Acute neuroinflammation elicited by TLR-3 systemic activation combined with early life stress induces working memory impairments in male adolescent mice

Toll-like Receptors (TLRs) are implicated with the pathogenesis of cognitive impairment induced by inflammation. Early life stress is associated with altered trajectories of neuroimmune signaling with implications for cognitive development. However, effects of TLR-3 activation on early life stress-related cognitive outcomes are understudied. We investigated the effects of maternal separation (MS) during postnatal development and a viral immune challenge during adolescence on working memory performance. BALB/c mice exposed to MS were separated from their dams daily for 180-min from postnatal day (PND) 2 to 15. At PND 45, animals were challenged with a single i.p. injection of either Poly (I:C) or sterile saline, and then subjected to a spatial working memory test in a Y-maze apparatus. Gene expression was determined by qPCR. Protein levels of oxidative stress markers were also assessed. A single peripheral administration of a TLR-3 agonist was able to induce working memory impairments in adolescent mice exposed to MS. At a molecular level, exposure to MS was associated with lower mRNA levels of Tlr3 in the medial prefrontal cortex (mPFC). However, when MS animals were exposed to Poly (I:C), a more robust activation of Tlr3, Il6 and Nfkb1 gene transcription was observed in these mice compared with control animals. These modifications did not result in oxidative stress. Finally, higher mRNA levels of Nfkb1 in the mPFC were correlated with lower working memory performance, suggesting that altered NF-\u3baB signaling might be related with poor cognitive functioning. These results have implications for how ELS affects neuroimmune signaling in the mPFC

Peripheral electrical nerve stimulation and rest-activity rhythm in Alzheimer's disease

Rest-activity rhythm disruption is a prominent clinical feature of Alzheimer's disease (AD). The origin of the altered rest-activity rhythm is believed to be degeneration of the suprachiasmatic nucleus (SCN). In accordance with the 'use it or lose it' hypothesis of Swaab [Neurobiol Aging 1991, 12: 317-324] stimulation of the SCN may prevent age-related loss of neurons and might reactivate nerve cells that are inactive but not lost. Previous studies with relatively small sample sizes have demonstrated positive effects of peripheral electrical nerve stimulation on the rest-activity rhythm in AD patients. The present randomized, placebo-controlled, parallel-group study was meant to replicate prior findings of electrical stimulation in AD in a substantially larger group of AD patients. The experimental group (n = 31) received peripheral electrical nerve stimulation and the placebo group (n = 31) received sham stimulation. Effects of the intervention on the rest-activity rhythm were assessed by using wrist-worn actigraphs. Near-significant findings on the rest-activity rhythm partially support the hypothesis that neuronal stimulation enhances the rest-activity rhythm in AD patients. Interestingly, post-hoc analyses revealed significant treatment effects in a group of patients who were not using acetylcholinesterase inhibitors concomitantly. We conclude that more research is needed before firm general conclusions about the effectiveness of electrical stimulation as a symptomatic treatment in AD can be drawn. In addition, the present post-hoc findings indicate that future studies on non-pharmacological interventions should take medication use into account

Intra-Individual Variability in Alzheimer's Disease and Cognitive Aging: Definitions, Context, and Effect Sizes

To explore different definitions of intra-individual variability (IIV) to summarize performance on commonly utilized cognitive tests (Mini Mental State Exam; Clock Drawing Test); compare them and their potential to differentiate clinically-defined populations; and to examine their utility in predicting clinical change in individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI).) were computed for each of these definitions in 500 simulated replicates using scores on the Mini Mental State Exam and Clock Drawing Test. IIV was computed based on test items separately (‘within test’ IIV) and the two tests together (‘across test’ IIV). The best performing definition was then used to compute IIV for a third test, the Alzheimer's Disease Assessment Scale-Cognitive, and the simulations and effect sizes were again computed. All effect size estimates based on simulated data were compared to those computed based on the total scores in the observed data. Association between total score and IIV summaries of the tests and the Clinician's Dementia Rating were estimated to test the utility of IIV in predicting clinically meaningful changes in the cohorts over 12- and 24-month intervals.ES estimates differed substantially depending on the definition of IIV and the test(s) on which IIV was based. IIV (coefficient of variation) summaries of MMSE and Clock-Drawing performed similarly to their total scores, the ADAS total performed better than its IIV summary.IIV can be computed within (items) or across (totals) items on commonly-utilized cognitive tests, and may provide a useful additional summary measure of neuropsychological test performance

A Cluster-Randomised Trial of Staff Education to Improve the Quality of Life of People with Dementia Living in Residential Care: The DIRECT Study

BACKGROUND: The Dementia In Residential care: EduCation intervention Trial (DIRECT) was conducted to determine if delivery of education designed to meet the perceived need of GPs and care staff improves the quality of life of participants with dementia living in residential care. METHODOLOGY/PRINCIPAL FINDINGS: This cluster-randomised controlled trial was conducted in 39 residential aged care facilities in the metropolitan area of Perth, Western Australia. 351 care facility residents aged 65 years and older with Mini-Mental State Examination ≤ 24, their GPs and facility staff participated. Flexible education designed to meet the perceived needs of learners was delivered to GPs and care facility staff in intervention groups. The primary outcome of the study was self-rated quality of life of participants with dementia, measured using the QOL-Alzheimer's Disease Scale (QOL-AD) at 4 weeks and 6 months after the conclusion of the intervention. Analysis accounted for the effect of clustering by using multi-level regression analysis. Education of GPs or care facility staff did not affect the primary outcome at either 4 weeks or 6 months. In a post hoc analysis excluding facilities in which fewer than 50% of staff attended an education session, self-rated QOL-AD scores were 6.14 points (adjusted 95%CI 1.14, 11.15) higher at four-week follow-up among residents in facilities randomly assigned to the education intervention. CONCLUSION: The education intervention directed at care facilities or GPs did not improve the quality of life ratings of participants with dementia as a group. This may be explained by the poor adherence to the intervention programme, as participants with dementia living in facilities where staff participated at least minimally seemed to benefit. TRIAL REGISTRATION: ANZCTR.org.au ACTRN12607000417482

Statistical Multiplicity in Systematic Reviews of Anaesthesia Interventions: A Quantification and Comparison between Cochrane and Non-Cochrane Reviews

BACKGROUND: Systematic reviews with meta-analyses often contain many statistical tests. This multiplicity may increase the risk of type I error. Few attempts have been made to address the problem of statistical multiplicity in systematic reviews. Before the implications are properly considered, the size of the issue deserves clarification. Because of the emphasis on bias evaluation and because of the editorial processes involved, Cochrane reviews may contain more multiplicity than their non-Cochrane counterparts. This study measured the quantity of statistical multiplicity present in a population of systematic reviews and aimed to assess whether this quantity is different in Cochrane and non-Cochrane reviews. METHODS/PRINCIPAL FINDINGS: We selected all the systematic reviews published by the Cochrane Anaesthesia Review Group containing a meta-analysis and matched them with comparable non-Cochrane reviews. We counted the number of statistical tests done in each systematic review. The median number of tests overall was 10 (interquartile range (IQR) 6 to 18). The median was 12 in Cochrane and 8 in non-Cochrane reviews (difference in medians 4 (95% confidence interval (CI) 2.0-19.0). The proportion that used an assessment of risk of bias as a reason for doing extra analyses was 42% in Cochrane and 28% in non-Cochrane reviews (difference in proportions 14% (95% CI -8 to 36). The issue of multiplicity was addressed in 6% of all the reviews. CONCLUSION/SIGNIFICANCE: Statistical multiplicity in systematic reviews requires attention. We found more multiplicity in Cochrane reviews than in non-Cochrane reviews. Many of the reasons for the increase in multiplicity may well represent improved methodological approaches and greater transparency, but multiplicity may also cause an increased risk of spurious conclusions. Few systematic reviews, whether Cochrane or non-Cochrane, address the issue of multiplicity

Understanding Actions of Others: The Electrodynamics of the Left and Right Hemispheres. A High-Density EEG Neuroimaging Study

Background: When we observe an individual performing a motor act (e.g. grasping a cup) we get two types of information on the basis of how the motor act is done and the context: what the agent is doing (i.e. grasping) and the intention underlying it (i.e. grasping for drinking). Here we examined the temporal dynamics of the brain activations that follow the observation of a motor act and underlie the observer’s capacity to understand what the agent is doing and why. Methodology/Principal Findings: Volunteers were presented with two-frame video-clips. The first frame (T0) showed an object with or without context; the second frame (T1) showed a hand interacting with the object. The volunteers were instructed to understand the intention of the observed actions while their brain activity was recorded with a high-density 128-channel EEG system. Visual event-related potentials (VEPs) were recorded time-locked with the frame showing the hand-object interaction (T1). The data were analyzed by using electrical neuroimaging, which combines a cluster analysis performed on the group-averaged VEPs with the localization of the cortical sources that give rise to different spatiotemporal states of the global electrical field. Electrical neuroimaging results revealed four major steps: 1) bilateral posterior cortical activations; 2) a strong activation of the left posterior temporal and inferior parietal cortices with almost a complete disappearance of activations in the right hemisphere; 3) a significant increase of the activations of the right temporo-parieta