The Suppression of Irrelevant Semantic Representations in Parkinson’s Disease

The impairment of lexical-semantic inhibition mechanisms in Parkinson’s disease (PD) remains a source of contention. In order to observe whether people with PD are able to suppress irrelevant semantic information during picture naming, the present study employed an object-based negative priming paradigm with 16 participants with PD and 13 healthy controls. The task required participants to name a red target image while ignoring a superimposed, green distractor image. The semantic relationship between the distractor image and the target image of the subsequent trial was manipulated, such that the distractor image was identical, semantically related, or semantically unrelated to said target image. The PD group and the control group were slower in naming a target image that had previously served as a distractor image, relative to naming a target image that was unrelated to the previous distractor image. Thus, a negative priming effect was present in both groups. Furthermore, no significant difference in the magnitude of this effect was observed between the control and PD groups. When considered in the context of existing literature surrounding negative priming in PD, these results suggest that inhibition is subserved by multiple, domain-specific mechanisms and that the inhibitory processing of visual-semantic stimuli is intact in PD

Treatment of diabetic retinopathy through neuropeptide Y-mediated enhancement of neurovascular microenvironment

Diabetic retinopathy (DR) is one of the most severe clinical manifestations of diabetes mellitus and a major cause of blindness. DR is principally a microvascular disease, although the pathogenesis also involves metabolic reactive intermediates which induce neuronal and glial activation resulting in disruption of the neurovascular unit and regulation of the microvasculature. However, the impact of neural/glial activation in DR remains controversial, notwithstanding our understanding as to when neural/glial activation occurs in the course of disease. The objective of this study was to determine a potential protective role of neuropeptide Y (NPY) using an established model of DR permissive to N‐methyl‐D‐aspartate (NMDA)‐induced excitotoxic apoptosis of retinal ganglion cells (RGC) and vascular endothelial growth factor (VEGF)‐induced vascular leakage. In vitro evaluation using primary retinal endothelial cells demonstrates that NPY promotes vascular integrity, demonstrated by maintained tight junction protein expression and reduced permeability in response to VEGF treatment. Furthermore, ex vivo assessment of retinal tissue explants shows that NPY can protect RGC from excitotoxic‐induced apoptosis. In vivo clinical imaging and ex vivo tissue analysis in the diabetic model permitted assessment of NPY treatment in relation to neural and endothelial changes. The neuroprotective effects of NPY were confirmed by attenuating NMDA‐induced retinal neural apoptosis and able to maintain inner retinal vascular integrity. These findings could have important clinical implications and offer novel therapeutic approaches for the treatment in the early stages of DR

L-Dopa modulates functional connectivity in striatal cognitive and motor networks: A double-blind placebo-controlled study

Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults. We examined the FC of 6 striatal regions of interest (ROIs) previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. Although L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions

Single Eye mRNA-Seq Reveals Normalisation of the Retinal Microglial Transcriptome Following Acute Inflammation

Background: Whether retinal microglia can maintain or restore immune homeostasis during and after inflammation is unclear. We performed single-eye mRNA-sequencing on microglia at different timepoints following a single inflammatory stimulus to characterise their transcriptome during and after resolution of endotoxin-induced uveitis (EIU). / Experimental Approach: Cx3cr1CreER:R26-tdTomato (C57BL/6) male heterozygotes were administered tamoxifen via different regimes at 4–5 weeks of age. Four weeks post-tamoxifen, mice were injected intravitreally with 10 ng lipopolysaccharide (endotoxin induced uveitis, EIU). Six-hundred retinal microglia were obtained by FACS from individual naïve retinas and at 4 h, 18 h, and 2 weeks following EIU induction. Samples were sequenced to a depth of up to 16.7 million reads using the SMART-Seq v4 Ultra Low Input RNA kit. The data was analysed using Partek software and Ingenuity Pathway Analysis. Genes were considered differentially-expressed (DEG) if the FDR step-up p-value was ≤0.05 and the fold-change was ≥±2. / Results: Flow cytometric analysis indicates that the Cx3cr1CreER:R26-tdTomato strain is both sensitive (>95% tagging) and specific (>95% specificity) for microglia when tamoxifen is administered topically to the eye for 3 days. During “early” activation, 613 DEGs were identified. In contrast, 537 DEGs were observed during peak cellular infiltrate and none at 2 weeks, compared to baseline controls (1,069 total unique DEGs). Key marker changes were validated by qPCR, flow cytometry, and fluorescence microscopy. C5AR1 was identified and validated as a robust marker of differentiating microglial subsets during an LPS response. / Conclusion: Using EIU to provide a single defined inflammatory stimulus, mRNA-Seq identified acute transcriptional changes in retinal microglia which returned to their original transcriptome after 2 weeks. Yolk-sac derived microglia are capable of restoring their homeostatic state after acute inflammation

Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis

Age-related decreases in autophagy contribute to the progression of age-related macular degeneration (AMD). We have now studied the interaction between autophagy impaired in retinal pigment epithelium (RPE) and the responses of macrophages. We find that dying RPE cells can activate the macrophage inflammasome and promote angiogenesis. In vitro, inhibiting rotenone-induced autophagy in RPE cells elicits caspase-3 mediated cell death. Co-culture of damaged RPE with macrophages leads to the secretion of IL-1β, IL-6 and nitrite oxide. Exogenous IL-6 protects the dysfunctional RPE but IL-1β causes enhanced cell death. Furthermore, IL-1β toxicity is more pronounced in dysfunctional RPE cells showing reduced IRAK3 gene expression. Co-culture of macrophages with damaged RPE also elicits elevated levels of pro-angiogenic proteins that promote ex vivo choroidal vessel sprouting. In vivo, impaired autophagy in the eye promotes photoreceptor and RPE degeneration and recruitment of inflammasome-activated macrophages. The degenerative tissue environment drives an enhanced pro-angiogenic response, demonstrated by increased size of laser-induced choroidal neovascularization (CNV) lesions. The contribution of macrophages was confirmed by depletion of CCR2 + monocytes, which attenuates CNV in the presence of RPE degeneration. Our results suggest that the interplay between perturbed RPE homeostasis and activated macrophages influences key features of AMD development

