Personality traits and behavioral and psychological symptoms in patients at an early stage of Alzheimer's disease.

OBJECTIVE: The origins of behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) are still poorly understood. Focusing on individual personality structure, we explored the relationship between premorbid personality and its changes over 5 years, and BPS in patients at an early stage of AD. METHOD: A total of 54 patients at an early stage of AD according to ICD-10 and NINCDS-ADRDA criteria and 64 control subjects were included. Family members filled in the Neuropsychiatric Inventory Questionnaire to evaluate their proxies' current BPS and the NEO Personality Inventory Revised twice, the first time to evaluate the participants' current personality and the second time to assess personality traits as they were remembered to be 5 years earlier. RESULTS: Behavioral and psychological symptoms, in particular apathy, depression, anxiety, and agitation, are frequent occurrences in early stage AD. Premorbid personality differed between AD patients and normal control, but it was not predictive of BPS in patients with AD. Personality traits clearly change in the course of beginning AD, and this change seems to develop in parallel with BPS as early signs of AD. CONCLUSIONS: Premorbid personality was not associated with BPS in early stage of AD, although complex and non-linear relationships between the two are not excluded. However, both personality and behavioral changes occur early in the course of AD, and recognizing them as possible, early warning signs of neurodegeneration may prove to be a key factor for early detection and intervention. Copyright © 2012 John Wiley & Sons, Ltd.

The costs of parasitism and anti-parasitic defense in the common vole

Résumé : Les relations entre un parasite et son hôte sont avant tout marquées par le coût pour l'hôte que représente la ponction de ressources au profit du parasite et ses conséquences sur les traits d'histoires de vie de l'hôte. Pour contenir la réduction de leur valeur reproductive, les hôtes ont acquis au cours de l'évolution des mécanismes soit de lutte contre les parasites, soit de réallocations des ressources. Curieusement les effets des ectoparasites sur la biologie de mammifères ont été peu étudiés. Dans une première expérience à long terme, nous avons examiné sous un angle intégratif si les puces Nosopsyllus fasciatus affectent certains paramètres physiologiques des campagnols des champs Microtus arvalis. Nous avons également testé si les puces peuvent réduire la longévité et si oui, si ce pourrait être dû à une accélération de la sénescence. Ensuite nous avons testé si la simple activation répétée du système immunitaire comme lors d'une infestation chronique pouvait aussi réduire la longévité. Dans une dernière expérience, nous avons d'abord testé si l'infestation par des puces de jeunes campagnols au stade néonatal (21 jours) pouvait modifier leur développement et leur phénotype adulte. Puis nous avons testé si la modification du phénotype adulte est une réponse prédite et potentiellement adaptative pour minimiser les effets des puces à l'âge adulte. Nos résultats montrent que l'infestation par des puces réduit la croissance subadulte, induit une forte anémie et une immunodépression, et augmente le métabolisme de repos. De plus les puces réduisent la longévité et la taille des testicules, réduisant fortement le succès reproducteur potentiel des individus parasités. La taille finale, c'est-à-dire le développement pré-adulte, détermine en grande part la longévité. La réduction de longévité ne devrait pas être due à l'investissement au profit du système immunitaire car l'activation chronique seule du système immunitaire ne réduit pas la longévité. L'infestation néonatale retarde légèrement le développement mais surtout modifie l'hématocrite et réduit les performances locomotrices des campagnols plus de 3 mois après l'infestation. Les effets immédiats du parasitisme sur la physiologie semblent bien supérieurs comparés aux effets à long terme. Nous n'avons pas d'éléments permettant d'affirmer que le parasitisme néonatal prépare les campagnols à faire face aux puces à l'âge adulte. Au contraire, le parasitisme néonatal interagit sur le parasitisme adulte pour augmenter le métabolisme de repos. Cette thèse offre une vision intégrative des mécanismes par lesquels les puces peuvent affecter la valeur reproductive de leurs hôtes. De façon générale, ces résultats 35 montrent l'importance des puces comme force de sélection chez les campagnols. Il est indispensable de prendre en compte les ectoparasites dans l'étude de l'écologie et des dynamiques de populations chez les mammifères. Summary : The relationship between a parasite and its host is fundamentally marked by the costs for host of the withdrawals of resources by parasite and the subsequent reduction in host life-history traits. Hosts have evolved a number of strategies to reduce these costs, either by fighting against the parasite directly or by reallocating resources to reduce costs on lifetime reproductive value. The effects of ectoparasites on burrowing mammals have been scarcely studied. In a first long-term experiment, we examined how fleas Nosopsyllus fasciatus affect physiological levels of the common vole, Microtus arvalis. We also examined whether fleas reduce longevity and if so, if it is due to an early senescence pattern. Then we tested if experimental activation of the immune system by repeated injections of an antigen could result in a shorter longevity. In the last experiment, we tested if short-lasting neonatal parasitism can have long-term effects on phenotype, and if these effects could induce a predictive response to reduce damages when parasitized at the adult stage. We found that parasitism by flea reduced subadult growth, induced anaemia and immunodepression, and increased energy consumption even when resting. Moreover fleas reduce longevity and testes size associated to splenomegaly, suggesting an overall reduction in fitness but we did not find any pattern of accelerated senescence explaining the early death of parasitized voles compared to non-parasitzed. The cost of mounting an immune response throughout life does not impair longevity, suggesting that it is the cost of parasitism that limits the longevity and not the immune investment. Neonatal infestation by fleas has long-term effects on physiology and reduces motor activity more than 3 months after infestation. The modification of physiology due to long-term effects seems weak compared to the immediate effects of adult infestation. We found no evidence that neonatal parasitism prepares voles to mount a predictive adaptive response in order to reduce effects of fleas on fitness components. On the contrary, neonatal parasitism seems to worsen the effect of adult parasitism. This thesis offers an integrative view of mechanisms by which fleas affect their host at the individual level. Overall, our results demonstrate the importance of fleas as a selective force in voles. These results highlight the importance of ectoparasitism in ecology of micromarnrnals and suggest a role in the dynamic of host populations.

