Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity.

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross-sectional study, we employed 11 C-Pittsburgh Compound-B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta-amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large-scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30-55, median age = 43.5) and a stark lack of anti-correlation. However, in contrast to typically developing controls (n = 20, ages 30-55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB-negative Down's syndrome group (n = 19, ages 30-48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB-positive (n = 15, ages 39-55, median age = 48.0) and PiB-negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome

Delineating the topography of amyloid-associated cortical atrophy in Down syndrome

Older adults with Down syndrome (DS) often have Alzheimer's disease (AD) neuropathologies. Although positron emission tomography imaging studies of amyloid deposition (beta amyloid, Aβ) have been associated with worse clinical prognosis and cognitive impairment, their relationships with cortical thickness remain unclear in people with DS. In a sample of 44 DS adults who underwent cognitive assessments, [C]-PiB positron emission tomography, and T1-weighted magnetization-prepared rapid gradient echo, we used mixed effect models to evaluate the spatial relationships between Aβ binding with patterns of cortical thickness. Partial Spearman correlations were used to delineate the topography of local Aβ-associated cortical thinning. [C]-PiB nondisplaceable binding potential was negatively associated with decreased cortical thickness. Locally, regional [C]-PiB retention was negatively correlated with cortical thickness in widespread cortices, predominantly in temporoparietal regions. Contrary to the prevailing evidence in established AD, we propose that our findings implicate Aβ in spatial patterns of atrophy that recapitulated the “cortical signature” of neurodegeneration in AD, conferring support to recent recommendations for earlier disease-interventions

Brain-predicted age in Down syndrome is associated with beta amyloid deposition and cognitive decline

Individuals with Down Syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological ageing. This includes brain atrophy, β-amyloid deposition, cognitive decline and Alzheimer’s Disease; factors indicative of brain ageing. Here we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [11C]-PiB positron emission tomography (PET) scans to index levels of cerebral β-amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants’ was +2.49 years, significantly greater than controls (p<0.001). The variability in brain-PAD was associated with the presence and the magnitude of PIB-binding and levels of cognitive performance. Our study indicates that DS is associated with premature structural brain ageing, and that age-related alterations in brain structure are associated with individual differences in the rate of β-amyloid deposition and cognitive impairment

Canadian Hydrogen Intensity Mapping Experiment (CHIME) Pathfinder

A pathfinder version of CHIME (the Canadian Hydrogen Intensity Mapping Experiment) is currently being commissioned at the Dominion Radio Astrophysical Observatory (DRAO) in Penticton, BC. The instrument is a hybrid cylindrical interferometer designed to measure the large scale neutral hydrogen power spectrum across the redshift range 0.8 to 2.5. The power spectrum will be used to measure the baryon acoustic oscillation (BAO) scale across this poorly probed redshift range where dark energy becomes a significant contributor to the evolution of the Universe. The instrument revives the cylinder design in radio astronomy with a wide field survey as a primary goal. Modern low-noise amplifiers and digital processing remove the necessity for the analog beamforming that characterized previous designs. The Pathfinder consists of two cylinders 37\,m long by 20\,m wide oriented north-south for a total collecting area of 1,500 square meters. The cylinders are stationary with no moving parts, and form a transit instrument with an instantaneous field of view of $\sim$100\,degrees by 1-2\,degrees. Each CHIME Pathfinder cylinder has a feedline with 64 dual polarization feeds placed every $\sim$30\,cm which Nyquist sample the north-south sky over much of the frequency band. The signals from each dual-polarization feed are independently amplified, filtered to 400-800\,MHz, and directly sampled at 800\,MSps using 8 bits. The correlator is an FX design, where the Fourier transform channelization is performed in FPGAs, which are interfaced to a set of GPUs that compute the correlation matrix. The CHIME Pathfinder is a 1/10th scale prototype version of CHIME and is designed to detect the BAO feature and constrain the distance-redshift relation.Comment: 20 pages, 12 figures. submitted to Proc. SPIE, Astronomical Telescopes + Instrumentation (2014

Longitudinal trajectories of amyloid deposition, cortical thickness, and tau in Down syndrome: A deep-phenotyping case report.

Introduction:Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. Methods:Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [11C]-PiB-PET, four structural magnetic resonance imagings, as well as a [18F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. Results:Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. Discussion:Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

&lt;p&gt;Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.&lt;/p&gt; &lt;p&gt;Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.&lt;/p&gt; &lt;p&gt;Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.&lt;/p&gt

Optical Tastebuds for Water Quality Testing

To achieve the UN Sustainable Development Goal of universal access to clean water and sanitation, we need to rethink centralized water systems with global net-zero carbon and sustainability in mind. One approach is to develop scalable off-grid systems that are reliable and easy to use and maintain. A major challenge for such systems is translating the standard laboratory-based monitoring of centralized systems to a more sustainable and scalable model for regularly and routinely monitoring system outputs, which consist of complex mixtures with varying concentrations of molecules and ions in water. Here, we demonstrate a preliminary sensor that, once fully developed, could allow for point-of-use measurements with a single output to monitor. Rather than developing multiple sensors to monitor the levels of each individual component in the water, our label-free, array-based design mimics the biological system of taste. The sensor is comprised of an array of nano-tastebuds made of tailored plasmonic metasurfaces. The combination of different signals from each nano-tastebud to the same sample yields a unique fingerprint for that sample. Through training, these fingerprints build an identification model. By integrating a fully developed sensor into decentralized water systems, we seek to provide non-expert end-users with an easy-to-read output capable of warning of imminent system failures