New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

A novel cyano functionalized silica-titania oxide sol-gel based ionic liquid for the extraction of hazardous chlorophenols from aqueous environments

In the present investigation a cyano functionalized silica-titania oxide sol-gel based ionic liquid (Si-Ti@CN/IL) has been successfully synthesised via sol-gel immobilization of cyanopropyltriethoxysilane and 1-benzyl-3-(trimethoxysilylpropyl)imidazolium chloride ionic liquid (BTMP-IM) on the silica-titania mixed oxide surface. The newly prepared Si-Ti@CN/IL was used as an adsorbent for the separation/preconcentration of chlorophenols from water samples prior to their HPLC-UV determination. Synthesis of Si-Ti@CN/IL was confirmed by Fourier transform infrared (FT-IR) spectroscopy, field emission scanning electron microscopy (FESEM), Brunauer-Emmett-Teller (BET), thermo gravimetric analysis (TGA), X-ray diffraction (XRD) and elemental (CHNS) analysis. During the extraction process, various kinds of interactions such as π-π interactions and hydrogen bonding between the anionic/cationic sites were monitored. The extraction of chlorophenols on Si-Ti@CN/IL is highly pH dependent and a significant percent extraction was achieved at pH = 2. The Si-Ti@CN/IL provided low limit of detection (LOD = 0.83-0.95 μg L-1) with a linearity range from 10-1000 μg L-1 (LOQ = 2.77-3.17 μg L-1). The field studies with high recovery (73.39-105.54%) as well as acceptable precision (%RSD 0.82-4.19) also supported the effectiveness of Si-Ti@CN/IL, which could be useful for the extraction of selected chlorophenols from tap water, lake water and leachate from landfill sites. The comparative data support Si-Ti@CN/IL as an effective extractant for selected chlorophenols

Magnetic solid phase extraction of polycyclic aromatic hydrocarbons and chlorophenols based on cyano-ionic liquid functionalized magnetic nanoparticles and their determination by HPLC-DAD

A magnetic solid-phase extraction (MSPE) procedure on the newly synthesized cyano-ionic liquid functionalized magnetic nanoparticles (MNP@CN/IL) was established and validated for the separation/preconcentration of polycyclic aromatic hydrocarbons (PAHs) and chlorophenols (CPs) from water samples prior to their HPLC-DAD determination. The new magnetic (MNP@CN/IL) adsorbent was characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), elemental analysis (CHNS), energy-dispersive X-ray spectroscopy (EDX), vibrating sample magnetometry (VSM), thermal gravimetric analysis (TGA) and transmission electron microscopy (TEM). The proposed method showed preconcentrations of 200 and 100 with low limits of detection (LOD = 0.40-0.59 and 0.35-0.67 μg L-1) with linearity ranges from 0.1-100 and 3-100 μg L-1 for PAHs and CPs, respectively. The extraction recoveries from environmental samples (leachate and sludge from a landfill site) ranged from 89.50-110.2% and 80.67-112.7% for PAHs and CPs, respectively, with satisfactory precision (% RSD less than 5%). The combination of cyano group and ionic liquid on the surface of the MNPs enhanced the extraction efficiency which might be due to π-π interactions as well as electrostatic interactions

Investigating gains in neurocognition in an Intervention Trial of Exercise (IGNITE): Protocol

Despite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches for improving neurocognitive health. Fortunately, moderate intensity exercise is a promising method for improving brain and cognitive health in late life, but its effectiveness remains a matter of skepticism and debate because of the absence of large, comprehensive, Phase III clinical trials. Here we describe the protocol for such a randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise), a study capable of more definitively addressing whether exercise influences cognitive and brain health in cognitively normal older adults. We are conducting a 12-month, multi-site, randomized dose-response exercise trial in 639 cognitively normal adults between 65 and 80 years of age. Participants are randomized to (1) a moderate intensity aerobic exercise condition of 150 min/week (N = 213), (2) a moderate intensity aerobic exercise condition at 225 min/week (N = 213), or (3) a light intensity stretching-and-toning control condition for 150 min/week (N = 213). Participants are engaging in 3 days/week of supervised exercise and two more days per week of unsupervised exercise for 12 months. A comprehensive cognitive battery, blood biomarkers and battery of psychosocial questionnaires is assessed at baseline, 6 and 12-months. In addition, brain magnetic resonance imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and positron emission tomography of amyloid deposition are assessed at baseline and at the 12-month follow-up. The results from this trial could transform scientific-based policy and health care recommendations for approaches to improve cognitive function in cognitively normal older adults

Meta-analysis of the association between variants in SORL1 and Alzheimer disease

10.1001/archneurol.2010.346Archives of Neurology68199-106ARNE

Array-Based Comparative Genomic Hybridization for the Genomewide Detection of Submicroscopic Chromosomal Abnormalities

Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using ∼3,500 flourescent in situ hybridization–verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome