 17 studies (2 animal and 15 human studies) on the relationship between rTMS treatment response and changes of inflammatory markers. Positive changes in microglial activity and anti-inflammatory effects were associated with behavioral improvement in animal models of depression. However, these findings have not been consistently replicated in human studies focusing on treatment-resistant depression. While several studies reported rTMS-induced alterations in peripheral inflammatory markers, only two could demonstrate their association to clinical treatment response. Notably, most studies showed poor or moderate quality in the bias assessment.

While certain human studies suggest an association between rTMS-induced anti-inflammatory effects and improvement in psychopathology, heterogeneity, and underpowered analyses constrain the generalizability of these results. The discrepancy between animal and human findings highlights the need for larger, standardized human studies.

(PROSPERO Registration: CRD42023492732).

Handgrip strength is a crucial indicator to monitor the change of cognitive function over time, but its mechanism still needs to be further explored. We sampled 59 monozygotic twin pairs to explore the potential mediating effect of DNA methylation (DNAm) on the association between handgrip strength and cognitive function. The initial step was the implementation of an epigenome-wide association analysis (EWAS) in the study participants, with the aim of identifying DNAm variations that are associated with handgrip strength. Following that, we conducted an assessment of the mediated effect of DNAm by the use of mediation analysis. In order to do an ontology enrichment study for CpGs, the GREAT program was used. There was a significant positive association between handgrip strength and cognitive function (β = 0.194, P < 0.001). The association between handgrip strength and DNAm of 124 CpGs was found to be statistically significant at a significance level of P < 1 × 10-4. Fifteen differentially methylated regions (DMRs) related to handgrip strength were found in genes such as SNTG2, KLB, CDH11, and PANX2. Of the 124 CpGs, 4 within KRBA1, and TRAK1 mediated the association between handgrip strength and cognitive function: each 1 kg increase in handgrip strength was associated with a potential decrease of 0.050 points in cognitive function scores, mediated by modifications in DNAm. The parallel mediating effect of these 4 CpGs was -0.081. The presence of DNAm variation associated with handgrip strength may play a mediated role in the association between handgrip strength and cognitive function.

Late-life inflammation has been linked to dementia risk and preclinical cognitive decline, but less is known about early adult inflammation and whether this could influence cognition in midlife. We aimed to identify inflammation levels through early adulthood and determine association of these trajectories with midlife cognition.

We used data from the Coronary Artery Risk Development in Young Adults study to identify inflammation trajectories (C-reactive protein [CRP] level <10 mg/L) over 18 years through early adulthood (age range 24-58) in latent class analysis and to assess associations with cognition 5 years after the last CRP measurement (age range 47-63). Six cognitive domains were evaluated from tests of verbal memory, processing speed, executive function, verbal and category fluency, and global cognition; poor cognitive performance was defined as a decline of ≥1 SD less than the mean on each domain. The primary outcome was poor cognitive performance. Logistic regression was used to adjust for demographics, smoking, alcohol use, physical activity, and APOE 4 status.

Among 2,364 participants, the mean (SD) age was 50.2 (3.5) years; 55% were female, and 57% were White. Three CRP trajectories emerged over 18 years: lower stable (45%), moderate/increasing (16%), and consistently higher (39%). Compared with lower stable CRP, both consistently higher (adjusted odds ratio [aOR] 1.67, 95% CI 1.23-2.26) and moderately/increasing (aOR 2.04, 95% CI 1.40-2.96) CRP had higher odds of poor processing speed; consistently higher CRP additionally had higher odds of poor executive function (aOR 1.36, 95% CI 1.00-1.88). For memory (moderately/increasing aOR 1.36, 95% CI 1.00-1.88; consistently higher aOR 1.18, 95% CI 0.90-1.54), letter fluency (moderately/increasing aOR 1.00, 95% CI 0.69-1.43; consistently higher aOR 1.05, 95% CI 0.80-1.39), category fluency (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), or global cognition (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), no association was observed.

Consistently higher or moderate/increasing inflammation starting in early adulthood may lead to worse midlife executive function and processing speed. Study limitations include selection bias due to loss to follow-up and reliance on CRP as the only inflammatory marker. Inflammation is important for cognitive aging and may begin much earlier than previously known.

Growing evidence implicates systemic inflammation in the loss of structural brain integrity in natural ageing and disorder development. Chronic stress and glucocorticoid exposure can potentiate inflammatory processes and may also be linked to neuronal atrophy, particularly in the hippocampus and the human neocortex. To improve understanding of emerging maladaptive interactions between stress and inflammation, this study examined evidence for glucocorticoid- and inflammation-mediated neurodegeneration in healthy mid-aged adults. N = 169 healthy adults (mean age = 39.4, 64.5% female) were sampled from the general population in the context of the ReSource Project. Stress, inflammation and neuronal atrophy were quantified using physiological indices of chronic stress (hair cortisol (HCC) and cortisone (HEC) concentration), systemic inflammation (interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP)), the systemic inflammation index (SII), hippocampal volume (HCV) and cortical thickness (CT) in regions of interest. Structural equation models were used to examine evidence for pathways from stress and inflammation to neuronal atrophy. Model fit indices indicated good representation of stress, inflammation, and neurological data through the constructed models (CT model: robust RMSEA = 0.041, robust χ2 = 910.90; HCV model: robust RMSEA <0.001, robust χ2 = 40.95). Among inflammatory indices, only the SII was positively associated with hair cortisol as one indicator of chronic stress (β = 0.18, p < 0.05). Direct and indirect pathways from chronic stress and systemic inflammation to cortical thickness or hippocampal volume were non-significant. In exploratory analysis, the SII was inversely related to mean cortical thickness. Our results emphasize the importance of considering the multidimensionality of systemic inflammation and chronic stress, with various indicators that may represent different aspects of the systemic reaction. We conclude that inflammation and glucocorticoid-mediated neurodegeneration indicated by IL-6 and hs-CRP and HCC and HEC may only emerge during advanced ageing and disorder processes, still the SII could be a promising candidate for detecting associations between inflammation and neurodegeneration in younger and healthy samples. Future work should examine these pathways in prospective longitudinal designs, for which the present investigation serves as a baseline.

To identify heterogeneous developmental trajectories of handgrip strength (HGS) in Chinese older adults and to explore the relationship between different developmental trajectories and motoric cognitive risk syndrome (MCR).

We used three waves of longitudinal data from the China Health and Retirement Longitudinal Study from 2011 to 2015, which involved 3773 older adults. Growth mixture modeling (GMM) was used to estimate trajectory classes for HGS, followed by binary logistic regression to explore the association between trajectory classes and MCR.

GMM analyses extracted four distinct trajectories of HGS: low level-declining group (16.0 %), upper middle level group (30.9 %), high level-steady group (9.5 %), and lower middle level group (43.6 %). In addition, we found that even after adjusting for important covariates, the odds of MCR prevalence were lower in the medium level-high group, high level-steady group, and medium level-low group compared with the low level-declining group.

Appreciable heterogeneity in HGS among older people in China was revealed. Only 9.5 % of older people with HGS in the high level-steady group. And poorer grip strength levels mean a higher risk of MCR. Therefore, interventions should be taken to maintain muscle mass and thus prevent MCR in older adults.

In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.

The deterioration of cognitive function with age has become a major public health issue. To date, the underlying mechanisms of the association between handgrip strength and cognitive function were poorly understood. This study aimed to examine the mediating effect of functional limitation in the longitudinal relationship between handgrip strength and subsequent cognitive function.

This research recruited 4416 participants aged 60 and above from wave 2015 and 2018 of the China Longitudinal Study of Health and Retirement (CHARLS). We conducted the linear regression model and bootstrap analyses to test the mediating role of functional limitation in the relationship between handgrip strength and cognitive function.

After adjusting the confounders, handgrip strength was positively associated with subsequent cognitive function (β = 0.12, P < 0.001) and was negatively associated with functional limitation (β = -0.14, P < 0.001). The mediation effect of functional limitation accounted for 23.33 % of the total effect regarding the handgrip strength with cognitive function, and the magnitude of mediation effect was a*b = 0.021 (95%CI: 0.017-0.027).

The variable of functional limitations was self-reported. And this study did not analyse the severity and duration of handgrip strength loss and functional limitations, which may lose some information.

Our findings revealed that handgrip strength not only directly influenced cognitive function among older individuals but also indirectly via functional limitation over 3-year follow-up. Physical exercise targeting handgrip strength and functional limitation may be an effective approach to prevent and delay cognitive decline.

The purpose of this study was to investigate the relationship between cognitive function and phase angle (PhA), an indicator of muscle quality.

This cross-sectional study enrolled outpatients who visited a memory clinic at the Nagoya University hospital from January 2016 to June 2022. We enrolled 153 participants with body composition measurements. Inclusion criteria were a Mini-Mental State Examination score of 20-30 and a clinical diagnosis of Alzheimer's dementia (AD) or amnesic mild cognitive impairment (aMCI). The background characteristics of the participants were compared according to AD and aMCI. Next, linear regression analysis was performed with PhA as the objective variable. In addition, logistic regression analysis was performed for AD diagnosis.

PhA was lower in the AD group (P = 0.009). In linear regression analysis, PhA consistently decreased with worsening ADAS score. In logistic regression analysis, high PhA was associated with absence of AD. Gender-specific analyses showed these associations existed only in men.

Our study of patients with AD and aMCI found that PhA decreased with worsening of cognitive function. Compared with aMCI, AD was associated with significantly lower PhA. Our results strengthen the limited evidence in the literature showing that low muscle quality is associated with poor cognitive function.

Studies examining the relationships between chronic inflammation, cognitive function and cognitive decline in older adults have yielded conflicting results. In a large cohort of older adults free from established dementia (n = 3270; 73.1 ± 7.9 years; 68.4% female), we evaluated the cross-sectional and longitudinal relationships between serum cytokines (IL-6, IL-10, TNF-α) and both global and domain-specific cognitive performance (Repeatable Battery for Assessment of Neuropsychological Status [RBANS]). Higher IL-6 (OR: 1.33; 1.06, 1.66, p = 0.01), TNF-α (OR: 1.35; 1.09, 1.67, p = 0.01) and IL-6:IL-10 Ratio (OR: 1.43; 1.17, 1.74, p = 0.001) were cross-sectionally associated with impaired global RBANS performance. For specific cognitive domains, greatest effect sizes were observed between higher TNF-α levels and poorer visual-spatial and attention performance. In a subset of participants (n = 725; 69.8 ± 5.5 years; 67.0% female) with repeat assessment performed at a median of 5.4 years, only higher baseline IL-6:IL-10 ratio was associated with impaired incident overall, immediate memory and visual-spatial performance. Associations were stronger in females, but not modified by age or APOE genotype.

The purpose of this study was to examine (a) the socioeconomic status (SES)-related inequalities associated with handgrip strength (HGS); and (b) the extent to which several demographic, health, and behavioral factors contributed to such SES disparities in HGS among older adults in India. Data were drawn from the 2017-2018 wave 1 of the Longitudinal Ageing Study of India (LASI). The study sample included 27,707 older adults (13,199 men and 14,508 women) aged 60 years and older. HGS was assessed using a handheld Smedley's Hand Dynamometer with a cut-off of 19.5 kg for men and 12.5 kg for women. Bivariate analysis showed the weighted percentage distribution of weak HGS across respondent characteristics. Multivariate logistic regression assessed factors linked to weak HGS. The concentration curve and index (CCI) was used to determine the inequalities in the prevalence of weak HGS by wealth index scores. Wagstaff's decomposition approach was used to test the contribution of each explanatory variable to weak HGS. Around 9% of older adults in this study reported a weak HGS. It was significantly higher among those aged 80 or older (19.21%) and males (15.55%). Weak HGS was concentrated among older adults from poor SES (CCI: 0.05, p < 0.001). A higher percentage of wealth-based inequality in weak HGS was explained by being underweight (38.83%), belonging to the richest wealth quintile (27.95%), and having a higher subjective social status (32.20%). Moreover, about 23.29% of the inequality in weak HGS was explained by Western region and 22.54% by female gender. Additionally, having a secondary level of education explained a higher percentage (22.09%) of inequality, followed by current working status (- 20.68%). Rural residence (13.08%), limitations in instrumental activities of daily living (IADL) (12.21%), and engagement in yoga-related activities (11.55%) explained a higher percentage of wealth-based inequalities. The findings provide evidence of significant SES-related inequalities in HGS and the contribution of various demographic, health, and behavioral factors to such inequality. As such, public health policies and programs focusing on reducing the burden of disability must consider the contribution of social and economic equity to the preservation of muscle strength among older adults.

