Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions. A total of 113 cases were selected retrospectively on the basis of a confirmed clinical and neuropathological diagnosis and snap-frozen brain blocks were provided by various tissue banks within the BrainNet Europe network. Total RNA was extracted from dissected snap-frozen tissue (< 100 mg) by the individual laboratories according to a BNE optimised common protocol using the RNeasy(r) tissue lipid mini kit (Qiagen Ltd, Crawley, UK) according to the manufacturer's instructions, and was stored at -80C until further use. Gene expression analysis was performed on the RNA samples using the Illumina whole genome HumanRef8 v2 BeadChip (Illumina, London, UK). All the labelling and hybridisation of the samples was carried out in a single experiment by the Imperial College group to reduce the technical variability. RNA samples were prepared for array analysis using the Illumina TotalPrep(tm)-96 RNA Amplification Kit (Ambion/Applied Biosystems, Warrington, UK). Finally, the BeadChips we re scanned using the Illumina BeadArray Reader. The data was extracted using BeadStudio 3.2 (Illumina). Data normalisation and gene differential expression analyses were conducted using the Rosetta error models available in the Rosetta Resolver(r) system (Rosetta Biosoftware, Seattle, Wa, USA). Two samples presented very low signal expression most likely due to hybridization problems and did not pass the quality control test. They are not represented here. One of the 2 samples was a replicate, therefore there was loss of only 1 case bringing the grand total of cases used to 112 (total of samples of 118 including 6 replicates).

Project description:Mathematical modelling is nowadays a pivotal tool for infectious diseases studies, completing regular biological investigations. The rapid growth of computer technology allowed for development of computational tools to address biological issues that could not be unravelled in the past. The global understanding of viral disease dynamics requires to account for all interactions at all levels, from within-host to between-herd, to have all the keys for development of control measures. A literature review was performed to disentangle modelling frameworks according to their major objectives and methodologies. One hundred and seventeen articles published between 1994 and 2020 were found to meet our inclusion criteria, which were defined to target papers representative of studies dealing with models of viral infection dynamics in pigs. A first descriptive analysis, using bibliometric indexes, permitted to identify keywords strongly related to the study scopes. Modelling studies were focused on particular infectious agents, with a shared objective: to better understand the viral dynamics for appropriate control measure adaptation. In a second step, selected papers were analysed to disentangle the modelling structures according to the objectives of the studies. The system representation was highly dependent on the nature of the pathogens. Enzootic viruses, such as swine influenza or porcine reproductive and respiratory syndrome, were generally investigated at the herd scale to analyse the impact of husbandry practices and prophylactic measures on infection dynamics. Epizootic agents (classical swine fever, foot-and-mouth disease or African swine fever viruses) were mostly studied using spatio-temporal simulation tools, to investigate the efficiency of surveillance and control protocols, which are predetermined for regulated diseases. A huge effort was made on model parameterization through the development of specific studies and methodologies insuring the robustness of parameter values to feed simulation tools. Integrative modelling frameworks, from within-host to spatio-temporal models, is clearly on the way. This would allow to capture the complexity of individual biological variabilities and to assess their consequences on the whole system at the population level. This would offer the opportunity to test and evaluate in silico the efficiency of possible control measures targeting specific epidemiological units, from hosts to herds, either individually or through their contact networks. Such decision support tools represent a strength for stakeholders to help mitigating infectious diseases dynamics and limiting economic consequences.

Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions.

Project description:BackgroundAdult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.ObjectiveWe examined the potential association between long-term exposure to particulate matter ≤2.5μm in aerodynamic diameter [fine particulate matter (PM2.5)] and disease aggravation in Alzheimer's (AD) and Parkinson's (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.MethodsWe used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000-2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual PM2.5 concentrations estimated by a prediction model at a 1-km2 resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y PM2.5 exposure. We allowed for nonlinear exposure-outcome relationships using penalized splines and accounted for potential confounders.ResultsWe found a positive nonlinear PM2.5-PD association that plateaued above 11 μg/m3 (RR=1.09, 95% CI: 1.04, 1.14 for a PM2.5 increase from 8.1 to 10.4 μg/m3). We also found a linear PM2.5-ALS positive association (RR=1.05, 95% CI: 1.01, 1.09 per 1-μg/m3 PM2.5 increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients <70 years of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.ConclusionOur findings suggest that annual increase in county-level PM2.5 concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual PM2.5 concentration in our study was 8.1 μg/m3, below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425.

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