Xiang-Fei Meng

Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis

Objective Recently, several large randomised controlled trials about the treatments of cognitive impairment or dementia due to Parkinsons disease (CIND-PD or PDD) and dementia with Lewy bodies (DLB) were completed. Here, we systematically reviewed the studies (including the recent reports) to provide updated evidence for the treatments of CIND-PD, PDD and DLB. Methods We searched Cochrane Dementia and Cognitive Improvement Group Specialised Register, Pubmed, Embase, and other sources for eligible trials. We selected global impression and cognitive function as primary efficacy outcomes, and dropouts and adverse events as safety outcomes. Furthermore, Meta-analysis and trial sequential analysis (TSA) were used here. Results Ten trials were included in this study. Cholinesterase inhibitors and memantine produced small global efficacy on clinicians’ global impression of change (CGIC), from a weighted mean difference of −0.40 (95% CI −0.77 to −0.03) to −0.65 (95% CI −1.28 to −0.01); however, cholinesterase inhibitors but not memantine significantly improved cognition on Mini-Mental State Examination (MMSE), from 1.04 (95% CI 0.43 to 1.65) to 2.57 (95% CI 0.90 to 4.23). Additionally, both of them had good safety outcomes, although rivastigmine showed an increased risk on adverse events than placebo (risk ratio, RR 1.19, TSA adjusted 95% CI 1.04 to 1.36), these events were usually mild or moderate, and the risk disappeared on serious adverse events. Conclusions Cholinesterase inhibitors and memantine slightly improve global impression; however, only cholinesterase inhibitors enhance cognitive function. Besides, all the drugs have good safety outcomes. But the limited trials precluded the generalisation of these outcomes.

Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis.

BACKGROUND In the past 20 years, substantial evidence from laboratory and epidemiologic studies have suggested that anti-inflammatory medications could defer or prevent the occurrence of Alzheimers disease (AD). However, several studies do not corroborate these findings. OBJECTIVE To evaluate the association of anti-inflammatory drug use on the incidence of AD. METHODS Pubmed, Embase, and Cochrane Library databases were searched up to March 2014. Studies evaluating the association between use of anti-inflammatory drugs and AD risk were included. Relative risks (RRs) with 95% confidence intervals (CIs) were meta-analyzed using random effects models and were grouped by anti-inflammatory type and duration of drug use. RESULTS In observational studies, use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with a reduced risk of AD (RR, 0.72; 95%CI, 0.62-0.84) compared to no use of NSAIDs, especially in long term users (RR, 0.36; 95%CI, 0.17-0.74); the risks of AD were also lower in both aspirin (RR, 0.77; 95%CI, 0.63-0.95) and non-aspirin NSAID users (RR, 0.65; 95%CI, 0.47-0.88) compared with nonusers; whereas the use of corticosteroids showed no significant association (RR, 0.62; 95%CI, 0.26-1.46). In the single randomized controlled trial (RCT), NSAID use showed no significant effect on AD risk among dementia-free individuals (p > 0.05). CONCLUSION Observational studies support the use of NSAIDs for prevention of AD, but RCT do not. Well-designed studies and innovative approaches are required to illuminate the exact relationship between NSAID use and AD risk. The appropriate dosage and duration of use to benefit and the safety are also needed to determine.

Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysis

Background A wide variety of pharmacological agents are used in the management of neuropsychiatric symptoms, which are common in Alzheimers disease (AD), but results from randomised controlled trials (RCTs) on the efficacy and safety of these agents are conflicting. Objectives To quantify the efficacy and safety of pharmacological treatment on neuropsychiatric symptoms in AD patients. Methods Systematic review and meta-analysis of RCTs comparing pharmacological agents with placebo on Neuropsychiatric Inventory (NPI) and safety outcomes in AD patients with neuropsychiatric symptoms. Results Cholinesterase inhibitors (ChEIs) and atypical antipsychotics improved NPI total scores (ChEIs: standardised mean difference (SMD) −0.12; 95% CI −0.23 to −0.02; atypical antipsychotics: SMD −0.21; 95% CI −0.29 to −0.12), but antidepressants (95% CI −0.35 to 0.37) and memantine (95% CI −0.27 to 0.03) did not. However, ChEIs and atypical antipsychotics increased risk of dropouts due to adverse events (ChEIs: risk ratio (RR) 1.64; 95% CI 1.12 to 2.42; atypical antipsychotics: RR 2.24; 95% CI 1.53 to 3.26) and on incidence of adverse events (ChEIs: RR 1.08; 95% CI 1.01 to 1.17; atypical antipsychotics: RR 1.17; 95% CI 1.05 to 1.31). For typical antipsychotics, no study was included. Conclusions ChEIs and atypical antipsychotics could improve neuropsychiatric symptoms in AD patients, but with bad safety outcomes.

Role of the mTOR signaling pathway in epilepsy.

