Journal Club: comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology.

Advances in neuroimaging, biomarkers, and clinical data have led to the hypothesis that the pathologic process of Alzheimer dementia begins decades prior to functional decline and diagnosis.1–3 High-profile clinical trial results have shown that biomarker changes can be made via pharmacologic intervention; however, the timing of this intervention has likely been too late to impact the cascade of neurodegenerative changes.4,5 In “Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology” by Monsell et al.,6 neuropathologic and clinical data were used to determine the risk of developing clinically significant cognitive impairment. This work represents a significant contribution because it examines a large cohort of autopsy data, which includes patients with Alzheimer dementia neuropathology who were clinically normal or diagnosed with mild cognitive impairment and Alzheimer-type dementia. The authors report a 3-fold increase in the risk of cognitive symptoms in association with quantifiable increases in neurofibrillary tangle pathology. Additionally, several other factors including APOE gene status, history of depression, and age impacted the clinical presentation. The ultimate goal of this investigation and similar studies is to facilitate the early and accurate identification of those at risk of developing Alzheimer dementia, such that potentially disease-modifying therapies may be considered

Comparing the fate and transport of MS2 bacteriophage and sodium fluorescein in a karstic chalk aquifer

Groundwater flow and contaminant migration tracing is a vital method of identifying and characterising pollutant source-pathway-receptor linkages in karst aquifers. Bacteriophages are an attractive alternative tracer to non-reactive fluorescent dye tracers, as high titres (>10¹² pfu mL−¹) can be safely released into the aquifer, offering improved tracer detectability. However, the interpretation of bacteriophage tracer breakthrough curves is complicated as their fate and transport are impacted by aquifer physicochemical conditions. A comparative tracer migration experiment was conducted in a peri-urban catchment in southeast England to characterise the behaviour of MS2 bacteriophage relative to sodium fluorescein dye in a karstic chalk aquifer. Tracers were released into a stream sink and detected at two abstraction boreholes located 3 km and 10 km away. At both sites, the loss of MS2 phage greatly exceeded that of the solute tracer. In contrast, the qualitative shape of the dye and phage breakthrough curves were visually very similar, suggesting that the bacteriophage arriving at each site was governed by comparable transport parameters to the non-reactive dye tracer. The colloid filtration theory was applied to explain the apparent contradiction of comparable tracer breakthrough patterns despite massive phage losses in the subsurface. One-dimensional transport models were also fitted to each breakthrough curve to facilitate a quantitative comparison of the transport parameter values. The model results suggest that the bacteriophage migrates through the conduit system slightly faster than the fluorescent dye, but that the former is significantly less dispersed. These results suggest that whilst the bacteriophage tracer cannot be used to predict receptor concentrations from transport via karstic flow paths, it can provide estimates for groundwater flow and solute contaminant transit times. This study also provides insight into the attenuation and transport of pathogenic viruses in karstic chalk aquifers

Intelligent upper-limb exoskeleton using deep learning to predict human intention for sensory-feedback augmentation

The age and stroke-associated decline in musculoskeletal strength degrades the ability to perform daily human tasks using the upper extremities. Although there are a few examples of exoskeletons, they need manual operations due to the absence of sensor feedback and no intention prediction of movements. Here, we introduce an intelligent upper-limb exoskeleton system that uses cloud-based deep learning to predict human intention for strength augmentation. The embedded soft wearable sensors provide sensory feedback by collecting real-time muscle signals, which are simultaneously computed to determine the user's intended movement. The cloud-based deep-learning predicts four upper-limb joint motions with an average accuracy of 96.2% at a 200-250 millisecond response rate, suggesting that the exoskeleton operates just by human intention. In addition, an array of soft pneumatics assists the intended movements by providing 897 newton of force and 78.7 millimeter of displacement at maximum. Collectively, the intent-driven exoskeleton can augment human strength by 5.15 times on average compared to the unassisted exoskeleton. This report demonstrates an exoskeleton robot that augments the upper-limb joint movements by human intention based on a machine-learning cloud computing and sensory feedback.Comment: 15 pages, 6 figures, 1 table, Submitted for possible publicatio

Adherence to behavioural interventions in multiple sclerosis: Follow-up meeting report (AD@MS-2)

After an initial meeting in 2013 that reviewed adherence to disease modifying therapy, the AD@MS group conducted a follow-up meeting in 2014 that examined adherence to behavioural interventions in MS (e.g. physical activity, diet, psychosocial interventions). Very few studies have studied adherence to behavioural interventions in MS. Outcomes beyond six months are lacking, as well as implementation work in the community. Psychological interventions need to overcome stigma and other barriers to facilitate initiation and maintenance of behaviour change. A focus group concentrated on physical activity and exercise as one major behavioural intervention domain in MS. The discussion revealed that patients are confronted with multiple challenges when attempting to regularly engage in physical activity. Highlighted needs for future research included an improved understanding of patients’ and health experts’ knowledge and attitudes towards physical activity as well as a need for longitudinal research that investigates exercise persistence

Resting state network profiles of Alzheimer disease and frontotemporal dementia: A preliminary examination

