Optimal dose and type of non-pharmacological treatments to improve cognitive function in people with Alzheimer's disease: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate and rank the effectiveness of specific non-pharmacological treatments (NPTs) in improving the global cognitive function in individuals with Alzheimer's disease (AD) and to examine the dose-response relationship. METHOD: We conducted a systematic search in PubMed, MEDLINE, Embase, PsycINFO, CENTRAL, WOS, and CNKI from their inception to 15 February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. RESULTS: We included 68 studies involving 5053 participants in this meta-analysis. The treatments with the highest cumulative probabilities for improving global cognitive function were transcranial direct current stimulation (tDCS), followed by physical exercise (PE), and repetitive transcranial magnetic stimulation (rTMS). Additionally, cognitive stimulation (CS), cognitive training CT), multidisciplinary program (MD), and reminiscence treatment (RT) also significantly improve the global cognitive function of people with AD. A non-linear dose-response association was observed for tDCS, PE, rTMS, CS, and CT with global cognitive improvement. Notably, no minimal threshold was identified for the beneficial effects of PE on cognition. The estimated minimal doses for clinically relevant changes in cognition were 33 min per week for tDCS, 330 MET-min per week for PE, and 8000 pulses per week for rTMS. CONCLUSION: tDCS, PE, and rTMS are the better effective NPTs for enhancing global cognitive function in individuals with AD. Properly dosing these treatments can yield significant clinical benefits. Our findings support the clinical utility of low-dose exercise in improving cognition in people with AD.

The effect of home-based exercise on motor and non-motor symptoms with Parkinson's disease patients: A systematic review and network meta-analysis.

OBJECTIVE: To evaluate the effects of home-based exercise in Parkinson's disease (PD) patients. DESIGN: A network meta-analysis of randomized controlled trials. METHODS: This study systematically searched PubMed, MEDLINE, Embase, Cochrane library and Web of Science. The quality of the literature was assessed using the Cochrane Risk of Bias 2.0 criteria. The data were pooled using R software. Results are presented as pooled standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: Thirty studies involving 2264 PD patients were included. Meta-analysis results showed that home-based exercise had a small effect in relieving overall motor symptoms in PD patients (SMD: -.28, 95% Crl [-.43; -.14]), improving quality of life (SMD = .15 [.03, .26]), walking speed (SMD = .30 [.04, .56]), balance ability (SMD = .18 [.04, .33]; p < .0001) and finger dexterity (SMD = .28 [.10, .46]). Mixed exercise (Mix) had better effects on improving motor symptoms and quality of life. In addition, the results of dose analysis showed that only mixed exercise exceeding 850 METs-min per week and more than 18 weeks can significantly alleviate the overall motor symptoms of PD patients. CONCLUSION: Home-based exercise was an effective form of therapy for alleviating motor symptoms. In addition, Mix appeared to be more suitable for PD patients engaging in home-based exercise. Existing evidence suggested that significant therapeutic effects were achieved with a Mix, with a weekly exercise volume exceeding 850 METs and a duration of more than 18 weeks. RELEVANCE TO CLINICAL PRACTICE: Home-based exercise had a small effect in relieving overall motor symptoms in PD patients, improving quality of life, walking speed, balance ability and finger dexterity. In terms of exercise dosage, we recommend the exercise period is no less than 18 weeks and the dose per is no less than 850 METs-min. No Patient or Public Contribution.

Effects of Tai Chi and Qigong on cognitive and physical functions in older adults: systematic review, meta-analysis, and meta-regression of randomized clinical trials.

BACKGROUND: Older adults experience age-related declines in physical and cognitive functions due to interactions between aging and chronic diseases. Tai Chi and Qigong (TCQ) might be beneficial in improving the physical function and delaying the cognitive decline of this population. The potential underlying mechanism was explored to determine the effects of TCQ on cognitive function via direct or indirect pathways. PURPOSE: The objective of this systematic review was to determine the effects of TCQ on cognitive and physical functions in older adults using meta-analysis, and to determine the impact of TCQ on cognitive function while controlling for physical function using a meta-regression approach. METHODS: A systematic search of 13 electronic databases (in English, Korean, and Chinese languages) identified 10,292 potentially eligible studies published between inception and May 2022. The bias in individual studies was assessed using the Cochrane Risk of Bias (version 2.0) tool. The heterogeneity of the studies was evaluated using a 95% prediction interval, and the meta-analysis and meta-regression were implemented using the Comprehensive Meta-Analysis (version 3) software. RESULTS: Our search identified 17 randomized studies (n = 2,365, mean age = 70.3 years). The results of the meta-analysis that used a random-effects model indicated that TCQ had significant effects on both cognitive (Hedges' g = 0.29, 95% confidence interval [CI] = 0.17 to 0.42) and physical (Hedges' g = 0.32, 95% CI = 0.19 to 0.44) functions. We used meta-regression to explore the effect size of TCQ in association with physical function level. The regression model was significant (Q = 25.01, p = .070), and 55% of the heterogeneity was explained by physical function as a moderator variable. The effects of TCQ on cognitive function remained significant in this model when controlling for the effect of physical function (ß = 0.46, p = .011). CONCLUSION: This meta-regression of 17 randomized studies strongly suggests that TCQ has beneficial effects on physical and cognitive functions in older adults. The effect of TCQ on cognitive function remained significant after taking into account the significant effects of physical function as a moderator. The findings imply the potential health benefits of TCQ by promoting cognitive function in older adults directly and indirectly through enhancing physical function. PROSPERO REGISTRATION NUMBER: *PROSPERO international prospective register of systematic reviews, registration ID CRD42023394358.

Prospect of neoadjuvant/adjuvant immunotherapy in early-stage triple-negative breast cancer.

China is bearing the growing burden of breast cancer globally, accounting for 18% of all new cases. Triple-negative breast cancer (TNBC) is aggressive, prone to early recurrence and metastasis, with a poor prognosis. Improving the prognosis at the early-stage of TNBC remains a challenge, due to the limited efficacy of traditional neoadjuvant/adjuvant chemotherapy. Early studies revealed that early-stage TNBC is more immunogenic. Several current clinical trials revealed that the combination with immunotherapy in the form of immune checkpoint inhibitors (ICIs) expands the treatment options for early-stage TNBC by improving the pathologic complete response (pCR), as well as long-term survival benefits. Correspondingly, Chinese Society of Clinical Oncology (CSCO) updated the breast cancer guidelines to include several recommendations regarding neoadjuvant/adjuvant immunotherapy. However, relevant immunotherapy data in Chinese patients with early-stage TNBC remain scarce. The cTRIO clinical trial (ChiCTR2100041675) is a multicenter phase II trial initiated by investigators to evaluate tislelizumab combined with nab-paclitaxel and carboplatin in neoadjuvant/ adjuvant therapy for Chinese patients with TNBC. In this review, we discuss the latest advances in clinical studies of neoadjuvant/adjuvant immunotherapy for early-stage TNBC, as well as potential challenges and strategies to improve the clinical outcomes. We introduce the study design of the cTRIO trial, which aims to make the clinical benefits more robust for early-stage TNBC patients in China.

Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.

The identification and interpretation of germline BRCA1/2 variants become increasingly important in breast and ovarian cancer (OC) treatment. However, there is no comprehensive analysis of the germline BRCA1/2 variants in a Chinese population. Here we performed a systematic review and meta-analysis on such variants from 94 publications. A total of 2,128 BRCA1/2 variant records were extracted, including 601 from BRCA1 and 632 from BRCA2. In addition, 414, 734, 449, and 307 variants were also recorded in the BIC, ClinVar, ENIGMA, and UMD databases, respectively, and 579 variants were newly reported. Subsequent analysis showed that the overall germline BRCA1/2 pathogenic variant frequency was 5.7% and 21.8% in Chinese breast and OC, respectively. Populations with high-risk factors exhibited a higher pathogenic variant percentage. Furthermore, the variant profile in Chinese is distinct from that in other ethnic groups with no distinct founder pathogenic variants. We also tested our in-house American College of Medical Genetics-guided pathogenicity interpretation procedure for Chinese BRCA1/2 variants. Our results achieved a consistency of 91.2-97.6% (5-grade classification) or 98.4-100% (2-grade classification) with public databases. In conclusion, this study represents the first comprehensive meta-analysis of Chinese BRCA1/2 variants and validates our in-house pathogenicity interpretation procedure, thereby providing guidance for further PARP inhibitor development and companion diagnostics in the Chinese population.

Ginsenoside Rg1 Exerts Anti-inflammatory Effects via G Protein-Coupled Estrogen Receptor in Lipopolysaccharide-Induced Microglia Activation.

Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease. Ginsenoside Rg1, the most active ingredient of ginseng, has been reported to exert neuroprotective effects via estrogen and glucocorticoid receptors. The present study evaluated the involvement of the G protein-coupled estrogen receptor (GPER) in the anti-inflammatory effects of ginsenoside Rg1 against lipopolysaccharide (LPS)-induced microglia activation in the BV2 microglial cell line and ventral mesencephalic primary microglial culture. The pharmacological blockade and lentivirus-mediated small interfering RNA (siRNA) knockdown of GPER were used to study the underlying mechanism. Rg1 attenuated LPS-induced upregulation of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA and protein levels. The GPER antagonist G15 blocked the inhibitory effects of Rg1 and the GPER-specific agonist G1 on LPS-induced microglia activation. Rg1 mimicked the effects of G1 by inhibiting the LPS-induced activation of nuclear transcription factor-kappa B (NF-κB) and mitogen activated protein kinase signaling pathways, which was also blocked by G15. Moreover, lentivirus-mediated siRNA knockdown of GPER inhibited the anti-inflammatory effects of Rg1. Taken together, our results indicate that GPER is involved in the anti-inflammatory effects of Rg1 against LPS-induced microglia activation. These findings provide a new biological target of Rg1 for the treatment of neuroinflammatory disorders.

Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra.

Accumulating clinical and experimental evidence suggests that chronic neuroinflammation is associated with dopaminergic neuronal death in Parkinson's disease (PD). Ginsenoside Rg1, the most active components of ginseng, possesses a variety of biological effects on the central nervous system, cardiovascular system and immune system. The present study aimed to evaluate the protective effects of ginsenoside Rg1 on lipopolysaccharide (LPS)-induced microglia activation and dopaminergic neuronal degeneration in rat substantia nigra (SN) and its potential mechanisms. Treatment with Rg1 could ameliorate the apomorphine-induced rotational behavior in LPS-lesioned rats. GR antagonist RU486 partly abolished the protective effect of Rg1. Rg1 treatment significantly attenuated LPS-induced loss of tyrosin hydroxlase (TH) positive neurons in substantial nigra par compacta (SNpc) and decreased content of dopamine (DA) and its metabolites in striatum of the lesioned side. Meanwhile, Rg1 significantly inhibited LPS-induced microglial activation and production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and nitric oxide (NO). These effects were abolished by co-treatment with RU486. In addition, Rg1 treatment significantly inhibited the LPS-induced phosphorylation of IκB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) in the lesioned side of substantial nigra. These effect could be also partly blocked by RU486. Taken together, these data indicate that Rg1 has protective effects on mesencephalic dopaminergic neurons from LPS-induced microglia inflammation. GR signaling pathway might be involved in the anti-inflammatory effect of Rg1.