Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer disease have given area under the curve (AUC) estimates of <80%. However, these have been based on ...the genetic analysis of clinical case–control series. Here, we apply the same analytic approaches to a pathological case–control series and show a predictive AUC of 84%. We suggest that this analysis has clinical utility and that there is limited room for further improvement using genetic data. Ann Neurol 2017;82:311–314.
The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. ...To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
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•Systems approach to LOAD based on large-scale human brain-tissue sampling•Molecular networks show strong remodeling effect in LOAD brains•Integrative network-based analysis implicates the immune/microglia network in LOAD•TYROBP implicated as key causal regulator within the immune/microglia module
An integrated systems approach leverages transcriptome data from postmortem brains of late-onset Alzheimer’s disease patients to identify key nodes that drive dysregulated or rewired networks in the disease state.
We present wearable dry electrodes made of silver nanowires for electrophysiological sensing such as electrocardiography and electromyography. The dry electrodes perform as well as the Ag/AgCl wet ...electrodes when the subject is resting and show fewer motion artifacts, but without the electrolytic gel. The nanowire electrodes show no signs of skin irritation, which is desirable for long-term health monitoring.
We present wearable dry electrodes made of silver nanowires for long-term electrophysiological sensing such as electrocardiography and electromyography.
We demonstrate a class of microstrip patch antennas that are stretchable, mechanically tunable, and reversibly deformable. The radiating element of the antenna consists of highly conductive and ...stretchable material with screen-printed silver nanowires embedded in the surface layer of an elastomeric substrate. A 3-GHz microstrip patch antenna and a 6-GHz 2-element patch array are fabricated. Radiating properties of the antennas are characterized under tensile strain and agree well with the simulation results. The antenna is reconfigurable because the resonant frequency is a function of the applied tensile strain. The antenna is thus well suited for applications like wireless strain sensing. The material and fabrication technique reported here could be extended to achieve other types of stretchable antennas with more complex patterns and multilayer structures.
Abstract While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer’s disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of ...risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59–58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L , HLA-DRA and RANBP3L . Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.
Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be ...discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability.
We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set.
SNP-based heritability of late onset Alzheimer's disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% SD = 8% on average when the APOE region is excluded and an additional 1% SD = 3% when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts.
The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.
Access to smartphone and data plan services may impact levels of connection and opportunities for health management for patients with a diagnosis of a serious mental illness. Such smartphone-based ...services provide opportunities that extend the reach of physical and mental health care programs. The purpose of this study was to explore barriers and facilitators faced by individuals with mental health challenges when accessing Medicaid SafeLink smartphones and data plans. Interview guides were developed using the Consolidated Framework for Implementation Research. Individual semi-structured interviews were conducted to collect qualitative data on 18 participants' experiences with SafeLink services. Two main themes were identified- barriers and facilitators. Sub-themes included monthly data limits, followed by account management (barriers), opportunities for safety, and connection (facilitators). Massachusetts SafeLink policies provide individuals with an opportunity for smartphone ownership. However, results imply that expanding the current policy's usage limits may provide additional opportunities for connection and access to health services.
Acer truncatum is an important ornamental, edible, and medicinal plant resource in China. Previous phytochemical research has focused on the leaf (AL) due to its long history as a tea for health. ...Other parts such as the branch (ABr), bark (ABa), fruit (AF), and root (AR) have drawn little attention regarding their metabolites and bioactivities. The strategy of an in-house chemical library combined with Progenesis QI informatics platform was applied to characterize the metabolites. A total of 98 compounds were characterized or tentatively identified, including 63 compounds reported from this species for the first time. Principal component analysis showed the close clustering of ABr, ABa, and AR, indicating that they share similar chemical components, while AL and AF clustered more distantly. By multiple orthogonal partial least-squares discriminant analyses (OPLS-DA), 52 compounds were identified as potential marker compounds differentiating these different plant parts. The variable influence on projection score from OPLS-DA revealed that catechin, procyanidins B2 or B3, and procyanidins C1 or C2 are the significant metabolites in ABa extracts, which likely contribute to its antioxidant and cytotoxic activities.
Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms ...of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1-3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease.
Abstract Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition ...characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease.
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