Objectives: This study aimed to investigate the association between sugar-sweetened beverages (SSB) consumption (including individual SSB) and cognitive function from the National Health and Nutrition Examination Survey (NHANES) and Food Patterns Equivalents Database (FPED) and whether it is age-dependent.Methods: Older adults aged 60 years old and over were included during the NHANES 2011-2014. SSB consumption was defined as the amount of added sugar obtained by connecting the NHANES and FPED. Cognitive function tests included the consortium to establish a registry for Alzheimer's disease test, Animal Fluency Test and Digit Symbol Substitution Test. We calculated z-score using the average of the total standardized scores on three cognitive tests to estimate the level of whole cognition. Multi-variable linear regression models and interaction analysis were conducted in this study.Results: For individual SSB types, increased carbonated soft drinks, sweetened tea, fruit drinks, energy drinks, and sport drinks were all significantly linked to declined cognitive function (P < 0.05), respectively. Nevertheless, interaction effects by age groups were not significant (P for interaction > 0.05).Discussion: SSB consumption (including individual SSB) was negatively associated with cognitive function, which was not age-dependent. Future studies may advance the knowledge in the field considering the association between SSB consumption and cognitive function.

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.

Psychotic disorders are severe mental disorders with poorly understood etiology. Biomarkers in the cerebrospinal fluid (CSF) could provide etiological clues and diagnostic tools for psychosis; however, an unbiased overview of CSF alterations in individuals with psychotic disorders is lacking. The objective of this study was to summarize all quantifiable findings in CSF from individuals with psychotic disorders compared to healthy controls (HC). Studies published before January 25th, 2023 were identified searching PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO. Screening, full-text review, data extraction, and risk of bias assessments were performed by two independent reviewers following PRISMA guidelines. Findings in patients and healthy controls were compared and summarized using random-effects analyses and assessment of publication bias, subgroup and sensitivity analyses were performed. 145 studies, covering 197 biomarkers, were included, of which 163 biomarkers have not previously been investigated in meta-analyses. All studies showed some degree of bias. 55 biomarkers measured in CSF were associated with psychosis and of these were 15 biomarkers measured in ≥2 studies. Patients showed increased levels of noradrenaline (standardized mean difference/SMD, 0.53; 95% confidence interval/CI, 0.16 to 0.90) and its metabolite 3-methoxy-4-hydroxyphenylglycol (SMD, 0.30; 95% CI: 0.05 to 0.55), the serotonin metabolite 5-hydroxyindoleacetic acid (SMD, 0.11; 95% CI: 0.01 to 0.21), the pro-inflammatory neurotransmitter kynurenic acid (SMD, 1.58; 95% CI: 0.34 to 2.81), its precursor kynurenine (SMD,0.99; 95% CI: 0.60 to 1.38), the cytokines interleukin-6 (SMD, 0.58; 95% CI: 0.39 to 0.77) and interleukin-8 (SMD, 0.43; 95% CI: 0.24 to 0.62), the endocannabinoid anandamide (SMD, 0.78; 95% CI: 0.53 to 1.02), albumin ratio (SMD, 0.40; 95% CI: 0.08 to 0.72), total protein (SMD, 0.29; 95% CI: 0.16 to 0.43), immunoglobulin ratio (SMD, 0.45; 95% CI: 0.06 to 0.85) and glucose (SMD, 0.48; 95% CI: 0.01 to 0.94). Neurotensin (SMD, -0.67; 95% CI: -0.89 to -0.46) and γ-aminobutyric acid (SMD, -0.29; 95% CI: -0.50 to -0.09) were decreased. Most biomarkers showed no significant differences, including the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid. These findings suggest that dysregulation of the immune and adrenergic system as well as blood-brain barrier dysfunction are implicated in the pathophysiology of psychotic disorders.

Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline.

To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer's disease).

We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement.

Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14-1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90-0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90-0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90-0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88-0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85-0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92-0.99).

Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance.

Dementia is a detrimental neuropathologic condition with considerable physical, mental, social, and financial impact on patients and society. Patients with metabolic syndrome (MetS), a group of diseases that occur in tandem and increase the risk of neurologic diseases, have a higher risk of dementia. The ratio between muscle and adipose tissue is crucial in MetS, as these contain many hormones, including myokines and adipokines, which are involved in crosstalk and local paracrine/autocrine interactions. Evidence suggests that abnormal adipokine and myokine synthesis and release may be implicated in various MetS, such as atherosclerosis, diabetic mellitus (DM), and dyslipidemia, but their precise role is unclear. Here we review the literature on adipokine and myokine involvement in MetS-induced dementia via glucose and insulin homeostasis regulation, neuroinflammation, vascular dysfunction, emotional changes, and cognitive function.

The nuclear factor of activated T cells-1 (NFAT1) is involved in both neuroinflammation and cognitive dysfunction. In this study, we examined the role of NFAT1 in sepsis-induced cognitive impairment in a mouse model.

Sepsis was established in adult mice by cecal ligation and puncture (CLP). Novel object recognition tests on days 14-21 and fear conditioning tests on days 22-23 post-surgery showed that CLP impaired both behaviors. BV2 microglia cells exposed to lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting NFAT1 on autophagy and inflammatory cytokines.

CLP increased the expression of NFAT1 in hippocampal microglia and induced hippocampal autophagy by downregulating p62, upregulating beclin-1 and autophagy-related gene-5, and increasing the ratio of microtubule-associated protein 1 light chain 3-I (LC3-I) to LC3-II. In addition, CLP shifted microglial polarization from M2 to M1 and the production of inflammatory cytokines, similar to the effects of lipopolysaccharide on BV2 microglia cells. Conversely, NFAT1 knockdown or the autophagy inhibitor 3-methyladenine attenuated the effects of CLP on autophagy and inflammation in vitro and in vivo, while rapamycin partially reversed the protective effects of NFAT1 inhibition.

This study suggests that NFAT1 downregulation attenuates sepsis-induced behavioral deficits by inhibiting autophagy, microglia polarization, and neuroinflammation..

How inflammation relates to intrinsic capacity (IC), the composite of physical and mental capacities, remains undefined. Our study aimed to investigate the cross-sectional and longitudinal associations between plasma inflammation-related biomarkers and IC in older adults.

This secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) included 1238 community-dwelling older individuals with IC assessments from 12 to 60 months. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor receptor-1 (TNFR-1), monocyte chemoattractant protein-1 (MCP-1) and growth differentiation factor-15 (GDF-15) were measured at 12 months. IC was operationalized as a score ranging from 0 to 100, derived from four domains: cognition, Mini-Mental State Examination; locomotion, Short Physical Performance Battery; psychological, Geriatric Depression Scale; and vitality, handgrip strength. A five-domain IC score (plus sensory) was investigated in a subsample (n = 535) with a 1-year follow-up as an exploratory outcome.

