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

The global Alzheimer\u27s Association round robin study on plasma amyloid β methods

Introduction: Blood-based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure Aβ and how they compare among centers and assays. Methods: Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass-spectrometric methods were used to measure plasma Aβ concentrations. Results: Correlations were weak for Aβ42 while Aβ40 correlations were stronger. The ratio Aβ42/Aβ40 did not improve the correlations and showed weak correlations. Discussion: The poor correlations for Aβ42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre-analytical sample handling and specificity, and cross-reactivity of different antibodies. Different methods might also measure different pools of plasma Aβ42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study

Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype

Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer\u27s disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues - one in the hinge region and one in the C-terminal region - and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD

Engineered 2D Ising interactions on a trapped-ion quantum simulator with hundreds of spins

The presence of long-range quantum spin correlations underlies a variety of physical phenomena in condensed matter systems, potentially including high-temperature superconductivity. However, many properties of exotic strongly correlated spin systems (e.g., spin liquids) have proved difficult to study, in part because calculations involving N-body entanglement become intractable for as few as N~30 particles. Feynman divined that a quantum simulator - a special-purpose "analog" processor built using quantum particles (qubits) - would be inherently adept at such problems. In the context of quantum magnetism, a number of experiments have demonstrated the feasibility of this approach. However, simulations of quantum magnetism allowing controlled, tunable interactions between spins localized on 2D and 3D lattices of more than a few 10's of qubits have yet to be demonstrated, owing in part to the technical challenge of realizing large-scale qubit arrays. Here we demonstrate a variable-range Ising-type spin-spin interaction J_ij on a naturally occurring 2D triangular crystal lattice of hundreds of spin-1/2 particles (9Be+ ions stored in a Penning trap), a computationally relevant scale more than an order of magnitude larger than existing experiments. We show that a spin-dependent optical dipole force can produce an antiferromagnetic interaction J_ij ~ 1/d_ij^a, where a is tunable over 0<a<3; d_ij is the distance between spin pairs. These power-laws correspond physically to infinite-range (a=0), Coulomb-like (a=1), monopole-dipole (a=2) and dipole-dipole (a=3) couplings. Experimentally, we demonstrate excellent agreement with theory for 0.05<a<1.4. This demonstration coupled with the high spin-count, excellent quantum control and low technical complexity of the Penning trap brings within reach simulation of interesting and otherwise computationally intractable problems in quantum magnetism.Comment: 10 pages, 10 figures; article plus Supplementary Material

Predicting continuous amyloid PET values with CSF and plasma Aβ42/Aβ40

INTRODUCTION: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer\u27s disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET. METHODS: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled. RESULTS: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aβ42/Aβ40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aβ42/Aβ40 predicted amyloid PET burden until a lower level (33.4 Centiloids). DISCUSSION: CSF Aβ42/Aβ40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aβ42/Aβ40 and may be useful in AD staging. HIGHLIGHTS: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/Aβ40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aβ42/Aβ40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aβ42/Aβ40.CSF Aβ42/Aβ40 may be useful in staging AD

Comparative analytical performance of multiple plasma Aβ42 and Aβ40 assays and their ability to predict positron emission tomography amyloid positivity

INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. HIGHLIGHTS: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aβ) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aβ42/40 predicted amyloid positron emission tomography status better than Aβ42 or Aβ40 alone

Developing the Global Health Cost Consortium Unit Cost Study Repository for HIV and TB: methodology and lessons learned.

Consistently defined, accurate, and easily accessible cost data are a valuable resource to inform efficiency analyses, budget preparation, and sustainability planning in global health. The Global Health Cost Consortium (GHCC) designed the Unit Cost Study Repository (UCSR) to be a resource for standardised HIV and TB intervention cost data displayed by key characteristics such as intervention type, country, and target population. To develop the UCSR, the GHCC defined a typology of interventions for each disease; aligned interventions according to the standardised principles, methods, and cost and activity categories from the GHCC Reference Case for Estimating the Costs of Global Health Services and Interventions; completed a systematic literature review; conducted extensive data extraction; performed quality assurance; grappled with complex methodological issues such as the proper approach to the inflation and conversion of costs; developed and implemented a study quality rating system; and designed a web-based user interface that flexibly displays large amounts of data in a user-friendly way. Key lessons learned from the extraction process include the importance of assessing the multiple uses of extracted data; the critical role of standardising definitions (particularly units of measurement); using appropriate classifications of interventions and components of costs; the efficiency derived from programming data checks; and the necessity of extraction quality monitoring by senior analysts. For the web interface, lessons were: understanding the target audiences, including consulting them regarding critical characteristics; designing the display of data in "levels"; and incorporating alert and unique trait descriptions to further clarify differences in the data