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Fentanyl is a potent, fast-acting synthetic opioid that has played a major role in the opioid overdose crisis in the United States for over five decades, with opioid-related deaths increasing sharply in recent years. This study investigates the behavioral, histological, and molecular changes in the hippocampus of rats subjected to sub-acute fentanyl exposure. Two groups of rats were studied: one group received multiple fentanyl injections over approximately one week, while the control group received no fentanyl. A battery of behavioral tests related to memory and depression-including the Y-maze, shuttle box, tail suspension test, elevated plus maze, Barnes maze, Morris water maze, and forced swimming test-was administered. Electrophysiological assessments, including field potential recording and electromyography (EMG), were conducted to evaluate neural activity. Western blot analysis was performed to quantify the expression of brain-derived neurotrophic factor (BDNF) and RE1-silencing transcription factor (REST), while immunohistochemical analyses assessed hippocampal cellular alterations. Results showed that sub-acute fentanyl administration impaired behavioral performance in memory assessment tests (Y maze ( Show less

This comprehensive review examines the synergistic effects of physical exercise and polyphenolic compounds, such as flavonoids, curcumin, and resveratrol, on spatial learning and memory. The interplay between these interventions highlights their potential to enhance cognitive function by promoting neurogenesis, synaptic plasticity, and resilience against oxidative stress and inflammation. Mechanistic insights reveal that exercise and polyphenols activate complementary neuroprotective pathways, including the upregulation of BDNF and CREB, as well as the modulation of antioxidant defenses via Nrf2. Evidence from both animal and human studies demonstrates significant improvements in spatial memory and hippocampal function when these strategies are combined. Despite promising findings, challenges related to bioavailability, dosing, and long-term efficacy remain, underscoring the need for further investigation. This review emphasizes the potential clinical applications of these combined approaches for preventing cognitive decline and promoting brain health during aging and in neurodegenerative conditions. Show less

The prevalence of neurodegenerative disorders continues to increase with population aging. Brain-derived neurotrophic factor is a biomarker of cognitive function and neuroprotection. Lactobacillus plantarum C29-fermented soybean (DW2009) has been suggested to enhance cognition by modulating brain-derived neurotrophic factor. This secondary analysis of a randomized, double-blind, placebo-controlled trial investigated the influence of sociodemographic and lifestyle factors on serum brain-derived neurotrophic factor responsiveness to DW2009 supplementation. One hundred adults (age: 55-85 years) with mild cognitive impairment were randomized 1:1 to receive DW2009 (800 mg/day) or placebo (800 mg/day) for 12 weeks. The participants were examined, and their cognitive clinical features and serum brain-derived neurotrophic factor (BDNF) levels were measured at baseline and after a 12-week period. We found that DW2009 significantly increased serum BDNF levels, especially in older men (≥ 68 years) and in those with lower educational attainment (≤ 11 years). Subgroup analysis also indicated that the effect of DW2009 was enhanced in participants who performed frequent physical activity (≥ 5 times/week) and those within the normal body mass index range (18.5-22.9 kg/m²). Our findings suggest that the increase in serum BDNF after DW2009 supplementation is dependent on baseline characteristics, although this interpretation requires confirmation. DW2009 intake was linked to increased serum BDNF levels in individuals with specific sociodemographic and lifestyle characteristics. These findings suggest that personalized supplementation strategies may optimize functional benefits for cognitive health. Show less

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and cognitive function, and its dysregulation is implicated in various neurodegenerative and neuropsychiatric disorders. To noninvasively monitor dynamic changes in Bdnf expression in vivo, we developed a novel transgenic mouse line, Bdnf-AkaLuc transgenic (Tg) mice, in which the coding region of BDNF was replaced in a BAC transgene with a mutant luciferase, AkaLuc. This luciferase is optimized for the synthetic substrate AkaLumine, which emits near-infrared bioluminescence suitable for deep-tissue imaging. This engineered bioluminescence imaging (BLI) system, termed AkaBLI, enables robust and highly sensitive detection of bioluminescence in the brains of living mice, significantly outperforming our previous Bdnf-Luciferase Tg model. Using this system, we successfully visualized activity-dependent Bdnf mRNA induction in response to pilocarpine-induced status epilepticus. To overcome the limitations of repeated imaging, we identified optimal BLI intervals and established a hairless Bdnf-AkaLuc Tg line, facilitating long-term longitudinal monitoring. Furthermore, by crossing Bdnf-AkaLuc Tg mice with 5xFAD Alzheimer's disease model mice, we successfully visualized reductions in Bdnf expression in the brains of living 5xFAD mice. Our study introduces a powerful tool for noninvasive, continuous visualization of Bdnf regulation under both physiological and disease-related conditions. This imaging approach holds potential for advancing our understanding of BDNF-related brain function and for evaluating therapeutic strategies targeting BDNF in neurological disorders. Show less

Acute physical exercise (PE) is known to influence the expression of many neurobiological markers and cognitive functions, but the time course and domain-specificity of such effects remain under debate. This study investigated whether a single bout of maximal incremental exercise can increase serum brain-derived neurotrophic factor (BDNF) levels, improving cognitive performance in healthy adults. Twenty-eight physically active males underwent a maximal incremental cycling test. BDNF serum concentrations were measured at three timepoints: before exercise, 15 min after, and 24 h post-exercise. Cognitive performance in verbal and visuo-spatial memory and convergent creative thinking was assessed before and 24 h post-exercise. Results showed a significant increase in serum BDNF 24 h after exercise, while no significant change was observed 15 min post-exercise. Cognitive assessments revealed improvements in verbal immediate recall and visuo-spatial working memory, but not in long-term verbal memory, visuo-spatial short-term memory, and convergent creative thinking. No significant correlations emerged between BDNF changes and cognitive performance changes. The dissociation between BDNF and behavior points to complex and likely time-dependent mechanisms underlying exercise-induced cognitive enhancements. These results support the effectiveness of acute PE as stimulus for BDNF neurotrophin production and as a non-pharmacological tool to boost specific cognitive functions, with implications for optimizing learning and cognitive performance in healthy populations. Show less

Schizophrenia is a severe mental disorder characterized by hallucinations, delusions and cognitive dysfunction, imposing a substantial burden on individuals and society. While antipsychotic medications such as risperidone effectively control positive symptoms, their efficacy in ameliorating cognitive impairment and aggressive behavior remains limited. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, has recently demonstrated potential in adjunctively improving cognitive and behavioral dimensional symptoms in schizophrenia patients. However, the effects of combined rTMS-risperidone therapy on these symptoms and associated serum biomarkers are not yet adequately supported by clinical evidence. This study aimed to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) combined with risperidone on cognitive function, aggressive behavior and serum biomarkers in patients with schizophrenia. Eighty patients were randomly assigned to a risperidone monotherapy group or a combination therapy group (40 each) for a 4-week intervention. Results showed that the combination group achieved significantly greater reductions in cognitive factor scores (11.39±2.44 vs. 12.84±2.13) and aggressive behavior scores compared to the monotherapy group (all P<0.05). Serum analysis revealed that the combination group also demonstrated superior modulation of biomarkers, including greater reductions in pro-inflammatory factors (TNF-α, IL-8, IL-18) and greater increases in anti-inflammatory (IL-10) and neurotrophic factors (BDNF, VEGF-A, FGF-2) (all P<0.05), while no significant differences were observed in PDGF-BB and HGF between the two groups. These findings suggest that rTMS combined with risperidone more effectively improves cognitive and aggressive symptoms in schizophrenia and is associated with favorable changes in serum inflammatory and neurotrophic markers. Show less

Neurotrophins are a class of proteins that maintain the health and phenotype of neuronal cells under normal physiological conditions. Nerve growth factor was the first neurotrophin to be discovered, supporting the survival and cholinergic phenotype of basal forebrain cholinergic neurons, which are crucial in maintaining cognitive function in healthy individuals. Nerve growth factor metabolism is altered in Alzheimer's disease and, along with the degeneration of basal forebrain cholinergic neurons and loss of cholinergic pathways in the affected brain, contributes to cognitive problems. These findings initiated the application of nerve growth factor supplementation as a regenerative strategy against Alzheimer's disease in the late 20 th century. Later decades witnessed the development of drugs that support cholinergic activity, namely, cholinesterase inhibitors offering small but persisting cognitive benefits in Alzheimer's disease patients. Further developments in the Alzheimer's disease field have witnessed the rise of anti-amyloid immunotherapies that target the amyloid plaques in Alzheimer's disease brains in an attempt to reduce disease pathology. Over the years, several reports have appeared in support of or undermining the therapeutic claims of each strategy, while many other therapeutic approaches are being presently tested. In this narrative review, we present broader perspectives regarding cholinergic therapeutic strategies against Alzheimer's disease, highlighting aspects in the Alzheimer's disease field that need to be addressed, and propose future perspectives. We provide a special focus on neurotrophic molecules, especially on nerve growth factor, due to its close association with cognitive pathways and its relationship with cholinergic pathways, since cholinesterase inhibitors remain a widely used medication for Alzheimer's disease patients even after 30 years of research. Show less

