Alpha-synucleinopathy and neuropsychological symptoms in a population-based cohort of the elderly

Introduction Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimer’s disease (AD), and that a more severe involvement of the cerebral cortex is correlated with increasing risk of dementia. This study examines the association of AS patterns and observed neuropsychological symptoms in brains of a population-representative donor cohort. Methods Brains donated in 2 out of 6 cognitive function and ageing study cohorts (Cambridgeshire and Nottingham) were examined. Over 80% were >80 years old at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein (using LB509 by Zymed Laboratories) was carried out in 208 brains to establish Braak stage and the pattern and severity of AS following the dementia with Lewy bodies (DLB) consensus recommendations. Dementia, specific neuropsychological measures as measured using the Cambridge cognitive examination, the presence of hallucinations and Parkinson’s disease were investigated. Results Four patterns of AS were observed: no AS pathology (n = 92), AS pathology following the DLB consensus guidelines (n = 33, of which five were ‘neocortical’), amygdala-predominant AS (n = 18), and other AS patterns (n = 33). Each group was subdivided according to high/low neurofibrillary tangles (NFT) Braak stage. Results showed no association between dementia and these patterns of AS, adjusting for the presence of NFT or not. The risk of visual hallucinations shows a weak association with AS in the substantia nigra (odds ratio (OR) = 3.2; 95% confidence interval (CI) 0.5 to 15.5; P = 0.09) and amygdala (OR = 3.0; 95% CI 0.7 to 12.3; P = 0.07). The analysis is similar for auditory hallucinations in subcortical regions. Conclusions Among the whole population of older people, AS does not increase the risks for dementia, irrespective of Braak stage of NFT pathology. There was no evidence that the pattern of AS pathology in cortical areas was relevant to the risk of hallucination. In general, the hypothesis that AS as measured using these methods per se is a key determinant of cognitive clinical phenotypes is not supported

D010 Mesenchymal stem cells protect cardiomyocytes from reperfusion injury through a paracrine activation of the PI3 kinase pathway

ObjectivesPrevious data suggest that implantation of mesenchymal stem cells (MSCs) improves heart function after myocardial infarction. We investigated whether protection afforded by MSCs might involve a paracrine activation of the PI3 kinase pathway in reperfused cardiomyocytes.MethodMSCs and neonatal rat cardiomyocytes (NRCs) were isolated and cultured separately. NRCs (2.106) were subjected to 5 hours of ischemia followed by 16 hours of reperfusion. At the time of reperfusion, NRCs (n=8-14/group) received either fresh medium (control group), or the following treatments: MSCs (2.105 MSCs in fresh medium), conditioned SN (MSCs supernatant alone (i.e. without MSCs) obtained after 8 hours of serum deprived culture), [conditioned SN + LY294002] (15 microM of LY294002 a specifi c inhibitor of PI3K), [conditioned SN + Wortmannin] (100 nM of wortmannin, a non specifi c inhibitor of PI3K), or CsA (200 nM in fresh medium) a potent inhibitor of the mitochondrial permeability transition pore. Cell death was assessed by LDH release in NRCs supernatant at the end of reperfusion.ResultsAs expected, LDH activity was dramatically reduced by CsA, averaging 4 % of control values. LDH activity was signifi cantly reduced by MSCs alone and by conditioned SN, averaging 29 % and 12 % of control value, respectively. Both LY294002 and wortmannin signifi cantly attenuated conditioned SN induced protection.Conclusionour data suggest that MSCs can protect NRCs from reperfusion injury through a paracrine activation of the PI3K pathway

Metaflammasome components in the human brain: a role in dementia with alzheimer's pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer's pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKβ and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKβ and IRS1. Cognitive scores showed a significant positive relationship with IKKβ and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer's participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex

Insights into the pathological basis of dementia from population based neuropathology studies

The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case-control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age related TDP-43 encephalopathy, ageing related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status have implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes

Vortex phase diagram in trapped Bose-Einstein condensation

The vortex phase diagram in the external rotation frequency versus temperature is calculated for dilute Bose-Einstein condensed gases. It is determined within the Bogoliubov-Popov theory for a finite temperature where the condensate and non-condensate fractions are treated in an equal footing. The temperature dependences of various thermodynamic instability lines for the vortex nucleation are computed to construct the phase diagram. Experiments are proposed to resolve a recent controversy on the vortex creation problem associated with the quantized vortex observation in $^{87}$Rb atom gases.Comment: 11 pages, 8 figure

