Joint association of sedentary time and physical activity with abnormal heart rate recovery in young and middle-aged adults.

BACKGROUND: Abnormal heart rate recovery (HRR), representing cardiac autonomic dysfunction, is an important predictor of cardiovascular disease. Prolonged sedentary time (ST) is associated with a slower HRR. However, it is not clear how much moderate-to-vigorous physical activity (MVPA) is required to mitigate the adverse effects of sedentary behavior on HRR in young and middle-aged adults. This study aimed to examine the joint association of ST and MVPA with abnormal HRR in this population. METHODS: A cross-sectional analysis was conducted on 1253 participants (aged 20-50 years, 67.8% male) from an observational study assessing cardiopulmonary fitness in Fujian Province, China. HRR measured via cardiopulmonary exercise tests on a treadmill was calculated as the difference between heart rate at peak exercise and 2 min after exercise. When the HRR was ≤ 42 beats·minute-1 within this time, it was considered abnormal. ST and MVPA were assessed by the IPAQ-LF. Individuals were classified as having a low sedentary time (LST [< 6 h·day-1]) or high sedentary time (HST [≥ 6 h·day-1]) and according to their MVPA level (low MVPA [0-149 min·week-1], medium MVPA [150-299 min·week-1], high MVPA [≥ 300 min·week-1]). Finally, six ST-MVPA groups were derived. Associations between ST-MVPA groups with abnormal HRR incidence were examined using logistic regression models. RESULTS: 53.1% of the young and middle-aged adults had less than 300 min of MVPA per week. In model 2, adjusted for possible confounders (e.g. age, sex, current smoking status, current alcohol consumption, sleep status, body mass index), HST was associated with higher odds of an abnormal HRR compared to LST (odds ratio (OR) = 1.473, 95% confidence interval (CI) = 1.172-1.852). Compared with the reference group (HST and low MVPA), the HST and high MVPA groups have a lower chance of abnormal HRR (OR, 95% CI = 0.553, 0.385-0.795). Compared with individuals with HST and low MVPA, regardless of whether MVPA is low, medium, or high, the odds of abnormal HRR in individuals with LST is significantly reduced (OR, 95% CI = 0.515, 0.308-0.857 for LST and low MVPA; OR, 95% CI = 0.558, 0.345-0.902 for LST and medium MVPA; OR, 95% CI = 0.476, 0.326-0.668 for LST and high MVPA). CONCLUSION: Higher amounts of MVPA appears to mitigate the increased odds of an abnormal HRR associated with HST for healthy young and middle-aged adults.

Electroacupuncture improves vascular cognitive impairment no dementia: A Randomized Clinical Trial.

BACKGROUND: Electroacupuncture (EA) could represent a clinically effective treatment strategy for patients with vascular cognitive impairment no dementia (VCIND). This randomized trial aims to explore the underlying mechanism of EA in VCIND patients through cognitive function assessment and neuroimaging assessment. METHODS: 140 eligible patients with VCIND were recruited and randomly divided into EA group (n = 70) and Control group (n = 70). The Montreal Cognitive Assessment (MoCA), and the Auditory Verbal Learning Test (AVLT), the Stroop color-naming task (STROOP), and the resting-state functional magnetic resonance imaging assessment. The EA group received treatment for 30 min/day, 5 times/week, for 8 weeks. RESULTS: EA intervention could increase the MoCA score and improve the neutral and consistency response of the STROOP test in VCIND patients (P < 0.05). fMRI functional connectivity analysis showed that, after EA, the default mode network (DMN) function of the posterior cingulate gyrus, left middle frontal gyrus, left anterior cingulate gyrus, left and right superior temporal gyrus, right insula, left precentral gyrus and other brain regions were significantly higher than that in the control group. The functional connectivity between the posterior cingulate gyrus-left middle frontal gyrus and the posterior cingulate gyrus-right superior temporal gyrus was positively correlated with cognitive function (P < 0.05). Gray Matter Volume increased in VCIND after EA(P < 0.05). CONCLUSIONS: EA can increase the functional connectivity between posterior cingulate gyrus-other gyri in VCIND patients. The functional connectivity is positively correlated with cognitive function.

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.

Electroacupuncture regulates Rab5a-mediating NGF transduction to improve learning and memory ability in the early stage of AD mice.

AIMS: Nerve growth factor (NGF) loss is a potential factor for the degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD), and Rab5a is a key regulatory molecule of NGF signaling transduction. Here, we investigated the changes of Rab5a in 5 × FAD mice and further explored the mechanism of Electroacupuncture (EA) treatment in improving cognition in the early stage of AD. METHODS: The total Rab5a and Rab5a-GTP in 5-month-old 5 × FAD mice and wild-type mice were detected using WB and IP technologies. 5 × FAD mice were treated with EA at the Bai hui (DU20) and Shen ting (DU24) acupoints for 4 weeks and CRE/LOXP technology was used to confirm the role of Rab5a in AD mediated by EA stimulation. The Novel Object Recognition and Morris water maze tests were used to evaluate the cognitive function of 5 × FAD mice. The Nissl, immunohistochemistry, and Thioflavin S staining were used to observe pathological morphological changes in the basal forebrain circuit. The Golgi staining was used to investigate the synaptic plasticity of the basal forebrain circuit and WB technology was used to detect the expression levels of cholinergic-related and NGF signal-related proteins. RESULTS: The total Rab5a was unaltered, but Rab5a-GTP increased and the rab5a-positive early endosomes appeared enlarged in the hippocampus of 5 × FAD mice. Notably, EA reduced Rab5a-GTP in the hippocampus in the early stage of 5 × FAD mice. EA could improve object recognition memory and spatial learning memory by reducing Rab5a activity in the early stage of 5 × FAD mice. Moreover, EA could reduce Rab5a activity to increase NGF transduction and increase the levels of phosphorylated TrkA, AKT, and ERK in the basal forebrain and hippocampus, and increase the expression of cholinergic-related proteins, such as ChAT, vAchT, ChT1, m1AchR, and m2AchR in the basal forebrain and ChAT, m1AchR, and m2AchR in the hippocampus, improving synaptic plasticity in the basal forebrain hippocampal circuit in the early stage of 5 × FAD mice. CONCLUSIONS: Rab5a hyperactivation is an early pathological manifestation of 5 × FAD mice. EA could suppress Rab5a-GTP to promote the transduction of NGF signaling, and enhance the synaptic plasticity of the basal forebrain hippocampal circuit improving cognitive impairment in the early stage of 5 × FAD mice.

Reference Standards of Cardiorespiratory Fitness Measured With the Cardiopulmonary Exercise Test Using the Treadmill in Chinese Adults Younger Than 60 Years.

PURPOSE: Cardiorespiratory fitness (CRF) is a strong predictor of cardiorespiratory diseases and varies by race. The purpose of this study was to provide CRF reference standards and a prediction equation for peak oxygen uptake (V˙O 2peak ) from treadmill-based cardiopulmonary exercise testing (CPX) in Chinese individuals. METHODS: Healthy participants (n = 4199) who completed a CPX using a treadmill were studied. The percentiles of V˙O 2peak were determined for four age groups (decades). A regression prediction model was developed from the derivation cohort (n = 3361), validated in the independent validation cohort (n = 838), and compared with the widely used Wasserman equation and the Fitness Registry and the Importance of Exercise National Database (FRIEND) equation. RESULTS: The mean V˙O 2peak values of four age groups (20-29, 30-39, 40-49, and 50-59 yr) were 42.6, 41.2, 38.7, and 35.9 mL/kg/min, respectively, for men, and 37.1, 34.7, 32.0, and 30.3 mL/kg/min, respectively, for women. The 50th percentiles of relative V˙O 2peak decreased with age for both sexes. The prediction equation was: Absolute V˙O 2peak (mL/min) = 236.68 - (504.64 × sex [male = 0; female = 1]) + (21.23× weight [kg]) - (14.31 × age [yr]) + (9.46 × height [cm]) (standard error of the estimate = 379.59 mL/min, R2 = 0.66, P < .001).Percentage predicted V˙O 2peak for the validation sample was 100.2%. The novel equation performed better than the other two equations. CONCLUSION: This study reports the first CRF reference standards and prediction equation generated from treadmill CPX in China. These reference standards provide a framework for interpreting the CRF of the Chinese population and could be useful information for a global CRF database.