Subjective cognitive decline in patients with mild cognitive impairment and healthy older adults: association with personality traits.

AIM: In normal aging, subjective cognitive decline (SCD) might reflect personality traits or affective states rather than objective cognitive decline. However, little is known on the correlates of SCD in mild cognitive impairment (MCI). The present study investigates SCD in MCI patients and healthy older adults, and explores the association of SCD with personality traits, affective states, behavioral and psychological symptoms (BPS), and episodic memory in patients with MCI as compared with healthy older adults. METHODS: A total of 55 patients with MCI and 84 healthy older adults were recruited. Standard instruments were used to evaluate SCD, episodic memory, BPS and affective states. Premorbid and current personality traits were assessed by proxies using the NEO Personality Inventory Revised. RESULTS: Patients with MCI generally reported SCD more often than healthy older adults. SCD was positively associated with depressive symptoms in both groups. With regard to personality, no significant relationship was found in the healthy older group, whereas agreeableness was significantly negatively related to SCD in the MCI group. No significant association was found between SCD and episodic memory. CONCLUSIONS: SCD is more prevalent in patients with MCI than in the healthy elderly, but it does not reflect an objective cognitive impairment. SCD rather echoes depressive symptoms in both patients with MCI and healthy subjects. The negative association of SCD with agreeableness observed in patients with MCI could indicate that MCI patients scoring high on the agreeableness trait would not report SCD in order to prevent their relatives worrying about their increasing cognitive difficulties.

Sex-dependent selection on an autosomal melanic female ornament promotes the evolution of sex ratio bias.

Sex-dependent selection often leads to spectacularly different phenotypes in males and females. In species in which sexual dimorphism is not complete, it is unclear which benefits females and males derive from displaying a trait that is typical of the other sex. In barn owls (Tyto alba), females exhibit on average larger black eumelanic spots than males but members of the two sexes display this trait in the same range of possible values. In a 12-year study, we show that selection exerted on spot size directly or on genetically correlated traits strongly favoured females with large spots and weakly favoured males with small spots. Intense directional selection on females caused an increase in spot diameter in the population over the study period. This increase is due to a change in the autosomal genes underlying the expression of eumelanic spots but not of sex-linked genes. Female-like males produced more daughters than sons, while male-like females produced more sons than daughters when mated to a small-spotted male. These sex ratio biases appear adaptive because sons of male-like females and daughters of female-like males had above-average survival. This demonstrates that selection exerted against individuals displaying a trait that is typical of the other sex promoted the evolution of specific life history strategies that enhance their fitness. This may explain why in many organisms sexual dimorphism is often not complete.