Epilepsy, a common neurological disorder and cause of significant morbidity and mortality, places an enormous burden on the individual and society. Presently, most drugs for epilepsy primarily suppress seizures as symptomatic therapies but do not possess actual antiepileptogenic or disease-modifying properties. The mTOR (mammalian target of rapamycin) signaling pathway is involved in major multiple cellular functions, including protein synthesis, cell growth and proliferation and synaptic plasticity, which may influence neuronal excitability and be responsible for epileptogenesis. Intriguing findings of the frequent hyperactivation of mTOR signaling in epilepsy make it a potential mechanism in the pathogenesis as well as an attractive target for the therapeutic intervention, and have driven the significant ongoing efforts to pharmacologically target this pathway. This review explores the relevance of the mTOR pathway to epileptogenesis and its potential as a therapeutic target in epilepsy treatment by presenting the current results on mTOR inhibitors, in particular, rapamycin, in animal models of diverse types of epilepsy. Limited clinical studies in human epilepsy, some paradoxical experimental data and outstanding questions have also been discussed.

Midlife Vascular Risk Factors and the Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis

BACKGROUND/OBJECTIVE We examine whether midlife vascular risk factors (VRFs) are associated with increased risk of incident Alzheimers disease (AD) in a systematic review and meta-analysis of published cohort studies. METHODS Original cohort studies were included if they reported adjusted combined odds ratio (COR) and corresponding 95% confidence intervals (CIs) or enough information to quantify the association between risk for AD in late-life and baseline VRFs of midlife. RESULTS There were positive and significant associations between high blood pressure (COR 1.31; 95% CI: 1.01-1.70), hypercholesterolemia (COR 1.72; 95% CI: 1.32-2.24), obesity (COR 1.88; 95% CI: 1.32-2.69), and diabetes mellitus in midlife (COR 1.4; 95% CI: 1.25-1.57). Smoking and hyperhomocysteinemia (although only one high-quality paper) were also associated with an increased risk of AD generally. CONCLUSIONS These results strengthen the epidemiological evidence that VRFs of midlife significantly increase risk for AD.

Non-Pharmacological Interventions for Patients with Mild Cognitive Impairment: A Meta-Analysis of Randomized Controlled Trials of Cognition-Based and Exercise Interventions

BACKGROUND Non-pharmacological interventions, including cognition-based intervention and physical exercise, are available for mild cognitive impairment (MCI), but their efficacy remains uncertain. OBJECTIVE To evaluate efficacy of cognition-based intervention and physical exercise on cognitive domains in patients with MCI. METHODS We searched MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews to identify randomized controlled trials (RCTs) that involved cognition-based intervention and physical exercise for persons who were diagnosed with MCI. The pooled weight mean difference or standard mean difference (SMD) were calculated using a random-effect model. RESULTS We found significant effects of cognition-based intervention on global cognitive function (SMD 0.37 [0.07, 0.68] p = 0.02). Besides, cognition-based intervention produced significant effects on executive function reported with TMT-B (SMD 0.8 [0.09, 1.5] p = 0.03) and delayed memory (SMD 0.31 [0.01, 0.61] p = 0.05). A beneficial improvement in global cognitive function was also seen in the exercise group compared to the control group (SMD 0.25 [0.08, 0.41] p = 0.003). CONCLUSIONS Both of cognition-based intervention and physical exercise had the potential to improve global cognitive function. Weak evidence of improvements was also observed for the domains of executive function and delayed memory following cognition-based intervention. Nevertheless, future standard RCTs are still needed to identify the clinical value of our results.

Meta-analysis of peripheral blood apolipoprotein E levels in Alzheimer's disease.

Background Peripheral blood Apolipoprotein E (ApoE) levels have been proposed as biomarkers of Alzheimer’s disease (AD), but previous studies on levels of ApoE in blood remain inconsistent. This meta-analysis was designed to re-examine the potential role of peripheral ApoE in AD diagnosis and its potential value as a candidate biomarker. Methods We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews for case-control studies measuring ApoE levels in serum or plasma from AD subjects and healthy controls. The pooled weighted mean difference (WMD) and 95% confidence interval (CI) were used to estimate the association between ApoE levels and AD risk. Results Eight studies with a total of 2250 controls and 1498 AD cases were identified and analyzed. The pooled WMD from a random-effect model of AD participants compared with the healthy controls was −5.59 mg/l (95% CI: [−8.12, −3.06]). The overall pattern in WMD was not varied by characteristics of study, including age, country, assay method, publication year, and sample type. Conclusions Our meta-analysis supports a lowered level of blood ApoE in AD patients, and indicates its potential value as an important risk factor for AD. Further investigation employing standardized assay for ApoE measurement are still warranted to uncover the precise role of ApoE in the pathophysiology of AD.

