A systematic review was conducted to identify risk factors associated with the onset and progression of Alzheimer's disease (AD). Moderate and high quality systematic reviews were eligible for inclusion. Primary studies reporting on non-genetic risk factors associated with neuropathologically or clinically confirmed AD were considered. Eighty one systematic reviews reporting on AD onset and 12 reporting on progression satisfied the eligibility criteria. Four hundred and thirty-two relevant primary studies reporting on onset were identified; however, only those published between 2010 and 2012 (n=65) were included in the qualitative synthesis. Several factors including statins, light-to-moderate alcohol consumption, compliance with a Mediterranean diet, higher educational attainment, physically and cognitively stimulating activities, and APOE e2 appeared to be associated with a decreased risk of AD onset. The evidence was suggestive of an increased risk of AD associated with head injury in males, age, diabetes mellitus, conjugated equine estrogen use with medroxyprogesterone acetate, current smoking, and lower social engagement. With respect to genetic factors, APOE e4 remained the strongest predictor of AD. Physical and cognitive activities were associated with a beneficial effect on cognitive function and other indicators of dementia progression while higher educational attainment was associated with faster cognitive decline. Although suggestive of an association, the current evidence for a majority of the identified putative factors for AD onset and progression was weak, at best due to conflicting findings across studies or inadequate evidence. Further research is required to confirm the etiological or protective role of a number of risk factors.

Risk factors associated with the onset and progression of Alzheimer's disease: A systematic review of the evidence.

Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer’s disease (AD). Additionally, the most common genetic risk factor of AD, APOE ϵ4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer’s disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.

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Involvement of Lipids in Alzheimer's Disease Pathology and Potential Therapies.

Introduction The adenosine triphosphate-binding cassette transporter A1 ( ABCA1 ) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways. Methods We tested whether a loss-of-function mutation in ABCA1 , N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals. Results N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE ( P  = 1 × 10 −11 ). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32–12.9) for AD, 2.46 (1.10–5.50) for cerebrovascular disease, and 8.28 (2.03–33.7) for the hemorrhagic stroke subtype. Discussion A loss-of-function mutation in ABCA1 , present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population.

Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease.

ATP-binding cassette transporter A1: from metabolism to neurodegeneration.

Alzheimer’s disease (AD) is one of the leading genetically complex and heterogeneous disorder that is influenced by both genetic and environmental factors. The underlying risk factors remain largely unclear for this heterogeneous disorder. In recent years, high throughput methodologies, such as genome-wide linkage analysis (GWL), genome-wide association (GWA) studies, and genome-wide expression profiling (GWE), have led to the identification of several candidate genes associated with AD. However, due to lack of consistency within their findings, an integrative approach is warranted. Here, we have designed a rank based gene prioritization approach involving convergent analysis of multi-dimensional data and protein-protein interaction (PPI) network modelling. Our approach employs integration of three different AD datasets- GWL,GWA and GWE to identify overlapping candidate genes ranked using a novel cumulative rank score (SR) based method followed by prioritization using clusters derived from PPI network. SR for each gene is calculated by addition of rank assigned to individual gene based on either p value or score in three datasets. This analysis yielded 108 plausible AD genes. Network modelling by creating PPI using proteins encoded by these genes and their direct interactors resulted in a layered network of 640 proteins. Clustering of these proteins further helped us in identifying 6 significant clusters with 7 proteins (EGFR, ACTB, CDC2, IRAK1, APOE, ABCA1 and AMPH) forming the central hub nodes. Functional annotation of 108 genes revealed their role in several biological activities such as neurogenesis, regulation of MAP kinase activity, response to calcium ion, endocytosis paralleling the AD specific attributes. Finally, 3 potential biochemical biomarkers were found from the overlap of 108 AD proteins with proteins from CSF and plasma proteome. EGFR and ACTB were found to be the two most significant AD risk genes. With the assumption that common genetic signals obtained from different methodological platforms might serve as robust AD risk markers than candidates identified using single dimension approach, here we demonstrated an integrated genomic convergence approach for disease candidate gene prioritization from heterogeneous data sources linked to AD.

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Genomic convergence and network analysis approach to identify candidate genes in Alzheimer's disease.

The osteogenic growth peptide (OGP) is a naturally occurring tetradecapeptide that has attracted considerable clinical interest as a bone anabolic agent and hematopoietic stimulator. In vitro studies have demonstrated that OGP directly regulates the bone marrow mesenchymal stem cells' (BMSCs) differentiation into osteoblasts. However, the exact mechanism of this process remains unknown. In the present study, we investigated the role of RhoA/ROCK signaling in differentiation along this lineage using human BMSCs. OGP treatment increased the mRNA level of bone morphogenetic protein-2 and alkaline phosphatase activity after osteogenic induction. Analysis of BMSCs induced in the presence of OGP revealed an increase in RhoA activity, and phosphorylation of FAK and cofilin. The ROCK-specific inhibitors, Y27632, blocked the OGP-induced regulation of BMSC differentiation. Taken together, these data suggest that OGP not only acts on BMSCs to stimulate osteogenic differentiation, but also in a dose-dependent manner, and this effect is mediated via the activation of RhoA/ROCK pathway.

