Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer’s disease patients

International audienceIdentification of blood-based biomarkers of Alzheimer’s disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C11]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Introduction: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. Results: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. Discussion: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

New insights into the chemical structure of Y2Ti2O7−δ nanoparticles in oxide dispersion-strengthened steels designed for sodium fast reactors by electron energy-loss spectroscopy

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Stability of nano-oxides upon heavy ion irradiation of an ODS material

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Military applications of hyperspectral imagery

Optical imaging, including infrared imaging, generally has many important applications, both civilian and military. In recent years, technological advances have made multi- and hyperspectral imaging a viable technology in many demanding military application areas. The aim of the CEPA JP 8.10 program has been to evaluate the potential benefit of spectral imaging techniques in tactical military applications. This unclassified executive summary describes the activities in the program and outlines some of the results. More specific results are given in classified reports and presentations. The JP 8.10 program started in March 2002 and ended in February 2005. The participating nations were France, Germany, Italy, Netherlands, Norway, Sweden and United-Kingdom, each with a contribution of 2 man-years per year. Essential objectives of the program were to: 1) analyze the available spectral information in the optronic landscape from visible to infrared; 2) analyze the operational utility of multi- and hyperspectral imaging for detection, recognition and identification of targets, including low-signature targets; 3) identify applications where spectral imaging can provide a strong gain in performance; 4) propose technical recommendations of future spectral imaging systems and critical components. Finally, a stated objective of the JP 8.10 program is to "ensure the proper link with the image processing community". The presentation is organized as follows. In a first step, the two trials (Pirrene and Kvarn) are presented including a summary of the acquired optical properties of the different landscape materials and of the spectral images. Then, a phenomenology study is conducted analyzing the spectral behavior of the optical properties, understanding the signal at the sensor and, by processing spectroradiometric measurements evaluating the potential to discriminate spectral signatures. Cameo-Sim simulation software is presented including first validation results and the generation of spectral synthetic images. Results obtained on measured and synthetic images are shown and discussed with reference to two main classes of image processing tasks: anomaly detection and signature based target detection. Furthermore, preliminary works on band selection are also presented which aim to optimize the spectral configuration of an image sensor. Finally, the main conclusions of the WEAG program CEPA JP8.10 are give