Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation

BACKGROUND: The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer's disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) METHODS: Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. RESULTS: In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). CONCLUSION: Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target

The effect of operating conditions on density stratification in a batch jig I: The influence on the equilibrium stratification profile

The study reported in this paper is the first in a series of two that investigated the influence of operating conditions on stratification in a batch jig. This paper focuses on an equilibrium study; the next on a kinetic study. Based on testwork and a detailed consideration of which operating conditions were relevant to the study, four factors were identified as being the primary operating variables influencing stratification in the test jig. These were the pulsion time, the pulsion hold-time; the amplitude of the jig cycle; and the depth of the particle bed in the jig. All other factors were found to be either dependent variables, or to exert no significant influence on stratification at equilibrium. Based on 32 equilibrium tests, it was found that the equilibrium stratification profile was essentially independent of operating conditions within a broad range of values. This finding has both theoretical and practical implications. The most significant of these is that the influence which operating variables have on jig performance appears to derive primarily from their influence on stratification kinetics and not from their influence on stratification at equilibrium

Benjamin Harrison Grave: American Marine Invertebrate Zoologist

Organismic and Evolutionary Biolog

Compulsive versifying after treatment of transient epileptic amnesia

Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy. This case complements previous observations of emergence of altered behavior with reduced seizure frequency in patients with temporal lobe epilepsy. Such cases suggest that reduced seizure frequency has the potential not only to stabilize or improve memory function, but also to trigger complex, specific behavioral alterations

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration

Dirac-like Plasmons in Honeycomb Lattices of Metallic Nanoparticles

Copyright © 2013 American Physical SocietyWe consider a two-dimensional honeycomb lattice of metallic nanoparticles, each supporting a localized surface plasmon, and study the quantum properties of the collective plasmons resulting from the near-field dipolar interaction between the nanoparticles. We analytically investigate the dispersion, the effective Hamiltonian, and the eigenstates of the collective plasmons for an arbitrary orientation of the individual dipole moments. When the polarization points close to the normal to the plane, the spectrum presents Dirac cones, similar to those present in the electronic band structure of graphene. We derive the effective Dirac Hamiltonian for the collective plasmons and show that the corresponding spinor eigenstates represent Dirac-like massless bosonic excitations that present similar effects to electrons in graphene, such as a nontrivial Berry phase and the absence of backscattering off smooth inhomogeneities. We further discuss how one can manipulate the Dirac points in the Brillouin zone and open a gap in the collective plasmon dispersion by modifying the polarization of the localized surface plasmons, paving the way for a fully tunable plasmonic analogue of graphene

A Pinned Polymer Model of Posture Control

A phenomenological model of human posture control is posited. The dynamics are modelled as an elastically pinned polymer under the influence of noise. The model accurately reproduces the two-point correlation functions of experimental posture data and makes predictions for the response function of the postural control system. The physiological and clinical significance of the model is discussed.Comment: uuencoded post script file, 17 pages with 3 figure

The Politics of Commerce : The Congress of Chambers of Commerce of the Empire, 1886-1914

Peer reviewedPublisher PD

How fear of falling can increase fall-risk in older adults: Applying psychological theory to practical observations

This article was made available through the Brunel Open Access Fund.It is widely reported that fear of falling (FOF) has a profound and largely detrimental effect on balance performance in older adults. However, the mechanisms by which FOF influence postural stability are poorly understood. In the current article, we use psychological theory to explain FOF-related changes to postural control. First, we review literature describing associations between FOF and the 'stiffening' strategies observed during control of posture, including observations of eye and head movements. Second, we present a framework illustrating the interactions between increased age, FOF, and altered attentional processes, which in turn influence balance performance and fall-risk. Psychological theory predicts that anxiety can cause attentional bias for threatening and task-irrelevant stimuli and compromise the efficiency of working memory resources. We argue that while the adoption of stiffening strategies is likely to be beneficial in avoiding a loss of balance during simple postural tasks, it will ultimately compromise performance in dynamic and highly demanding functional tasks. The adoption of stiffening strategies leads to inadequate acquisition of the sensory information necessary to plan and execute dynamic and interactive movements. We conclude with some suggestions for future research.This research was supported by The Royal Society (IE131576) and British Academy (SG132820)

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation