Human central nervous system (CNS) ApoE isoforms are increased by age, differentially altered by amyloidosis, and relative amounts reversed in the CNS compared with plasma

The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF β-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden

Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Alzheimer\u27s disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether a regional correlation exists between Abeta and p-tau in the human brain. Recent studies in cerebrospinal fluid (CSF) have suggested that tau phosphorylation at specific sites such as T217 is modified at an early stage of AD when amyloid plaques become detectable. We applied biochemical and mass spectrometry methods in human brain samples with and without Abeta plaque pathology to measure site-specific phosphorylation occupancies in soluble and insoluble tau. Our quantitative results identified multiple residues specifically hyper-phosphorylated in AD, including at sites T111, T153, S184 (or S185), T205, S208, T217, S262, and S285 in brain soluble tau. In contrast, the most enriched phosphorylated residues in brain insoluble tau were T111, S113, T153, T181, S199, S202, T205, T217, T231, S262, and S396. Tau phosphorylation occupancies in the insoluble fraction were relatively constant across brain regions, suggesting that tau has a consistent phosphorylation pattern once it has aggregated into NFTs. We did not find regional association between Abeta42 and insoluble tau. However, the phosphorylation profile of soluble tau in AD brain was highly correlated to that in AD CSF, which was analyzed in a previous study. We also found a higher regional association between total Abeta42 and soluble tau phosphorylation occupancy at residues T111, T153 and T217 in the brain. This study provides insights into regional interactions between amyloidosis and specific tau phosphorylated residues in the human brain and may explain the specific increases of tau species phosphorylation observed in AD CSF

The burden of unintentional drowning: Global, regional and national estimates of mortality from the global burden of disease 2017 study

Background: Drowning is a leading cause of injury-related mortality globally. Unintentional drowning (International Classification of Diseases (ICD) 10 codes W65-74 and ICD9 E910) is one of the 30 mutually exclusive and collectively exhaustive causes of injury-related mortality in the Global Burden of Disease (GBD) study. This study\u27s objective is to describe unintentional drowning using GBD estimates from 1990 to 2017.Methods: Unintentional drowning from GBD 2017 was estimated for cause-specific mortality and years of life lost (YLLs), age, sex, country, region, Socio-demographic Index (SDI) quintile, and trends from 1990 to 2017. GBD 2017 used standard GBD methods for estimating mortality from drowning.Results: Globally, unintentional drowning mortality decreased by 44.5% between 1990 and 2017, from 531 956 (uncertainty interval (UI): 484 107 to 572 854) to 295 210 (284 493 to 306 187) deaths. Global age-standardised mortality rates decreased 57.4%, from 9.3 (8.5 to 10.0) in 1990 to 4.0 (3.8 to 4.1) per 100 000 per annum in 2017. Unintentional drowning-associated mortality was generally higher in children, males and in low-SDI to middle-SDI countries. China, India, Pakistan and Bangladesh accounted for 51.2% of all drowning deaths in 2017. Oceania was the region with the highest rate of age-standardised YLLs in 2017, with 45 434 (40 850 to 50 539) YLLs per 100 000 across both sexes.Conclusions: There has been a decline in global drowning rates. This study shows that the decline was not consistent across countries. The results reinforce the need for continued and improved policy, prevention and research efforts, with a focus on low- and middle-income countries

Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)

It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared

Quantifying regional α -synuclein, amyloid β, and tau accumulation in Lewy body dementia

OBJECTIVE: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions. METHODS: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs. RESULTS: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case. INTERPRETATION: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes

Wild Felids as Hosts for Human Plague, Western United States

Plague seroprevalence was estimated in populations of pumas and bobcats in the western United States. High levels of exposure in plague-endemic regions indicate the need to consider the ecology and pathobiology of plague in nondomestic felid hosts to better understand the role of these species in disease persistence and transmission

Ante- and postmortem tau in autosomal dominant and late-onset Alzheimer\u27s disease

