23 research outputs found
Chitinases as biomarkers of disease aggressiveness in Amyotrophic lateral sclerosis: perspectives through the D50 progression model
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition with no cure. Biomarkers that capture the disease’s clinical heterogeneity are therefore urgently needed. This body of work aimed to characterize the biomarker profile of the chitinases, a group of immunomodulatory enzymes. We used a translational approach combining a clinical cohort and pre-clinical murine models to show that key chitinases (CHIT1, CHI3L1, CHI3L2) are upregulated in the cerebrospinal fluid (CSF) of ALS patients and multiple cellular sources, including glia and neurons, drive this. The novel D50 disease progression model was used to show that extent of this dysregulation is predictive of overall disease aggressiveness, thus highlighting the clinical utility of chitinases
Blood–Brain Barrier Disruption Is Not Associated With Disease Aggressiveness in Amyotrophic Lateral Sclerosis
The pathogenesis of the fatal neurodegenerative condition amyotrophic lateral sclerosis (ALS) remains to be fully understood. Blood–brain barrier damage (BBBD) has been implicated as an exacerbating factor in several neurodegenerative conditions, including ALS. Therefore, this cross-sectional study used the novel D50 progression model to assess the clinical relevance of BBBD within a cohort of individuals with either ALS ( n = 160) or ALS mimicking conditions ( n = 31). Routine laboratory parameters in cerebrospinal fluid (CSF) and blood were measured, and the ratio of CSF to serum albumin levels (Qalb) was used as a proxy measure of BBBD. In the univariate analyses, Qalb levels correlated weakly with disease aggressiveness (as indicated by individual D50 values) and physical function (as measured by ALS Functional Rating Scale). However, after adjustment for cofactors in the elastic net regularization, only having limb-onset disease was associated with BBBD. The results reported here emphasize the clinical heterogeneity of ALS and the need for additional longitudinal and multi-modal studies to fully clarify the extent and effect of BBBD in ALS
Developing a Neuroimaging Biomarker for Amyotrophic Lateral Sclerosis: Multi-Center Data Sharing and the Road to a “Global Cohort”
Neuroimaging in Amyotrophic Lateral Sclerosis (ALS) has steadily evolved from an academic exercise to a powerful clinical tool for detecting and following pathological change. Nevertheless, significant challenges need to be addressed for the translation of neuroimaging as a robust outcome-metric and biomarker in quality-of-care assessments and pharmaceutical trials. Studies have been limited by small sample sizes, poor replication, incomplete patient characterization, and substantial differences in data collection and processing. This has been further exacerbated by the substantial heterogeneity associated with ALS. Multi-center transnational collaborations are needed to address these methodological limitations and achieve representation of rare phenotypes. This review will use the example of the Neuroimaging Society in ALS (NiSALS) to discuss the set-up of a multi-center data sharing ecosystem and the flow of information between various stakeholders. NiSALS' founding objective was to establish best practices for the acquisition and processing of MRI data and establish a structure that allows continuous data sharing and therefore augments the ability to fully describe patients. The practical challenges associated with such a system, including quality control, legal, ethical, and logistical constraints, will be discussed, as will be recommendations for future collaborative endeavors. We posit that “global cohorts” of well-characterized sub-populations within the disease spectrum are needed to fully understand the complex interplay between neuroimaging and other clinical metrics used to study ALS
Reaction to Endoplasmic Reticulum Stress via ATF6 in Amyotrophic Lateral Sclerosis Deteriorates With Aging
Amyotrophic lateral sclerosis (ALS) is a multisystemic neurodegenerative disorder. Given that peripheral blood mononuclear cells (PBMCs) serve as a “window to the central nervous system” we aimed to answer whether endoplasmic reticulum (ER) stress in ALS-PBMCs is related to disease aggressiveness. We studied ER stress in the PBMCs of 49 patients with ALS and 31 age- and sex-matched healthy controls. The expression of a main ER stress marker, activating transcription factor 6 (ATF6), was significantly higher in ALS compared to controls, but did not correlate with age, disease severity, disease duration and disease progression rate. When ATF6 expression levels were plotted against relative D50 (rD50)-derived disease phases derived from the D50 ALS model, two distinct clusters of patients were observed: cluster 1, with progressively increasing ATF6 expression levels and cluster 2, which demonstrated stable ATF6 expression over the disease course. Individuals in the two clusters did not significantly differ in terms of ALS Functional Rating Scale-Revised (ALSFRS-R), disease aggressiveness, disease duration and subtype. However, patients with the increasing ATF6 level were significantly younger, indicating that aging processes might be related to ER stress in ALS. Our data suggest that the reaction to ER stress during disease course may be compromised in older patients with ALS
Physics Potential of the ICAL detector at the India-based Neutrino Observatory (INO)
The upcoming 50 kt magnetized iron calorimeter (ICAL) detector at the
India-based Neutrino Observatory (INO) is designed to study the atmospheric
neutrinos and antineutrinos separately over a wide range of energies and path
lengths. The primary focus of this experiment is to explore the Earth matter
effects by observing the energy and zenith angle dependence of the atmospheric
neutrinos in the multi-GeV range. This study will be crucial to address some of
the outstanding issues in neutrino oscillation physics, including the
fundamental issue of neutrino mass hierarchy. In this document, we present the
physics potential of the detector as obtained from realistic detector
simulations. We describe the simulation framework, the neutrino interactions in
the detector, and the expected response of the detector to particles traversing
it. The ICAL detector can determine the energy and direction of the muons to a
high precision, and in addition, its sensitivity to multi-GeV hadrons increases
its physics reach substantially. Its charge identification capability, and
hence its ability to distinguish neutrinos from antineutrinos, makes it an
efficient detector for determining the neutrino mass hierarchy. In this report,
we outline the analyses carried out for the determination of neutrino mass
hierarchy and precision measurements of atmospheric neutrino mixing parameters
at ICAL, and give the expected physics reach of the detector with 10 years of
runtime. We also explore the potential of ICAL for probing new physics
scenarios like CPT violation and the presence of magnetic monopoles.Comment: 139 pages, Physics White Paper of the ICAL (INO) Collaboration,
Contents identical with the version published in Pramana - J. Physic
Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology
Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology
Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons
Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.peer-reviewe
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Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks
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