Tai Chi-Induced Exosomal LRP1 is Associated With Memory Function and Hippocampus Plasticity in aMCI Patients.

OBJECTIVES: The study was designed to identify the potential peripheral processes of circulating exosome in response to Tai Chi (TC) exercise and the possibility of its loaded cargos in mediating the effects of TC training on cognitive function among older adults with amnestic mild cognitive impairment (aMCI). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter randomized controlled trial. One hundred community-dwelling old adults with aMCI were randomly assigned (1:1) to experimental (n = 50) and control groups (n = 50). INTERVENTION: The experimental group participated in TC exercise 5 times/week, with each session lasting 60 minutes for 12 weeks. Both experimental and control groups received health education every 4 weeks. MEASUREMENTS: The primary outcome was global cognitive function. Neurocognitive assessments, MRI examination, and large-scale proteomics analysis of peripheric exosome were conducted at baseline and after 12-week training. Outcome assessors and statisticians were blinded to group allocation. RESULTS: A total of 96 participants (96%) completed all outcome measurements. TC training improved global cognitive function (adjusted mean difference [MD] = 1.9, 95%CI 0.93-2.87, p <0.001) and memory (adjusted MD = 6.42, 95%CI 2.09-10.74, p = 0.004), increased right hippocampus volume (adjusted MD = 88.52, 95%CI 13.63-163.4, p = 0.021), and enhanced rest state functional connectivity (rsFC) between hippocampus and cuneus, which mediated the group effect on global cognitive function (bootstrapping CIs: [0.0208, 1.2826], [0.0689, 1.2211]) and verbal delay recall (bootstrapping CI: [0.0002, 0.6277]). Simultaneously, 24 differentially expressed exosomal proteins were detected in tandem mass tag-labelling proteomic analysis. Of which, the candidate protein low-density lipoprotein receptor-related protein 1 (LRP1) was further confirmed by parallel reaction monitoring and ELISA. Moreover, the up-regulated LRP1 was both positively associated with verbal delay recall and rsFC (left hippocampus-right cuneus). CONCLUSION: TC promotes LRP1 release via exosome, which was associated with enhanced memory function and hippocampus plasticity in aMCI patients. Our findings provided an insight into potential therapeutic neurobiological targets focusing on peripheric exosome in respond to TC exercise.

Efficacy and safety of acupuncture combined with rehabilitation training for poststroke cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: Accumulated evidence has proven that both acupuncture and rehabilitation therapy are beneficial for stroke sequelae. However, there is no systematic review to identify the efficacy and safety of acupuncture combined with rehabilitation training for poststroke cognitive impairment (PSCI). Therefore, the aim of this study was to assess the efficacy and safety of acupuncture combined with rehabilitation therapy for patients with PSCI. METHODS: We searched nine databases, including PubMed, Embase, Scopus, Web of Science, EBSCO, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wan Fang, from their inception to September 2022. Randomized controlled trials (RCTs) examining the effect of acupuncture combined with rehabilitation on PSCI were included. The primary outcomes were the Mini-Mental State Examination (MMSE) score, Montreal Cognitive Assessment (MoCA) score, Modified Barthel Index (MBI) score, and Fugl-Meyer Assessment (FMA) score. The quality of the methodology was evaluated by Cochrane's risk of bias tool. Meta-analyses were performed by Revman 5.3 software. RESULTS: A total of 18 RCTs involving 1654 patients were included. The overall methodological quality of the included studies was low. Pooled results demonstrated that acupuncture combined with rehabilitation could significantly improve the clinical efficacy of PSCI (OR=3.23, 95% CI: 2.13 to 4.89), MMSE score (MD= 2.85, 95% CI: 2.56 to 3.15), MoCA score (MD= 2.18, 95% CI: 1.38 to 2.97), MBI score (MD= 9.23, 95% CI: 5.62 to 12.84), and FMA score (MD=5.72, 95% CI: 3.48 to 7.96). CONCLUSIONS: Acupuncture combined with rehabilitation may produce better outcomes than rehabilitation alone in the treatment of PSCI. However, the safety of combined interventions is still unclear. Therefore, research with more rigorous study designs and RCTs with larger sample sizes is still needed.

The impact of physical activity on blood inflammatory cytokines and neuroprotective factors in individuals with mild cognitive impairment: a systematic review and meta-analysis of randomized-controlled trials.

BACKGROUND: Accumulated evidence has proved that both neuroinflammation and neuroprotection existing at the stage of mild cognitive impairment (MCI) may mediate its progression, which can conversely be modulated by physical activity (PA). However, further research is needed to clarify which factors are involved in that process. OBJECTIVES: To identify the impact of PA on inflammatory cytokines and neuroprotective factors in individuals with MCI. METHODS: Four databases [PubMed, Cochrane Library, Cochrane Library (Trials), Embase and Web of Science Core Collection] were searched from their inception to October 2021 for randomized-controlled trials (RCTs) assessing the biochemical effect of PA on biomarkers in participants with MCI. Pooled effect size was calculated by the standardized mean difference (SMD). RESULTS: A total of 13 RCTs involving 514 participants by reporting 8 inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, -6, -8, -10, -15, C-reactive protein (CRP) and interferon-γ (IFN-γ) and 5 neuroprotective factors (brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), irisin] were included. The meta-analysis showed that PA had positive effects on decreasing TNF-α (SMD = - 0.32, 95% CI - 0.58 to 0.07, p = 0.01; I2 = 32%) and CRP (SMD = - 0.68, 95% CI - 1.05 to 0.32, p = 0.0002; I2 = 18%), while significantly improving BDNF (SMD = 0.32, 95% CI 0.09-0.56, p = 0.007; I2 = 42%) and IGF-1 (SMD = 0.42, 95% CI 0.03-0.81, p = 0.03; I2 = 0%). CONCLUSION: PA had a certain effect on inhibiting inflammatory cytokines but promoting neuroprotective factors in individuals with MCI which may provide a possible explanation for the potential molecular mechanism of PA on cognitive improvement.

Prefrontal Cortex Hemodynamics and Functional Connectivity Changes during Performance Working Memory Tasks in Older Adults with Sleep Disorders.

OBJECTIVE: Older adults with sleep disorders (SDs) show impaired working memory abilities, and working memory processes are closely related to the prefrontal cortex (PFC). However, the neural mechanism of working memory impairment in older adults with SD remains unclear. This study aimed to investigate changes in PFC function among older adults with SD when carrying out the N-back task by functional near-infrared spectroscopy (fNIRS). METHOD: A total of 37 older adults with SDs were enrolled in this study and matched with 37 healthy older adults by gender, age, and years of education. Changes in PFC function were observed by fNIRS when carrying out the N-back task. RESULTS: The accuracy on the 0-back and 2-back tasks in the SD group was significantly lower than that in the healthy controls (HC) group. The oxygenated hemoglobin (oxy-Hb) concentration of channel 8 which located in the dorsolateral prefrontal cortex (DLPFC) was significantly reduced in the SD group during the 2-back task, and the channel-to-channel connectivity between the PFC subregions was significantly decreased. CONCLUSIONS: These results suggest that patients with sleep disorders have a weak performance of working memory; indeed, the activation and functional connectivity in the prefrontal subregions were reduced in this study. This may provide new evidence for working memory impairment and brain function changes in elderly SDs.

The Prognostic Value of Domain-Specific Cognitive Abilities Assessed by Chinese Version of Oxford Cognitive Screen on Determining ADLs Recovery in Patients with Post-Stroke Cognitive Impairment.

Background: Poststroke cognitive impairment (PSCI) has been increasingly recognized in patients. However, it remains unclear whether ADLs recovery is more susceptible to domain-specific cognitive abilities after a stroke. Therefore, the study was designed to investigate the cognitive functions of patients with PSCI at admission by using the Chinese (Putonghua) Version of the Oxford Cognitive Screen (OCS-P) as well as to identify the prognostic value of domain-specific cognitive abilities on the recovery of ADLs when discharged. Methods: A total of 153 hospitalized stroke patients were included in this prospective study. Cognitive function was assessed by OCS-P when participants were admitted to the hospital. The ADLs were measured at admission and discharge, and recovery was estimated by the improvement between admission and discharge. A diagnostic model using logistic regression was constructed to identify the prognostic value of domain-specific cognitive abilities for ADLs. The efficacy and accuracy of the diagnostic model were assessed by receiver operating characteristic (ROC) and Hosmer-Lemeshow's goodness of fit test. The diagnostic model was validated by 10-fold cross-validation and presented as a nomogram. Results: The score of OCS-P was 60(49.75, 69). The most frequently impaired cognitive domain was number writing (60.8%), followed by verbal memory (52.9%). Multivariate logistic regression showed executive dysfunction was a risk prognostic factor of ADLs recovery (P < 0.001, OR = 3.176 [95% CI, 1.218∼8.278]). The ROC curve of the diagnostic model was 0.839, with a good diagnostic efficacy. Hosmer-Lemeshow test showed diagnostic model had good calibration ability (χ 2 = 8.939.3, P=0.347 > 0.05). The average error rate after adjustment of 10-fold cross-validation was 20.93%, within the acceptable range. Conclusions: Post-stroke patients generally suffered from multidimensional cognitive impairments. Executive dysfunction screened with OCS-P at clinical admission was a reliable and accessible predictive factor ADLs recovery in patients with PSCI. Early targeted rehabilitation programs are suggested to make them as earlier as possible, especially for those having executive dysfunction while hospitalized.

Effects of exercise interventions on executive function in old adults with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials.

AIMS: To assess the effect of exercise interventions on subdomains of executive function (EF) in older adults with mild cognitive impairment (MCI). METHODS: Nine electronic databases were comprehensively searched from their inception to February 2021. Randomized controlled trials examining the effect of exercise training on EF in MCI were included. RESULTS: Twenty-four eligible articles involving 2278 participants were identified. The results showed that exercise interventions had positive benefits on working memory, switching and inhibition in MCI. Subgroup analysis based on exercise prescriptions revealed that both aerobatic exercise and mind-body exercise had similar positive effect size on working memory. However, only mind-body exercise had significant effect on switching. Exercise training with moderate frequency (3-4 times/week) had larger effect size than low frequency (1-2 times/week) and only moderate frequency had positive benefits on switching. Both short (4-12 weeks), medium (13-24 weeks) and long (more than 24 weeks) exercise duration significantly ameliorate working memory and switching, however with short duration having slight larger effect sizes than medium and long. CONCLUSION: Exercise significantly improves three subdomains of EF in MCI, especially mind-body exercise. Exercise training sticking to at least 4 weeks with 3-4 times a week tends to have larger effect size.

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer's disease: a meta-analysis and systematic review.

Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aß1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).