Synthetic osteogenic growth peptide promotes differentiation of human bone marrow mesenchymal stem cells to osteoblasts via RhoA/ROCK pathway

A meta-analysis of plate fixation versus intramedullary nailing for humeral shaft fractures

ATP-binding cassette transporter A1 (ABCA1) is a membrane-associated protein which has attracted considerable attention as a candidate gene for Alzheimer’s disease (AD) based on its function as a key factor in lipid metabolism by mediating cellular cholesterol efflux, the rate-limiting step in the production of nascent high-density lipoprotein (HDL) particles. The relationship between ABCA1 common variations (R219 K rs2230806, I883 M rs4149313 and R1587 K rs2230808) and AD has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 12,248 subjects to evaluate the effect of ABCA1 on genetic susceptibility for AD. Overall, the summary OR of AD was 1.01 (95 % CI: 0.93–1.10; P = 0.77), 1.10 (95 % CI: 0.96–1.26; P = 0.16), and 1.08 (95 % CI: 0.96–1.23; P = 0.21) for R219 K, I883 M and R1587 K polymorphism, respectively. No significant results were observed in dominant and recessive when compared with wild genotype for these polymorphisms. In the stratified analyses by ethnicity and sample size, no evidence of any gene-disease association was obtained. In conclusion, the present meta-analysis does not support the notion that common SNPs on ABCA1 is a major genetic risk factor for AD.

Quantitative assessment of the effect of ABCA1 gene polymorphism on the risk of Alzheimer's disease.

This study is to reveal the characteristics of autophagy and the effect of neuroserpin (NSP) treatment on autophagy during the process of functional recovery following spinal cord injury (SCI). After the clip compress rat model of SCI had been made, autophagy‑associated proteins, including LC3‑II, beclin‑1 and p62, were evaluated at 2, 4, 24, 72 h, and 168 h in the experimental group, and the sham group as control. Transmission electron microscopy (TEM) was further used for autophagy detection at 4 and 72 h. All the male rats were randomly divided into three groups: Sham, vehicle and NSP group. NSP or an equal volume of saline vehicle was administered via intrathecal injection immediately after SCI. Each group was further divided into subgroups for the following experiments: i)Western blot (LC3‑II and p62); ii) Immunofluorescent double staining (LC3/MAP‑2/DAPI); iii) Nissl staining and Basso Beattie Bresnahan (BBB score) for NSP neuroprotection evaluation. Our results revealed both LC3‑II and p62 expression trended upward at 24, 72 and 168 h after SCI. The LC3‑II peaked at 72 h, while p62 peaked at 24 h. Beclin‑1 dropped significantly at 72 and 168 h. TEM results showed that autophagosomes largely accumulated at 72 h after SCI when compared with the sham group. Western blot analysis showed that LC3‑II and p62 were markedly decreased with NSP treatment at 72 h after injury compared with that of the vehicle‑group. Immunofluorescent double labeling indicated that accumulation of autophagosomes was reduced in the NSP group. Further, post‑SCI treatment with NSP improved the BBB scale and increased the number of anterior horn motor neurons. Together, this study demonstrates that autophagic flux is impaired, meanwhile NSP restores autophagic flux and promotes functional recovery after SCI in rats.

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Neuroserpin restores autophagy and promotes functional recovery after acute spinal cord injury in rats.

This study aimed to examine sleep quality and risk factors associated with sleep disturbance in patients undergoing total joint arthroplasty (TJA) managed with an enhanced recovery protocol from preoperatively until 12 weeks postoperatively in order to provide suggestions for improving the prevention and treatment of sleep disturbance in these patients. The Chinese versions of the Pittsburgh Sleep Quality Index (CPSQI) and Epworth Sleepiness Scale (CESS) were used to evaluate sleep quality. Pain was measured by a visual analog scale (VAS). Neuropsychological status was also assessed, using the Center for Epidemiological Studies Depression Scale (CESD) and Zung Self-Rating Anxiety Scale (ZSAS). Of 107 patients (66% women), the prevalence of sleep disturbance was as high as 60% preoperatively. CPSQI score significantly increased postoperatively from baseline to 2 weeks before decreasing rapidly to a lower level than preoperative baseline. CESS scores of postoperative weeks 1 and 2 increased significantly compared with baseline and decreased significantly after 4 weeks, and a positive correlation was found between CESS and CPSQI score. VAS score significantly decreased from baseline over all time points in the postoperative period. A good sleeper group was more likely to suffer from severe sleep disturbance after surgery than a poor sleeper group with a bigger increase of CPSQI score. Multivariate logistic regression analysis indicated that pain and anxiety were risk factors associated with postoperative sleep disturbance. Sleep disturbance is highly prevalent among patients undergoing TJA. More attention and multimodal approaches with well-controlled pain, mental counseling, and possibly preemptive use of sleep medication may improve sleep quality in TJA patients to promote recovery.

Yunchao Shao

Papers

Synthetic osteogenic growth peptide promotes differentiation of human bone marrow mesenchymal stem cells to osteoblasts via RhoA/ROCK pathway

A meta-analysis of plate fixation versus intramedullary nailing for humeral shaft fractures

Quantitative assessment of the effect of ABCA1 gene polymorphism on the risk of Alzheimer's disease.

Neuroserpin restores autophagy and promotes functional recovery after acute spinal cord injury in rats.

Prospective assessment and risk factors of sleep disturbances in total hip and knee arthroplasty based on an Enhanced Recovery After Surgery concept