The role of coffee and potential mediators in subclinical atherosclerosis: insights from Mendelian randomization study.

Background and aims: Coffee contains many bioactive compounds, and its inconsistent association with subclinical atherosclerosis has been reported in observational studies. In this Mendelian randomization study, we investigated whether genetically predicted coffee consumption is associated with subclinical atherosclerosis, as well as the role of potential mediators. Methods: We first conducted a two-sample Mendelian randomization analysis to examine the causal effect of coffee and its subtypes on subclinical atherosclerosis inferred from coronary artery calcification (CAC). Next, the significant results were validated using another independent dataset. Two-step Mendelian randomization analyses were utilized to evaluate the causal pathway from coffee to subclinical atherosclerosis through potential mediators, including blood pressure, blood lipids, body mass index, and glycated hemoglobin. Mendelian randomization analyses were performed using the multiplicative random effects inverse-variance weighted method as the main approach, followed by a series of complementary methods and sensitivity analyses. Results: Coffee, filtered coffee, and instant coffee were associated with the risk of CAC (ß = 0.79, 95% CI: 0.12 to 1.47, p = 0.022; ß = 0.66, 95% CI: 0.17 to 1.15, p = 0.008; ß = 0.66, 95% CI: 0.20 to 1.13, p = 0.005; respectively). While no significant causal relationship was found between decaffeinated coffee and CAC (ß = -1.32, 95% CI: -2.67 to 0.04, p = 0.056). The association between coffee and CAC was validated in the replication analysis (ß = 0.27, 95% CI: 0.07 to 0.48, p = 0.009). Body mass index mediated 39.98% of the effect of coffee on CAC (95% CI: 9.78 to 70.19%, p = 0.009), and 5.79% of the effect of instant coffee on CAC (95% CI: 0.54 to 11.04%, p = 0.030). Conclusion: Our study suggests that coffee other than decaffeinated coffee increases the risk of subclinical atherosclerosis inferred from CAC. Body mass index mediated 39.98 and 5.79% of the causal effects of coffee and instant coffee on CAC, respectively. Coffee should be consumed with caution, especially in individuals with established cardiovascular risk factors, and decaffeinated coffee appears to be a safer choice.

Anemia in Heart Failure: A Perspective from 20-Year Bibliometric Analysis.

Background & Objective: Anemia in patients with heart failure (HF) is a growing concern. However, there has no bibliometric analysis in this area up to now. The aim of this study is to explore the status and trends in the field of anemia in HF through the bibliometric analysis, and to provide an outlook on future research. Methods: We retrieved publications from the Web of Science Core Collection database, and the following data analysis and visualization tools were utilized to perform data processing, statistical computing and graphics generation: VOSviewer (v.1.6.18), CiteSpace (v.6.2 R5), Scimago Graphica (v.1.0.36), Biblimatrix and Microsoft Excel. Results: We identified a total of 3490 publications from 2004 to 2023. The publications in the field of anemia in HF are growing steadily. The United States, the United Kingdom, and Italy were the leading countries in this area. Stefan D Anker, as the most influential author, held the most total citations and publications. Harvard University was the most productive institution in this area. The European Journal of Heart Failure had published the most papers. Through the analysis of co-citations, 14 major clusters based on cluster labels were identified. Keyword analysis showed that mortality, outcome, prevalence, and risk were the most frequent keywords, and the potential research hotspots in the future will be intravenous iron and iron deficiency. Conclusion: This study provides a comprehensive analysis of countries, authors, institutions, journals, co-cited references, and keywords in the field of anemia in HF through bibliometric analysis and data visualization. The status, hotspots and future trends in this field offer a reference for in-depth research. Further studies are necessary in the future to broaden the spectrum of research in this field, to evaluate comprehensive approaches to treating anemia in patients with HF, and to find rational targets for the management of anemia.

