Chen-Chen Tan

Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy

Neurodegenerative diseases, such as Alzheimers disease Parkinsons disease, Huntingtons disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.

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.

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.

Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy

MicroRNAs (miRNAs) open up a new field for molecular diagnosis for cancer and other diseases based on their stability in serum. However, the role of circulating miRNAs in plasma/serum in epilepsy diagnosis is still unclear. The aim of this study was to evaluate whether miRNAs can be used as biomarkers for drug-resistant epilepsy. We measured the differences in serum miRNA levels between 30 drug-resistant patients and 30 drug-responsive epilepsy patients in discovery and training phases using Illumina HiSeq2000 sequencing followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. The selected miRNAs were then validated in 77 drug-resistant epilepsy patients, 81 drug-responsive epilepsy patients and 85 healthy controls by qRT-PCR. We found that circulating miRNAs are differentially expressed between drug-resistant group and drug-responsive group. MiR-194-5p, -301a-3p, -30b-5p, -342-5p and -4446-3p were significantly deregulated in drug-resistant group compared to drug-responsive group and control group. Among these 5 miRNAs, miR-301a-3p had the best diagnostic value for drug-resistant epilepsy with 80.5% sensitivity and 81.2% specificity, and was negatively associated with seizure severity. These provide the rationale for further confirmation studies in larger prospective cohorts and in other ethnics.

Genome-wide microRNA expression profiles in hippocampus of rats with chronic temporal lobe epilepsy

The expression and functions of microRNAs (miRNAs) in chronic temporal lobe epilepsy (TLE), the most common type of refractory epilepsy in adults, are poorly understood currently. In this study, status epilepticus evoked by amygdala stimulation was used to establish rat chronic TLE model. Two months later, high-throughput sequencing was employed to investigate miRNA expression profile in rat hippocampus, and six miRNAs were confirmed to be differentially expressed. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that most of the target genes for these six miRNAs were associated with neuronal apoptosis. Meanwhile, the levels of miR-423-3p and miR-296-5p were correlated with the activity of caspase-3, an apoptosis indicator. Additionally, the loading of miR-423-3p was increased in RNA-induced silencing complex whilst caspase-6, a target of miR-423-3p, was reduced in chronic TLE rats. Collectively, our findings suggest that miRNAs may exert anti-apoptotic effects in chronic TLE.

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.