Inhibition of a novel Dickkopf-1-LDL receptor-related proteins 5 and 6 axis prevents diabetic cardiomyopathy in mice.

BACKGROUND AND AIMS: Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure-lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. METHODS: The roles of serum DKK1 and DKK1-LRP5/6 signalling in diabetic injuries were investigated in human and diabetic mice. RESULTS: Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. Notably, LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and hypertension, as well as ß-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used anti-hypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. CONCLUSIONS: These findings establish a novel DKK1-LRP5/6-GPCR pathway in inducing diabetic injuries and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects. Thus, monitoring and therapeutic elimination of blood DKK1 may be a promising strategy to attenuate diabetic injuries.

The modulation effects of the mind-body and physical exercises on the basolateral amygdala-temporal pole pathway on individuals with knee osteoarthritis.

Background/Objective: To investigate the modulatory effects of different physical exercise modalities on connectivity of amygdala subregions and its association with pain symptoms in patients with knee osteoarthritis (KOA). Methods: 140 patients with KOA were randomly allocated either to the Tai Chi, Baduanjin, Stationary cycling, or health education group and conducted a 12 week-long intervention in one of the four groups. The behavioral, magnetic resonance imaging (MRI), and blood data were collected at baseline and the end of the study. Results: Compared to the control group, all physical exercise modalities lead to significant increases in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (pain relief) and serum Programmed Death-1 (PD-1) levels. Additionally, all physical exercise modalities resulted in decreased resting state functional connectivity (rsFC) of the basolateral amygdala (BA)-temporal pole and BA-medial prefrontal cortex (mPFC). The overlapping BA-temporal pole rsFC observed in both Tai Chi and Baduanjin groups was significantly associated with pain relief, while the BA-mPFC rsFC was significantly associated with PD-1 levels. In addition, we found increased fractional anisotropy (FA) values, a measurement of water diffusion anisotropy of tissue that responded to changes in brain microstructure, within the mind-body exercise groups' BA-temporal pole pathway. The average FA value of this pathway was positively correlated with KOOS pain score at baseline across all subjects. Conclusions: Our findings suggest that physical exercise has the potential to modulate both functional and anatomical connectivity of the amygdala subregions, indicating a possible shared pathway for various physical exercise modalities.

The altered hippocampal functional connectivity and serum brain-derived neurotrophic factor level predict cognitive decline in patients with knee osteoarthritis.

Patients with knee osteoarthritis (KOA) often suffer from cognitive decline and increased dementia risk, but the neurobiological mechanisms remain unclear. In this study, we evaluated cognitive performance and collected brain magnetic resonance imaging (MRI) data and blood samples from cognitively normal KOA patients at baseline sessions and reevaluated their cognition after 5 years. We also collected MRI data from matched healthy controls. Results showed that KOA patients exhibited dysregulated functional connectivities between the hippocampus and thalamus/superior frontal gyrus compared with healthy controls. The altered hippocampal functional connectivities were associated with serum brain-derived neurotrophic factor (BDNF) levels and spatial expression of genes enriched in synaptic plasticity. The hippocampus-thalamus functional connectivity was significantly correlated with patients' memory scores. Moreover, the baseline hippocampus-thalamus functional connectivity and BDNF levels significantly predicted the development of cognitive decline in KOA patients in the follow-up session. Our findings provide insight into the neurobiological underpinnings of KOA and cognitive decline.

