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BackgroundThe fronto-cerebellar functional network has been proposed to subserve cognitive processing speed. This study aims to elucidate how the long-range frontal-to-cerebellar effective connectivity contributes to faster speed.MethodsIn total, 60 healthy participants were randomly allocated to three five-daily sessions of transcranial magnetic stimulation conditions, namely intermittent theta-burst stimulation (iTBS, excitatory), continuous theta-burst stimulation (CTBS, inhibitory), or a sham condition. The sites of the stimulations were the right pre-supplementary motor area (RpSMA), medial cerebellar vermis VI (MCV6), and vertex, respectively. Performances in two reaction time tasks were recorded at different time points.ResultsPost-stimulation speeds revealed marginal decreases in the simple but not complex task. Nevertheless, participants in the excitatory RpSMA and inhibitory MCV6 conditions showed direct and negative path effects on faster speeds compared to the sham condition in the simple reaction time (SRT) task (β = −0.320, p = 0.045 and β = −0.414, p = 0.007, respectively). These path effects were not observed in the SDMT task.DiscussionRpSMA and MCV6 were involved in promoting the path effects of faster reaction times on simple cognitive task. This study offers further evidence to support their roles within the long-range frontal-to-cerebellar connectivity subserving cognitive processing speed. The enhancement effects, however, are likely limited to simple rather than complex mental operations.

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 Aβ1–42, 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).

IntroductionLow physical activity (LPA) is associated with several major non-communicable diseases (NCDs) and premature mortality. In this study, we aimed to assess the global burden and trends in disease attributable to LPA (DALPA) from 1990 to 2019.MethodsAnnual age-standardized disability-adjusted life years (DALYs) and death rates of DALPA [all-cause and five specific causes (ischaemic heart disease, diabetes mellitus, stroke, colon and rectal cancer, and breast cancer)] by sex, age, geographical region and social deprivation index (SDI) score from 1990 to 2019 were available from the Global Burden of Disease (GBD) study 2019. The estimated annual percentage changes (EAPCs) were calculated to quantify the changing trend. A generalized linear model (GLM) was used to explore the relationship between DALYs/death rates of DALPA and sociodemographic factors.ResultsGlobally, in 2019, the age-standardized DALYs and death rates of DALPA were 198.42/100,000 (95% UI: 108.16/100,000–360.32/100,000) and 11.10/100,000 (95% UI: 5.66/100,000–19.51/100,000), respectively. There were 15.74 million (8.51–28.61) DALYs and 0.83 million (0.43–1.47) deaths attributable to LPA. Overall, age-standardized DALYs and death rates presented significant downward trends with EAPCs [−0.68% (95% CI: −0.85– −0.50%) for DALYs and −1.00% (95% CI: −1.13– −0.86%) for deaths] from 1990 to 2019. However, age-standardized DALYs and death rates of diabetes mellitus attributable to LPA were substantially increased [EAPC: 0.76% (95% CI: 0.70–0.82%) for DALYs and 0.33% (95% CI: 0.21–0.51%) for deaths]. In the 15–49 age group, DALPA presented significant upward trends [EAPC: 0.74% (95% CI: 0.58–0.91%) for DALYs and 0.31% (95% CI: 0.1–0.51%) for deaths]. The GLM revealed that higher gross domestic product and current health expenditure (% of GDP) were negatively associated with DALYs and death rates of DALPA.ConclusionAlthough global age-standardized DALYs and death rates of DALPA presented downward trends, they still cause a heavy burden worldwide. These rates showed upward trends in the diabetic and 15–49 age groups, which need more attention and health interventions.