The mean age of the 1238 participants was 76.2 years (SD = 4.3); 63.7% were female. Their initial four-domain IC scores averaged 78.9 points (SD = 9.3), with a yearly decline of 1.17 points (95% CI = -1.30 to -1.05; P < 0.001). We observed significant associations of lower baseline IC with higher CRP, IL-6, TNFR-1 and GDF-15, after controlling age, sex, MAPT group allocation and educational level [CRP: adjusted β (95% CI) = -1.56 (-2.64 to -0.48); P = 0.005; IL-6: adjusted β = -3.16 (-4.82 to -1.50); P < 0.001; TNFR-1: adjusted β = -6.86 (-10.25 to -3.47); P < 0.001; GDF-15: adjusted β = -7.07 (-10.02 to -4.12); P < 0.001]. Higher TNFR-1, MCP-1 and GDF-15 were associated with faster decline in four-domain IC over 4 years [TNFR-1: adjusted β (95% CI) = -1.28 (-2.29 to -0.27); P = 0.013; MCP-1: adjusted β = -1.33 (-2.24 to -0.42); P = 0.004; GDF-15: adjusted β = -1.42 (-2.26 to -0.58); P = 0.001]. None of the biomarkers was significantly associated with the five-domain IC decline.

Inflammation was associated with lower IC in older adults. Among all plasma biomarkers, TNFR-1 and GDF-15 were consistently associated with IC at the cross-sectional and longitudinal levels.

Frailty is a new concept in rheumatology that can help identify people more likely to have less favorable outcomes. Sarcopenia and inflammaging can be regarded as the biological foundations of physical frailty. Frailty is becoming more widely accepted as an indicator of ageing and is linked to an increased risk of negative outcomes such as falls, injuries, and mortality. Frailty identifies a group of older adults that seem poorer and more fragile than their age-matched counterparts, despite sharing similar comorbidities, demography, sex, and age. Several studies suggest that inflammation affects immune-mediated pathways, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and by disrupting homeostatic signaling. Frailty is more common in the community-dwelling population as people get older, ranging from 7 to 10% in those over 65 years up to 40% in those who are octogenarians. Different parameters have been validated to identify frailty. These primarily relate to two conceptual models: Fried's physical frailty phenotype and Rockwood's cumulative deficit method. Immune-mediated rheumatic diseases (IMRDs), such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, and vasculitis, are leading causes of frailty in developing countries. The aim of this review was to quantitatively synthesize published literature on the prevalence of frailty in IMRDs and to summarize current evidence on the relevance and applicability of the most widely used frailty screening tools.

Schizophrenia is a complex psychiatric disorder that includes positive and negative symptoms but also debilitating cognitive deficits. Current pharmacological interventions do not target these deficits. Recent evidence suggests a connection between some inflammatory markers (including C-reactive protein) and cognitive impairment, but did not address other inflammatory markers. In the current study, we try to fill the gap by focusing on the association of Interleukin-6 (IL-6), IL-1β, Tumor Necrosis Factor-α and CRP with cognitive dysfunction.

PUBMED and Web of Science databases were searched for all studies published until July 2022. A total of 25 studies were included in an analysis of the association between cognitive performance and variation in IL-6, IL-1β, TNF-α and CRP.

A total of 2398 patients were included in this study. Meta-analyses results showed a significant inverse relationship between performance in five cognitive domains (attention-processing speed, executive function, working memory, verbal and visual learning and memory) and systemic IL-6, IL-1β, TNF-α and CRP plasma levels in patients with schizophrenia. The meta-analyses results showed a significant decline in the cognitive performances with the evaluated inflammatory markers with effect sizes ranging from -0.136 to -0.181 for IL-6, -0.188 to -0.38 for TNF-α -0.372 to -0.476 for IL-1β and - 0.168 to -0.311 for CRP.

Findings from the current study shows that cognitive deficits are reflective of elevated proinflammatory biomarkers (IL-6, IL-1β, TNF-α and CRP) levels. The results obtained indicate relatedness between inflammation and cognitive decline in patients with schizophrenia. Understanding the underlying pathways between them could have a significant impact on the disease progression and quality of life in schizophrenia patients.

Delirium represents a significant health care burden, diagnosed in more than 2 million elderly Americans each year. In the surgical population, delirium remains the most common complication among elderly patients, and is associated with longer hospital stays, higher costs of care, increased mortality, and functional impairment. The pathomechanism of disease is poorly understood, with current diagnostic approaches somewhat subjective and arbitrary, and definitive diagnostic biomarkers are currently lacking. Despite the recent interest in delirium research, biomarker discovery for it remains new. Most attempts to discover biomarkers are targeted studies that seek to assess the involvement of one or more members of a focused panel of candidates in delirium. For a more unbiased, system-biology view, we searched literature from Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane Central, Web of Science, SCOPUS, and Dimensions between 2016 and 2021 for untargeted proteomic discovery studies for biomarkers of delirium conducted on human geriatric subjects. Two reviewers conducted an independent review of all search results and resolved discordance by consensus. From an overall search of 1172 publications, 8 peer-reviewed studies met our defined inclusion criteria. The 370 unique perioperative biomarkers identified in these reports are enriched in pathways involving activation of the immune system, inflammatory response, and the coagulation cascade. The most frequently identified biomarker was interleukin-6 (IL-6). By reviewing the distribution of protein biomarker candidates from these studies, we conclude that a panel of proteins, rather than a single biomarker, would allow for discriminating delirium cases from noncases. The paucity of hypothesis-generating studies in the peer-reviewed literature also suggests that a system-biology view of delirium pathomechanisms has yet to fully emerge.

Ambient fine particulate matter (PM_2.5) exposures during pregnancy could lead to adverse birth outcomes, including neurobehavioral development defects. However, limited studies explored the effects and potential epigenetic mechanisms of maternal PM_2.5 exposure on offspring spatial memory defects. This study aims to explore the effects and underlying epigenetic mechanisms of maternal concentrated ambient PM_2.5 exposure in male mice offspring with spatial memory defects. Pregnant female C57BL/6 mice were exposed daily to concentrated ambient PM_2.5 (CAP) or filtered air (FA) throughout gestation, with the concentration of particulates (102.99 ± 78.74 μg/m³) and (2.78 ± 1.19 μg/m³), respectively. Adult male mice offspring were subsequently assessed for spatial learning and memory ability using Morris Water Maze tests and locomotor activities in open field tests. The hippocampus of the male mice offspring was harvested to test mRNA expression and DNA methylation. Results from the probe test of Morris Water Maze showed that the mice offspring in the CAP group had shorter swimming distance travelled in the target quadrant, shorter duration in the target quadrant, and less number of entries into the target quadrant (p < 0.05), suggesting spatial memory impairments. The acquisition trials of Morris Water Maze did not show a significant difference in learning ability between the groups. The mRNA level of interleukin 6 (IL-6) in the CAP group hippocampus (10.80 ± 7.03) increased significantly compared to the FA group (1.08 ± 0.43). Interestingly, the methylation levels of the CpG sites in the IL-6 promoter region declined significantly in the CAP group, (5.66 ± 0.83)% vs. (4.79 ± 0.48)%. Prenatal exposure to concentrated ambient PM_2.5 induced long-lasting spatial memory defects in male mice offspring. The underlying biological mechanism might be mediated by an inflammatory reaction which is regulated by DNA methylation.

Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60-79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11-0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08-0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.

Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function.

To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up.

387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains.

Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition.

IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials.

The development of mild cognitive impairment (MCI) and Alzheimer's disease (AD) may be associated with an inflammatory process. Inflammatory cytokines may be a surrogate for systemic inflammation leading to worsening neurological function. We aim to investigate the association between cognitive impairment and inflammation by pooling and analyzing the data from previously published studies.

We performed a systematic literature search on MEDLINE, PubMed, Embase, Web of Science, and Scopus for prospective longitudinal and cross-sectional studies evaluating the relationship between inflammation and cognitive functions.