OBJECTIVES/SPECIFIC AIMS: Recent evidence from resting-state fMRI studies have shown that brain network connectivity is altered in patients with neurodegenerative disorders. However, few studies have examined the complete connectivity patterns of these well-reported RSNs using a whole brain approach and how they compare between dementias. Here, we used advanced connectomic approaches to examine the connectivity of RSNs in Alzheimer disease (AD), Frontotemporal dementia (FTD), and age-matched control participants. METHODS/STUDY POPULATION: In total, 44 participants [27 controls (66.4±7.6 years), 13 AD (68.5.63±13.9 years), 4 FTD (59.575±12.2 years)] from an ongoing study at Indiana University School of Medicine were used. Resting-state fMRI data was processed using an in-house pipeline modeled after Power et al. (2014). Images were parcellated into 278 regions of interest (ROI) based on Shen et al. (2013). Connectivity between each ROI pair was described by Pearson correlation coefficient. Brain regions were grouped into 7 canonical RSNs as described by Yeo et al. (2015). Pearson correlation values were then averaged across pairs of ROIs in each network and averaged across individuals in each group. These values were used to determine relative expression of FC in each RSN (intranetwork) and create RSN profiles for each group. RESULTS/ANTICIPATED RESULTS: Our findings support previous literature which shows that limbic networks are disrupted in FTLD participants compared with AD and age-matched controls. In addition, interactions between different RSNs was also examined and a significant difference between controls and AD subjects was found between FP and DMN RSNs. Similarly, previous literature has reported a disruption between executive (frontoparietal) network and default mode network in AD compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Our approach allows us to create profiles that could help compare intranetwork FC in different neurodegenerative diseases. Future work with expanded samples will help us to draw more substantial conclusions regarding differences, if any, in the connectivity patterns between RSNs in various neurodegenerative diseases

Validation of Walk Score® for Estimating Neighborhood Walkability: An Analysis of Four US Metropolitan Areas

Neighborhood walkability can influence physical activity. We evaluated the validity of Walk Score® for assessing neighborhood walkability based on GIS (objective) indicators of neighborhood walkability with addresses from four US metropolitan areas with several street network buffer distances (i.e., 400-, 800-, and 1,600-meters). Address data come from the YMCA-Harvard After School Food and Fitness Project, an obesity prevention intervention involving children aged 5–11 years and their families participating in YMCA-administered, after-school programs located in four geographically diverse metropolitan areas in the US (n = 733). GIS data were used to measure multiple objective indicators of neighborhood walkability. Walk Scores were also obtained for the participant’s residential addresses. Spearman correlations between Walk Scores and the GIS neighborhood walkability indicators were calculated as well as Spearman correlations accounting for spatial autocorrelation. There were many significant moderate correlations between Walk Scores and the GIS neighborhood walkability indicators such as density of retail destinations and intersection density (p < 0.05). The magnitude varied by the GIS indicator of neighborhood walkability. Correlations generally became stronger with a larger spatial scale, and there were some geographic differences. Walk Score® is free and publicly available for public health researchers and practitioners. Results from our study suggest that Walk Score® is a valid measure of estimating certain aspects of neighborhood walkability, particularly at the 1600-meter buffer. As such, our study confirms and extends the generalizability of previous findings demonstrating that Walk Score is a valid measure of estimating neighborhood walkability in multiple geographic locations and at multiple spatial scales

LEECH: A 100 Night Exoplanet Imaging Survey at the LBT

In February 2013, the LEECH (LBTI Exozodi Exoplanet Common Hunt) survey began its 100-night campaign from the Large Binocular Telescope atop Mount Graham in Arizona. LEECH nearly complements other high-contrast planet imaging efforts by observing stars in L' band (3.8 microns) as opposed to the shorter wavelength near-infrared bands (1-2.3 microns). This part of the spectrum offers deeper mass sensitivity for intermediate age (several hundred Myr-old) systems, since their Jovian-mass planets radiate predominantly in the mid-infrared. In this proceedings, we present the science goals for LEECH and a preliminary contrast curve from some early data.Comment: IAUS 299 Proceeding

Nucleosome occupancy reveals regulatory elements of the CFTR promoter

Access to regulatory elements of the genome can be inhibited by nucleosome core particles arranged along the DNA strand. Hence, sites that are accessible by transcription factors may be located by using nuclease digestion to identify the relative nucleosome occupancy of a genomic region. In order to define novel cis regulatory elements in the ∼2.7-kb promoter region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, we define its nucleosome occupancy. This profile reveals the precise positions of nucleosome-free regions (NFRs), both cell-type specific and others apparently unrelated to CFTR-expression level and offer the first high-resolution map of the chromatin structure of the entire CFTR promoter in relevant cell types. Several of these NFRs are strongly bound by nuclear factors in a sequence-specific manner, and directly influence CFTR promoter activity. Sequences within the NFR1 and NFR4 elements are highly conserved in many human gene promoters. Moreover, NFR1 contributes to promoter activity of another gene, angiopoietin-like 3 (ANGPTL3), while NFR4 is constitutively nucleosome-free in promoters genome wide. Conserved motifs within NFRs of the CFTR promoter also show a high level of protection from DNase I digestion genome-wide, and likely have important roles in the positioning of nucleosome core particles more generally

Noncardiac genetic predisposition in sudden infant death syndrome.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible