Enhancing socio-communicative functions in an MCI patient with intra-nasal insulin: a case report.

This report examines extended intra-nasal insulin treatment [INI] for an Insulin Resistant early Mild Cognitive Impairment [MCI] patient. Patient [EJ] also had medial temporal lobe [MTL] damage, poor short-term memory, significant irritability, and social and linguistic withdrawal at treatment start. Compared to baseline, nine months INI treatment increased grey matter volume, lowered beta-amyloid levels, and improved MCI and FAS scores. Patient also increased pragmatic capacities in social conversation and procedural memory. These findings align with results from prior clinical trials on INI and suggest that treatment can slow neurodegenerative disease progression in early MCI patients.

Activation changes in patients with post-stroke cognitive impairment receiving intermittent theta burst stimulation: A functional near-infrared spectroscopy study.

BACKGROUND: Intermittent theta burst stimulation (iTBS) has demonstrated efficacy in patients with cognitive impairment. However, activation patterns and mechanisms of iTBS for post-stroke cognitive impairment (PSCI) remain insufficiently understood. OBJECTIVE: To investigate the activation patterns and potential benefits of using iTBS in patients with PSCI. METHODS: A total of forty-four patients with PSCI were enrolled and divided into an iTBS group (iTBS and cognitive training) or a control group (cognitive training alone). Outcomes were assessed based on the activation in functional near-infrared spectroscopy (fNIRS), as well as Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) and the modified Barthel Index (MBI). RESULTS: Thirty-eight patients completed the interventions and assessments. Increased cortical activation was observed in the iTBS group after the interventions, including the right superior temporal gyrus (STG), left frontopolar cortex (FPC) and left orbitofrontal cortex (OFC). Both groups showed significant improvements in LOTCA and MBI after the interventions (p < 0.05). Furthermore, the iTBS group augmented superior improvement in the total score of MBI and LOTCA compared to the control group, especially in visuomotor organization and thinking operations (p < 0.05). CONCLUSION: iTBS altered activation patterns and improved cognitive function in patients with PSCI. The activation induced by iTBS may contribute to the improvement of cognitive function.

Eye movements as predictor of cognitive improvement after cognitive remediation therapy in patients with schizophrenia.

Aim: Baseline cognitive functions of patients predicted the efficacy of cognitive remediation therapy (CRT), but results are mixed. Eye movement is a more objective and advanced assessment of cognitive functions than neuropsychological testing. We aimed to investigate the applicability of eye movements in predicting cognitive improvement after patients with schizophrenia were treated with CRT. Methods: We recruited 79 patients with schizophrenia to complete 8 weeks of CRT and assessed their cognitive improvement outcomes. Eye movements were assessed by prosaccades, antisaccades, and free-viewing tasks at baseline, and neuropsychological tests in four cognitive domains were assessed before and after treatment to calculate treatment outcomes. Predictors of demographic information, clinical characteristics, and eye movement measures at baseline on cognitive improvement outcomes were analyzed using logistic regression analysis. We further compared the predictive performance between eye movement measurements and neuropsychological test regarding the effect of CRT on cognitive improvement, and explored factors that could be affect the treatment outcomes in different cognitive domains. Results: As operationally defined, 33 patients showed improved in cognition (improved group) and 46 patients did not (non-improved group) after CRT. Patients with schizophrenia being employed, lower directional error rate in antisaccade task, and lower the gap effect (i.e., the difference in saccadic latency between the gap condition and overlap condition) in prosaccade task at baseline predicted cognitive improvement in CRT. However, performance in the free-viewing task not associated with cognitive improvement in patients in CRT. Our results show that eye-movement prediction model predicted the effect of CRT on cognitive improvement in patients with schizophrenia better than neuropsychological prediction model in CRT. In addition, baseline eye-movements, cognitive reserve, antipsychotic medication dose, anticholinergic cognitive burden change, and number of training sessions were associated with improvements in four cognitive domains. Conclusion: Eye movements as a non-invasiveness, objective, and sensitive method of evaluating cognitive function, and combined saccadic measurements in pro- and anti-saccades tasks could be more beneficial than free-viewing task in predicting the effect of CRT on cognitive improvement in patients with schizophrenia.

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia. Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical. Results: In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094. Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.

Another cause of treatable dementia: rapid cognitive improvement after carotid endarterectomy. Illustrative case.

BACKGROUND: Revascularization techniques in cervical internal carotid artery (ICA) stenosis are indicated to prevent the onset or recurrence of ischemic events in the setting of atherosclerotic carotid artery disease. Recent reports, case series, and comparative studies have suggested that revascularization techniques may also improve cognitive outcome in both symptomatic and asymptomatic patients, thus raising the question of whether another surgically treatable dementia has presented itself. OBSERVATIONS: A 70-year-old right-handed female with a history of hypertension, diabetes, and bilateral silent cerebral infarcts was evaluated for progressive cognitive impairment over a 1-year period, which was associated with a severe left cervical ICA stenosis. Carotid endarterectomy (CEA) was indicated as a revascularization technique, and the patient showed significant neurocognitive improvement as early as one month postoperatively, consistent with blood flow restoration to the left hemisphere on control imaging. LESSONS: This case serves as a reminder that CEA may improve the cognitive outcome of patients previously impaired by uncomplicated severe cervical ICA atherosclerotic disease, which can be another cause of treatable dementia. Further prospective studies may help to assess this potential benefit.

Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 µM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

Temporal processing tele-intervention improves language, attention, and memory in children with neurodevelopmental disorders.

Objective: Temporal processing is the brain's ability to process rapid successive stimuli, and children with neurodevelopmental disorders showed temporal processing deficits. Empirical evidence suggests that in-person intervention on temporal processing improves various cognitive functions of these children, and the present study aimed to study the effects of temporal processing tele-intervention (TPT) on the cognitive functions of children with neurodevelopmental disorders. Methods: Ninety-five children with neurodevelopmental disorders were recruited and randomly assigned to remotely receive either TPT or conventional language remediation (CLR) in 20 parallel group-based intervention sessions once per week. Their cognitive functions were assessed before and after the intervention. Results: The TPT group demonstrated a specific and significant improvement in working memory (p < .001). While there was an overall significant improvement in sustained attention in terms of processing speed after both types of intervention (p = .006), the positive effects of TPT might be more prominent than that of CLR given the significant pre-post difference after receiving TPT (p = .012) but not CLR (p = .21). Regarding rapid naming accuracy which had marginally significant improvement after the intervention (p = .03), the trend of improvement in TPT (p = .05) also seemed more apparent than that of CLR (p = .18). Finally, the TPT group had significant improvement in word knowledge (p < .001), rapid naming speed (p < .001), sustained attention in terms of accuracy (p < .001), and verbal learning and memory (p < .01) to an extent similar to that of the CLR group. Conclusions: These findings suggest that TPT can be a potential intervention for improving cognitive functions in children with neurodevelopmental disorders. Clinical trial registration number: NCT05428657 at ClinicalTrials.gov (https://clinicaltrials.gov/).

Carnitine metabolites and cognitive improvement in patients with schizophrenia treated with olanzapine: a prospective longitudinal study.

Objective: Cognitive impairment is one of the core symptoms of schizophrenia, which is stable and lifelong. L-carnitine has been shown to improve cognitive function and decrease the rate of cognitive deterioration in patients with Alzheimer's disease. However, it remains unclear regarding the role of L-carnitine and its metabolites in cognitive functions in schizophrenia after treatment with olanzapine. The purpose of this study was to evaluate the relationship between changes in plasma levels of L-carnitine metabolites and cognitive improvement after olanzapine treatment. Methods: This was a prospective longitudinal study. In this study, we recruited 25 female patients with first episode schizophrenia (FES) who were drug naïve at baseline and received 4 weeks of olanzapine monotherapy. Cognitive function was assessed at baseline and 4-week follow-up using the RBANS. Plasma L-carnitine metabolite levels were determined by a metabolomics technology based on untargeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Results: We found that the immediate memory index, delayed memory index and RBANS composite score were significantly increased at the 4-week follow-up after treatment. A total of 7 differential L-carnitine metabolites were identified in FES patients after olanzapine monotherapy. In addition, we found that changes in butyrylcarnitine were positively correlated with improvements in language index and RBANS composite score. Further regression analyses confirmed the association between reduced butyrylcarnitine levels and cognitive improvement after olanzapine monotherapy in FES patients. Conclusion: Our study shows that cognitive improvement after olanzapine treatment was associated with changes in L-carnitine metabolite levels in patients with FES, suggesting a key role of L-carnitine in cognition in schizophrenia.

Does Carotid Intervention Improve Cognitive Function?

Carotid artery disease has been linked to baseline cognitive impairment, even in asymptomatic patients. Therefore, there has been a persistent interest in investigating the impact of carotid revascularization on cognitive functions, but the results have been heterogeneous. Our recent prospective evaluation showed improved cognitive scores across multiple cognitive measures following carotid intervention. Herein, we summarize the studies published to date, identify the potential contributors to the inconsistency of post-interventional cognitive outcomes, and explore further opportunities in cognitive evaluations.

Cognitive Gain in Digital Foreign Language Learning.

This systematic review examines the potential of digital language learning in contributing to students' cognitive gains. The study reviews existing research on the relationship between digital language learning and cognitive benefits, with a focus on enhanced problem-solving skills, memory, and multitasking ability. The research questions explored in this study are (1) does digital language learning contribute to cognitive gains in foreign language education? and (2) what are the pedagogical implications for cognitive improvement in digital foreign language education? The study employs the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology to identify and analyze relevant research articles. The results of the review suggest that working with printed texts may be more effective for cognitive gains compared to electronic texts. Additionally, implementing more senses through digital language education appears to be beneficial for cognitive gains. Thus, several pedagogical implications emerge for promoting cognitive improvement in digital foreign language education. Firstly, it is crucial to implement techniques and strategies that best align with students' language needs in a digital learning environment, whether it involves pen-and-paper activities or a flipped classroom approach. Secondly, exposing students to a variety of techniques that engage multiple senses can have a positive impact on cognitive gains. Finally, providing students with feedback is essential to maintain their motivation and foster continued progress in their foreign language studies.

Quadrato motor training (QMT) influences IL-1ß expression and creativity: Implications for inflammatory state reduction and cognitive enhancement.

Mind-body practices and meditation have been increasingly studied in recent years due to their beneficial effects on cognition, and physical and psychological health. Growing evidence suggests that these practices could be utilized as interventions to impact age-related biological processes, such as cognitive decline, inflammation, and homeostatic dysregulation. Indeed, it has been reported that mindful meditation may induce neuroplasticity in brain regions involved in control of attention, emotional regulation, and self-awareness. In the current research we studied the effects of a recently developed movement meditation, named the Quadrato Motor Training (QMT), on the proinflammatory cytokine Interleukin-1beta (IL-1ß), utilizing a pre-post design. In addition to its role in the immune system, IL-1ß is also an important mediator of neuroimmune responses related to sickness behavior, and plays a role in complex cognitive processes, such as synaptic plasticity, neurogenesis, and neuromodulation. Thirty healthy participants were divided in two groups, one performing QMT for 2 months, and one passive control group. Salivary IL-1ß expression was examined by ELISA to measure protein levels and by qRT-PCR to quantify mRNA. In addition, the methylation profile of the IL-1ß promoter was examined. All participants further conducted the Alternate Uses Task (AUT) and Hidden Figure Test (HFT), to measure their creativity and spatial cognition. The results showed that, following QMT practice, IL-1ß protein level decreased and creativity increased, compared to the control group. These data demonstrate that QMT may help reduce inflammatory states and promote cognitive improvement, highlighting the importance of non-pharmacological approaches to health and well-being.

GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation and Neurotrophic Factors to Reverse Age-Associated Cognitive Decline: Implications for Improving Brain Health in Aging.

Cognitive decline frequently occurs with increasing age, but mechanisms contributing to age-associated cognitive decline (ACD) are not well understood and solutions are lacking. Understanding and reversing mechanisms contributing to ACD are important because increased age is identified as the single most important risk factor for dementia. We reported earlier that ACD in older humans is associated with glutathione (GSH) deficiency, oxidative stress (OxS), mitochondrial dysfunction, glucose dysmetabolism and inflammation, and that supplementing GlyNAC (glycine and N-acetylcysteine) improved these defects. To test whether these defects occur in the brain in association with ACD, and could be improved/reversed with GlyNAC supplementation, we studied young (20-week) and old (90-week) C57BL/6J mice. Old mice received either regular or GlyNAC supplemented diets for 8 weeks, while young mice received the regular diet. Cognition and brain outcomes (GSH, OxS, mitochondrial energetics, autophagy/mitophagy, glucose transporters, inflammation, genomic damage and neurotrophic factors) were measured. Compared to young mice, the old-control mice had significant cognitive impairment and multiple brain defects. GlyNAC supplementation improved/corrected the brain defects and reversed ACD. This study finds that naturally-occurring ACD is associated with multiple abnormalities in the brain, and provides proof-of-concept that GlyNAC supplementation corrects these defects and improves cognitive function in aging.

Resonance Scanning as an Efficiency Enhancer for EEG-Guided Adaptive Neurostimulation.

Electroencephalogram (EEG)-guided adaptive neurostimulation is an innovative kind of non-invasive closed-loop brain stimulation technique that uses audio-visual stimulation on-line modulated by rhythmical EEG components of the individual. However, the opportunity to enhance its effectiveness is a challenging task and needs further investigation. The present study aims to experimentally test whether it is possible to increase the efficiency of EEG-guided adaptive neurostimulation by pre- strengthening the modulating factor (subject's EEG) through the procedure of resonance scanning, i.e., LED photostimulation with the frequency gradually increasing in the range of main EEG rhythms (4-20 Hz). Thirty-six university students in a state of exam stress were randomly assigned to two matched groups. One group was presented with the EEG-guided adaptive neurostimulation alone, whereas another matched group was presented with the combination of resonance scanning and EEG-guided adaptive neurostimulation. The changes in psychophysiological indicators after stimulation relative to the initial level were used. Although both types of stimulation led to an increase in the power of EEG rhythms, accompanied by a decrease in the number of errors in the word recognition test and a decrease in the degree of emotional maladjustment, these changes reached the level of significance only in experiments with preliminary resonance scanning. Resonance scanning increases the brain's responsiveness to subsequent EEG-guided adaptive neurostimulation, acting as a tool to enhance its efficiency. The results obtained clearly indicate that the combination of resonance scanning and EEG-guided adaptive neurostimulation is an effective way to reach the signs of cognitive improvement in stressed individuals.

Improvement of cognition across a decade after stroke correlates with the integrity of functional brain networks.

BACKGROUND AND OBJECTIVE: We recently reported improvements of working memory across 10 years post stroke among middle-aged individuals. However, the mechanisms underlying working-memory recovery are largely unknown. This study investigated the associations between long-term improvement of working memory and resting-state functional connectivity in two frontoparietal networks: the frontoparietal network and the dorsal attention network. METHODS: Working memory was repeatedly assessed by the Digit Span Backwards task in 21 persons, within 1 year after stroke onset and again 10 years post stroke onset. Brain functional connectivity was examined by resting state functional magnetic resonance imaging at the 10-year follow-up. RESULTS: A significant improvement of working memory was found among 21 persons after stroke (median age = 64) at the 10-year follow-up compared to the within-one-year assessment. The magnitude of performance improvement on the Digit Span Backwards task was significantly positively correlated with stronger brain connectivity in the frontoparietal network (r = 0.51, p = 0.018) measured at the 10-year follow-up only. A similar association was observed in the dorsal attention network (r = 0.43, p = 0.052) but not in a visual network (r = -0.17, p = 0.46) that served as a control network. The association between functional connectivity within the above-mentioned networks and Digit Span Backwards scores at 10-year after stroke was in the same direction but did not reach significance. CONCLUSIONS: The present work relate stronger long-term performance improvement on the Digit Span Backwards task with higher integrity of frontoparietal network connectivity.

Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement.

Phosphodiesterase 4 (PDE4), the largest member of PDE family, is highly expressed in mammalian brain. It selectively hydrolyzes the second messenger cyclic adenosine monophosphate (cAMP), a correlate of brain functions including learning, memory and cognitive abilities. Its inhibition is beneficial to counteract cognitive deficits. Thus, targeting PDE4 may be a viable strategy for cognitive improvement. Currently, many PDE4 inhibitors have been discovered but with a great hurdle in clinical development due to adverse effects such as emesis. Analysis of PDE4 subtypes and discovery of subtype specific regulators indicate therapeutic benefits with improved safety in preclinical and clinical models. Herein, we summarize PDE4 structure, describe PDE4 mediated signaling pathways, review the role of individual PDE4 subtypes and discuss the development of PDE4 inhibitors for cognitive improvement, trying to give an insight into the strategy for cognitive improvement with PDE4 inhibitors in future.

ß2-Microglobulin exacerbates neuroinflammation, brain damage, and cognitive impairment after stroke in rats.

ß2-Microglobulin (ß2M), a component of the major histocompatibility complex class I molecule, is associated with aging-related cognitive impairment and Alzheimer's disease. Although upregulation of ß2M is considered to be highly related to ischemic stroke, the specific role and underlying mechanistic action of ß2M are poorly understood. In this study, we established a rat model of focal cerebral ischemia by occlusion of the middle cerebral artery. We found that ß2M levels in the cerebral spinal fluid, serum, and brain tissue were significantly increased in the acute period but gradually decreased during the recovery period. RNA interference was used to inhibit ß2M expression in the acute period of cerebral stroke. Tissue staining with 2,3,5-triphenyltetrazolium chloride and evaluation of cognitive function using the Morris water maze test demonstrated that decreased ß2M expression in the ischemic penumbra reduced infarct volume and alleviated cognitive deficits, respectively. Notably, glial cell, caspase-1 (p20), and Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation as well as production of the inflammatory cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor-α were also effectively inhibited by ß2M silencing. These findings suggest that ß2M participates in brain injury and cognitive impairment in a rat model of ischemic stroke through activation of neuroinflammation associated with the NLRP3 inflammasome.

Efficacy of CPAP duration and adherence for cognitive improvement in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials.

PURPOSE: Obstructive sleep apnea (OSA) can impair cognition. Continuous positive airway pressure (CPAP) is a recommended treatment for OSA but its effectiveness on cognitive improvement is uncertain, a finding which may be biased by various durations and adherence to treatment with CPAP. In a meta-analysis assessing high-quality randomized controlled trials (RCTs), we estimated whether or not CPAP benefits cognition in patients with OSA. METHODS: PRISMA criteria were followed in the performance of this meta-analysis. The weighted mean difference (WMD) and 95% confidence interval (CI) of six neuropsychological scores covering eight cognitive domains were used to evaluate the benefit between CPAP and non-CPAP interventions. Subgroups of different therapeutic durations and adherence, which were divided into short-term (< 8 weeks) and long-term (≥ 12 weeks) durations, and poor (nighttime < 4 h/night) and good (nighttime ≥ 4 h/night) adherence were also analyzed. RESULTS: Among 16 RCTs, 1529 participants with OSA were included. Comparing the CPAP group and the control group for all treatment durations and adherence, a mild improvement for digit span forward which reflected short-term memory was observed (WMD[95%CI] = 0.67[0.03,1.31], p = 0.04). Trail making test-part B, which reflected executive function was improved for participants with OSA who had good adherence to CPAP (WMD[95%CI] = - 6.24[- 12.60,0.12], p = 0.05). Patients with OSA who received short-term CPAP treatment (WMD[95%CI] = - 7.20[- 12.57, - 1.82], p = 0.009) had a significant improvement in executive function when compared with controls. There was no statistical difference for all scales between long-term (≥ 12 weeks) CPAP treatment group and control group. CONCLUSION: The effectiveness of CPAP on cognitive improvement in patients with OSA is limited, although good adherence to CPAP can mildly benefit executive function with short-term effectiveness.

Effects of exergames on mood and cognition in healthy older adults: A randomized pilot study.

The elderly population is increasing and the implementation of stimulating training to promote active aging has become a research issue. This study aimed at investigating the effects of a cognitive-motor exergame training on cognitive functions and mood, in healthy older adults. A randomized controlled pilot study was conducted to compare a cognitive-motor exergame training with a passive control group. The training consisted of 8 sessions of 45 min each, including 10 interactive activities focused on several cognitive functions such as memory, processing speed and executive functions, all requiring motor planning and execution. A total of 57 participants were administered a battery of cognitive tests before and after the training. A mixed-effect ANOVA with group (experimental vs. control) as between factor and time (pre-and post-test) as within factor, was performed to evaluate the effect of the exergame training on cognitive abilities and mood. Results showed significant interaction effects in processing speed [STROOPC: F (1,53.4) = 9.04, p = 0.004, R 2 = 0.82], inhibition [3backs' false alarms: F (1,47.5) = 5.5, p = 0.02, R 2 = 0.79], and mood [Beck Depression Inventory: F (1,55) = 4.15, p = 0.04, R 2 = 0.6]. Even though post-hoc analyses did not provide statistical evidence supporting the interactions, overall data showed a trend toward better scores only for the experimental group, suggesting a potential improvement in information processing speed, working memory and mood. Exergaming may be a motivating and enjoyable approach to healthy and active aging.

Design, synthesis and evaluation of fused hybrids with acetylcholinesterase inhibiting and Nrf2 activating functions for Alzheimer's disease.

Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory (eeAChE IC50 = 0.07 ± 0.01 µM; hAChE IC50 = 0.38 ± 0.04 µM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H2O2 and Aß1-42 aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and Aß1-42. At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.