The effect of exercise intervention on balance capacity among type 2 diabetes mellitus (T2DM) patients has not been evaluated. The objective of this systematic review and meta-analysis is to investigate the effect of exercise intervention on balance capacity among T2DM patients compared to the control group (usual care, waitlist, no-treatment, education). We conducted a comprehensive literature search through PubMed, EMBASE, Physiotherapy Evidence Database (PEDro), Cochrane library, Web of Science (WOS) from inception to August 2020. The literature language was limited to English. Randomized controlled trials (RCTs) or quasi-experimental (Q-E) trials that examined the effect of exercise intervention on balance capacity among T2DM patients were included. We used the standard methods of meta-analysis to evaluate the outcomes of exercise intervention for balance capacity of T2DM patients. A total of 14 trials (11 RCTs and 3 Q-E trials) involving 883 participants were eligible. The meta-analysis of some studies demonstrated that exercise intervention could significantly improve Berg Balance Scale (BBS) (MD = 2.56; 95%CI [0.35, 4.77]; P = .02), SLST (Single Leg Stance Test) under the eyes-open (EO) condition (MD = 3.63; 95%CI [1.79, 5.47]; P = .0001) and eyes-close (EC) condition (MD = 0.41; 95%CI [0.10, 0.72]; P = .01) compared to control group. There was no significant difference in Time Up and Go Test (TUGT) (MD = −0.75; 95%CI [−1.69, 0.19]; P = .12) and fall efficacy (SMD = −0.44; 95%CI [−0.86, −0.01]; P = .05). Narrative review of some studies indicated that exercise intervention could improve postural stability measured by Sensory Organization Test (SOT) and Center of Pressure (COP) variables, etc. This systematic review and meta-analysis summarized that exercise intervention could improve balance capacity in T2DM patients. However, further studies with high quality are required to evaluate its effect.

ObjectiveThis study explored whether acupuncture affects the maintenance of long-term potentiation (LTP)-like plasticity induced by transcranial magnetic stimulation (TMS) and the acquisition of motor skills following repetitive sequential visual isometric pinch task (SVIPT) training.MethodsThirty-six participants were recruited. The changes in the aftereffects induced by intermittent theta-burst stimulation (iTBS) and followed acupuncture were tested by the amplitude motor evoked potential (MEP) at pre-and-post-iTBS for 30 min and at acupuncture-in and -off for 30 min. Secondly, the effects of acupuncture on SVIPT movement in inducing error rate and learning skill index were tested.ResultsFollowing one session of iTBS, the MEP amplitude was increased and maintained at a high level for 30 min. The facilitation of MEP was gradually decreased to the baseline level during acupuncture-in and did not return to a high level after needle extraction. The SVIPT-acupuncture group had a lower learning skill index than those in the SVIPT group, indicating that acupuncture intervention after SVIPT training may restrain the acquisition ability of one’s learning skills.ConclusionAcupuncture could reverse the LTP-like plasticity of the contralateral motor cortex induced by iTBS. Subsequent acupuncture may negatively affect the efficacy of the acquisition of learned skills in repetitive exercise training.

Stroke is a disease of the leading causes of mortality and disability across the world, but the benefits of drugs curative effects look less compelling, intracellular calcium overload is considered to be a key pathologic factor for ischemic stroke. Gualou Guizhi decoction (GLGZD), a classical Chinese medicine compound prescription, it has been used to human clinical therapy of sequela of cerebral ischemia stroke for 10 years. This work investigated the GLGZD improved prescription against intracellular calcium overload could decreased the concentration of [Ca2+]i in cortex and striatum neurone of MCAO rats. GLGZD contains Trichosanthin and various small molecular that they are the potential active ingredients directed against NR2A, NR2B, FKBP12 and Calnodulin target proteins/enzyme have been screened by computer simulation. “Multicomponent systems” is capable to create pharmacological superposition effects. The Chinese medicine compound prescriptions could be considered as promising sources of candidates for discovery new agents.

Recovery following stroke involves neurogenesis and axonal remodeling within the ischemic brain. Gualou Guizhi decoction (GLGZD) is a Chinese traditional medicine used for the treatment of post-stroke limb spasm. GLGZD has been reported to have neuroprotective effects in cerebral ischemic injury. However, the effects of GLGZD on neurogenesis and axonal remodeling following cerebral ischemia remain unknown. In this study, a rat model of focal cerebral ischemia/reperfusion was established by middle cerebral artery occlusion. Neurological function was assessed immediately after reperfusion using Longa's 5-point scoring system. The rats were randomly divided into vehicle and GLGZD groups. Rats in the sham group were given sham operation. The rats in the GLGZD group were intragastrically administered GLGZD, once daily, for 14 consecutive days. The rats in the vehicle and sham groups were intragastrically administered distilled water. Modified neurological severity score test, balance beam test and foot fault test were used to assess motor functional changes. Nissl staining was performed to evaluate histopathological changes in the brain. Immunofluorescence staining was used to examine cell proliferation using the marker 5-bromo-2′-deoxyuridine (BrdU) as well as expression of the neural precursor marker doublecortin (DCX), the astrocyte marker glial fibrillary acidic protein (GFAP) and the axon regeneration marker growth associated protein-43 (GAP-43). GLGZD substantially mitigated pathological injury, increased the number of BrdU, DCX and GFAP-immunoreactive cells in the subventricular zone of the ischemic hemisphere, increased GAP-43 expression in the cortical peri-infarct region, and improved motor function. These findings suggest that GLGZD promotes neurological functional recovery by increasing cell proliferation, enhancing axonal regeneration, and increasing the numbers of neuronal precursors and astrocytes in the peri-infarct area.

Objective(s): Stroke may cause severe neuronal damage. The sesamin have been demonstrated to possess neuroprotection by its antioxidant and anti-inflammatory properties. One sesamin derivative was artificially composited, 1, 2-bis [(3-methoxyphenyl) methyl] ethane-1, 2-dicaroxylic acid (MMEDA) had been developed to study its antioxidative activity and neuroprotection. Materials and Methods: The infaction of Sprague Dawley (SD) rats and hypoxia models of BV-2 microglia or PC12 cells were investigated for in vivo and in vitro test respectively. Lipid peroxidation and reactive oxygen species (ROS), prostaglandin E2 (PGE2) and related signaling pathways from hypoxic cells were analyzed by ELISA or Western blot assay, respectively. Results: MMEDA showed a protective effect when given 90 min after the focal cerebral ischemia. The neuroprotection of MMEDA was further confirmed by attenuating ROS and PGE2 release from hypoxic BV-2 or PC12 cells. MMEDA significantly reduced hypoxia-induced JNK and caspase-3 (survival and apoptotic pathways) in PC12 cells. Conclusion: The neuroprotective effect of MMEDA on ischemia/hypoxia models was involved with its antioxidative activity and anti-inflammatory effects. These results suggest that MMEDA exert effective neuroprotection against ischemia/hypoxia injury.

Salidroside, a phenylpropanoid glycoside, is the main bioactive component of Rhodiola rosea L. Salidroside has prominent anti-stroke effects in cerebral ischemia/reperfusion models. However, the underlying mechanisms of its actions are poorly understood. This study examined the anti-stroke effects of salidroside in middle cerebral artery occlusion (MCAO)-induced rat model of stroke and its potential mechanisms involving the dopaminergic system. Salidroside administration increased the levels of dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in the ipsilateral striatum after induction of transient ischemia, which were assessed using microdialysis with high-performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). Furthermore, treatment with salidroside ameliorated neurobehavioral impairment, assessed with the modified neurological severity scores (mNSS), the balance beam test, and the foot fault test. Moreover, enzyme-linked immunosorbent assay (ELISA) suggested that MCAO-induced reduction in monoamine oxidase (MAO) was inhibited by salidroside. Immunohistochemical and immunofluorescence analyses revealed high level of tyrosine hydroxylase (TH) in the ipsilateral striatal caudate putamen (CPu) after cerebral ischemia/reperfusion, which could be further elevated by salidroside. In addition, salidroside could reverse the decreased immunoreactivity of TH in the substantia nigra pars compacta (SNpc). These results suggest that the anti-stroke effects of salidroside in MCAO-induced cerebral ischemia/reperfusion may involve the modulation of monoamine metabolism in the striatum and SNpc, which may be related to the function of the dopaminergic system in the rat brain.

