Unlocking the Potential of Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease: A Meta-Analysis of Randomized Clinical Trials to Optimize Intervention Strategies.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an advanced and noninvasive technology that uses pulse stimulation to treat cognitive impairment. However, its specific effects have always been mixed with those of cognitive training, and the optimal parameter for Alzheimer's disease (AD) intervention is still ambiguous. Objective: This study aimed to summarize the therapeutic effects of pure rTMS on AD, excluding the influence of cognitive training, and to develop a preliminary rTMS treatment plan. Methods: Between 1 January 2010 and 28 February 2023, we screened randomized controlled clinical trials from five databases (PubMed, Web of Science, Embase, Cochrane, and ClinicalTrials. gov). We conducted a meta-analysis and systematic review of treatment outcomes and rTMS treatment parameters. Result: A total of 4,606 articles were retrieved. After applying the inclusion and exclusion criteria, 16 articles, comprising 655 participants (308 males and 337 females), were included in the final analysis. The findings revealed that rTMS significantly enhances both global cognitive ability (p = 0.0002, SMD = 0.43, 95% CI = 0.20-0.66) and memory (p = 0.009, SMD = 0.37, 95% CI = 0.09-0.65). Based on follow-up periods of at least 6 weeks, the following stimulation protocols have demonstrated efficacy for AD: stimulation sites (single or multiple targets), frequency (20 Hz), stimulation time (1-2 s), interval (20-30 s), single pulses (≤2500), total pulses (>20000), duration (≥3 weeks), and sessions (≥20). Conclusions: This study suggests that rTMS may be an effective treatment option for patients with AD, and its potential therapeutic capabilities should be further developed in the future.

Predicting response to repetitive transcranial magnetic stimulation in patients with chronic insomnia disorder using electroencephalography: A pilot study.

Predicting responsvienss to repetitive transcranial magnetic stimulation (rTMS) can facilitate personalized treatments with improved efficacy; however, predictive features related to this response are still lacking. We explored whether resting-state electroencephalography (rsEEG) functional connectivity measured at baseline or during treatment could predict the response to 10-day rTMS targeted to the right dorsolateral prefrontal cortex (DLPFC) in 36 patients with chronic insomnia disorder (CID). Pre- and post-treatment rsEEG scans and the Pittsburgh Sleep Quality Index (PSQI) were evaluated, with an additional rsEEG scan conducted after four rTMS sessions. Machine-learning approaches were employed to assess the ability of each connectivity measure to distinguish between responders (PSQI improvement > 25%) and non-responders (PSQI improvement ≤ 25%). Furthermore, we analyzed the connectivity trends of the two subgroups throughout the treatment. Our results revealed that the machine learning model based on baseline theta connectivity achieved the highest accuracy (AUC = 0.843) in predicting treatment response. Decreased baseline connectivity at the stimulated site was associated with higher responsiveness to TMS, emphasizing the significance of functional connectivity characteristics in rTMS treatment. These findings enhance the clinical application of EEG functional connectivity markers in predicting treatment outcomes.

Functional connectivity changes are correlated with sleep improvement in chronic insomnia patients after rTMS treatment.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been increasingly used as a treatment modality for chronic insomnia disorder (CID). However, our understanding of the mechanisms underlying the efficacy of rTMS is limited. Objective: This study aimed to investigate rTMS-induced alterations in resting-state functional connectivity and to find potential connectivity biomarkers for predicting and tracking clinical outcomes after rTMS. Methods: Thirty-seven patients with CID received a 10-session low frequency rTMS treatment applied to the right dorsolateral prefrontal cortex. Before and after treatment, the patients underwent resting-state electroencephalography recordings and a sleep quality assessment using the Pittsburgh Sleep Quality Index (PSQI). Results: After treatment, rTMS significantly increased the connectivity of 34 connectomes in the lower alpha frequency band (8-10 Hz). Additionally, alterations in functional connectivity between the left insula and the left inferior eye junction, as well as between the left insula and medial prefrontal cortex, were associated with a decrease in PSQI score. Further, the correlation between the functional connectivity and PSQI persisted 1 month after the completion of rTMS as evidenced by subsequent electroencephalography (EEG) recordings and the PSQI assessment. Conclusion: Based on these results, we established a link between alterations in functional connectivity and clinical outcomes of rTMS, which suggested that EEG-derived functional connectivity changes were associated with clinical improvement of rTMS in treating CID. These findings provide preliminary evidence that rTMS may improve insomnia symptoms by modifying functional connectivity, which can be used to inform prospective clinical trials and potentially for treatment optimization.