The Efficacy of Wearable Cueing Devices on Gait and Motor Function in Parkinson Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To summarize the efficacy of wearable cueing devices for improving gait and motor function of patients with Parkinson disease (PWP). DATA SOURCES: PubMed, Embase, and Cochrane CENTRAL databases were searched for papers published in English, from inception to October 23, 2022. STUDY SELECTION: Randomized controlled trials focusing on the effects of wearable cueing devices on gait and motor function in PWP were included. DATA EXTRACTION: Two reviewers independently selected articles and extracted the data. The Cochrane Bias Risk Assessment Tool was used to assess risk of bias and the Grading of Recommendations Assessment, Development and Evaluation was used to evaluate the quality of evidence. DATA SYNTHESIS: Seven randomized controlled trials with 167 PWP were included in the meta-analysis. Significant effect of wearable cueing devices on walking speed (mean difference [MD]=0.07 m/s, 95% confidence interval [CI]: [0.05, 0.09], P<.00001) was detected; however, after sensitivity analysis, no significant overall effect on walking speed was noted (MD=0.04 m/s, 95% CI: [-0.03, 0.12], P=.25). No significant improvements were found in stride length (MD=0.06 m, 95% CI: [0.00, 0.13], P=.05), the Unified Parkinson's Disease Rating Scale-III score (MD=-0.61, 95% CI: [-4.10, 2.88], P=.73), Freezing of Gait Questionnaire score (MD=-0.83, 95% CI: [-2.98, 1.33], P=.45), or double support time (MD=-0.91, 95% CI: [-3.09, 1.26], P=.41). Evidence was evaluated as low quality. CONCLUSIONS: Wearable cueing devices may result in an immediate improvement on walking speed; however, there is no evidence that their use results in a significant improvement in other gait or motor functions.

Intermittent theta-burst stimulation combined with physical therapy as an optimal rehabilitation in Parkinson's disease: study protocol for a randomised, double-blind, controlled trial.

BACKGROUND: First-line rehabilitative strategies to improve motor deficits are based on functional training (physical or occupational therapy), which has been demonstrated to facilitate neural reorganisation. Accumulating evidence suggests that non-invasive brain stimulation techniques, such as repetitive TMS (rTMS), may enhance neuroplasticity, thereby facilitating neural reorganisation and recovery from Parkinson's disease. Evidence also shows that intermittent theta-burst stimulation (iTBS) can improve motor function and quality of life in patients by promoting the excitability and neural remodelling of cerebral cortex. We aimed to combine iTBS stimulation with physiotherapy to improve the rehabilitation effect compared to physiotherapy alone in patients with Parkinson's disease. METHODS: This randomised, double-blind clinical trial will enrol 50 Parkinson's disease patients aged 45-70 years with Hoehn and Yahr scale scores of 1-3. Patients are randomly assigned to either the iTBS + physiotherapy or sham-iTBS + physiotherapy group. The trial consists of a 2-week double-blind treatment period and a 24-week follow-up period. iTBS and sham-iTBS will be administered twice daily for 10 days based on physiotherapy. The primary outcome will be the third part of Movement Disorders-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) from the baseline to the first 2 days following completion hospitalised intervention. The secondary outcome will be 39-item Parkinson's Disease Questionnaire (PDQ-39) at 4 weeks, 12 weeks and 24 weeks after intervention. Tertiary outcomes are clinical evaluations and mechanism study outcomes such as NMSS, 6MWD, 10MT, TUG, BBS, MRI, and EEG, the length of time between the drug needs to be adjusted when symptoms fluctuate. DISCUSSION: The aim of this study is to demonstrate that iTBS can promote overall function and quality of life in Parkinson's disease patients using physiotherapy and that this efficacy may be associated with altered neuroplasticity in exercise-related brain regions. The iTBS combined with physiotherapy training model will be evaluated during a 6-month follow-up period. With significant improvement in quality of life and motor function, iTBS combined with physiotherapy can be considered as a first-line rehabilitation option for Parkinson's disease. The potential of iTBS to enhance neuroplasticity in the brain should have a more positive impact in increasing the generality and efficiency of physiotherapy, improving the quality of life and overall functional status of patients with Parkinson's disease. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200056581. Registered on 8 February 2022.

Effects of three kinds of anti-amyloid-ß drugs on clinical, biomarker, neuroimaging outcomes and safety indexes: A systematic review and meta-analysis of phase II/III clinical trials in Alzheimer's disease.

OBJECTIVE: To investigate the effects of the three kinds of anti-amyloid-ß (Aß) drugs on cognitive and other functions, fluid and neuroimaging biomarkers, and safety on patients with Alzheimer's disease (AD), and rank the three kinds of anti-Aß drugs. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and AlzForum from inception to January 21, 2023 to include randomized controlled clinical trials. Random effects meta-analyses were performed. RESULTS: Forty-one clinical trials (20929 participants, 9167 male) were included. Anti-Aß drugs had significant but relatively low efficacy in preventing cognitive decline (ADAS-Cog SMD -0.07, 95% CI: -0.10 to -0.03, p < 0.001; CDR-SOB -0.05, -0.09 to -0.01, p = 0.017). Instrumental variable meta-analysis and trial sequential analysis confirmed the reliability of the pooled estimation. Beneficial effects were also observed by assessing other cognitive and activity of daily living scales and biomarkers, with acceptable safety of anti-Aß drugs. Meta-regression demonstrated significant association between higher baseline mini-mental statement examination scores (MMSE) and better cognitive protective effects on cognitive function (ADAS-Cog ß: -0.02, -0.05 to 0.00, p = 0.017) and clearance of pathological productions of anti-Aß drugs. Network meta-analysis ranked the passive immunotherapy drugs to have the best cognitive efficacy, followed by active immunotherapy and small molecule drugs. CONCLUSION: Anti-Aß drugs have relatively low efficacy in preventing cognitive decline, and they reduce pathological productions with acceptable safety. Patients with higher baseline MMSE scores benefit more from anti-Aß drugs. Passive immunotherapy anti-Aß drugs show relatively better efficacy than active immunotherapy and small molecule anti-Aß drugs.

Cerebrospinal Fluid sTREM2 in Alzheimer's Disease Is Associated with Both Amyloid and Tau Pathologies but not with Cognitive Status.

BACKGROUND: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is considered a biomarker of microglial activation. The relationships between CSF sTREM2 levels and Alzheimer's disease (AD) CSF core biomarkers, cognitive status, and neurodegeneration remain unclear. OBJECTIVE: To assess the association between CSF sTREM2 levels and AD progression and other AD hallmarks. METHODS: Using the Alzheimer's Disease Neuroimaging Initiative database, we investigated 1,035 participants, including 310 cognitively normal controls, 527 patients with mild cognitive impairment, and 198 patients with dementia. They were grouped according to CSF pathology (A/T profile) severity. CSF sTREM2 levels were compared between the groups, and linear regression analysis was performed to evaluate the factors affecting sTREM2 levels. The predictive effectiveness of sTREM2 levels was tested, and the correlation with other indicators was explored. The increase rate was assessed using linear mixed-effects models. RESULTS: Higher CSF sTREM2 levels were associated with older age as well as higher CSF p-tau or t-tau and amyloid-ß levels (all p < 0.001), but not with cognitive status. sTREM2 levels were not correlated with the baseline or longitudinal scale and neuroimaging result changes, and could not predict clinical conversion, but were correlated with multiple non-amyloid-ß and non-tau CSF cytokines related to inflammation and neurodegeneration (p < 0.0001). The increased sTREM2 expression rate did not change among groups. CONCLUSION: CSF sTREM2 levels were jointly determined by age, amyloid-ß, and tau pathologies, leading to complex AD cognitive continuum changes. Although sTREM2 levels could not predict cognitive deterioration and neurodegeneration, they could reflect the microglial state as a non-specific biomarker.

Effects of different kinds of anti-Alzheimer's disease drugs on cognitive improvement: protocol for a systematic review and network meta-analysis of phase III clinical trials.

BACKGROUND: Alzheimer's disease is a neurodegenerative disease characterized by progressive cognitive decline and dysfunction of independent living ability, with huge economic and healthy burden worldwide. However, there is still a lack of effective long-term drugs to improve cognitive function and reduce or halt disease progression. Phase III clinical trials of anti-AD drugs based on different hypotheses were in the pipeline, and this protocol for a systematic review and meta-analysis aims to determine what is the most effective direction for the development of drugs on cognitive improvement. METHODS/DESIGN: We will search the following literature databases for eligible studies from inception to December 2021: Ovid MEDLINE, Ovid Embase, PubMed MEDLINE, and Cochrane Central Register of Controlled Trials. Google Scholar, ClinicalTrials.gov registration platform, and the AlzForum website will also be searched for additional studies. Studies will be included irrespective of publication status or language. Phase III clinical trials reporting on the effect of anti-AD drugs on participants with AD will be included. Two independent reviewers will screen the hit articles and identify phase III clinical trials, extract data, and assess the quality of each study individually. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias. For each kind of drugs based on the corresponding hypothesis, we will compare the study design and demographic features of the clinical trials and include appropriate studies in the network meta-analysis. The primary outcomes will be the indicators of cognitive improvement. The secondary outcomes will be activities of daily living, neuroimaging changes, biomarkers, and safety. Through network meta-analysis, we will suggest the hypothesis that most likely to improve cognitive function and provide the ranks of all kinds of drugs. We will give recommendation grade of each comparison using the Confidence In Network Meta-Analysis (CINeMa) tool. DISCUSSION: This study will provide helpful evidence for further drug development and clinical practice for treating Alzheimer's disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021251507.

Cryptotanshinone Attenuates Amyloid-ß42-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3ß Pathway in HT22 Cells.

The pathological characteristics of Alzheimer's disease (AD) include formation of senile plaques resulting from amyloid-ß (Aß) deposition and neurofibrillary tangles caused by tau hyperphosphorylation. Reducing tau hyperphosphorylation is crucial for treatment of AD. Network pharmacology analysis showed that CTS may reduce tau hyperphosphorylation by regulating the phosphatidylinositol 3 kinases/protein kinase B/ glycogen synthase kinase-3ß (PI3K/Akt/GSK3ß) pathway. We investigated the ability of cryptotanshinone (CTS) to reduce Aß-induced tau hyperphosphorylation and characterized the underlying mechanisms. Amyloid-ß42 oligomers (AßO) were used to establish an AD model in HT22 cells. The expression levels of tau and related proteins in PI3K/Akt/GSK3ß pathway were measured using western blot and immunofluorescence staining. The above-mentioned proteins were then evaluated in an okadaic acid (OKA)-induced AD cell model to verify the results. Synapse-associated proteins including post-synaptic density protein-95 (PSD95) and synaptophysin were also evaluated. We found that CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231 in AßO- and OKA-induced cell models. Moreover, we also found that CTS reversed AßO-induced reductions in the levels of PSD95 and synaptophysin. We used LY294002 to block PI3K and the results showed that CTS exerted neuroprotective effects through regulation of the PI3K/Akt/GSK3ß signaling pathway. In summary, we showed for the first time that CTS inhibited AD-related tau hyperphosphorylation and reduced the effects of AßO on the expression levels of PSD95 and synaptophysin via the PI3K/Akt/GSK3ß pathway in HT22 cells.

The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer's Disease Continuum: A Longitudinal Study.

BACKGROUND: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer's disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. OBJECTIVE: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. METHODS: CSF GAP-43 was analyzed in 788 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-ß (Aß), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. RESULTS: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aß-positive CN), prodromal (Aß-positive MCI), and dementia (Aß-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. CONCLUSION: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

Resting-state functional reorganisation in Alzheimer's disease and amnestic mild cognitive impairment: protocol for a systematic review and meta-analysis.

INTRODUCTION: The incidence of Alzheimer's disease (AD) is increasing rapidly, causing a growing burden to health and economic worldwide. Several clinical trials in the past decade failed to find solutions, and there remains a lack of an effective treatment. The evidence suggests that early intervention for neurodegeneration would likely be effective in preventing cognitive decline. Cognitive decline in AD occurs continuously over a long period; however, there remains a lack of simple, rapid and accurate approach for diagnosis of amnestic mild cognitive impairment or subjective cognitive decline due to underlying Alzheimer's pathology. Resting-state functional MRI (rs-fMRI) determines the functional activities of the human brain non-invasively. The amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF) and regional homogeneity (ReHo) are rs-fMRI indicators with high repeatability. They have been studied as early diagnostic imaging markers for other diseases and may be promising markers also for AD. METHODS AND ANALYSIS: The following electronic literature databases will be searched from inception to December 2021: Medline-Ovid, Medline-PubMed, EMBase-Ovid, Cochrane Central and ClinicalTrials.gov. Two independent reviewers will select studies with eligible criteria, extract data and assess the quality of the original studies with our quality assessment tool individually. Missing data will be requested by sending emails to the corresponding authors. Brain regions will be presented for ALFF/fALFF and ReHo by performing activation likelihood estimation with the Seed-based d Mapping-Permutation of subject images V.6.21 software. Meta-regression will be performed to determine the potential brain regions that may strongly correlate with cognitive decline progression. Subgroup analysis, funnel plot, Egger's test and sensitivity analysis will be conducted to detect and explain potential heterogeneity. ETHICS AND DISSEMINATION: This study does not require formal ethical approval. The findings will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42021229009.

Cerebral blood flow in mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis.

BACKGROUND: Reduced cerebral blood flow (CBF) contributes to the pathophysiology of Alzheimer's disease (AD). However, it is unclear whether there is a spatial-temporal-specific pattern of changed CBF in AD progression. METHODS: We systematically screened literature databases for cross-sectional and longitudinal studies reporting resting CBF or CBF velocity (CBFv) among patients with AD, mild cognitive impairment (MCI), and healthy controls (HCs). Standardised mean differences (SMDs) for CBF and mean differences (MDs) for CBFv were calculated. Quality assessments, meta-analysis, subgroup analysis, and meta-regression were subsequently performed (PROSPERO: CRD42020207548). RESULTS: Overall, 244 studies comprising 13,644 participants and 60 regions were included. Compared with HCs, AD subjects had decreased resting CBF throughout the brain (SMD range: -1.87 to -0.32), especially within the posterior cingulate and temporal-parietal regions. However, MCI subjects presented decreased CBF in ten regions with modest effects (SMD range: -0.86 to -0.25), especially in the precuneus. We identified the decreased CBF in the temporal, parietal, and hippocampal regions was associated with the lower AD Mini-Mental State Examination scores. CONCLUSIONS: Our findings suggest that the spatial-temporal pattern of CBF decreased from the precuneus, posterior cingulate and temporal-parietal regions to broader areas with progression from HC to MCI to AD, supporting the incorporation of CBF into the AD research framework.

Clinical Characteristics and Long-Term Prognosis of Anti-LGI1 Encephalitis: A Single-Center Cohort Study in Beijing, China.

Background: This study aimed to analyze the clinical characteristics of anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis patients and investigate prognostic factors by using a large-sample and long-term follow-up cohort. Methods: The clinical data of 45 patients (29 males; mean age, 57.0 years) from May 2014 to August 2019 were collected. All patients were followed up by face-to-face interviews in the third month after discharge and then by telephone and/or face-to-face interviews every 6 months until November 2020. We evaluated each patient's response to the initial treatments at the first interview and divided them into "responders" and "nonresponders." Relapses were recorded. At the end of follow-up, each patient was evaluated and reclassified into "complete recovery" or "unhealed" groups. Intergroup differences were assessed. Results: All patients presented with seizures at the initial consultation. Other common manifestations included cognitive dysfunction (82.2%), psychiatric disturbance (66.7%), sleep disorder (54.5%), and hyponatremia (66.7%). During the follow-up period (32.8 ± 13.5 months), six patients experienced relapse within 6-37 months. We observed that the patients who did not respond to the initial treatments and those who relapsed all had a poor long-term prognosis. The patients in the "unhealed" group were older (p = 0.009), had a lower incidence of generalized tonic-clonic seizures (p = 0.041), and had a higher probability of cerebrospinal fluid (CSF) abnormalities (p = 0.024) than those in the "complete recovery" group. Conclusion: Anti-LGI1 encephalitis was characterized by seizures, cognitive impairment, psychiatric disturbance, and sleep disorders and was often accompanied by hyponatremia. Patients who responded poorly to the initial treatments and those patients who relapsed had dismal long-term prognoses. Advanced age and CSF abnormalities may be risk factors for poor prognosis, but these still need to be verified.

Effect of antiamyloid-ß drugs on Alzheimer's disease: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease with a complex aetiology involving multiple targets and pathways. With the continuous growth of the ageing population, the burden of AD is increasing year by year. However, there has not been new drug approved for over a decade. In addition, the efficacy of memantine and cholinesterase inhibitors is not satisfactory. As amyloid-ß (Aß) is regarded as the core pathological change and the trigger mechanism of AD, anti-Aß therapy may be an effective therapy. In recent years, a lot of clinical trials have been carried out in this field, but the results have not been well summarised and analysed. METHODS AND ANALYSIS: In this study, we will study the effect of anti-Aß antibodies versus placebo on the clinical efficacy, biomarkers, neuroimaging and safety in different stages of AD, as well as the factors that may affect the efficacy. Drugs that only target the existing Aß are regarded as anti-Aß antibodies. Following electronic databases will be searched from inception to April 2021: Medline-Ovid, EMBase-Ovid, Cochrane Central and clinical trial registration platform ClinicalTrials.gov. After identifying eligible studies through screening title, abstract and read full text of each retrieved literature, we will contact the correspondence authors for additional information and grey literatures. To get more reliable results, random effect model will be conducted for meta-analysis and analysis of subgroups or subsets. Funnel plot, Egger's test and sensitivity analysis will be conducted to explore potential heterogeneity. Meta-regression will be conducted to identify the factors that may affect clinical efficacy. Evidence quality assessment and trial sequential analysis will be conducted to assess the quality of evidence and confirm the reliability of the results in this study. ETHICS AND DISCUSSION: This study does not require formal ethical approval. The findings will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42020202370.

