Population-based neuropathological studies of dementia: design, methods and areas of investigation – a systematic review

Background Prospective population-based neuropathological studies have a special place in dementia research which is under emphasised. Methods A systematic review of the methods of population-based neuropathological studies of dementia was carried out. These studies were assessed in relation to their representativeness of underlying populations and the clinical, neuropsychological and neuropathological approaches adopted. Results Six studies were found to be true population-based neuropathological studies of dementia in the older people: the Hisayama study (Japan); Vantaa 85+ study (Finland); CC75C study (Cambridge, UK); CFAS (multicentre, UK); Cache County study (Utah, USA); HAAS (Hawaï, USA). These differ in the core characteristics of their populations. The studies used standardised neuropathological methods which facilitate analyses on: clinicopathological associations and confirmation of diagnosis, assessing the validity of hierarchical models of neuropathological lesion burden; investigating the associations between neuropathological burden and risk factors including genetic factors. Examples of findings are given although there is too little overlap in the areas investigated amongst these studies to form the basis of a systematic review of the results. Conclusion Clinicopathological studies based on true population samples can provide unique insights in dementia. Individually they are limited in power and scope; together they represent a powerful source to translate findings from laboratory to populations

Neural codes formed by small and temporally precise populations in auditory cortex

The encoding of sensory information by populations of cortical neurons forms the basis for perception but remains poorly understood. To understand the constraints of cortical population coding we analyzed neural responses to natural sounds recorded in auditory cortex of primates (Macaca mulatta). We estimated stimulus information while varying the composition and size of the considered population. Consistent with previous reports we found that when choosing subpopulations randomly from the recorded ensemble, the average population information increases steadily with population size. This scaling was explained by a model assuming that each neuron carried equal amounts of information, and that any overlap between the information carried by each neuron arises purely from random sampling within the stimulus space. However, when studying subpopulations selected to optimize information for each given population size, the scaling of information was strikingly different: a small fraction of temporally precise cells carried the vast majority of information. This scaling could be explained by an extended model, assuming that the amount of information carried by individual neurons was highly nonuniform, with few neurons carrying large amounts of information. Importantly, these optimal populations can be determined by a single biophysical marker—the neuron's encoding time scale—allowing their detection and readout within biologically realistic circuits. These results show that extrapolations of population information based on random ensembles may overestimate the population size required for stimulus encoding, and that sensory cortical circuits may process information using small but highly informative ensembles

To beta block or not to beta block; that is the question

The fast-acting β-1 blocker esmolol has been the center of attention since the landmark article by Morrelli and colleagues suggesting that, in patients with sepsis, reducing heart rate by administering esmolol can result in a survival benefit. However, the use of esmolol for the treatment of sepsis and the underlying mechanism responsible for this benefit remain controversial. This commentary discusses the study by Jacquet-Lagrèze and colleagues, who in a pig model of sepsis tested the hypothesis that administration of esmolol to reduce heart rate may correct sepsis-induced sublingual and gut microcirculatory alterations which are known to be associated with adverse outcome

A wave driver theory for vortical waves propagating across junctions with application to those between rigid and compliant walls

A theory is described for propagation of vortical waves across alternate rigid and compliant panels. The structure in the fluid side at the junction of panels is a highly vortical narrow viscous structure which is idealized as a wave driver. The wave driver is modelled as a ‘half source cum half sink’. The incoming wave terminates into this structure and the outgoing wave emanates from it. The model is described by half Fourier–Laplace transforms respectively for the upstream and downstream sides of the junction. The cases below cutoff and above cutoff frequencies are studied. The theory completely reproduces the direct numerical simulation results of Davies & Carpenter (J. Fluid Mech., vol. 335, 1997, p. 361). Particularly, the jumps across the junction in the kinetic energy integral, the vorticity integral and other related quantities as obtained in the work of Davies & Carpenter are completely reproduced. Also, some important new concepts emerge, notable amongst which is the concept of the pseudo group velocity

Regional ischemia in hypertrophic Langendorff-perfused rat hearts

Myocardial hypertrophy decreases the muscle mass-to-vascularization ratio, thereby changing myocardial perfusion. The effect of these changes on myocardial oxygenation in hypertrophic Langendorff-perfused rat hearts was measured using epimyocardial NADH videofluorimetry, whereby ischemic myocardium displays a high fluorescence intensity. Hypertrophic hearts, in contrast to control hearts, developed ischemic areas during oxygen-saturated Langendorff perfusion. Reoxygenation of control hearts after a hypoxic episode resulted in a swift decrease of fluorescence in a heterogeneous pattern of small, evenly dispersed, highly fluorescent patches. Identical patterns could be evoked by occluding capillaries with microspheres 5.9 micrometer in diameter. Ten seconds after reoxygenation there were no more dysoxic areas, whereas reoxygenation in hypertrophic hearts showed larger ischemic areas that took significantly longer to return to normoxic fluorescence intensities. Hypothesizing that the larger areas originate at a vascular level proximal to the capillary network, we induced hypoxic patterns by embolizing control hearts with microspheres 9.8 and 15 micrometer in diameter. The frequency distribution histograms of these dysoxic surface areas matched those of hypertrophic hearts and differed significantly from those of hearts embolized with 5.9-micrometer microspheres. These results suggest the existence of areas in hypertrophic Langendorff-perfused hearts with suboptimal vascularization originating at the arteriolar and/or arterial level

Mean-field analysis of the majority-vote model broken-ergodicity steady state

We study analytically a variant of the one-dimensional majority-vote model in which the individual retains its opinion in case there is a tie among the neighbors' opinions. The individuals are fixed in the sites of a ring of size $L$ and can interact with their nearest neighbors only. The interesting feature of this model is that it exhibits an infinity of spatially heterogeneous absorbing configurations for $L \to \infty$ whose statistical properties we probe analytically using a mean-field framework based on the decomposition of the $L$-site joint probability distribution into the $n$-contiguous-site joint distributions, the so-called $n$-site approximation. To describe the broken-ergodicity steady state of the model we solve analytically the mean-field dynamic equations for arbitrary time $t$ in the cases n=3 and 4. The asymptotic limit $t \to \infty$ reveals the mapping between the statistical properties of the random initial configurations and those of the final absorbing configurations. For the pair approximation ($n=2$) we derive that mapping using a trick that avoids solving the full dynamics. Most remarkably, we find that the predictions of the 4-site approximation reduce to those of the 3-site in the case of expectations involving three contiguous sites. In addition, those expectations fit the Monte Carlo data perfectly and so we conjecture that they are in fact the exact expectations for the one-dimensional majority-vote model

A micro-perfusion chamber for single-cell fluorescence measurements

Abstract A versatile closed micro-perfusion chamber designed for single-cell fluorescence measurements under maximum microscopic magnification is described. Glass coverslips with adherent cells can be attached to the top or bottom of the chamber, depending on whether an inverted or an upright microscope is used. Eight conical holes drilled in the side of the chamber serve for the insertion of plugs with attachments for perfusion, rapid injection of small amounts of reagents, temperature measurements or for heating the interior of the chamber. Materials used in the construction of the chamber are non-toxic and resistant to standard sterilization procedures. Perfusion and temperature properties of the chamber are described. Single cell fluorescence measurements are presented in human monocyte-derived macrophages in which NAD(P)H and intracellular calcium are measured

On the new translational shape invariant potentials

Recently, several authors have found new translational shape invariant potentials not present in classic classifications like that of Infeld and Hull. For example, Quesne on the one hand and Bougie, Gangopadhyaya and Mallow on the other have provided examples of them, consisting on deformations of the classical ones. We analyze the basic properties of the new examples and observe a compatibility equation which has to be satisfied by them. We study particular cases of such equation and give more examples of new translational shape invariant potentials.Comment: 9 pages, uses iopart10.clo, version

Constructing Integrable Third Order Systems:The Gambier Approach

We present a systematic construction of integrable third order systems based on the coupling of an integrable second order equation and a Riccati equation. This approach is the extension of the Gambier method that led to the equation that bears his name. Our study is carried through for both continuous and discrete systems. In both cases the investigation is based on the study of the singularities of the system (the Painlev\'e method for ODE's and the singularity confinement method for mappings).Comment: 14 pages, TEX FIL

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