A Comparison of the Outcomes of Open Trigger Release versus Ultrasound-Guided Modified Small Needle-Knife Percutaneous Release for Treatment of Trigger Digits.

Background: The aim of this randomised prospective study is to compare the outcomes of traditional open trigger digit release versus ultrasound-guided modified small needle-knife (SNK) percutaneous release in the treatment of trigger digits. Methods: Patients with grade 2 and above trigger digits were enrolled into the study and randomly assigned to traditional open surgery (OS) or ultrasound-guided modified SNK percutaneous release group. The patients were followed up for 7, 30 and 180 days after treatment and data with regard to visual analogue scale (VAS) score and Quinnell grading (QG) was collected and compared between the two groups. Results: A total of 72 patients were enrolled in the study with 30 in the OS group and 42 in the SNK group. VAS scores and QG of the two groups significantly decreased at 7 days and 30 days after treatment compared to before treatment, but there was no significant difference between the two groups. There was also no differences between the two groups at 180 days and between the values at 30 days and 180 days. Conclusions: The outcomes of ultrasound-guided SNK percutaneous release is similar to traditional OS. Level of Evidence: Level II (Therapeutic).

Dual-targeted repetitive transcranial magnetic stimulation modulates brain functional network connectivity to improve cognition in mild cognitive impairment patients.

Background: Mild cognitive impairment (MCI) is a condition between normal aging and dementia; nearly 10-15% of MCI patients develop dementia annually. There are no effective interventions for MCI progression. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has attempted to improve the overall cognitive function of MCI patients. However, it does not affect episodic memory improvement. Methods: In this study, we engaged 15 clinically diagnosed MCI patients and normal controls to explore the effect of dual-targeted rTMS on progressing cognitive function, particularly episodic memory in MCI patients. Resting-state EEG recordings and neuropsychological assessments were conducted before and after the intervention. EEG features were extracted using an adaptive algorithm to calculate functional connectivity alterations in relevant brain regions and the mechanisms of altered brain functional networks in response to dual-target rTMS. Results: The study revealed that the functional brain connectivity between the right posterior cingulate gyrus (PCC) and the right dorsal caudate nucleus (DC) was significantly reduced in MCI patients compared to normal controls (p < 0.001). Dual-target rTMS increased the strength of the reduced functional connectivity (p < 0.001), which was related to cognitive enhancement (p < 0.05). Conclusion: This study provides a new stimulation protocol for rTMS intervention. Improving the functional connectivity of the right PCC to the right DC is a possible mechanism by which rTMS improves overall cognitive and memory function in MCI patients.

SIRT1/Notch1 signal axis involves in the promoting effect of Segetalin B on bone formation.

Phytoestrogens are a class of potential natural medicines for treating postmenopausal osteoporosis (PMOP). Segetalin B (SB) is a cyclic peptide compound showing estrogenic activity. This study reports the effect of SB on bone formation among ovariectomized (OVX) rats. The bone marrow mesenchymal stem cells (BMSCs) from OVX rats were cultured in vitro. Alizarin Red staining was utilized to observe the effect of SB on the mineralization of BMSCs. The levels of alkaline phosphatase (ALP), osteocalcin, bone morphogenetic protein (BMP-2), and Sirtuin 1 (SIRT1) activities were detected. The OVX rats were treated with SB in vivo. Micro-CT was utilized for imaging analysis. Urine calcium and phosphorus, and ALP activity in bone marrow were assayed. Western blot analysis and immunofluorescence were incorporated to detect protein expressions in vitro and in vivo. The results showed that SB dose-dependently promoted mineralization of OVX rat-derived BMSCs in vitro increased the level of Osteocalcin, BMP-2, ALP, and SIRT1 activity. Moreover, it upregulated expressions of Runx2, Osterix, and SIRT1, downregulated expressions of Notch intracellular domain (NICD), acetyl-NICD, and hairy and enhancer of split 1 (Hes1). In addition, SB treatment significantly decreased bone loss, inhibited calcium and phosphorus loss, elevated ALP activity, upregulated Runx2, Osterix, and SIRT1, and downregulated NICD and Hes1 in OVX rats in vivo. However, EX527, a SIRT1-selective inhibitor, could reverse the above effects of SB in vitro or in vivo. These results indicate that SB is a potential natural medicine to improve PMOP. Thus, its mechanism of promoting bone formation involves the SIRT1/Notch1 signaling axis.