A total of 79 articles were included in our systematic review and meta-analysis. Pooled estimates from cross-sectional studies have demonstrated an increased level of C-reactive protein (CRP) [Hedges's g 0.35, 95% CI (0.16, 0.55), p < 0.05], IL-1β [0.94, 95% CI (-0.04, 1.92), p < 0.05], interleukin-6 (IL-6) [0.46, 95% CI (0.05, 0.88), p < 0.005], TNF alpha [0.22, 95% CI (-0.24, 0.68), p < 0.05], sTNFR-1 [0.74, 95% CI (0.46, 1.02), p < 0.05] in AD compared to controls. Similarly, higher levels of IL-1β [0.17, 95% CI (0.05, 0.28), p < 0.05], IL-6 [0.13, 95% CI (0.08, 0.18), p < 0.005], TNF alpha [0.28, 95% CI (0.07, 0.49), p < 0.05], sTNFR-1 [0.21, 95% CI (0.05, 0.48), p < 0.05] was also observed in MCI vs. control samples. The data from longitudinal studies suggested that levels of IL-6 significantly increased the risk of cognitive decline [OR = 1.34, 95% CI (1.13, 1.56)]. However, intermediate levels of IL-6 had no significant effect on the final clinical endpoint [OR = 1.06, 95% CI (0.8, 1.32)].

The data from cross-sectional studies suggest a higher level of inflammatory cytokines in AD and MCI as compared to controls. Moreover, data from longitudinal studies suggest that the risk of cognitive deterioration may increase by high IL-6 levels. According to our analysis, CRP, antichymotrypsin (ACT), Albumin, and tumor necrosis factor (TNF) alpha may not be good surrogates for neurological degeneration over time.

To evaluate the effect of overall peripheral inflammatory levels on cognitive function, we explored the relationship between established biomarkers of peripheral inflammation (circulating C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]) and cognitive decline by performing a review of observational studies and creating an updated summary.

We included literatures exploring the relationship between peripheral levels of CRP, IL-6, and TNF-α and subsequent cognitive decline, published until July 2022, by searching the following databases: PubMed, Embase, Web of Science, the Cochrane Library, ClinicalTrials, CNKI, and VIP databases. We used random-effects models to pool the odds ratios (ORs) for the risks of subsequent cognitive decline in older adults with high levels of peripheral inflammation. We initially screened out 501 literatures, of which only 17 were ultimately eligible. Overall, there were 19,516 older individuals included in our meta-analysis, and 2134 of them experienced subsequent cognitive change.

Individuals with high levels of peripheral inflammation may have 14% more chance to develop subsequent cognitive decline than those with low levels (OR = 1.14, 95% CI: 1.03-1.27; p < 0.00001). In the subgroup analysis, the incidence of cognitive decline was higher in individuals with high levels of IL-6. This study further demonstrates the link between systemic inflammation and cognitive status.

Detecting CRP, IL-6, and TNF-α in peripheral blood is necessary, as they may become effective indicators for forthcoming cognitive performance.

Lower cognitive functioning in old age has been associated with personality traits or systemic inflammatory markers. Associations have also been found between personality traits and inflammatory markers. However, no study has explored the inter-relationships between these three components simultaneously. The present study aims to better understand the inter-relationships among personality traits, inflammatory markers, and cognitive performance in elderly individuals without dementia.

This study utilizes a network analysis approach, a statistical method that allows visualization of the data's unique pairwise associations. We performed a cross-sectional analysis on 720 elderly individuals without dementia, using data from Colaus|PsyColaus, a population-based study conducted in Lausanne, Switzerland. The Revised NEO Five-Factor Inventory (NEO-FFI-R) was used to assess personality traits, and interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were used as peripheral inflammatory markers. Cognitive domains were investigated using the Mini-Mental State Examination (MMSE), the Verbal Fluency Test, the Stroop Test, the DO40, and the Free and Cued Selective Reminding (FCSR) test.

Openness was associated with verbal fluency and Agreeableness with immediate free recall. In contrast, no association between inflammatory markers and personality traits or cognition was identified.

In elderly individuals without dementia, a high level of Openness or Agreeableness was associated with executive functioning/semantic memory and episodic memory, respectively.