Effects of Exercise Training Under Hypoxia versus Normoxia on Cognitive Function in Clinical and Non-Clinical Populations: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare the effects of exercise training under hypoxia versus normoxia on cognitive function in clinical and non-clinical populations. DATA SOURCES: From inception to June 13th, 2022, a systematic search was performed on PubMed, Web of Science, Embase, Scopus, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomized controlled trials comparing the effects of exercise under hypoxic vs normoxic on cognition in clinical and non-clinical populations were included. The systematic search generated 14,894 relevant studies, of which 12 were finally included. DATA EXTRACTION: Two reviewers independently extracted data from included studies. Results were expressed as standardized mean difference (SMD). Each included study was assessed using the Cochrane Risk of Bias 1.0 (RoB1.0) tool. Finally, the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to rate the certainty of evidence for each outcome. DATA SYNTHESIS: Overall, 12 studies with a total of 338 participants met the inclusion criteria. The pooled results suggested that hypoxia exercise had a small but not statistically significant positive effect on overall cognitive function (SMD=0.064, 95% confidence interval (CI): -0.156-0.284, P=.567, very low-certainty evidence), when compared with normoxic exercise. Regarding the domain-specific cognitive functions, there was a medium and significant positive effect on memory (SMD=0.594, 95% CI: 0.068 to 1.120, P=.027, very low-certainty evidence), while effects on visuospatial function (SMD=0.490, 95% CI: -0.030 to 1.010, P=.065, very low-certainty evidence), attention (SMD=0.037, 95% CI: -0.340 to 0.414, P=.847, very low-certainty evidence), executive function (SMD=0.096, 95% CI: -0.268 to 0.460, P=.605, very low-certainty evidence), and processing speed (SMD=-0.145, 95% CI: -0.528 to 0.239, P=.459, very low-certainty evidence) were not statistically significant. CONCLUSIONS: The current pooled results revealed that hypoxic exercise was related to improved cognitive performance. Nevertheless, exercise under hypoxia did not have a significant advantage in cognitive promotion when compared with exercise under normoxia.

Effects of computerized cognitive training on structure‒function coupling and topology of multiple brain networks in people with mild cognitive impairment: a randomized controlled trial.

BACKGROUND: People with mild cognitive impairment (MCI) experience a loss of cognitive functions, whose mechanism is characterized by aberrant structure‒function (SC-FC) coupling and topological attributes of multiple networks. This study aimed to reveal the network-level SC-FC coupling and internal topological changes triggered by computerized cognitive training (CCT) to explain the therapeutic effects of this training in individuals with MCI. METHODS: In this randomized block experiment, we recruited 60 MCI individuals and randomly divided them into an 8-week multidomain CCT group and a health education control group. The neuropsychological outcome measures were the Montreal Cognitive Assessment (MoCA), Chinese Auditory Verbal Learning Test (CAVLT), Chinese Stroop Color-Word Test (SCWT), and Rey-Osterrieth Complex Figure Test (Rey CFT). The brain imaging outcome measures were SC-FC coupling and topological attributes using functional MRI and diffusion tensor imaging methods. We applied linear model analysis to assess the differences in the outcome measures and identify the correspondence between the changes in the brain networks and cognitive functions before and after the CCT. RESULTS: Fifty participants were included in the analyses after the exclusion of three dropouts and seven participants with low-quality MRI scans. Significant group × time effects were found on the changes in the MoCA, CAVLT, and Rey CFT recall scores. The changes in the SC-FC coupling values of the default mode network (DMN) and somatomotor network (SOM) were higher in the CCT group than in the control group (P(unc.) = 0.033, P(unc.) = 0.019), but opposite effects were found on the coupling values of the visual network (VIS) (P(unc.) = 0.039). Increasing clustering coefficients in the functional DMN and SOM and subtle changes in the nodal degree centrality and nodal efficiency of the right dorsal medial prefrontal cortex, posterior cingulate cortex, left parietal lobe, somatomotor area, and visual cortex were observed in the CCT group (P < 0.05, Bonferroni correction). Significant correspondences were found between global cognitive function and DMN coupling values (P(unc.) = 0.007), between immediate memory and SOM as well as FPC coupling values (P(unc.) = 0.037, P(unc.) = 0.030), between delayed memory and SOM coupling values (P(unc.) = 0.030), and between visual memory and VIS coupling values (P(unc.) = 0.007). CONCLUSIONS: Eight weeks of CCT effectively improved global cognitive and memory functions; these changes were correlated with increases in SC-FC coupling and changes in the topography of the DMN and SOM in individuals with MCI. The CCT regimen also modulated the clustering coefficient and the capacity for information transformation in functional networks; these effects appeared to underlie the cognitive improvement associated with CCT. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000034012. Registered on 21 June 2020.

Electroacupuncture protective effects after cerebral ischemia are mediated through miR-219a inhibition.

BACKGROUND: Electroacupuncture (EA) is a complementary and alternative therapy which has shown protective effects on vascular cognitive impairment (VCI). However, the underlying mechanisms are not entirely understood. METHODS: Rat models of VCI were established with cerebral ischemia using occlusion of the middle cerebral artery or bilateral common carotid artery. The brain structure and function imaging were measured through animal MRI. miRNA expression was detected by chip and qPCR. Synaptic functional plasticity was detected using electrophysiological techniques. RESULTS: This study demonstrated the enhancement of Regional Homogeneity (ReHo) activity of blood oxygen level-dependent (BOLD) signal in the entorhinal cortical (EC) and hippocampus (HIP) in response to EA treatment. miR-219a was selected and confirmed to be elevated in HIP and EC in VCI but decreased after EA. N-methyl-D-aspartic acid receptor1 (NMDAR1) was identified as the target gene of miR-219a. miR-219a regulated NMDAR-mediated autaptic currents, spontaneous excitatory postsynaptic currents (sEPSC), and long-term potentiation (LTP) of the EC-HIP CA1 circuit influencing synaptic plasticity. EA was able to inhibit miR-219a, enhancing synaptic plasticity of the EC-HIP CA1 circuit and increasing expression of NMDAR1 while promoting the phosphorylation of downstream calcium/calmodulin-dependent protein kinase II (CaMKII), improving overall learning and memory in VCI rat models. CONCLUSION: Inhibition of miR-219a ameliorates VCI by regulating NMDAR-mediated synaptic plasticity in animal models of cerebral ischemia.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Computerized Cognitive Training Enhances Episodic Memory by Down-Modulating Posterior Cingulate-Precuneus Connectivity in Older Persons With Mild Cognitive Impairment: A Randomized Controlled Trial.

OBJECTIVE: The neural mechanisms underlying the beneficial effects of a computerized cognitive training (CCT) program for improving episodic memory in older persons with mild cognitive impairment (MCI) remain unclear. This study aimed to use both functional and structural brain changes to elucidate the treatment effects of CCT on enhancing episodic memory. DESIGN, SETTING, AND PARTICIPANTS: Single-blinded, multicenter randomized controlled trial on 60 older adults with MCI in Fuzhou, China. INTERVENTION: Participants were randomly assigned to either an 8-week 24-hour CCT program or a health education program as the control. MEASUREMENTS: Clinical outcomes included changes in scores on the immediate and/or delayed recall subtests of the Chinese auditory verbal learning test (CAVLT) and rey complex figure test (CFT), and changes in gray matter volume and the functional connectivity of the posterior cingulate cortex (PCC) and hippocampus in the Papez circuit on magnetic resonance imaging. RESULTS: Significant group-by-time effects showed greater improvements in both immediate and delayed recall scores of CAVLT and delayed recall scores of Rey CFT in participants receiving the CCT program compared to those in the health education program. Among the CCT participants, seed-based analyses revealed decreases in functional connectivity of the PCC and hippocampus with neural substrates in the parietal and occipital regions. The decreased PCC and precuneus connectivity were found to mediate patients' improvements in immediate recall function. CONCLUSION: An 8-week CCT program was effective for improving episodic memory in older individuals with MCI. The decrease in connectivity originating from the PCC and hippocampus is suggestive of potential plastic changes in the Papez circuit, which could have alleviated the age-related compensatory mechanism. The findings of this study also shed light on expanding the content and extending the frequency and duration of the CCT program in future studies.

Effects of Tai Chi Chuan on Cognitive Function in Adults 60 Years or Older With Type 2 Diabetes and Mild Cognitive Impairment in China: A Randomized Clinical Trial.

Importance: Type 2 diabetes (T2D) is associated with the progression of cognitive dysfunction. Physical activity benefits cognition, but no evidence from randomized clinical trials has shown whether tai chi chuan has better long-term benefits than fitness walking in cognitive function for patients with T2D and mild cognitive impairment (MCI). Objective: To compare the effectiveness of tai chi chuan, a mind-body exercise, for improving cognitive function in older adults with T2D and MCI, with fitness walking. Design, Setting, and Participants: This randomized clinical trial was conducted between June 1, 2020, and February 28, 2022, at 4 sites in China. Participants included 328 adults (aged ≥60 years) with a clinical diagnosis of T2D and MCI. Interventions: Participants were randomized in a 1:1:1 ratio to a tai chi chuan group, a fitness walking group, or a control group. The tai chi chuan group received 24-form simplified tai chi chuan. The fitness walking group received fitness walking training. Both exercise groups took the training for 60 min/session, 3 times/wk, for 24 weeks in a supervised setting. All 3 groups were provided with a 30-minute diabetes self-management education session, once every 4 weeks for 24 weeks. The participants were followed up for 36 weeks. Main Outcomes and Measures: The primary outcome was the global cognitive function measured at 36 weeks by the Montreal Cognitive Assessment (MoCA). Secondary outcomes included MoCA at 24 weeks and other cognitive subdomain measures and blood metabolic indices at 24 and 36 weeks. Results: A total of 328 participants (mean [SD] age, 67.55 [5.02] years; mean [SD] T2D duration, 10.48 [6.81] years; 167 [50.9%] women) were randomized to the tai chi chuan group (n = 107), fitness walking group (n = 110), or control group (n = 111) and included in the intention-to-treat analysis. At 36 weeks, the tai chi chuan group showed improved MoCA scores compared with the fitness walking group (mean [SD], 24.67 [2.72] vs 23.84 [3.17]; between-group mean difference, 0.84 [95% CI, 0.02-1.66]; P = .046) in the intention-to-treat analysis. The per-protocol analysis data set and subgroup analysis at 36 weeks showed similar results. Based on the generalized linear models, the treatment effects were similar in each group after adjusting for self-reported dietary calories and physical activity. There were 37 nonserious adverse events (tai chi chuan group, 8; fitness walking group, 13; control group, 16) unrelated to the study with no statistically significant difference among the 3 groups (P = .26). Conclusions and Relevance: In this randomized clinical trial including older adults with T2D and MCI, tai chi chuan was more effective than fitness walking in improving global cognitive function. The findings support a long-term benefit, suggesting the potential clinical use of tai chi chuan as an exercise intervention to improve cognitive function for older adults with T2D and MCI. Trial Registration: ClinicalTrials.gov Identifier: NCT04416841.

Increased low frequency fluctuation in the brain after acupuncture treatment in CSVDCI patients: A randomized control trial study.

Background: Cerebral small vessel disease (CSVD) is one of two cognition-impairing diseases. Acupuncture (Acu) is a flexible treatment with few adverse effects and is thus widely used to treat neurological problems. Methods: We recruited a total of 60 patients and assigned them to two groups (n = 30 each group). During the study, some participants were excluded by quality control, and a total of 44 subjects (25 Acu and 19 controls) were completed to investigate the therapeutic efficacy of acupuncture on CSVD cognitive impairment (CSVDCI). The following demographic and clinical variables were compared between the two groups: gender, age, education, smoking, alcohol, Montreal cognitive assessment (MoCA), symbol digit modalities test (SDMT), verbal fluency test (VFT), digit span task (DST), Boston naming test (BNT) scores, and amplitude of low-frequency fluctuation (ALFF) under the typical band (0.01-0.08 Hz). Mixed effect analysis was utilized to test for differences between the two groups before and after the treatment. Results: Following acupuncture treatment, the Acu group scored higher on MoCA, SDMT, VFT, DST, and BNT compared to controls (P < 0.05). The brain regions showing substantially greater ALFF values in the Acu group were the right inferior temporal gyrus, left middle occipital gyrus, left superior occipital gyrus, left insula, bilateral postcentral gyrus, right superior parietal gyrus, right cerebellum, right precuneus, and right precentral gyrus (P < 0.005, no correction). The ALFF values in the right inferior temporal gyrus (P = 0.027), left middle occipital gyrus (P = 0.005), left superior occipital gyrus (P = 0.011), and right superior parietal gyrus (P = 0.043) were positively associated with MoCA. Conclusion: We found that acupuncture modulates the functional activity of temporal, occipital, and parietal regions of the brain in CSVDCI patients.

An Effective Test (EOmciSS) for Screening Older Adults With Mild Cognitive Impairment in a Community Setting: Development and Validation Study.

BACKGROUND: Early detection of mild cognitive impairment (MCI) symptoms is an important step to its diagnosis and intervention. We developed a new screening test called "Efficient Online MCI Screening System" (EOmciSS) for use in community-dwelling older adults. It is a self-paced cognitive test to be completed within 10 minutes on tablets or smartphones in homes or care centers for older adults. OBJECTIVE: This study aims to test the validity of EOmciSS for identifying community-dwelling older adults with MCI risks. METHODS: Participants (N=827) completed EOmciSS and other screening tests for MCI. The psychometric properties tested were "subscale item difficulty," "discriminative index," "internal consistency," and "construct validity." We also tested between-group discrimination using the cross-validation method in an MCI group and a normal cognitive function (NCF) group. RESULTS: A total of 3 accuracy factors and 1 reaction time factor explained the structure of the 20 item factors. The difficulty level of accuracy factors (ie, "trail making," "clock drawing," "cube copying," "delayed recall") was 0.63-0.99, whereas that of the reaction time factor was 0.77-0.95. The discriminative index of the medium-to-high-difficulty item factors was 0.39-0.97. The internal consistency (Cronbach α) ranged from .41 (for few item factors) to .96. The training data set contained 9 item factors (CC-Acc1, P<.001; CD-Acc1, P=.07; CD-Acc2, P=.06; CD-Acc3, P<.001; TM-Acc4, P=.07; DR-Acc1, P=.03; RS, P=.06; DR-RT1, P=.02; and DR-RT2, P=.05) that were significant predictors for an MCI classification versus NCF classification. Depressive symptoms were identified as significant factors (P<.001) influencing the performance of participants, and were an integral part of our test system. Age (P=.15), number of years of education (P=.18), and proficiency in using an electronic device (P=.39) did not significantly influence the scores nor classification of participants. Application of the MCI/NCF cutoff score (7.90 out of 9.67) to the validation data set yielded an area under the curve of 0.912 (P<.001; 95% CI 0.868-0.955). The sensitivity was 84.9%, specificity was 85.1%, and the Youden index was 0.70. CONCLUSIONS: EOmciSS was valid and reliable for identifying older adults with significant risks of MCI. Our results indicate that EOmciSS has higher sensitivity and specificity than those of the Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment and the Computerized Cognitive Screen. The user interface, online operation, and self-paced format allowed the test system to be operated by older adults or their caregivers in different settings (eg, home or care centers for older adults). Depressive symptoms should be an integral part in future MCI screening systems because they influence the test performance and, hence, MCI risk. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000039411; http://www.chictr.org.cn/showprojen.aspx?proj=62903.

Ischemic stroke rehabilitation through optogenetic modulation of parvalbumin neurons in the contralateral motor cortex.

BACKGROUND: Based on the theory of interhemispheric inhibition and the bimodal balance-recovery model in stroke, we explored the effects of excitation/inhibition (E/I) of parvalbumin (PV) neurons in the contralateral primary motor cortex (cM1) connecting the ipsilateral M1 (iM1) via the corpus callosum (cM1-CC-iM1) of ischemic stroke rats by optogenetic stimulation. METHODS: We tested this by injecting anterograde and retrograde virus in rats with middle cerebral artery occlusion (MCAO), and evaluated the neurological scores, motor behavior, volume of cerebral infarction and the E/I balance of the bilateral M1 two weeks after employing optogenetic treatment. RESULTS: We found that concentrations of Glu and GABA decreased and increased, respectively, in the iM1 of MCAO rats, and that the former increased in the cM1, suggesting E/I imbalance in bilateral M1 after ischemic stroke. Interestingly, optogenetic stimulation improved M1 E/I imbalance, as illustrated by the increase of Glu in the iM1 and the decrease of GABA in both iM1 and cM1, which were accompanied by an improvement in neurological deficit and motor dysfunction. In addition, we observed a reduced infarct volume, an increase in the expression of the NMDAR and AMPAR, and a decrease in GAD67 in the iM1 after intervention. CONCLUSIONS: Optogenetic modulation of PV neurons of the iM1-CC-cM1 improve E/I balance, leading to reduced neurological deficit and improved motor dysfunction following ischemic stroke in rats.

Causal influences of salience/cerebellar networks on dorsal attention network subserved age-related cognitive slowing.

Age-related cognitive slowing is a prominent precursor of cognitive decline. Functional neuroimaging studies found that cognitive processing speed is associated with activation and coupling among frontal, parietal and cerebellar brain networks. However, how the reciprocal influences of inter- and intra-network coupling mediate age-related decline in processing speed remains insufficiently studied. This study examined how inter- and intra-brain network influences mediate age-related slowing. We were interested in the fronto-insular salience network (SN), frontoparietal dorsal attention network (DAN), cerebellar network (CN) and default mode network (DMN). Reaction time (RT) and functional MRI data from 84 participants (aged 18-75) were collected while they were performing the Arrow Task in visual or audial forms. At the subject level, effective connectivities (ECs) were estimated with regression dynamic causal modelling. At the group level, structural equation models (SEMs) were used to model latent speed based on age and the EC mediators. Age was associated with decreased speed and increased inter-network effective connectivity. The CN exerting influence on the DAN (CN → DAN EC) mediated, while the SN → DAN EC suppressed age-related slowing. The DMN and intra-network ECs did not seem to play significant roles in slowing due to ageing. Inter-network connectivity from the CN and SN to the DAN contributes to age-related slowing. The seemingly antagonizing influences of the CN and SN indicate that increased task-related automaticity and decreased effortful control on top-down attention would promote greater speed in older individuals.

Targeting lactate-related cell cycle activities for cancer therapy.

Lactate has long been considered as a metabolic by-product of aerobic glycolysis for cancer. However, more and more studies have shown that lactate can regulate cancer progression via multiple mechanisms such as cell cycle regulation, immune suppression, energy metabolism and so on. A recent discovery of lactylation attracted a lot of attention and is already a hot topic in the cancer field. In this review, we summarized the latest functions of lactate and its underlying mechanisms in cancer. We also included our analysis of protein lactylation in different rat organs and compared them with other published lactylation data. The unresolved challenges in this field were discussed, and the potential application of these new discoveries of lactate-related cell cycle activities for cancer target therapy was speculated.

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.