Bone marrow mesenchymal stem cells-derived exosomes mediate nuclear receptor coactivator-3 expression in osteoblasts by delivering miR-532-5p to influence osteonecrosis of the femoral head development.

Exosomes (Exo) originated from bone marrow mesenchymal stem cells (BMSCs) have therapeutic impacts on osteonecrosis of the femoral head (ONFH), and microRNA (miR)-532-5p has been confirmed to participate in ONFH progression. In the research, it was figured out whether BMSCs-Exo could relieve ONFH by delivering miR-532-5p. MG-63 cells were treated with DEX to construct an ONFH cell model in vitro. The effects of Exo and miR-532-5p on the cell viability, lactate dehydrogenase (LDH) content, and apoptosis of BMSCs were detected. The ONFH rat model was established, and the effect of BMSCs-Exo delivering miR-532-5p on the pathological damage of ONFH rats was evaluated. Changes in nuclear receptor coactivator-3 (NCOA3) and apoptotic proteins were assessed by western blot. The relationship between miR-532-5p and NCOA3 was verified by dual luciferase reporter experiments. miR-532-5p was elevated in vivo and in vitro ONFH-models, while NCOA3 expression was reduced. Overexpression of miR-532-5p aggravated DEX toxicity in osteoblasts, decreased cell viability, and promoted apoptosis. Knockdown of miR-532-5p made Exo further attenuate the toxic effect of DEX on osteoblasts and inhibited apoptosis. The protective effect of miR-532-5p-delivering Exo on osteoblasts was reversed by NCOA3 silencing. In addition, in vivo experiments also confirmed that knockdown of miR-532-5p enhanced the therapeutic effect of Exo on ONFH rats. This study demonstrates that miR-532-5p-delivering BMSCs-Exo inhibits osteoblast viability and promote apoptosis by targeting NCOA3, thereby aggravating ONFH development.

Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months. METHODS: This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses. DISCUSSION: If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide. TRIAL REGISTRATION: ClinicalTrials. gov NCT05034029 . Registered on 30 Sept 2021.

Electroencephalographic connectivity predicts clinical response to repetitive transcranial magnetic stimulation in patients with insomnia disorder.

BACKGROUND: Accumulating evidence suggests that low frequency repetitive transcranial magnetic stimulation (rTMS), which generally decreases cortical excitability and remodels plastic connectivity, improves sleep quality in patients with insomnia disorder. However, the effects of rTMS vary substantially across individuals and treatment is sometimes unsatisfactory, calling for biomarkers for predicting clinical outcomes. OBJECTIVE: This study aimed to investigate whether functional connectivity of the target network in electroencephalography is associated with the clinical response to low frequency rTMS in patients with insomnia disorder. METHODS: Twenty-five patients with insomnia disorder were subjected to 10 sessions of treatment with 1 Hz rTMS over the right dorsolateral prefrontal cortex. Resting-state electroencephalography was collected before rTMS. Pittsburgh Sleep Quality Index, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Mini-Mental State Exam were performed before and after rTMS treatment, with a follow-up after one month. Electroencephalographic connectivity was measured by the power envelope connectivity at the source level. Partial least squares regression identified models of connectivity that maximally accounted for the rTMS response. RESULTS: Scores of Pittsburgh Sleep Quality Index, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale were decreased after rTMS and one-month later. Baseline weaker connectivity of a network in the beta and alpha bands between a brain region approximating the stimulated right dorsolateral prefrontal cortex and areas located in the frontal, insular, and limbic cortices was associated with a greater change in Pittsburgh Sleep Quality Index and Hamilton Depression Rating Scale following rTMS. CONCLUSIONS: Low frequency rTMS could improve sleep quality and depressive moods in patients with insomnia disorder. Moreover, electroencephalographic functional connectivity would potentially be a robust biomarker for predicting the therapeutic effects.

Effects of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment: A Meta-Analysis of Randomized Controlled Trials.

Background: Mild cognitive impairment (MCI) is an intermediary state between normal aging and dementia. It has a high risk of progression in patients with Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique used to improve cognitive deficits in patients with MCI and AD. Although previous meta-analyses included studies carried on patients with MCI and AD, few studies have analyzed patients with MCI independently. This meta-analysis aimed to evaluate the effects and safety of rTMS on cognition function in patients with MCI and factors that may influence such effects. Methods: Data used in this study were searched and screened from different databases, including PubMed, Web of Science, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chinese Technical Periodicals (VIP), Wanfang Database, and China BioMedical Literature Database (SinoMed). The retrieved studies were carefully reviewed, data were extracted, and the quality of data was assessed. Results: A total of 12 studies involving 329 patients with MCI were included in the present meta-analysis. The analyses results revealed that rTMS improved cognitive function [standardized mean difference (SMD) = 0.83, 95% confidence interval (CI) = 0.44-1.22, p = 0.0009] and memory function (SMD = 0.73, 95% CI = 0.48-0.97, p < 0.00001) in the MCI + rTMS active group when compared to the sham stimulation group. The showed that: (1) cognitive improvement was more pronounced under high-frequency rTMS stimulation of multiple sites, such as the bilateral dorsolateral prefrontal cortex and (2) more than 10 rTMS stimulation sessions produced higher improvement on cognition function in patients with MCI. Conclusions: This study shows that rTMS can improve cognitive function in patients with MCI, especially when applied at high frequency, multi-site, and for a prolonged period. However, further studies are required to validate these findings and explore more effective stimulation protocols and targets. Systematic Review Registration: [http://www.crd.york.ac.uk/PROSPERO/], identifier: CRD 42021238708.

Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex Modulates Electroencephalographic Functional Connectivity in Alzheimer's Disease.

Background: Increasing evidence demonstrates that repetitive transcranial magnetic stimulation (rTMS) treatment of the dorsolateral prefrontal cortex is beneficial for improving cognitive function in patients with Alzheimer's disease (AD); however, the underlying mechanism of its therapeutic effect remains unclear. Objectives/Hypothesis: The aim of this study was to investigate the impact of rTMS to the dorsolateral prefrontal cortex on functional connectivity along with treatment response in AD patients with different severity of cognitive impairment. Methods: We conducted a 2-week treatment course of 10-Hz rTMS over the left dorsolateral prefrontal cortex in 23 patients with AD who were split into the mild or moderate cognitive impairment subgroup. Resting state electroencephalography and general cognition was assessed before and after rTMS. Power envelope connectivity was used to calculate functional connectivity at the source level. The functional connectivity of AD patients and 11 cognitively normal individuals was compared. Results: Power envelope connectivity was higher in the delta and theta bands but lower in the beta band in the moderate cognitive impairment group, compared to the cognitively normal controls, at baseline (p < 0.05). The mild cognitive impairment group had no significant abnormities. Montreal Cognitive Assessment scores improved after rTMS in the moderate and mild cognitive impairment groups. Power envelope connectivity in the beta band post-rTMS was increased in the moderate group (p < 0.05) but not in the mild group. No significant changes in the delta and theta band were found after rTMS in both the moderate and mild group. Conclusion: High-frequency rTMS to the dorsolateral prefrontal cortex modulates electroencephalographic functional connectivity while improving cognitive function in patients with AD. Increased beta connectivity may have an important mechanistic role in rTMS therapeutic effects.

Identifying Mild Cognitive Impairment in Parkinson's Disease With Electroencephalogram Functional Connectivity.

OBJECTIVE: Cognitive impairment occurs frequently in Parkinson's disease (PD) and negatively impacts the patient's quality of life. However, its pathophysiological mechanism remains unclear, hindering the development of new therapies. Changes in brain connectivity are related to cognitive impairment in patients with PD, with the dorsolateral prefrontal cortex (DLPFC) being considered the essential region related to PD cognitive impairment. Nevertheless, few studies have focused on the global connectivity responsible for communication with the DLPFC node, the posterior division of the middle frontal gyrus (PMFG) in patients with PD; this was the focus of this study. METHODS: We applied resting-state electroencephalography (EEG) and calculated a reliable functional connectivity measurement, the debiased weighted phase lag index (dWPLI), to examine inter-regional functional connectivity in 68 patients with PD who were classified into two groups according to their cognitive condition. RESULTS: We observed that altered left and right PMFG-based functional connectivity associated with cognitive impairment in patients with PD in the theta frequency bands under the eyes closed condition (r = -0.426, p < 0.001 and r = -0.437, p < 0.001, respectively). Exploratory results based on the MoCA subdomains indicated that poorer visuospatial function was associated with higher right PMFG-based functional connectivity (r = -0.335, p = 0.005), and poorer attention function was associated with higher left and right PMFG-based functional connectivity (r = -0.380, p = 0.001 and r = -0.256, p = 0.035, respectively). Further analysis using logistic regression and receiver operating characteristic (ROC) curves found that this abnormal functional connectivity was an independent risk factor for cognitive impairment [odds ratio (OR): 2.949, 95% confidence interval (CI): 1.294-6.725, p = 0.01 for left PMFG; OR: 11.278, 95% CI: 2.578-49.335, p = 0.001 for right PMFG, per 0.1 U], and provided moderate classification power to discriminate between cognitive abilities in patients with PD [area under the ROC curve (AUC) = 0.770 for left PMFG; AUC = 0.809 for right PMFG]. CONCLUSION: These preliminary findings indicate that abnormal PMFG-based functional connectivity patterns associated with cognitive impairment in the theta frequency bands under the eyes closed condition and altered functional connectivity patterns have the potential to act as reliable biomarkers for identifying cognitive impairment in patients with PD.