Antemortem tau positron emission tomography imaging suggests elevated tau pathology in autosomal dominant versus late-onset Alzheimer\u27s disease at equivalent clinical stages, but does not implicate the specific tau pathologies responsible. Here we made stereological measurements of tau neurofibrillary tangles, neuritic plaques, and neuropil threads and found compared to late-onset Alzheimer\u27s disease, autosomal dominant Alzheimer\u27s disease showed even greater tangle and thread burdens. Regional tau burden resembled that observed in tau imaging of a separate cohort at earlier clinical stages. Finally, our results suggest tau imaging measures total tau burden in Alzheimer\u27s disease, composed predominantly of tangle and thread pathology

Child abuse in England and Wales 2003–2013: Newspaper reporting versus reality

This study examined how child abuse and neglect were reported in a sample of 459 newspaper articles between 2003 and 2013 in England and Wales. The results were compared with data on child abuse and neglect over the same decade. Sexual abuse was by far the most commonly reported, in both tabloid and broadsheet newspapers. Although neglect and emotional abuse are the most common causes of child protection plans in England and Wales, neglect and emotional abuse are relatively invisible in newspaper articles, as is physical abuse. Possible explanations for this disproportionate focus on sexual abuse, which has also been found in Australia and the United States, include the fact that sexual abuse cases reach the criminal courts more often than other forms of child victimisation. Although broadsheet papers were more likely than tabloid newspapers to comment on causes and solutions beyond the individual perpetrator committing a crime, the majority of articles in broadsheet papers still did not frame either the causes or the solutions in broader terms. It seems possible that the notion of the decontextualised ‘evil’ perpetrator serves to distance journalist and reader alike from the pervasiveness and pain of child abuse. The article concludes with ideas to improve the accuracy and utility of the coverage of child abuse and neglect in newspapers

ENM2020 : A FREE ONLINE COURSE AND SET OF RESOURCES ON MODELING SPECIES NICHES AND DISTRIBUTIONS

The field of distributional ecology has seen considerable recent attention, particularly surrounding the theory, protocols, and tools for Ecological Niche Modeling (ENM) or Species Distribution Modeling (SDM). Such analyses have grown steadily over the past two decades-including a maturation of relevant theory and key concepts-but methodological consensus has yet to be reached. In response, and following an online course taught in Spanish in 2018, we designed a comprehensive English-language course covering much of the underlying theory and methods currently applied in this broad field. Here, we summarize that course, ENM2020, and provide links by which resources produced for it can be accessed into the future. ENM2020 lasted 43 weeks, with presentations from 52 instructors, who engaged with >2500 participants globally through >14,000 hours of viewing and >90,000 views of instructional video and question-and-answer sessions. Each major topic was introduced by an "Overview" talk, followed by more detailed lectures on subtopics. The hierarchical and modular format of the course permits updates, corrections, or alternative viewpoints, and generally facilitates revision and reuse, including the use of only the Overview lectures for introductory courses. All course materials are free and openly accessible (CC-BY license) to ensure these resources remain available to all interested in distributional ecology.Peer reviewe

Continental-scale dynamics of avian influenza in U.S. waterfowl are driven by demography, migration and temperature

Emerging diseases of wildlife origin are increasingly spilling over into humans and domestic animals. Surveillance and risk assessments for transmission between these populations are informed by a mechanistic understanding of the pathogens in wildlife reservoirs. For avian influenza viruses (AIV), much observational and experimental work in wildlife has been conducted at local scales, yet fully understanding their spread and distribution requires assessing the mechanisms acting at both local, (e.g., intrinsic epidemic dynamics), and continental scales, (e.g., long‐distance migration). Here, we combined a large, continental‐scale dataset on low pathogenic, Type A AIV in the United States with a novel network‐based application of bird banding/recovery data to investigate the migration‐based drivers of AIV and their relative importance compared to well‐characterised local drivers (e.g. demography, environmental persistence). We compared among regression models reflecting hypothesized ecological processes and evaluated their ability to predict AIV in space and time using within and out‐of‐sample validation. We found that predictors of AIV were associated with multiple mechanisms at local and continental scales. Hypotheses characterising local epidemic dynamics were strongly supported, with age, the age‐specific aggregation of migratory birds in an area and temperature being the best predictors of infection. Hypotheses defining larger, network‐based features of the migration processes, such as clustering or between‐cluster mixing explained less variation but were also supported. Therefore, our results support a role for local processes in driving the continental distribution of AIV