Using the A/T/N framework to examine driving in preclinical Alzheimer’s disease

The A/T/N classification system is the foundation of the 2018 NIA-AA Research Framework and is intended to guide the Alzheimer disease (AD) research agenda for the next 5–10 years. Driving is a widespread functional activity that may be particularly useful in investigation of functional changes in pathological AD before onset of cognitive symptoms. We examined driving in preclinical AD using the A/T/N framework and found that the onset of driving difficulties is most associated with abnormality of both amyloid and tau pathology, rather than amyloid alone. These results have implications for participant selection into clinical trials and for the application time of interventions aimed at prolonging the time of safe driving among older adults with preclinical AD

Creating a driving profile for older adults using GPS devices and naturalistic driving methodology

Background/Objectives: Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. Our objective was to describe the process and associated challenges in adapting an existing, commercial, off-the-shelf (COTS), in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers. Design: The Azuga G2 Tracking DeviceTM was installed in each participant’s vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven.  Setting: The Knight Alzheimer’s Disease Research Center at Washington University School of Medicine. Participants: Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance.  Participants were aged 65+ years and had normal cognition. Measurements:  Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations.  Temporal components included number of trips taken during different times of the day.  Behavioral components included number of hard braking, speeding and sudden acceleration events. Methods:  Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS.  Results: Primary locations were confirmed to be 100% accurate when compared to known addresses.  Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns.  Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night.  Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period. Conclusions: Compared to cameras and highly instrumented vehicle in other naturalistic studies, the compact COTS device was quickly installed and transmitted high volumes of data. Driving Profiles for older adults can be created and compared month-to-month or year-to-year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions

Spatial Awareness is Related to Moderate Intensity Running during a Collegiate Rugby Match

International Journal of Exercise Science 9(5): 599-606, 2016. The purpose of the present study was to evaluate the relationship between spatial awareness, agility, and distance covered in global positioning system (GPS) derived velocity zone classifications during a collegiate rugby match. Twelve American collegiate rugby union players (mean±SD; age: 21.2±1.4 y; weight: 85.0±16.0 kg; 7 forwards & 5 backs) on a single team volunteered to participate in this investigation. The distances travelled at low (walking/jogging; \u3c2.7m/s), moderate (cruising/striding; 2.7-5.0 m/s), and high intensities (running/sprinting; \u3e5.0 m/s) were measured for each player using GPS sensors and normalized according to playing time during an official USA Rugby match. Spatial awareness was measured as visual tracking speed from one core session of a 3-dimensional multiple-object-tracking speed (3DMOTS) test (1.35±0.59 cm·sec-1). Agility was assessed utilizing the pro agility (5.05±0.28 sec) and t drill (10.62±0.39 sec). Analysis of variance revealed that athletes travelled the greatest distance during walking/jogging (39.5±4.5 m·min-1) and least distance during running/sprinting (4.9±3.5 m·min-1). Pearson product moment correlations revealed that only distance covered while cruising/striding (20.9±6.5 m·min-1) was correlated to spatial awareness (r=0.798, p=0.002). Agility did not correlate to distance covered at any velocity zone or spatial awareness. Spatial awareness, as determined by 3DMOTS, appears to be related to the moderate intensity movement patterns of rugby union athletes

A horizon scan of future threats and opportunities for pollinators and pollination

Background. Pollinators, which provide the agriculturally and ecologically essential service of pollination, are under threat at a global scale. Habitat loss and homogenisation, pesticides, parasites and pathogens, invasive species, and climate change have been identified as past and current threats to pollinators. Actions to mitigate these threats, e.g., agri-environment schemes and pesticide-use moratoriums, exist, but have largely been applied post-hoc. However, future sustainability of pollinators and the service they provide requires anticipation of potential threats and opportunities before they occur, enabling timely implementation of policy and practice to prevent, rather than mitigate, further pollinator declines. Methods.Using a horizon scanning approach we identified issues that are likely to impact pollinators, either positively or negatively, over the coming three decades. Results.Our analysis highlights six high priority, and nine secondary issues. High priorities are: (1) corporate control of global agriculture, (2) novel systemic pesticides, (3) novel RNA viruses, (4) the development of new managed pollinators, (5) more frequent heatwaves and drought under climate change, and (6) the potential positive impact of reduced chemical use on pollinators in non-agricultural settings. Discussion. While current pollinator management approaches are largely driven by mitigating past impacts, we present opportunities for pre-emptive practice, legislation, and policy to sustainably manage pollinators for future generations

Absolute Winding Number Differentiates Mouse Spatial Navigation Strategies With Genetic Risk for Alzheimer’s Disease

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease

Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism s

ABSTRACT Crystal structures of CYP2B35 and CYP2B37 from the desert woodrat were solved in complex with 4-(4-chlorophenyl)imidazole (4-CPI). The closed conformation of CYP2B35 contained two molecules of 4-CPI within the active site, whereas the CYP2B37 structure demonstrated an open conformation with three 4-CPI molecules, one within the active site and the other two in the substrate access channel. To probe structurefunction relationships of CYP2B35, CYP2B37, and the related CYP2B36, we tested the O-dealkylation of three series of related substrates-namely, 7-alkoxycoumarins, 7-alkoxy-4-(trifluoromethyl)coumarins, and 7-alkoxy-4-methylcoumarinswith a C1-C7 side chain. CYP2B35 showed the highest catalytic efficiency (k cat /K M ) with 7-heptoxycoumarin as a substrate, followed by 7-hexoxycoumarin. In contrast, CYP2B37 showed the highest catalytic efficiency with 7-ethoxy-4-(trifluoromethyl) coumarin (7-EFC), followed by 7-methoxy-4-(trifluoromethyl) coumarin (7-MFC). CYP2B35 had no dealkylation activity with 7-MFC or 7-EFC. Furthermore, the new CYP2B-4-CPI-bound structures were used as templates for docking the 7-substituted coumarin derivatives, which revealed orientations consistent with the functional studies. In addition, the observation of multiple -Cl and -NH-p interactions of 4-CPI with the aromatic side chains in the CYP2B35 and CYP2B37 structures provides insight into the influence of such functional groups on CYP2B ligand binding affinity and specificity. To conclude, structural, computational, and functional analysis revealed striking differences between the active sites of CYP2B35 and CYP2B37 that will aid in the elucidation of new structure-activity relationships