The aim of this study was to investigate the time-dependent effects of acupuncture on the excitability and long-term potentiation- (LTP-) like plasticity induced by paired-associative stimulation (PAS) over the primary motor cortex (M1). The present examination is the first to report the influence of acupuncture on the motor-evoked potential (MEP) throughout the treatment process, including baseline (before acupuncture), the needle in situ, and the needle removal. Subsequently, the LTP-like plasticity induced by paired-associative stimulation (PAS) was explored, which consisted of 200 pairs of electrical stimulation of the ulnar nerve at the first dorsal interosseous (FDI), followed by transcranial magnetic stimulation (TMS) over the bilateral M1. TMS-MEP amplitudes over the bilateral M1 in resting conditions were measured throughout the whole treatment process. Finally, we confirmed the behavioral measurements. Significant changes were found in both the contralateral and ipsilateral acupuncture sizes as compared to the baseline values. Our results indicated that acupuncture modulated the excitability of M1, and the synaptic plasticity was time-dependent. We concluded that acupuncture should be combined with rehabilitation techniques to improve the motor function in stroke patients. Therefore, we put forward the combined application of the acupuncture timing and rehabilitation for higher therapeutic effectiveness. This trial was registered in the Chinese Clinical Trial Registry (registration no. ChiCTR-IPR-1900020515).

Salidroside, the main active ingredient extracted from Rhodiola crenulata, has been shown to be neuroprotective in ischemic cerebral injury, but the underlying mechanism for this neuroprotection is poorly understood. In the current study, the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was investigated in a rat model of middle cerebral artery occlusion. Salidroside (30 mg/kg) reduced infarct size, improved neurological function and histological changes, increased activity of superoxide dismutase and glutathione-S-transferase, and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion. Furthermore, salidroside apparently increased Nrf2 and heme oxygenase-1 expression. These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved. The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.

Objective(s): Stroke may cause severe neuronal damage. The sesamin have been demonstrated to possess neuroprotection by its antioxidant and anti-inflammatory properties. One sesamin derivative was artificially composited, 1, 2-bis [(3-methoxyphenyl) methyl] ethane-1, 2-dicaroxylic acid (MMEDA) had been developed to study its antioxidative activity and neuroprotection. Materials and Methods: The infaction of Sprague Dawley (SD) rats and hypoxia models of BV-2 microglia or PC12 cells were investigated for in vivo and in vitro test respectively. Lipid peroxidation and reactive oxygen species (ROS), prostaglandin E2 (PGE2) and related signaling pathways from hypoxic cells were analyzed by ELISA or Western blot assay, respectively. Results: MMEDA showed a protective effect when given 90 min after the focal cerebral ischemia. The neuroprotection of MMEDA was further confirmed by attenuating ROS and PGE2 release from hypoxic BV-2 or PC12 cells. MMEDA significantly reduced hypoxia-induced JNK and caspase-3 (survival and apoptotic pathways) in PC12 cells. Conclusion: The neuroprotective effect of MMEDA on ischemia/hypoxia models was involved with its antioxidative activity and anti-inflammatory effects. These results suggest that MMEDA exert effective neuroprotection against ischemia/hypoxia injury. [ABSTRACT FROM AUTHOR]

Post-stroke memory dysfunction (PMD) is one of the most common forms of cognitive impairment among stroke survivors. However, only a limited number of studies have directly investigated the neural mechanisms associated with memory decline. The aim of the present study was to identify dynamic changes in the functional organization of the default mode network (DMN) and the dorsal attention network of patients with PMD. A total of 27 patients with PMD who experienced a stroke in the right hemisphere were enrolled in the current study, along with 27 healthy control subjects matched by age, sex, and educational level. A behavioral examination and functional magnetic resonance imaging scan were performed. The data were analyzed using an independent component analysis method. The results revealed a significantly increased functional connectivity between the DMN and prefrontal cortex (left middle/inferior frontal and left precentral gyri), temporal regions (left superior temporal gyrus), and bilateral and posterior cingulate gyri/precuneus (P<0.001). There was also a significantly decreased functional connectivity between the DMN and right middle temporal gyrus, left uvula, and right inferior parietal lobule, and between the dorsal attention network and prefrontal cortex (left precentral/inferior and right inferior/middle frontal gyri), right inferior parietal gyrus, and right insula (P<0.001). These results suggest that the stroke affected both the lesioned and contralesional hemispheres. The prefrontal cortex, temporal regions, insula, and posterior cingulate gyrus/precuneus serve a crucial role in memory processing. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effect of electroacupuncture (EA) on cognitive deficits, and the underlying mechanism following cerebral ischemia-reperfusion (I/R) via the calmodulin (CaM)-calmodulin-dependent protein kinase type IV (CaMKIV)-cyclic adenosine monophosphate response elements binding protein (CREB) intracellular signaling pathway in the hippocampus. In total, 45 adult female Sprague-Dawley rats were randomly divided into three groups, namely the sham group, the middle cerebral artery occlusion (MCAO) group and the MCAO + EA group. Rats in the MCAO and MCAO + EA groups were modeled for post-stroke cognitive impairment. EA was performed at the Baihui and Shenting acupuncture points for 30 min/day for one week in the MCAO + EA group. Behavioral testing was analyzed using a step-down apparatus, while 2,3,5-triphenyl tetrazolium chloride was used to detect the infarct volume and lesion size. In addition, CaM activity was assessed by cyclic nucleotide-dependent phosphodiesterase analysis, and the protein expression levels of CaM, CaMKIV, phosphorylated (p)-CaMKIV, CREB and p-CREB were analyzed by western blot analysis. The cerebral I/R injured rat model in the MCAO group was established successfully with regard to the infarct volume and neuronal lesion size, as compared with the sham group. EA was demonstrated to effectively improve the cognitive ability, as measured by the step-down apparatus test, and decrease the infarct volume when compared with the MCAO group (P<0.05). The step-down apparatus test for the EA-treated rats revealed improved learning and reduced memory impairment when compared with the MCAO group. Furthermore, CaM activity and CaM protein expression levels in the MCAO + EA group were lower compared with those in the MCAO group (P<0.05). By contrast, the protein expression levels of CaMKIV, p-CaMKIV, CREB and p-CREB were significantly reduced in the MCAO group when compared with the sham group (P<0.05), although the expression levels increased following EA treatment when compared with the MCAO group (P<0.05). Therefore, cognitive repair benefited from EA, and the main intracellular signaling pathway in the hippocampus was mediated by CaM-CaMKIV-CREB. EA effectively inhibited the expression and activity of CaM, while further enhancing the expression of CaMKIV and CREB, and their associated phosphorylated functions. [ABSTRACT FROM AUTHOR]

Aims. To evaluate the efficacy of Chinese herbal medicines (CHMs) plus conventional treatment in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods and Results. Participants (n = 808) with ACS who underwent PCI from thirteen hospitals of mainland China were randomized into two groups: CHMs plus conventional treatment group (treatment group) or conventional treatment alone group (control group). All participants received conventional treatment, and participants in treatment group additionally received CHMs for six months. The primary end point was the composite of cardiac death, nonfatal recurrent MI, and ischemia-driven revascularization. Secondary endpoint was the composite of readmission for ACS, stroke, or congestive heart failure. The safety endpoint involved occurrence of major bleeding events. The incidence of primary endpoint was 2.7% in treatment group versus 6.2% in control group (HR, 0.43; 95% CI, 0.21 to 0.87; P = 0.015). The incidence of secondary endpoint was 3.5% in treatment group versus 8.7% in control group (HR, 0.39; 95% CI, 0.21 to 0.72; P = 0.002).No major bleeding events were observed in any participant. Conclusion. Treatment with CHMs plus conventional treatment further reduced the occurrence of cardiovascular events in patients with ACS after PCI without increasing risk of major bleeding. [ABSTRACT FROM AUTHOR]