Efficacy of Vitamins B Supplementation on Mild Cognitive Impairment and Alzheimer`s Disease: A Systematic Review and Meta-Analysis

Despite B vitamin supplementation playing an important role in cognitive function, the exact effect remains unknown. The aim of this study was to systematically review and quantitatively synthesize the efficacy of treatment with vitamins B supplementation in slowing the rate of cognitive, behavioral, functional and global decline in individuals with MCI or AD. A systematic literature search in PubMed, EMBASE, International Pharmaceutical Abstracts, clinicaltrials. gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry was conducted on April 2014, with no limit of date. Five trials met the eligibility criteria and were selected for this meta-analysis. Meta-analysis showed moderate beneficial effects of vitamins B supplementation on memory (SMD 0.60, 95% CI 0.20, 1.00), whereas no significant difference on general cognitive function (WMD -0.10, 95% CI -0.80, 0.59), executive function (SMD 0.05, 95% CI -0.11, 0.21) and attention (WMD -0.03, 95% CI -1.20, 1.14) were found in MCI patients. In addition, no significantly cognitive benefits on the Alzheimers Disease Assessment Scale (ADAS-cog) (WMD 1.01, 95% CI -0.68, 2.70) and Mini Mental State Examination (MMSE) (WMD -0.22, 95% CI -1.00, 0.57), functional (SMD 0.13, 95% CI -0.05, 0.31), behavioral (SMD 0.04, 95% CI -0.16, 0.25) or global (WMD 0.07, 95% CI -0.48, 0.62) change were observed in AD patients. Collectively, weak evidence of benefits was observed for the domains of memory in patients with MCI. Nevertheless, future standard RCTs are still needed to determine whether it was still significant in larger populations. However, the data does not yet provide adequate evidence of an effect of vitamins B on general cognitive function, executive function and attention in people with MCI. Similarly, folic acid alone or vitamins B in combination are unable to stabilize or slow decline in cognition, function, behavior, and global change of AD patients.

Rate of early onset Alzheimer's disease: a systematic review and meta-analysis.

It is generally accepted that the population rate of early onset Alzheimers disease (EOAD) in Alzheimers disease (AD) is 1-2%. However, the true population based rate of EOAD has never been verified by a systematic review and meta-analysis. We used electronic searches of Cochrane Library, Embase, Medline and PubMed databases to identify published related studies. The systematic review and meta-analysis was then to be conducted to calculate a pooled rate of EOAD and make comparisons between studies and geographic distribution. A total of 13 papers were included in our systematic review and meta-analysis. The rate of EOAD, 5.5% [95% confidence interval (CI): 0.039-0.079, P<0.001], was generated after pooled analysis of all studies in random effect model. The pooled analysis of the rate in developed country was 5.9% (95% CI: 0.040-0.085, P<0.001). The pooled analysis of the rate in developing countries was 4.4% (95% CI: 0.028-0.066, P<0.001). Our study showed that the rate of EOAD in AD is 5.5%, not 1-2% as usually demonstrated. And our results indicated that the rate in developed countries was relative higher than in developing countries. Further trials with larger samples across more countries and more careful designed of experiments are required to confirm whether our findings are truly significant.

Physiotherapy Intervention in Alzheimer's Disease: Systematic Review and Meta-Analysis

BACKGROUND Many studies reported that physiotherapy interventions are available to treat Alzheimers disease (AD), but the efficacy remains uncertain. OBJECTIVE To evaluate the effectiveness of physiotherapy intervention on AD. METHODS The data sources were searched from literature databases, journals, and reference lists from 1 January 1990 to the end of 1 April 2014. Randomized and non-randomized controlled trials with physiotherapy intervention were included in our meta-analysis. Jadad score and Newcastle-Ottawa scale were used to assess the quality of included trials. Outcome measures were cognition function, physical function, activity of daily life (ADL) and neuropsychiatric inventory (NPI). RESULTS 23 trials met the inclusion standard finally. Significant changes were seen in cognitive function: Mini-Mental State Examination score (weighted mean difference (WMD): 1.84, 95% confidence interval (CI): [0.76, to, 2.93], p < 0.0001), and verbal fluency (standard mean difference (SMD): 0.34, 95% CI: [0.01 to 0.66], p = 0.04). Other outcomes are also significant, they were timed up and go test (SMD: 0.56, 95% CI: [0.30 to 0.83], p < 0.0001), berg functional balance scale (SMD: 1.11, 95% CI: [0.37 to 1.84], p = 0.003), 6-min walk distance test (SMD: 141.45, 95% CI: [11.72 to 271.18], p = 0.03), ADL (SMD: 0.78, 95% CI: [0.33 to 1.23], p = 0.0007) and NPI (SMD: -0.69, 95% CI: [-1.31 to -0.07], p = 0.03). CONCLUSION The available data indicate that physiotherapy intervention may have benefits in AD. However, current data are not definitive; more carefully designed and conducted observational studies are needed to definitively establish that whether physiotherapy intervention can effectively alleviate symptoms of AD.