Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

No abstract

Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage

This paper reports the development of a ∼30 m resolution two‐dimensional hydrodynamic model of the conterminous U.S. using only publicly available data. The model employs a highly efficient numerical solution of the local inertial form of the shallow water equations which simulates fluvial flooding in catchments down to 50 km2 and pluvial flooding in all catchments. Importantly, we use the U.S. Geological Survey (USGS) National Elevation Dataset to determine topography; the U.S. Army Corps of Engineers National Levee Database to explicitly represent known flood defenses; and global regionalized flood frequency analysis to characterize return period flows and rainfalls. We validate these simulations against the complete catalogue of Federal Emergency Management Agency (FEMA) Special Flood Hazard Area (SFHA) maps and detailed local hydraulic models developed by the USGS. Where the FEMA SFHAs are based on high‐quality local models, the continental‐scale model attains a hit rate of 86%. This correspondence improves in temperate areas and for basins above 400 km2. Against the higher quality USGS data, the average hit rate reaches 92% for the 1 in 100 year flood, and 90% for all flood return periods. Given typical hydraulic modeling uncertainties in the FEMA maps and USGS model outputs (e.g., errors in estimating return period flows), it is probable that the continental‐scale model can replicate both to within error. The results show that continental‐scale models may now offer sufficient rigor to inform some decision‐making needs with dramatically lower cost and greater coverage than approaches based on a patchwork of local studies.

Ecosystem services, Biodiversity, Land use, Private returns to landowners, Net social benefits, Tradeoffs,

Despite broad recognition of the value of the goods and services provided by nature, existing tools for assessing and valuing ecosystem services often fall short of the needs and expectations of decision makers. Here we address one of the most important missing components in the current ecosystem services toolbox: a comprehensive and generalizable framework for describing and valuing water quality-related services. Water quality is often misrepresented as a final ecosystem service. We argue that it is actually an important contributor to many different services, from recreation to human health. We present a valuation approach for water quality-related services that is sensitive to different actions that affect water quality, identifies aquatic endpoints where the consequences of changing water quality on human well-being are realized, and recognizes the unique groups of beneficiaries affected by those changes. We describe the multiple biophysical and economic pathways that link actions to changes in water qualityrelated ecosystem goods and services and provide guidance to researchers interested in valuing these changes. Finally, we present a valuation template that integrates biophysical and economic models, links actions to changes in service provision and value estimates, and considers multiple sources of water quality-related ecosystem service values without double counting. O ne of the fundamental challenges of mainstreaming ecosystem services into decision making involves linking ecosystem processes with changes in human well-being (1). This is especially true for water quality-related ecosystem goods and services. Water quality is highly valued by the public, and information on water quality values is increasingly demanded by decision makers. However, there is no generalizable framework for linking changes in water quality to changes in multiple ecosystem goods and services. This is problematic because limiting ecosystem service assessments to those services with direct use value and market prices systematically undervalues ecosystem services and fails to achieve a full accounting of all of the environmental and economic tradeoffs associated with decisions.Valuing water quality changes is particularly challenging relative to other ecosystem goods and services. Changing water quality affects many aspects of human well-being, and benefits and/or costs accrue to different groups of beneficiaries at varying spatial and temporal scales. This complexity contrasts with other ecosystem services, such as carbon sequestration, for which emissions are aggregated into a global atmospheric pool. Each unit increase in carbon emissions results in a more or less constant loss in value (i.e., costs associated with climate change). By contrast, each unit improvement in water quality may affect only a local area, the value of which varies widely with spatial context and may have strongly diminishing marginal benefits (e.g., additional reductions in nutrient pollution entering a clean lake generate minimal new benefits, and t...

Background: The pathologic outcome of patients diagnosed with mild cognitive impairment (MCI) following progression to dementia is poorly understood. Objective: To determine the pathologic substrates of dementia in cases with prior diagnosis of amnestic MCI. Design and Setting: Community-based cohort. Patients: Thirty-four subjects followed up prospectively as part of a community-based study who were diagnosed with amnestic MCI, progressed to clinical dementia, and underwent subsequent postmortem brain analysis. Main Outcome Measures: Neuropathologic analyses resulted in assignment of a primary pathologic diagnosis and included staging of Alzheimer pathologic abnormalities and identification of contributing vascular disease, Lewy bodies, and argyrophilic grains. Results: Although the majority of subjects progressed both clinically and pathologically to Alzheimer disease (AD), 10 (29%) of them developed non-AD primary Author Affiliations are listed at the end of this article.

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.