Classification of Cognitive Impairment and Healthy Controls Based on Transcranial Magnetic Stimulation Evoked Potentials.

Backgrounds: Nowadays, risks of Cognitive Impairment (CI) [highly suspected Alzheimer's disease (AD) in this study] threaten the quality of life for more older adults as the population ages. The emergence of Transcranial Magnetic Stimulation-Electroencephalogram (TMS-EEG) enables noninvasive neurophysiological investi-gation of the human cortex, which might be potentially used for CI detection. Objectives: The aim of this study is to explore whether the spatiotemporal features of TMS Evoked Potentials (TEPs) could classify CI from healthy controls (HC). Methods: Twenty-one patients with CI and 22 HC underwent a single-pulse TMS-EEG stimulus in which the pulses were delivered to the left dorsolateral prefrontal cortex (left DLPFC). After preprocessing, seven regions of interest (ROIs) and two most reliable TEPs' components: N100 and P200 were selected. Next, seven simple and interpretable linear features of TEPs were extracted for each region, three common machine learning algorithms including Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbor (KNN) were used to detect CI. Meanwhile, data augmentation and voting strategy were used for a more robust model. Finally, the performance differences of features in classifiers and their contributions were investigated. Results: 1. In the time domain, the features of N100 had the best performance in the SVM classifier, with an accuracy of 88.37%. 2. In the aspect of spatiality, the features of the right frontal region and left parietal region had the best performance in the SVM classifier, with an accuracy of 83.72%. 3. The Local Mean Field Power (LMFP), Average Value (AVG), Latency and Amplitude contributed most in classification. Conclusions: The TEPs induced by TMS over the left DLPFC has significant differences spatially and temporally between CI and HC. Machine learning based on the spatiotemporal features of TEPs have the ability to separate the CI and HC which suggest that TEPs has potential as non-invasive biomarkers for CI diagnosis.

Application of Structural and Functional Connectome Mismatch for Classification and Individualized Therapy in Alzheimer Disease.

While machine learning approaches to analyzing Alzheimer disease connectome neuroimaging data have been studied, many have limited ability to provide insight in individual patterns of disease and lack the ability to provide actionable information about where in the brain a specific patient's disease is located. We studied a cohort of patients with Alzheimer disease who underwent resting state functional magnetic resonance imaging and diffusion tractography imaging. These images were processed, and a structural and functional connectivity matrix was generated using the HCP cortical and subcortical atlas. By generating a machine learning model, individual-level structural and functional anomalies detection and characterization were explored in this study. Our study found that structural disease burden in Alzheimer's patients is mainly focused in the subcortical structures and the Default mode network (DMN). Interestingly, functional anomalies were less consistent between individuals and less common in general in these patients. More intriguing was that some structural anomalies were noted in all patients in the study, namely a reduction in fibers involving parcellations in the right anterior cingulate. Alternately, the functional consequences of connectivity loss were cortical and variable. Integrated structural/functional connectomics might provide a useful tool for assessing AD progression, while few concerns have been made for analyzing the mismatch between these two. We performed a preliminary exploration into a set of Alzheimer disease data, intending to improve a personalized approach to understanding individual connectomes in an actionable manner. Specifically, we found that there were consistent patterns of white matter fiber loss, mainly focused around the DMN and deep subcortical structures, which were present in nearly all patients with clinical AD. Functional magnetic resonance imaging shows abnormal functional connectivity different within the patients, which may be used as the individual target for further therapeutic strategies making, like non-invasive stimulation technology.