BackgroundPredicting cognitive function across dementia stages remains challenging. Plasma biomarkers and electroencephalogram (EEG) features may provide complementary information, but their combined predictive value requires further study.ObjectiveTo evaluate the feasibility of integrating plasma biomarkers and EEG features to predict cognitive function in dementia and examine their correlations.MethodsFrom September 2023 to October 2024, 75 patients from two medical centers with mild cognitive impairment, mild dementia, or moderate dementia were enrolled. Resting-state 19-channel EEG data yielded 2737 time-frequency and connectivity features. Plasma biomarkers included tau, p-Tau181, Aβ Show less

Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effects of fermented red quinoa (FRQ) in an alcohol-exposed mouse model, with a focus on cognitive function. Male C57BL/6J mice were randomized into three groups for a 28-day study: a normal control, an alcohol-treated group gavaged with ethanol (1 mL/100 g·BW), and a group receiving the same ethanol dose co-administered with FRQ powder (human equivalent dose: 9 g/60 kg·BW). Our results demonstrated that fermentation with Lactobacillus kisonensis significantly increased the content of phenolic compounds (e.g., quercetin and veratric acid) in FRQ. FRQ intervention improved cognitive function, ameliorated synaptic structural impairment and blood-brain barrier disruption, and attenuated hepatic steatosis. The protective mechanisms involved three pathways: 1) The specific phenolic compounds in FRQ promoted alcohol metabolism by regulating ADH/ALDH activity, leading to reduced acetaldehyde levels. As a primary initiating pathway, this metabolic enhancement dominantly attenuated subsequent oxidative stress and inflammation, mitigating injury in the liver, brain, and colon. 2) It directly modulated AP-1 subunits (ΔFOSB/JUND), restored BDNF, and rebalanced the glutamate/GABA systems. 3) It regulated the gut-liver-brain axis by remodeling the gut microbiota (e.g., enriching butyrate-producing Butyricicoccus), reinforcing intestinal barrier integrity, and thereby suppressing systemic LPS translocation and inflammation. In conclusion, FRQ mitigates alcohol-induced cognitive and hepatic damage via multiple mechanisms, highlighting its promise as an integrative dietary intervention. Show less

Exercise has been shown to support brain health, cognitive function, and increase levels of brain-derived neurotrophic factor (BDNF). While BDNF is known to support the central nervous system through improved brain metabolism, vasculature, neurotransmission and synaptic plasticity, the association between exercise-induced changes in BDNF concentrations and exercise-related cognitive improvements is still unclear. This study investigated the relationship between exercise-induced changes in plasma BDNF (pBDNF) and serum BDNF (sBDNF), and haemodynamic indicators of prefrontal cortex function in sedentary adults. Participants (n = 23, female = 7) were randomized into intervention (12-week cycling programme) and control groups (no intervention). Participants completed V̇O Show less

To synthesise existing research on the impact of gestational diabetes mellitus (GDM) on fetal neural development and subsequent cognitive function in offspring. A systematic review was conducted following PRISMA guidelines. PubMed, Cochrane Library, and ClinicalTrials.gov were searched from January 1964 to October 2024. Studies comparing offspring of mothers with GDM to those without were included. Quality was assessed using the Newcastle-Ottawa Scale (NOS). Seventeen studies met the inclusion criteria. The findings suggest that GDM is linked to subtle yet significant neurodevelopmental modifications, encompassing delays in communication and language proficiency, behavioural dysregulation, as well as heightened susceptibility to autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Electrophysiological investigations revealed alterations in cortical activity and extended auditory responses, while neuroimaging studies documented structural variations, including changes in the dimensions of the corpus callosum, ventricular size, and sulcal maturation. Molecular investigations uncovered dysregulated microRNAs that play a role in neurogenesis. Numerous studies emphasised the dose-dependent effects of maternal glucose concentrations and the protective impact of effective glycemic control. Maternal GDM is associated with alterations in fetal brain structure and function, which may predispose offspring to neurodevelopmental risks. While not all deficits persist, these findings highlight the potential value of early glycemic control and postnatal monitoring for at-risk infants. Further longitudinal research is needed to distinguish causal GDM effects from environmental confounders. Show less

