Systemic and central nervous system neuroinflammatory signatures of neuropsychiatric symptoms and related cognitive decline in older people.

Neuroinflammation may contribute to psychiatric symptoms in older people, in particular in the context of Alzheimer's disease (AD). We sought to identify systemic and central nervous system (CNS) inflammatory alterations associated with neuropsychiatric symptoms (NPS); and to investigate their relationships with AD pathology and clinical disease progression. We quantified a panel of 38 neuroinflammation and vascular injury markers in paired serum and cerebrospinal fluid (CSF) samples in a cohort of cognitively normal and impaired older subjects. We performed neuropsychiatric and cognitive evaluations and measured CSF biomarkers of AD pathology. Multivariate analysis determined serum and CSF neuroinflammatory alterations associated with NPS, considering cognitive status, AD pathology, and cognitive decline at follow-up visits. NPS were associated with distinct inflammatory profiles in serum, involving eotaxin-3, interleukin (IL)-6 and C-reactive protein (CRP); and in CSF, including soluble intracellular cell adhesion molecule-1 (sICAM-1), IL-8, 10-kDa interferon-γ-induced protein, and CRP. AD pathology interacted with CSF sICAM-1 in association with NPS. Presenting NPS was associated with subsequent cognitive decline which was mediated by CSF sICAM-1. Distinct systemic and CNS inflammatory processes are involved in the pathophysiology of NPS in older people. Neuroinflammation may explain the link between NPS and more rapid clinical disease progression

Plasma Proteomic Profiles of Cerebrospinal Fluid-Defined Alzheimer's Disease Pathology in Older Adults.

Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimer's disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia. Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis. We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n = 72) or without (n = 48) cognitive impairment. CSF Aβ1-42, tau, and phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Aβ1-42 > 0.0779, and presence of amyloidosis was defined as CSF Aβ1-42 < 724 pg/mL. Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%. Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD

Nab: Measurement Principles, Apparatus and Uncertainties

The Nab collaboration will perform a precise measurement of 'a', the electron-neutrino correlation parameter, and 'b', the Fierz interference term in neutron beta decay, in the Fundamental Neutron Physics Beamline at the SNS, using a novel electric/magnetic field spectrometer and detector design. The experiment is aiming at the 10^{-3} accuracy level in (Delta a)/a, and will provide an independent measurement of lambda = G_A/G_V, the ratio of axial-vector to vector coupling constants of the nucleon. Nab also plans to perform the first ever measurement of 'b' in neutron decay, which will provide an independent limit on the tensor weak coupling.Comment: 12 pages, 6 figures, 1 table, talk presented at the International Workshop on Particle Physics with Slow Neutrons, Grenoble, 29-31 May 2008; to appear in Nucl. Instrum. Meth. in Physics Research

Markers of neuroinflammation associated with Alzheimer's disease pathology in older adults.

In vitro and animal studies have linked neuroinflammation to Alzheimer's disease (AD) pathology. Studies on markers of inflammation in subjects with mild cognitive impairment or AD dementia provided inconsistent results. We hypothesized that distinct blood and cerebrospinal fluid (CSF) inflammatory markers are associated with biomarkers of amyloid and tau pathology in older adults without cognitive impairment or with beginning cognitive decline. To identify blood-based and CSF neuroinflammation marker signatures associated with AD pathology (i.e. an AD CSF biomarker profile) and to investigate associations of inflammation markers with CSF biomarkers of amyloid, tau pathology, and neuronal injury. Cross-sectional analysis was performed on data from 120 older community-dwelling adults with normal cognition (n=48) or with cognitive impairment (n=72). CSF Aβ1-42, tau and p-tau181, and a panel of 37 neuroinflammatory markers in both CSF and serum were quantified. Least absolute shrinkage and selection operator (LASSO) regression was applied to determine a reference model that best predicts an AD CSF biomarker profile defined a priori as p-tau181/Aβ1-42 ratio >0.0779. It was then compared to a second model that included the inflammatory markers from either serum or CSF. In addition, the correlations between inflammatory markers and CSF Aβ1-42, tau and p-tau181 levels were assessed. Forty-two subjects met criteria for having an AD CSF biomarker profile. The best predictive models included 8 serum or 3 CSF neuroinflammatory markers related to cytokine mediated inflammation, vascular injury, and angiogenesis. Both models improved the accuracy to predict an AD biomarker profile when compared to the reference model. In analyses separately performed in the subgroup of participants with cognitive impairment, adding the serum or the CSF neuroinflammation markers also improved the accuracy of the diagnosis of AD pathology. None of the inflammatory markers correlated with the CSF Aβ1-42 levels. Six CSF markers (IL-15, MCP-1, VEGFR-1, sICAM1, sVCAM-1, and VEGF-D) correlated with the CSF tau and p-tau181 levels, and these associations remained significant after controlling for age, sex, cognitive impairment, and APOEε4 status. The identified serum and CSF neuroinflammation biomarker signatures improve the accuracy of classification for AD pathology in older adults. Our results suggest that inflammation, vascular injury, and angiogenesis as reflected by CSF markers are closely related to cerebral tau pathology

Alzheimer disease pathology and the cerebrospinal fluid proteome.

Altered proteome profiles have been reported in both postmortem brain tissues and body fluids of subjects with Alzheimer disease (AD), but their broad relationships with AD pathology, amyloid pathology, and tau-related neurodegeneration have not yet been fully explored. Using a robust automated MS-based proteomic biomarker discovery workflow, we measured cerebrospinal fluid (CSF) proteomes to explore their association with well-established markers of core AD pathology. Cross-sectional analysis was performed on CSF collected from 120 older community-dwelling adults with normal (n = 48) or impaired cognition (n = 72). LC-MS quantified hundreds of proteins in the CSF. CSF concentrations of β-amyloid 1-42 (Aβ <sub>1-42</sub> ), tau, and tau phosphorylated at threonine 181 (P-tau181) were determined with immunoassays. First, we explored proteins relevant to biomarker-defined AD. Then, correlation analysis of CSF proteins with CSF markers of amyloid pathology, neuronal injury, and tau hyperphosphorylation (i.e., Aβ <sub>1-42</sub> , tau, P-tau181) was performed using Pearson's correlation coefficient and Bonferroni correction for multiple comparisons. We quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF Aβ <sub>1-42</sub> levels (p value ≤ 0.05 with correlation coefficient (R) ≥ 0.38). We identified 50 additional CSF proteins associated with CSF tau and 46 proteins associated with CSF P-tau181 (p value ≤ 0.05 with R ≥ 0.37). The majority of those proteins that showed such associations were brain-enriched proteins. Gene Ontology annotation revealed an enrichment for synaptic proteins and proteins originating from reelin-producing cells and the myelin sheath. We used an MS-based proteomic workflow to profile the CSF proteome in relation to cerebral AD pathology. We report strong evidence of previously reported CSF proteins and several novel CSF proteins specifically associated with amyloid pathology or neuronal injury and tau hyperphosphorylation

Precision Measurement of PArity Violation in Polarized Cold Neutron Capture on the Proton: the NPDGamma Experiment

The NPDGamma experiment at the Los Alamos Neutron Science Center (LANSCE) is dedicated to measure with high precision the parity violating asymmetry in the $\gamma$ emission after capture of spin polarized cold neutrons in para-hydrogen. The measurement will determine unambiguously the weak pion-nucleon-nucleon ($\pi NN$) coupling constant {\it f$^1_{\pi}$}Comment: Proceedings of the PANIC'05 Conference, Santa Fe, NM, USA, October 24-28, 2005, 3 pages, 2 figure

A measurement of parity-violating gamma-ray asymmetries in polarized cold neutron capture on 35Cl, 113Cd, and 139La

An apparatus for measuring parity-violating asymmetries in gamma-ray emission following polarized cold neutron capture was constructed as a 1/10th scale test of the design for the forthcoming n+p->d+gamma experiment at LANSCE. The elements of the polarized neutron beam, including a polarized 3He neutron spin filter and a radio frequency neutron spin rotator, are described. Using CsI(Tl) detectors and photodiode current mode readout, measurements were made of asymmetries in gamma-ray emission following neutron capture on 35Cl, 113Cd, and 139La targets. Upper limits on the parity-allowed asymmetry $s_n \cdot (k_{\gamma} \times k_n)$ were set at the level of 7 x 10^-6 for all three targets. Parity-violating asymmetries $s_n \cdot k_{\gamma}$ were observed in 35Cl, A_gamma = (-29.1 +- 6.7) x 10^-6, and 139La, A_gamma = (-15.5 +- 7.1) x 10^-6, values consistent with previous measurements.Comment: 19 pages, 4 figures, submitted to Nucl. Instr. and Meth.

One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond.

Hyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur-containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one-carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults. Cross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one-carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/β-Amyloid 1-42 peptide chain [Aβ1-42] >0.0779) to establish a reference benchmark. Two other LASSO-determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) ε4 carrier status. The diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Aβ1-42, tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine, glycine, methionine, SAH, SAM, serine, cysteine, and Hcy and reached a diagnostic accuracy of 87.5%. CSF SAH and 5-MTHF were associated with CSF tau and p-tau181. Plasma one-carbon metabolites were able to diagnose subjects with a positive CSF profile of AD pathology in APOE ε4 carriers. We observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p-tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE ε4 carriers

Ab initio Quantum and ab initio Molecular Dynamics of the Dissociative Adsorption of Hydrogen on Pd(100)

The dissociative adsorption of hydrogen on Pd(100) has been studied by ab initio quantum dynamics and ab initio molecular dynamics calculations. Treating all hydrogen degrees of freedom as dynamical coordinates implies a high dimensionality and requires statistical averages over thousands of trajectories. An efficient and accurate treatment of such extensive statistics is achieved in two steps: In a first step we evaluate the ab initio potential energy surface (PES) and determine an analytical representation. Then, in an independent second step dynamical calculations are performed on the analytical representation of the PES. Thus the dissociation dynamics is investigated without any crucial assumption except for the Born-Oppenheimer approximation which is anyhow employed when density-functional theory calculations are performed. The ab initio molecular dynamics is compared to detailed quantum dynamical calculations on exactly the same ab initio PES. The occurence of quantum oscillations in the sticking probability as a function of kinetic energy is addressed. They turn out to be very sensitive to the symmetry of the initial conditions. At low kinetic energies sticking is dominated by the steering effect which is illustrated using classical trajectories. The steering effects depends on the kinetic energy, but not on the mass of the molecules. Zero-point effects lead to strong differences between quantum and classical calculations of the sticking probability. The dependence of the sticking probability on the angle of incidence is analysed; it is found to be in good agreement with experimental data. The results show that the determination of the potential energy surface combined with high-dimensional dynamical calculations, in which all relevant degrees of freedon are taken into account, leads to a detailed understanding of the dissociation dynamics of hydrogen at a transition metal surface.Comment: 15 pages, 9 figures, subm. to Phys. Rev.