Alzheimer's Disease Classification With a Cascade Neural Network.

Classification of Alzheimer's Disease (AD) has been becoming a hot issue along with the rapidly increasing number of patients. This task remains tremendously challenging due to the limited data and the difficulties in detecting mild cognitive impairment (MCI). Existing methods use gait [or EEG (electroencephalogram)] data only to tackle this task. Although the gait data acquisition procedure is cheap and simple, the methods relying on gait data often fail to detect the slight difference between MCI and AD. The methods that use EEG data can detect the difference more precisely, but collecting EEG data from both HC (health controls) and patients is very time-consuming. More critically, these methods often convert EEG records into the frequency domain and thus inevitably lose the spatial and temporal information, which is essential to capture the connectivity and synchronization among different brain regions. This paper proposes a cascade neural network with two steps to achieve a faster and more accurate AD classification by exploiting gait and EEG data simultaneously. In the first step, we propose attention-based spatial temporal graph convolutional networks to extract the features from the skeleton sequences (i.e., gait) captured by Kinect (a commonly used sensor) to distinguish between HC and patients. In the second step, we propose spatial temporal convolutional networks to fully exploit the spatial and temporal information of EEG data and classify the patients into MCI or AD eventually. We collect gait and EEG data from 35 cognitively health controls, 35 MCI, and 17 AD patients to evaluate our proposed method. Experimental results show that our method significantly outperforms other AD diagnosis methods (91.07 vs. 68.18%) in the three-way AD classification task (HC, MCI, and AD). Moreover, we empirically found that the lower body and right upper limb are more important for the early diagnosis of AD than other body parts. We believe this interesting finding can be helpful for clinical researches.

Rutin suppresses FNDC1 expression in bone marrow mesenchymal stem cells to inhibit postmenopausal osteoporosis.

A previous study revealed that rutin is the main component of Eucommia flavonoids that exerts a protective effect against osteopenia. The bone density and trabecular bone number of osteoporosis model rats can be significantly improved after treatment with rutin. Further study using whole gene expression profiling revealed that FNDC1, a fibronectin type III domain-containing protein, may be a novel bone metabolism-related factor that is decreased in rutin-treated rats. The mechanism underlying the effects of rutin treatment on osteoporosis is important to explore. Micro-CT, western blotting, quantitative PCR, transmission electron microscopy, and Alizarin Red mineralization staining assays were performed to evaluate bone density, FNDC1 expression and autophagy to determine whether FNDC1 might play a significant role in rutin-inhibited trabecular bone loss in rats. FNDC1 expression was high in the osteoporosis group, whereas rutin treatment facilitated FNDC1 downregulation. In addition, rutin promoted bone marrow mesenchymal stem cell autophagy by inhibiting phosphorylated Akt in osteoporosis. In summary, our study shows that rutin could regulate FNCD1 level and autophagy through the Akt/mTOR signaling pathway to provide a novel therapeutic strategy for osteoporosis.

Kaempferol promotes bone formation in part via the mTOR signaling pathway.

Previous research indicates that kaempferol (Kae) promotes osteogenesis, but its underlying mechanism of action remains unclear. The present study hypothesized that the osteogenic effects of Kae were mediated through mammalian target of rapamycin (mTOR). To validate this hypothesis, bone marrow mesenchymal stem cells (BMSCs) from ovariectomized (OVX) rats were differentiated into osteoblasts. The bone mineral density and bone microarchitecture of the OVX rats was measured in vivo, while osteogenesis was evaluated in vitro via Alizarin Red S staining and alkaline phosphatase activity measurements in cultured BMSCs. The levels of phosphorylated eukaryotic translation initiation factor 4E­binding protein 1 (p­4E/BP1) and phosphorylated ribosomal protein S6 kinase B1 (p­S6K), and the expression of Runt­related transcription factor 2 and Osterix, were concurrently quantified by western blot analysis. The data suggested that Kae prevented OVX­induced osteoporosis in rats by promoting osteoblastogenesis. Furthermore, treatment with Kae in rat BMSCs enhanced mineralization, elevated ALP activity, increased the expression levels of Runx­2 and Osterix and increased the levels of p­S6K and decreased the levels of p­4E/BP1 and, consistent with its ability to promote osteoblast differentiation. In contrast, treatment with rapamycin, an mTOR inhibitor, produced the opposite phenotype. Taken together, these data suggested that the protective effects of Kae in BMSCs and in the OVX rat model resulted from the induction of osteogenesis via mTOR signaling, or at least partially via the regulation of downstream effectors of the mTOR pathway.

LncRNA SNHG5 promotes the progression of osteosarcoma by sponging the miR-212-3p/SGK3 axis.

BACKGROUND: Long non-coding RNA (lncRNA) SNHG5 has been found to play an important role in tumors. Nevertheless, the function and mechanism of lncRNA SNHG5 in osteosarcoma (OS) remains unclear. The purpose of this study was to investigate whether lncRNA SNHG5 can regulate the occurrence and development of OS cells. METHODS: We performed quantitative real time PCR to detect the expression of lncRNA SNHG5 in OS cells. 143B, MG63 (knockdown) and U2OS, U2R (overexpression) cell lines were chosen for the function study of SNHG5. The effect of SNHG5, miR-212-3p, and SGK3 in OS cells was explored by MTT assays, clony formation, flow cytometry, transwell assays, wound healing assays, and cell spreading assays. Quantitative real-time PCR, Western blot analysis and luciferase assays were used to detect the interaction between lncRNA SNHG5 and miR-212-3p. RESULTS: In this study, knockdown of lncRNA SNHG5 suppressed the growth and metastasis of OS cells, whereas the overexpression of SNHG5 produced an opposite result. Mechanistically, lncRNA SNHG5 functions as a sponger against miR-212-3p and suppresses the miR-212-3p/SGK3 signaling pathway. Introduction of miR-212-3p mimics or inhibitors reverses SNHG5 overexpression or silences the exerted tumor promoting or suppressing effect. In addition, our results showed that the function of SNHG5 can be rescued by miR-212-3p and can regulate the growth and metastasis of OS cells via SGK3, the downstream target of miR-212-3p. CONCLUSIONS: In summary, our study demonstrated that lncRNA SNHG5 can regulate the proliferation and metastasis of OS cells through the miR-212-3p/SGK3 axis. This axis may provide a new target for future clinical treatment.

Downregulation of lncRNA TUG1 is involved in ankylosing spondylitis and is related to disease activity and course of treatment.

Long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) promotes osteosarcoma, while its involvement in other bone diseases, such as ankylosing spondylitis (AS) is unknown. Expression of TUG1 in serum and open sacroiliac biopsies of AS patents and healthy controls was detected by real-time quantitative PCR (qRT-PCR). Ankylosing spondylitis disease activity score (ASDAS) system was used to evaluate disease activity. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of lncRNA TUG1 for AS. Chi-square test was performed to analyze the correlations between TUG1 expression and patients' clinicopathological data. Patients were divided into 2 groups (high and low expression groups) according to the median expression level of TUG1 and were followed-up for 5 years after discharge. Treatment courses and rehospitalization rate were compared between two groups. It was observed that TUG1 expression level was significantly lower in AS patients than in healthy controls in both serum and biopsies. Reduced expression level of TUG1 distinguished AS patients from controls. LncRNA TUG1 expression was significantly correlated with patients' smoking habits, disease activity, and course of disease. Patients in high expression group showed longer hospitalization time and higher rehospitalization rate. We therefore conclude that expression of lncRNA TUG1 was inhibited in AS patients and downregulation of lncRNA TUG1 is related to higher disease activity, longer course of treatment and higher rehospitalization rate.

[HPLC fingerprint study for the quality evaluation of atractylodis macrocephalae rhizoma].

OBJECTIVE: To establish an HPLC fingerprint analysis method for Atractylodis Macrocephalae Rhizoma (warm dried). METHODS: Took methanol extract of Atractylodis Macrocephalae Rhizoma as sample by ultrasonic processing, HPLC analysis was carried out on Sinochrom ODS-BP (4.6 mm x 250 mm, 5 microm) chromatographic column with mobile phase of acetonitrile (A)-water (B), gradient elution with a flow at 1.0 mL/min, ultraviolet detection wavelength at 242 nm and column temperature at 30 degrees C. RESULTS: An HPLC fingerprint analysis method for Atractylodis Macrocephalae Rhizoma was developed. Eight common peaks were obtained and three peaks were identified. CONCLUSION: The method is accurate and credible which can be used for quality control of Atractylodis Macrocephalae Rhizoma (warm dried).