Association of accelerated long-term forgetting and senescence-related blood-borne factors in asymptomatic individuals from families with autosomal dominant Alzheimer's disease.

BACKGROUND: Accelerated long-term forgetting has been identified in preclinical Alzheimer's disease (AD) and is attributed to a selective impairment of memory consolidation in which the hippocampus plays a key role. As blood may contain multiple senescence-related factors that involved in neurogenesis and synaptic plasticity in the hippocampus, we tested whether there is an association between blood-borne factors and accelerated long-term forgetting in asymptomatic individuals from families with autosomal dominant AD (ADAD). METHODS: We analyzed data of 39 asymptomatic participants (n = 18 ADAD mutation carriers, n = 21 non-carriers) from the Chinese Familial Alzheimer's Disease Network (CFAN) study. Long-term forgetting rates were calculated based on recall or recognition of two materials (word list and complex figure) at three delays comprising immediate, 30 min, and 7 days. Peripheral blood concentrations of candidate pro-aging factors (CC chemokine ligand 11 [CCL11] and monocyte chemotactic protein 1 [MCP1]) and rejuvenation factors (growth differentiation factor 11 [GDF11], thrombospondin-4 [THBS4], and secreted protein acidic and rich in cysteine like 1 [SPARCL1]) were evaluated in all participants. RESULTS: Despite normal performance on standard 30-min delayed testing, mutation carriers exhibited accelerated forgetting of verbal and visual material over 7 days in comparison with matched non-carriers. In the whole sample, lower plasma THBS4 was associated with accelerated long-term forgetting in list recall (ß = -0.46, p = 0.002), figure recall (ß = -0.44, p = 0.004), and list recognition (ß = -0.37, p = 0.010). Additionally, higher plasma GDF11 and CCL11 were both associated with accelerated long-term forgetting (GDF11 versus figure recall: ß = 0.39, p = 0.007; CCL11 versus list recognition: ß = 0.44, p = 0.002). CONCLUSIONS: Accelerated long-term forgetting is a cognitive feature of presymptomatic AD. Senescence-related blood-borne factors, especially THBS4, GDF11, and CCL11, may be promising biomarkers for the prediction of accelerated long-term forgetting.

Effect of Tai Chi on post-stroke non-motor disorders: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the state of evidence for the beneficial and harmful effects of Tai Chi on non-motor disorders in post-stroke patients. DESIGN: Systematic review and meta-analysis of published studies. SUBJECTS: Stroke survivors who received conventional rehabilitation therapy or Tai Chi training. DATA SOURCES: We searched seven electronic literature databases and one clinical registry platform to collect data from randomized controlled trials published up to July 26, 2020. RESULTS: A total of 11 randomized controlled trials with 723 stroke survivors met the inclusion criteria, of which six were included in the meta-analysis. Among the 11 studies, one was assessed as "low", eight were assessed as "moderate", and only two were assessed as "high" for the assessment of methodologic quality. Compared to patients who received conventional rehabilitation therapy, those who received Tai Chi training showed greater improvement in scores of depression (standardized mean difference (SMD) [95% confidence interval (CI)] = 0.36 [0.10, 0.61], Grading of Recommendations Assessment, Development, and Evaluation [GRADE]: very low). There were no differences in the improvements in post-stroke global mental disorders (mean difference (MD [95% CI] = 6.15 [-3.05, 15.36], GRADE: moderate) or sleep disorders (MD [95% CI] = 0.33 [-1.51, 1.81], GRADE: low) between Tai Chi and control groups. CONCLUSION: Tai Chi may alleviate post-stroke depression in stroke survivors but has no clear effects on post-stroke cognitive and sleep disorders.

Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study.

BACKGROUND: China has a large population of older people, but has not yet undertaken a comprehensive study on the prevalence, risk factors, and management of both dementia and mild cognitive impairment (MCI). METHODS: For this national cross-sectional study, 46 011 adults aged 60 years or older were recruited between March 10, 2015, and Dec 26, 2018, using a multistage, stratified, cluster-sampling method, which considered geographical region, degree of urbanisation, economic development status, and sex and age distribution. 96 sites were randomly selected in 12 provinces and municipalities representative of all socioeconomic and geographical regions in China. Participants were interviewed to obtain data on sociodemographic characteristics, lifestyle, medical history, current medications, and family history, and then completed a neuropsychological testing battery administered by a psychological evaluator. The prevalence of dementia (Alzheimer's disease, vascular dementia, and other dementias) and MCI were calculated and the risk factors for different groups were examined using multivariable-adjusted analyses. FINDINGS: Overall age-adjusted and sex-adjusted prevalence was estimated to be 6·0% (95% CI 5·8-6·3) for dementia, 3·9% (3·8-4·1) for Alzheimer's disease, 1·6% (1·5-1·7) for vascular dementia, and 0·5% (0·5-0·6) for other dementias. We estimated that 15·07 million (95% CI 14·53-15·62) people aged 60 years or older in China have dementia: 9·83 million (9·39-10·29) with Alzheimer's disease, 3·92 million (3·64-4·22) with vascular dementia, and 1·32 million (1·16-1·50) with other dementias. Overall MCI prevalence was estimated to be 15·5% (15·2-15·9), representing 38·77 million (37·95-39·62) people in China. Dementia and MCI shared similar risk factors including old age (dementia: odds ratios ranging from 2·69 [95% CI 2·43-2·98] to 6·60 [5·24-8·32]; MCI: from 1·89 [1·77-2·00] to 4·70 [3·77-5·87]); female sex (dementia: 1·43 [1·31-1·56]; MCI: 1·51 [1·43-1·59]); parental history of dementia (dementia: 7·20 [5·68-9·12]; MCI: 1·91 [1·48-2·46]); rural residence (dementia: 1·16 [1·06-1·27]; MCI: 1·45 [1·38-1·54]); fewer years of education (dementia: from 1·17 [1·06-1·29] to 1·55 [1·38-1·73]; MCI: from 1·48 [1·39-1·58] to 3·48 [3·25-3·73]); being widowed, divorced, or living alone (dementia: from 2·59 [2·30-2·90] to 2·66 [2·29-3·10]; MCI: from 1·58 [1·44-1·73] to 1·74 [1·56-1·95]); smoking (dementia: 1·85 [1·67-2·04]; MCI: 1·27 [1·19-1·36]), hypertension (dementia: 1·86 [1·70-2·03]; MCI: 1·62 [1·54-1·71] for MCI), hyperlipidaemia (dementia: 1·87 [1·71-2·05]; MCI: 1·29 [1·21-1·37]), diabetes (dementia: 2·14 [1·96-2·34]; MCI: 1·44 [1·35-1·53]), heart disease (dementia: 1·98 [1·73-2·26]; MCI: 1·17 [1·06-1·30]), and cerebrovascular disease (dementia: 5·44 [4·95-5·97]; MCI: 1·49 [1·36-1·62]). Nine of these risk factors are modifiable. INTERPRETATION: Dementia and MCI are highly prevalent in China and share similar risk factors. A prevention strategy should be developed to target the identified risk factors in the MCI population to thwart or slow down disease progression. It is also crucial to optimise the management of dementia and MCI as an important part of China's public health system. FUNDING: Key Project of the National Natural Science Foundation of China, National Key Scientific Instrument and Equipment Development Project, Mission Program of Beijing Municipal Administration of Hospitals, Beijing Scholars Program, Beijing Brain Initiative from Beijing Municipal Science & Technology Commission, Project for Outstanding Doctor with Combined Ability of Western and Chinese Medicine, and Beijing Municipal Commission of Health and Family Planning.

The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer's disease.

INTRODUCTION: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. METHODS: In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE ε4 were analyzed across groups. RESULTS: The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE ε4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57-5.45, P < .001). DISCUSSION: APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention.

Acupuncture Enhances Communication between Cortices with Damaged White Matters in Poststroke Motor Impairment.

Stroke is a leading cause of motor disability. Acupuncture is an effective therapeutic strategy for poststroke motor impairment. However, its mechanism is still elusive. Twenty-two stroke patients having a right-hemispheric subcortical infarct and 22 matched healthy controls were recruited to undergo diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) scanning. The resting-state fMRI was implemented before and after needling at GB34 (Yanglingquan). The stroke patients presented a substantially reduced fractional anisotropy value in the right superior longitudinal fasciculus (SLF), corticospinal tract, and corpus callosum. The structural integrity of the frontoparietal part of the SLF (SLF-FP) correlated with the motor scores of lower limbs in stroke patients. This corticocortical association bundle originated from the premotor cortex (PM) and the adjacent supplementary motor area (SMA), known as secondary motor areas, and terminated in the supramarginal gyrus (SMG). After acupuncture intervention, the corresponding functional connectivity between the PM/SMA and SMG was enhanced in stroke patients compared with healthy controls. These findings suggested that the integrity of the SLF is a potential neuroimaging biomarker for motor disability of lower limbs following a stroke. Acupuncture could increase the communication between the cortices connected by the impaired white matter tracts, implying the neural mechanism underlying the acupuncture intervention.

Effect of Tai Chi for post-stroke mental disorders and sleep disorders: A protocol for systematic review and meta-analysis.

BACKGROUND: Post-stroke mental disorders (PSMDs) and post-stroke sleep disorders (PSSDs) are very common in stroke patients. Recently, Tai Chi (TC) as a form of Chinese traditional mind-body exercise has been gradually applied to stroke rehabilitation although its efficacy for PSMD and PSSD varies across different studies. The aim of this study is to explore the therapeutic effect of TC training for PSMD and PSSD. METHODS: This review will only include randomized controlled trials (RCTs). Search strategy will be performed in 3 English databases, 4 Chinese databases, and the WHO International Clinical Trials Registry Platform. All English or Chinese RCTs, published from inception to February 28, 2019, will be sought. Two reviewers will screen, select studies, extract data, and assess quality independently. Primary outcomes are clinical scales, mainly including "Hamilton depression scale," "Hamilton anxiety scale," and "Pittsburgh sleep quality index." The methodological quality including the risk of bias of the included studies will be evaluated using a modified assessment form, which is based on Cochrane assessment tool and Physiotherapy Evidence Database scale. Review Manager Software (Revman5.3) will be used for heterogeneity assessment, generating funnel-plots, data synthesis, subgroup analysis, and sensitivity analysis. We will use GRADE system to evaluate the quality of our evidence. RESULTS: We will provide some more practical and targeted results investigating the effect of TC exercise for PSMD and PSSD in the current meta-analysis. Meanwhile, we will ascertain study progress of TC for PSMD and PSSD and find out defects or inadequacies of previous studies, so that future researchers could get beneficial guidance for more rigorous study. CONCLUSION: The stronger evidence about TC's rehabilitative effect and safety for PSMD and PSSD will be provided for clinicians and policymakers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018106608. ETHICS AND DISSEMINATION: We do not apply for formal ethical approval from ethics committee because all of the study data in our review will be obtained in an anonymous way. Findings of this study are projected to be disseminated through peer-review publications.

Tai Chi for Stroke Rehabilitation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Stroke is a major cause of poor health and has numerous complications. Tai Chi (TC) may have positive effects on the rehabilitation of stroke survivors, but recent clinical findings have not been included in previously published reviews. Objectives: We conducted this systematic review and meta-analysis to determine the effectiveness of all types of TC vs. conventional rehabilitation therapy for all aspects of stroke survivors' rehabilitation that have been studied. Method: We searched seven electronic literature databases (three in English, four in Chinese) and one clinical registry platform using established strategies to identify randomized controlled trials performed up to October 2017. Screening, quality assessment, and data collection were performed by two researchers separately, using the same standard. The results were analyzed using RevMan 5.3.0. The quality of evidence was evaluated with GRADEpro. Results: A total of 21 studies with 1,293 stroke survivors met inclusion criteria; 14 were included in the quantitative synthesis to evaluate four aspects and five outcomes. Nine studies indicated that TC was able to improve independent activities of daily living (ADL), especially TC vs. conventional rehabilitation therapy [mean difference (MD) [95% confidence interval (CI)] = 9.92 [6.82, 13.02], P < 0.00001]. Five studies reported significant effects of TC plus conventional rehabilitation therapy in increasing scores on the Fugl-Meyer Assessment for the upper limb [MD (95%CI) = 8.27 [4.69, 11.84], P < 0.0001], lower limb [MD (95%CI) = 2.75 [0.95, 4.56], P = 0.003], and overall [MD (95%CI) = 4.49 [1.92, 7.06], P = 0.0006]. The Berg Balance Scale revealed significant improvements according to pooled estimates for TC vs. conventional rehabilitation therapy [MD (95%CI) = 5.23 [3.42, 7.05], P < 0.00001]. TC plus conventional rehabilitation therapy also improved walking ability as measured by the Holden scale [MD (95%CI) = 0.61 [0.38, 0.85], P < 0.00001] and up-and-go time [MD (95%CI) = 2.59 [1.76, 3.43], P < 0.00001]. Conclusion: TC has an overall beneficial effect on ADL, balance, limb motor function, and walking ability among stroke survivors, based on very low-quality evidence, and may also improve sleep quality, mood, mental health, and other motor function. Well-designed, higher-quality trials with longer-term follow-up periods are needed to develop better-quality evidence.