To investigate the effect of pterostilbene (PTE), a natural dimethyl ether analog of resveratrol with higher bioavailability, on cognitive recovery after cerebral ischemia reperfusion (IR) injury and its potential mechanisms. Mice were subjected to middle cerebral artery occlusion and assigned to Sham, IR, PTE+IR, and PTE+Zinc Protoporphyrin (ZnPP)+IR groups. Cognitive function was assessed using the Morris water maze. Cerebral infarct volume was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and neuronal apoptosis was determined via TUNEL assay. The protein levels of postsynaptic density protein 95 (PSD-95), phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs) in the hippocampus were measured by western blot. PTE treatment significantly reduced cerebral infarct volume, alleviated cognitive deficits, and inhibited neuronal apoptosis in the hippocampus. At the molecular level, PTE up-regulated the expression of PSD-95, p-CREB, and BDNF, while down-regulating HDAC (1, 2, 3, 4, 7) levels. The beneficial effects of PTE were partially reversed by the HO-1 inhibitor ZnPP. PTE ameliorates cognitive impairment induced by cerebral IR injury, potentially through activating the BDNF/CREB pathway and inhibiting HDAC expression. This suggests PTE as a promising neuroprotective agent for post-stroke cognitive recovery. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD. Show less

BackgroundCognitive decline represents a major challenge in aging populations. Probiotics have been proposed to influence cognitive function through gut-brain interactions, but clinical findings remain inconsistent.ObjectiveThis study evaluated the effects of probiotic supplementation on cognitive function as the primary outcome, and on BDNF levels, inflammatory markers, and oxidative stress biomarkers as secondary outcomes in adults aged 50 years and older.MethodsA systematic search of PubMed, EBSCO, ProQuest, and Google Scholar was conducted through 1 May 2024 using predefined search terms related to probiotics, cognitive function, BDNF, inflammation, and antioxidant activity. Study quality was assessed using the RoB 2 tool. Meta-analyses were performed using random-effects models, and publication bias was explored using Egger's test where study counts permitted.ResultsSixteen studies demonstrated significant improvement in cognitive function among participants receiving probiotics compared to placebo. Cognitive function, measured using the Mini-Mental State Examination (MMSE), yielded a standardized mean difference (SMD) of 0.747 (95% CI 0.307-1.186) which corresponds to moderate-to-large effects. In comparison, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) showed significant results with an SMD of 0.340 (95% CI 0.032-1.366) which corresponds to small-to-moderate effects. Probiotics also led to significant changes in several biochemical parameters, including BDNF, TNF-α, 8-OHdG, IL-6, IL-10, MDA, TAC, and GSH. Multi-strain probiotics showed better results compared to single-strain.ConclusionsProbiotic supplementation may offer modest cognitive benefits in aging populations, particularly in studies enrolling cognitively impaired individuals, but substantial heterogeneity and limited biomarker evidence restrict the certainty of these findings. Larger, longer-duration, and standardized trials are needed to clarify the clinical relevance and potential biological pathways underlying probiotic effects on cognition. Show less

Human Immunodeficiency Virus (HIV) remains a global epidemic and is frequently associated with neurocognitive impairment, known as HIV-Associated Neurocognitive Disorder (HAND). Brain-Derived Neurotrophic Factor (BDNF), which regulates neuroplasticity, learning, and memory, may play a key role in this process. This study aimed to investigate the correlation between BDNF, CD4 levels, and cognitive function in patients with HIV. We conducted a cross-sectional study at Adam Malik General Hospital, Medan, Indonesia, from July 2024 to January 2025. Fifty-eight HIV-positive patients aged 18-60 years with CD4 ≥200 cells/mm³ and on antiretroviral therapy for at least 4 months were included. Blood samples were analyzed for serum BDNF (ELISA) and CD4 counts. Cognitive function was assessed using the Stroop Test, and correlations were examined with Spearman's test Result: Participants had a mean age of 38.77 ± 9.28 years; 79.3% were male. The mean BDNF level was 1.08 ± 0.59 ng/mL, the mean CD4 count was 512.60 ± 331.08 cells/mm³, and the mean Stroop Test score was 68.75 ± 24.60 seconds. A significant negative correlation was observed between BDNF and Stroop performance (r = -0.288, p = 0.028), indicating that higher BDNF was associated with better cognitive function. No significant correlation was found between CD4 and cognitive function (p = 0.336) Discussion: These findings suggest that reduced BDNF may contribute to cognitive impairment in HIV, whereas CD4 levels may not directly reflect neurocognitive status, particularly in patients with CD4 ≥200. BDNF levels are significantly correlated with cognitive function in HIV-positive patients, underscoring its potential role as a biomarker for HAND. Show less

While mindfulness has demonstrated efficacy in enhancing executive function in non-athletes through improved present-moment awareness and acceptance of current experiences, particularly regarding attention regulation and cognitive control, its neurocognitive mechanisms and the effects and underlying mechanisms of mindfulness-based intervention (MBI) on different executive functioning skills in athletic populations remain poorly understood. The purpose of this randomized controlled trial tackles a novel and important topic by investigating the beneficial effects of 12-week MBI on executive functioning skills in baseball players-a population that faces unique cognitive and physical demands, and the associated neurophysiological and biochemical regulation mechanisms. Thirty-four baseball players were randomly divided into the MBI group (11M/6F) and the control group (11M/6F). Executive functioning skills (N-back task for working memory, Stroop task for inhibitory control, and Switching task for cognitive flexibility) were tested before and after the intervention. Functional near-infrared spectroscopy (fNIRS) was used to record quantified hemodynamic responses in the prefrontal cortex through oxygenated hemoglobin concentration (Oxy-Hb) monitoring during the performance of executive function tasks. Biomarkers of cognitive function, including BDNF, IL-6, TNF-α, and Cortisol, were measured using enzyme-linked immunosorbent assays (ELISA). MBI partially improved all three executive function skills, with increased Oxy-Hb level in L-FPA during the task of working memory, increased Oxy-Hb level in R-VLPFC during the task of inhibitory control, and decreased Oxy-Hb level in R-FPA, M-FPA, and L-DLPFC during the task of cognitive flexibility. Furthermore, MBI increased circulating BDNF level and decreased IL-6 and Cortisol levels. In addition, our correlation analyses showed that improvement in executive function (improved behavioral performances and changes in Oxy-Hb levels) were associated with changes in Cortisol and inflammatory cytokines (TNF-α and IL-6). A 12-week MBI partially improved three components of executive function in baseball players. This enhancement may be attributed to the MBI-induced reductions in Cortisol and inflammatory cytokines (such as TNF-α and IL-6), which altered blood oxygen contents in specific brain regions, thereby promoting executive function. Show less

Recent evidence highlights a fundamental link between masticatory function and brain health. Once regarded solely as a peripheral motor activity for food processing and occlusal balance, mastication is now recognized as a key factor in maintaining and enhancing cognitive function across the lifespan. This narrative review was conducted using relevant keywords through searches in PubMed, Scopus, and Web of Science, as well as manual searching of the bibliographies of journal articles. Basic research has shown that chewing stimulates neurogenesis in the hippocampus, resulting in increased neuronal and synaptic density, as well as the upregulation of brain-derived neurotrophic factor (BDNF), which leads to improvements in memory and cognition. This effect has been documented in both animal and clinical research, particularly among the elderly, and is supported by data from national health programs, which indicate that adequate prosthodontic rehabilitation can help preserve cognitive function. Etiopathogenetic insights suggest that loss of posterior teeth, rather than overall tooth count, is particularly detrimental, as these teeth are essential for effective mastication. Proposed mechanisms involve exercise-induced myokines, such as Cathepsin B, and chewing-induced neprilysin production, which may mediate hippocampal neuroprotection. Collectively, these findings support a paradigm shift: mastication should be promoted as a preventive strategy for both oral and neural health. Public health efforts and clinical practices should integrate education on maintaining posterior dentition, promoting diets with adequate texture, and supporting prosthetic rehabilitation to sustain neuromuscular activity, thereby protecting cognitive function from early development through old age. Show less

Growing evidence highlights that long-term orbital flight may lead to structural changes in brains and cognitive impairments in astronauts. However, effective strategies to counteract these effects remain limited. Compound Gastrodia elata Formula (CGEF), composed of Gastrodia elata Bl., Polygonatum sibirium Red., and Poria cocos (Schw.) Wolf has been shown to improve learning and memory. The present study aimed to evaluate the effects and underlying mechanisms of CGEF in attenuating cognitive deficiency induced by simulated weightlessness in mice. A cognitive impairment model was induced in mice using Hindlimb unloading (HU) method. Cognitive function was assessed through Object recognition test (ORT), the Morris water maze (MWM), and the Step-down Test (SDT). Serum and hippocampus levels of inflammatory markers, including Interleukin-1 beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α), and Interleukin-6 (IL-6) were evaluated using ELISA. Neurotransmitter concentrations in the hippocampus and cortex were measured using LC-MS/MS. While Brain-derived neurotrophic factor (BDNF) / Tropomyosin receptor kinase B (TrkB) protein expression signaling pathway in hippocampus was evaluated by western blot. Results showed that CGEF treatment significantly reversed the memory deficits induced by four weeks of HU exposure. Furthermore, CGEF treatment markedly suppressed the production of inflammatory factors. It also assisted in the recovery of neurotransmitter balance and regulated tryptophan metabolism to improve cognitive disorder. Western blotting analysis revealed that CGEF treatment upregulated the expression of Synaptophysin, Postsynaptic density 95 proteins, while also activating the brain-derived neurotrophic factor-Tropomyosin receptor kinase B pathway. These findings suggest that CGEF has substantial potential for development as an aerospace health product to improve memory decline associated with spaceflight. Show less

Studies have shown that sarcopenia and its related parameters are associated with cognition. Preclinical evidence suggests that myokines, such as irisin, Brain-Derived Neurotrophic Factor(BDNF), myostatin and Insulin-like Growth Factor-1(IGF-1) might explain this relationship. This study aimed to explore the associations between sarcopenia-related parameters and cognition, and whether myokines influence this association. Exploratory, cross-sectional analysis of data from the Exercise and Nutrition for Healthy AgeiNg (ENHANce,NCT03649698) study. Participants were older adults(≥65 years) with EWGSOP2-defined sarcopenia. Cognitive functioning was assessed by Mini-Mental State Examination(MMSE), Repeatable Battery for the Assessment of Neuropsychological Status(RBANS), Trail Making Test A&B(TMT), Stroop and Maze Test. Sarcopenia-related parameters were measured: Handgrip Strength, Chair Stand Test, appendicular Lean Mass(aLM), Gait Speed (GS) and Short Physical Performance Battery(SPPB). Serum myokines(IGF-1, irisin, myostatin, BDNF) were determined through ELISA. Associations between cognition and sarcopenia-related parameters were analyzed using multivariable regression, adjusting for potential confounders including myokines. Fifty-eight participants were included in this analysis (76.2 ± 6.7 years, ♀:65.5%). After adjustment for age, sex, body mass index, aLM was associated with MMSE(β = 0.193,p = 0.012), RBANS Total(β = 0.196,p = 0.007) and RBANS Attention(β = 0.215,p = 0.002), CST was associated with RBANS Language(β = -0.314,p = 0.030), SPPB was associated with Maze time(β = -0.364,p = 0.004) and TMT-B (β = -0.333,p = 0.013) and GS was associated with TMT-A(β = -0.324,p = 0.045). After adjustments for BDNF& IGF-1, the association between GS and TMT-A became non-significant. Irisin and myostatin did not influence the sarcopenia-cognition associations. Sarcopenia-related parameters are associated with global and specific cognitive domains. BDNF may, partially, explain the association between muscle mass and MMSE. Additional research with larger sample size is needed to confirm these findings. Show less

Hyposalivation affects cognitive function. However, its impact on hippocampus-dependent memory remains unclear. Saliva contains brain-derived neurotrophic factor (BDNF), which is also synthesized in the hippocampus and can pass through the blood-brain barrier (BBB) to influence hippocampal plasticity. Therefore, we hypothesized that hyposalivation reduces peripheral BDNF availability, leading to decreased hippocampal BDNF levels and cognitive impairment. In this study, this relationship was investigated using an in vivo model of sialadenectomy-induced hyposalivation. A total of 24 8-week-old male ddY mice were divided into control and extraction (EXT) groups. The EXT group underwent submandibular and sublingual salivary gland extractions, whereas the control group underwent a sham operation. Saliva was collected at baseline (0 weeks) and at 2- and 3-weeks postoperatively. Cognitive function was assessed using the Y-maze, fear conditioning (FC), novel object recognition (NOR), and object location tests (OLT). Anxiety-like behavior was evaluated using the open field test (OFT) and elevated plus-maze (EPM) tests. Hippocampi were collected at 3 weeks post-operation for BDNF quantification using enzyme-linked immunosorbent assay, and its concentration in subregions of the hippocampus was determined by semi-quantitative analysis. Hyposalivation significantly impaired spatial working memory in the Y-maze test and contextual fear memory in the FC, both of which are hippocampus-dependent. NOR showed only a transient deficit at 24 h during the 2-week period (no significant difference in 3-week post-operation), whereas long-term spatial memory measured by the OLT exhibited a persistent 24-h impairment at both 2 and 3 weeks, indicating reduced long-term spatial memory rather than accelerated decay. No significant differences were observed in anxiety-like behavior. Although sialoadenectomy significantly reduced salivary secretion and total salivary BDNF output, the concentration of BDNF in saliva in both groups remained unchanged at 2- and 3-weeks post-operation. However, hippocampal BDNF levels were significantly lower in the EXT group than in the control group. These findings suggest that hyposalivation may selectively impair hippocampus-related spatial memory without affecting recognition memory or anxiety-related behaviors. Show less

The effects of different exercise intensities on cognitive outcomes and brain-derived neurotrophic factor (BDNF) concentrations in adolescents with overweight/obesity are not yet fully elucidated. This study aimed: (a) to compare the prevalence of responders to cognitive function and BDNF concentration in adolescents with overweight/obesity participating in a 12-week intervention with high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), and (b) to analyze whether cardiorespiratory fitness (CRF) can explain differences in inter-individual variability between responders and non-responders. Adolescents with overweight/obesity were assigned to HIIT (n = 15), MICT (n = 14), or CG (n = 24). Anthropometrics, body composition, CRF, basal BDNF, and cognitive performance (Trial Making Test (TMT) and Stroop Test (ST)) were evaluated pre- and post-intervention. Training was performed on stationary bikes (3×/week for 12 weeks). The prevalence of responders in ST and TMT was higher in the HIIT group than in CG (93-62%, p = 0.029; 67-33%, p = 0.043), with no differences in MICT. No group differences were found for BDNF responders (HIIT:73%-MICT:71%-CG:46%, p = 0.263). ST and TMT responders had greater CRF improvements than non-responders. HIIT elicited a higher prevalence of cognitive responders than CG. CRF improvements may partially explain individual variability in responsiveness to cognitive outcomes. This is the first study to examine and compare inter-individual variability in cognitive function and BDNF levels following MICT and HIIT interventions in adolescents with overweight/obesity; Exercise intensity and improvements in cardiorespiratory fitness are key factors for optimizing the cognitive effects of interventions in youth with overweight; Twelve weeks of supervised HIIT and MICT training led to increased rates of cognitive responders among adolescents with overweight/obesity. Show less

Preserving brain health is essential to maintaining quality of life and cognitive function with age. Exercise plays an essential role. Aerobic exercise such as running and cycling can enhance brain plasticity through increasing gray matter volume in the cerebellum and temporal lobe, as well as the density of connections in the brain's frontal and motor areas via upregulating brain-derived neurotrophic factor (BDNF) and serotonin systems. Anaerobic exercise, such as weightlifting, primarily increases gray matter volume in the basal ganglia and increases the density of connections in the posterior lobe of the cerebellum. In midlife, aerobic exercise can increase white matter integrity and cortical thickness in primary motor and somatosensory areas, while in older age it improves specific markers of cognitive function, such as episodic memory. With regards to neurodegenerative diseases, aerobic exercise has been linked to improved memory performance and reduced hippocampal atrophy in Alzheimer's disease. In Parkinson disease, aerobic exercise has shown to reduce brain atrophy, improve motor function and cognitive control, while anaerobic exercise improves motor performance and information processing. Overall, both aerobic and anaerobic exercises are integral and complementary to preserving brain health through effects on cognitive function and brain structure. Show less

Chronic stress, a key contributor to neurological disorders, is mechanistically linked to hypothalamic-pituitary-adrenal (HPA) axis dysregulation, neuroinflammation, and hippocampal neuronal apoptosis. Current therapeutic approaches remain limited in efficacy and safety. Schisandrol A, a neuroactive lignan from Show less

The aging process is associated with gradual cognitive decline resulting from deficits in synaptic plasticity, the brain's natural ability to adapt and reshape its neural circuitry. This review highlights the importance of synaptic plasticity in cognitive function. It provides a full overview of the molecular, cellular, and systemic mechanisms involved in enhanced or diminished synaptic plasticity in the aging brain. We also go over issues in neurotransmitter systems, calcium signaling, neurotrophic support (ex., BDNF-TrkB), cellular signaling pathways (e.g. mTOR, CaMK, CREB, and MAPK/ERK), and neuroinflammation, oxidative stress, and vascular integrity, all of which redirect the trajectory of synaptic failure associated with cognitive decline in aging. Therapeutic approaches toward increasing or restoring synaptic plasticity are evaluated, including pharmacological (e.g., nootropics, cholinesterase inhibitors, NMDA receptor modulators), natural (e.g., curcumin, resveratrol, bacoside A), and new interventions (e.g., psychoplastogens, gene therapy, nanocarriers, and digital therapeutics). Lifestyle approaches, especially physical exercise, cognitive training, intermittent fasting, and mindfulness approaches to stimulation, have highly potent effects on plasticity enhancements and employ multiple neurobiological mechanisms. Despite much promise, there remain substantial translational challenges, including limited clinical efficacy, lack of personalized biomarkers, and ethical considerations concerning cognitive enhancement. As we look ahead, a multidisciplinary integrative approach that includes molecular therapeutics, lifestyle interventions, and next-generation neurotechnologies will be most useful for protecting cognitive health and enhancing brain resilience in aging individuals. This review highlights the immediate necessity for personalized, ethical, and evidence-based approaches to take advantage of synaptic plasticity for healthy cognitive aging. Show less

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK-ERK-CREB-BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline. Show less

Theogallin, a tea-derived polyphenol enriched in newly developed cultivars such as MK5601, has been shown to have cognitive benefits. However, its biological and mechanistic effects of theogallin remain unclear. Herein, we investigated the transcriptomic profiles of six mouse tissues after oral theogallin administration. Theogallin induced tissue-enriched transcriptional responses, particularly in the brain, where it activated memory-related and neuronal activity-related pathways through the upregulation of immediate-early genes (IEGs). These transcriptional changes closely resembled brain-derived neurotrophic factor (BDNF)-induced neuronal activation and contrasted with gene expression patterns associated with Alzheimer's disease. In aged mice, theogallin improved recognition memory and increased the expression of IEGs-associated proteins, while reducing neurodegeneration-linked markers. Theogallin also enhanced neuronal gene expression in SH-SY5Y cells, supporting a direct neuromodulatory role and further promoting neurite outgrowth. Therefore, theogallin is a functional enhancer of neuronal activation with potential therapeutic relevance for age-related cognitive decline and neurodegenerative disorders. Show less

Docosahexaenoic acid (DHA), one of the most critical polyunsaturated fatty acids, is vital for the neurological growth and cognitive function of infants and children. Approximately 98% of DHA in breast milk exists as triglycerides, with 60% esterified at the sn-2 position. To demonstrate the necessity of mimicking the form of DHA present in breast milk in nutritional food for young children, this study administered diets with varying sn-2 DHA contents (10%, 30%, and 50%) to four groups of mice and analyzed their behavioral performance, brain DHA concentration, expression of brain fatty acid transport proteins, histopathology, and expression of synaptic-related proteins in the hippocampus after 4 weeks. The results showed that compared with the control group, mice in the 50% sn-2 DHA group exhibited superior learning and memory capabilities in behavioral tests, with the most pronounced behavioral improvements in mice, which correlated with higher brain DHA accumulation (from 0.870 ± 0.055 mg/g brain to 1.809 ± 0.132 mg/g brain, p < 0.05), increased levels of MFSD2A (1.40-fold, p > 0.05), FABP5 (2.36-fold, p < 0.05), FATP1 (1.47-fold, p < 0.05), and ACSL6 (1.48-fold, p < 0.05), improved hippocampal neuron morphology, and enhanced the level of BDNF (1.55-fold, p < 0.05), SYN (1.45-fold, p < 0.05), and PSD-95 (1.57-fold, p < 0.05). These findings establish a foundation for developing DHA nutritional supplements. Show less

Prosopis cineraria is traditionally used to enhance cognitive function and manage mental disorders. Its stem bark is valued in ethnomedicine, but its potential anti-Alzheimer's disease (AD) effects are scientifically unexplored. This research has examined the neuroprotective effects of the ethyl acetate fraction of P. cineraria bark (Pc-EA) against AlCl Diseased rats were treated with Pc-EA (30, 100, and 300 mg/kg) for 42 days. Cognitive and affective functions were evaluated with behavioral tests on days 29-42. Biochemical assays measured oxidative stress and cholinesterase activity, while RT-PCR quantified neuroinflammatory markers. Histopathological examination was performed to evaluate the integrity of hippocampal regions. Bioactive compounds were identified by phytochemical profiling (HPLC, GC-MS), and molecular docking was performed to assess binding interactions with acetylcholinesterase. AlCl Pc-EA demonstrated multi-targeted neuroprotection in AlCl Show less

Aim: To summarise current knowledge on the effects of intermittent fasting on cognitive functions and neuroprotective mechanisms, with particular attention to Alzheimer's disease and Parkinson's disease. Materials and Methods: A narrative review based on twelve peer-reviewed publications on the effects of intermittent fasting on cognitive function, neuroprotection, and circadian rhythms. Preclinical data and selected clinical studies indicate that intermittent fasting improves memory, attention, and executive functions, which is associated with activation of autophagy, reduction of oxidative stress, improved mitochondrial function, and increased levels of brain-derived neurotrophic factor. In Parkinson's disease, intermittent fasting limits alpha-synuclein aggregation and protects dopaminergic neurons, whereas in Alzheimer's disease it reduces beta-amyloid deposition and enhances synaptic plasticity. Intermittent fasting also influences the gut-brain axis and circadian rhythm alignment, which may further support neuroprotection. Conclusions: Intermittent fasting is a promising adjunct strategy in the management of neurodegenerative diseases. However, well-designed, randomised clinical trials are needed to confirm its effectiveness and safety. Show less