Glacier velocities and dynamic ice discharge from the Queen Elizabeth Islands, Nunavut, Canada

Recent studies indicate an increase in glacier mass loss from the Canadian Arctic Archipelago as a result of warmer summer air temperatures. However, no complete assessment of dynamic ice discharge from this region exists. We present the first complete surface velocity mapping of all ice masses in the Queen Elizabeth Islands and show that these ice masses discharged ~2.6 ± 0.8 Gt a−1 of ice to the oceans in winter 2012. Approximately 50% of the dynamic discharge was channeled through non surge-type Trinity and Wykeham Glaciers alone. Dynamic discharge of the surge-type Mittie Glacier varied from 0.90 ± 0.09 Gt a−1 during its 2003 surge to 0.02 ± 0.02 Gt a−1 during quiescence in 2012, highlighting the importance of surge-type glaciers for interannual variability in regional mass loss. Queen Elizabeth Islands glaciers currently account for ~7.5% of reported dynamic discharge from Arctic ice masses outside Greenland.We thank NSERC, Canada Foundation for Innovation, Ontario Research Fund, ArcticNet, Ontario Graduate Scholarship, University of Ottawa and the NSERC Canada Graduate Scholarship for funding. RADARSAT-2 data were provided by MacDonald, Dettwiler and Associates under the RADARSAT-2 Government Data Allocation administrated by the Canadian Space Agency. Support to DB is provided through the Climate Change Geosciences Program, Earth Sciences Sector, Natural Resources Canada (ESS Contribution #20130293). We also acknowledge support from U.K NERC for grants R3/12469 and NE/K004999 to JAD.This is the accepted version of an article published in Geophysical Research Letters. An edited version of this paper was published by AGU. Copyright (2014) American Geophysical Union. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/2013GL058558/abstract;jsessionid=6A3AD907C4383DA5D4E20C4924D6EC18.f02t02

Environmental conditioning in the control of macrophage thrombospondin-1 production

Thrombospondin-1 (TSP-1) is a multifunctional protein which is secreted into the extracellular matrix during inflammation, where it modulates numerous components of the immune infiltrate. Macrophages are a source of TSP-1, which they produce in response to TLR4 mediated signals. Their production of TSP-1 is regulated by environmental signals that establish a threshold for the level of protein secretion that can be induced by LPS stimulation. Th1 and Th2 cytokines raise this threshold which leads to less TSP-1 production, while signals that promote the generation of regulatory macrophages lower it. TSP-1 plays no direct role in the regulation of its own secretion. In vivo in uveitis, in the presence of TLR-4 ligands, TSP-1 is initially produced by recruited macrophages but this decreases in the presence of inflammatory cytokines. The adaptive immune system therefore plays a dominant role in regulating TSP-1 production in the target organ during acute inflammation

An fMRI investigation of the effects of attempted naming on word retrieval in aphasia

In healthy controls, picture naming performance can be facilitated by a single prior exposure to the same picture ("priming"). This priming phenomenon is utilized in the treatment of aphasia, which often includes repeated picture naming as part of a therapeutic task. The current study sought to determine whether single and/or multiple exposures facilitate subsequent naming in aphasia and whether such facilitatory effects act through normal priming mechanisms. A functional magnetic resonance imaging paradigm was employed to explore the beneficial effects of attempted naming in two individuals with aphasia and a control group. The timing and number of prior exposures was manipulated, with investigation of both short-term effects (single prior exposure over a period of minutes) and long-term effects (multiple presentations over a period of days). Following attempted naming, both short-term and long-term facilitated items showed improvement for controls, while only the long-term condition showed benefits at a behavioral level for the participants with aphasia. At a neural level, effects of long-term facilitation were noted in the left precuneus for one participant with aphasia, a result also identified for the equivalent contrast in controls. It appears that multiple attempts are required to improve naming performance in the presence of anomia and that for some individuals with aphasia the source of facilitation may be similar to unimpaired mechanisms engaged outside the language network

Multisession transcranial direct current stimulation facilitates verbal learning and memory consolidation in young and older adults

This study investigated effects of multisession transcranial direct-current stimulation on learning and maintenance of novel memory content and scrutinised effects of baseline cognitive status and the role of multi-session tDCS on overnight memory consolidation. In a prospective, randomized, double-blind, parallel-group, sham-tDCS controlled design, 101 healthy young and older adults completed a five-day verbal associative learning paradigm while receiving multisession tDCS to the task-relevant left prefrontal cortex. In older adults, active multisession tDCS enhanced recall performance after each daily training session. Effects were maintained the next morning and during follow-up assessments (one week; three months). In young adults, multisession tDCS significantly increased long-term recall. Unlike previous findings in the motor domain, beneficial effects of multisession tDCS on cognitive learning and memory were not exclusively due to enhanced memory consolidation. Positive stimulation effects were primarily found in participants with lower baseline learning ability, suggesting that multisession tDCS may counteract memory impairment in health and disease