Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay

BACKGROUND: Currently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer's Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer's and Parkinson's disease (PD). RESULTS: Thirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2-activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid β-42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r(2) ≥ 0.39, p ≤ 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r(2) ≥ 0.4, p ≤ 0.03) with phosphorylated-tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups. CONCLUSIONS: Using proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD

An atmosphere&ndash;wave regional coupled model: improving predictions of wave heights and surface winds in the southern North Sea

The coupling of models is a commonly used approach when addressing the complex interactions between different components of earth systems. We demonstrate that this approach can result in a reduction of errors in wave forecasting, especially in dynamically complicated coastal ocean areas, such as the southern part of the North Sea &ndash; the German Bight. Here, we study the effects of coupling of an atmospheric model (COSMO) and a wind wave model (WAM), which is enabled by implementing wave-induced drag in the atmospheric model. The numerical simulations use a regional North Sea coupled wave&ndash;atmosphere model as well as a nested-grid high-resolution German Bight wave model. Using one atmospheric and two wind wave models simultaneously allows for study of the individual and combined effects of two-way coupling and grid resolution. This approach proved to be particularly important under severe storm conditions as the German Bight is a very shallow and dynamically complex coastal area exposed to storm floods. The two-way coupling leads to a reduction of both surface wind speeds and simulated wave heights. In this study, the sensitivity of atmospheric parameters, such as wind speed and atmospheric pressure, to the wave-induced drag, in particular under storm conditions, and the impact of two-way coupling on the wave model performance, is quantified. Comparisons between data from in situ and satellite altimeter observations indicate that two-way coupling improves the simulation of wind and wave parameters of the model and justify its implementation for both operational and climate simulations

CSF pro-orexin and amyloid-β38 expression in Alzheimer's disease and frontotemporal dementia

There is an unmet need for markers that can stratify different forms and subtypes of dementia. Because of similarities in clinical presentation, it can be difficult to distinguish between Alzheimer's disease (AD) and frontotemporal dementia (FTD). Using a multiplex targeted proteomic LC-MS/MS platform, we aimed to identify cerebrospinal fluid proteins differentially expressed between patients with AD and FTD. Furthermore analysis of 2 confirmed FTD genetic subtypes carrying progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations was performed to give an insight into the differing pathologies of these forms of FTD. Patients with AD (n = 13) demonstrated a significant (p 2-fold reduction (p < 0.0001) in the FTD group compared to controls and a similar 1.83-fold reduction compared to the AD group (p < 0.001). Soluble TREM2 was elevated in both dementia groups but did not show any difference between AD and FTD. A further analysis comparing FTD subgroups revealed slightly lower levels of proteins apolipoprotein E, CD166, osteopontin, transthyretin, and cystatin C in the GRN group (n = 9) compared to the C9orf72 group (n = 7). These proteins imply GRN FTD elicits an altered inflammatory response to C9orf72 FTD

Advances in multiple sclerosis research in 2009

The following review summarizes the progress in multiple sclerosis research published in the Journal of Neurology in 2009

The response of perennial and temporary headwater stream invertebrate communities to hydrological extremes

The headwaters of karst rivers experience considerable hydrological variability, including spates and streambed drying. Extreme summer flooding on the River Lathkill (Derbyshire, UK) provided the opportunity to examine the invertebrate community response to unseasonal spate flows, flow recession and, at temporary sites, streambed drying. Invertebrates were sampled at sites with differing flow permanence regimes during and after the spates. Following streambed drying at temporary sites, dewatered surface sediments were investigated as a refugium for aquatic invertebrates. Experimental rehydration of these dewatered sediments was conducted to promote development of desiccation-tolerant life stages. At perennial sites, spate flows reduced invertebrate abundance and diversity, whilst at temporary sites, flow reactivation facilitated rapid colonisation of the surface channel by a limited number of invertebrate taxa. Following streambed drying, 38 taxa were recorded from the dewatered and rehydrated sediments, with Oligochaeta being the most abundant taxon and Chironomidae (Diptera) the most diverse. Experimental rehydration of dewatered sediments revealed the presence of additional taxa, including Stenophylax sp. (Trichoptera: Limnephilidae) and Nemoura sp. (Plecoptera: Nemouridae). The influence of flow permanence on invertebrate community composition was apparent despite the aseasonal high-magnitude flood events

On the sui generis value capture of new digital technologies: the case of AI

Digital technologies are emerging at a fast rate, with applications ranging from farming to recruitment. Much of the research on these technologies has concerned optimization and applications, with less focus on the regulation and governance of these systems and how they might bring about foundational and theoretical shifts. Indeed, much of the literature is concerned with forwarding technical approaches, and the potential opportunities and harms, without offering theoretical or philosophical perspectives; few have asked what a digital thing is, what the ontological nature and state of phenomena produced and expressed by digital things are, and if there are distinctions between the conceptions of digital and non-digital technologies. We forward this discussion by investigating the question of what value is being expressed by an algorithm, which we conceptualize in terms of a digital asset, which we define as a valued digital thing that is derived from a particular digital technology

Radiation Tolerance of SiGe BiCMOS Monolithic Silicon Pixel Detectors without Internal Gain Layer

A monolithic silicon pixel prototype produced for the MONOLITH ERC Advanced project was irradiated with 70 MeV protons up to a fluence of 1 x 10^16 1 MeV n_eq/cm^2. The ASIC contains a matrix of hexagonal pixels with 100 {\mu}m pitch, readout by low-noise and very fast SiGe HBT frontend electronics. Wafers with 50 {\mu}m thick epilayer with a resistivity of 350 {\Omega}cm were used to produce a fully depleted sensor. Laboratory tests conducted with a 90Sr source show that the detector works satisfactorily after irradiation. The signal-to-noise ratio is not seen to change up to fluence of 6 x 10^14 n_eq /cm^2 . The signal time jitter was estimated as the ratio between the voltage noise and the signal slope at threshold. At -35 {^\circ}C, sensor bias voltage of 200 V and frontend power consumption of 0.9 W/cm^2, the time jitter of the most-probable signal amplitude was estimated to be 21 ps for proton fluence up to 6 x 10 n_eq/cm^2 and 57 ps at 1 x 10^16 n_eq/cm^2 . Increasing the sensor bias to 250 V and the analog voltage of the preamplifier from 1.8 to 2.0 V provides a time jitter of 40 ps at 1 x 10^16 n_eq/cm^2.Comment: Submitted to JINS