From Feshbach-Resonance Managed Bose-Einstein Condensates to Anisotropic Universes: Some Applications of the Ermakov-Pinney equation with Time-Dependent Nonlinearity

In this work we revisit the topic of two-dimensional Bose-Einstein condensates under the influence of time-dependent magnetic confinement and time-dependent scattering length. A moment approach reduces the examination of moments of the wavefunction (in particular, of its width) to an Ermakov-Pinney (EP) ordinary differential equation (ODE). We use the well-known structure of the solutions of this nonlinear ODE to ``engineer'' trapping and interatomic interaction conditions that lead to condensates dispersing, breathing or even collapsing. The advantage of the approach is that it is fully tractable analytically, in excellent agreement with our numerical observations. As an aside, we also discuss how similar time-dependent EP equations may arise in the description of anisotropic scalar field cosmologies.Comment: 9 pages, 4 figure

Stationary solutions of the one-dimensional nonlinear Schroedinger equation: I. Case of repulsive nonlinearity

All stationary solutions to the one-dimensional nonlinear Schroedinger equation under box and periodic boundary conditions are presented in analytic form. We consider the case of repulsive nonlinearity; in a companion paper we treat the attractive case. Our solutions take the form of stationary trains of dark or grey density-notch solitons. Real stationary states are in one-to-one correspondence with those of the linear Schr\"odinger equation. Complex stationary states are uniquely nonlinear, nodeless, and symmetry-breaking. Our solutions apply to many physical contexts, including the Bose-Einstein condensate and optical pulses in fibers.Comment: 11 pages, 7 figures -- revised versio

Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain

Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention

Asteroseismology of Eclipsing Binary Stars in the Kepler Era

Eclipsing binary stars have long served as benchmark systems to measure fundamental stellar properties. In the past few decades, asteroseismology - the study of stellar pulsations - has emerged as a new powerful tool to study the structure and evolution of stars across the HR diagram. Pulsating stars in eclipsing binary systems are particularly valuable since fundamental properties (such as radii and masses) can determined using two independent techniques. Furthermore, independently measured properties from binary orbits can be used to improve asteroseismic modeling for pulsating stars in which mode identifications are not straightforward. This contribution provides a review of asteroseismic detections in eclipsing binary stars, with a focus on space-based missions such as CoRoT and Kepler, and empirical tests of asteroseismic scaling relations for stochastic ("solar-like") oscillations.Comment: 28 pages, 12 figures, 2 tables; Proceedings of the AAS topical conference "Giants of Eclipse" (AASTCS-3), July 28 - August 2 2013, Monterey, C

A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II.

Dramatic global increases in future numbers of people with dementia have been predicted. No multicentre population-based study powered to detect changes over time has reported dementia incidence. MRC Cognitive Function and Ageing Study (CFAS) undertook baseline interviews in populations aged 65+ years in England and Wales (1989-1994). Three areas (CFAS I) were selected for new sampling two decades later (2008-2011) with same geographical boundaries, sampling and approach methods (CFAS II). At 2 years CFAS I interviewed 5,156 (76% response) with 5,288 interviewed in CFAS II (74% response). Here we report a 20% drop in incidence (95% CI: 0-40%), driven by a reduction in men across all ages above 65. In the UK we estimate 209,600 new dementia cases per year. This study was uniquely designed to test for differences across geography and time. A reduction of age-specific incidence means that the numbers of people estimated to develop dementia in any year has remained relatively stable.CFAS II has been supported by the UK Medical Research Council (Research Grant: G06010220) and received additional support from the National Institute for Health Research (NIHR), comprehensive clinical research networks in West Anglia, Nottingham City and Nottinghamshire County NHS Primary Care trusts and the dementias and neurodegenerative disease research Network (DeNDRoN) in Newcastle. MRC CFAS I was funded by the MRC (Research Grant: G9901400) and the National Health Service (NHS). F.E.M. is supported by the MRC (Research Grant: U105292687). This research was done within the UK National Institute of Health Research collaboration for leadership in applied health research and care for Cambridgeshire and Peterborough (CLAHRC EoE), the Biomedical Research Centre infrastructures at Cambridge and Newcastle upon Tyne. We thank the participants, their families, the general practitioners and their staff, the primary care trusts and CCGs for their cooperation and support. We thank the CFAS II fieldwork interviewers at Cambridge, Nottingham and Newcastle for their valuable contribution. Funding was given by UK Medical Research Council.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1139