Epistasis and maternal effects in experimental adaptation to chronic nutritional stress in Drosophila.

Based on ecological and metabolic arguments, some authors predict that adaptation to novel, harsh environments should involve alleles showing negative (diminishing return) epistasis and/or that it should be mediated in part by evolution of maternal effects. Although the first prediction has been supported in microbes, there has been little experimental support for either prediction in multicellular eukaryotes. Here we use a line-cross design to study the genetic architecture of adaptation to chronic larval malnutrition in a population of Drosophila melanogaster that evolved on an extremely nutrient-poor larval food for 84 generations. We assayed three fitness-related traits (developmental rate, adult female weight and egg-to-adult viability) under the malnutrition conditions in 14 crosses between this selected population and a nonadapted control population originally derived from the same base population. All traits showed a pattern of negative epistasis between alleles improving performance under malnutrition. Furthermore, evolutionary changes in maternal traits accounted for half of the 68% increase in viability and for the whole of 8% reduction in adult female body weight in the selected population (relative to unselected controls). These results thus support both of the above predictions and point to the importance of nonadditive effects in adaptive microevolution.

Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment.

Innate receptors for adaptive immunity.

Pattern recognition receptors (PRRs) are commonly known as sensor proteins crucial for the early detection of microbial or host-derived stress signals by innate immune cells. Interestingly, some PRRs are also expressed and functional in cells of the adaptive immune system. These receptors provide lymphocytes with innate sensing abilities; for example, B cells express Toll-like receptors, which are important for the humoral response. Strikingly, certain other NOD-like receptors are not only highly expressed in adaptive immune cells, but also exert functions related specifically to adaptive immune system pathways, such as regulating antigen presentation. In this review, we will focus particularly on the current understanding of PRR functions intrinsic to B and T lymphocytes; a developing aspect of PRR biology.

Regulation of adaptive behaviour during fasting by hypothalamic Foxa2.

The lateral hypothalamic area is considered the classic 'feeding centre', regulating food intake, arousal and motivated behaviour through the actions of orexin and melanin-concentrating hormone (MCH). These neuropeptides are inhibited in response to feeding-related signals and are released during fasting. However, the molecular mechanisms that regulate and integrate these signals remain poorly understood. Here we show that the forkhead box transcription factor Foxa2, a downstream target of insulin signalling, regulates the expression of orexin and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain (Nes-Cre/+;Foxa2T156A(flox/flox) genotype) results in increased neuronal MCH and orexin expression and increased food consumption, metabolism and insulin sensitivity. Spontaneous physical activity of these animals in the fed state is significantly increased and is similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass. Our results demonstrate that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behaviour and physiological responses.

The role of chemokines in cancer immune surveillance by the adaptive immune system.

Chemokines are key molecules involved in the migration and homeostasis of immune cells. However, also tumor cells use chemokine signals for different processes such as tumor progression and metastasis. It is thus unclear whether chemokines, through their immunostimulatory roles, contribute to the repression of tumor cells by tumor immunosurveillance or whether chemokines act primarily as growth factors and chemoattractants for primary and metastatizing tumors, respectively. Research of recent years, using gene knockout mice, recombinant chemokines, and agents able to block chemokine actions, has provided further insight into the diverse functions of chemokines. Here, we review the current knowledge on the complex actions of chemokines at the interface of the immune system and the tumor.

Local-global splitting for spatiotemporal-adaptive multiscale methods

We present a novel spatiotemporal-adaptive Multiscale Finite Volume (MsFV) method, which is based on the natural idea that the global coarse-scale problem has longer characteristic time than the local fine-scale problems. As a consequence, the global problem can be solved with larger time steps than the local problems. In contrast to the pressure-transport splitting usually employed in the standard MsFV approach, we propose to start directly with a local-global splitting that allows to locally retain the original degree of coupling. This is crucial for highly non-linear systems or in the presence of physical instabilities. To obtain an accurate and efficient algorithm, we devise new adaptive criteria for global update that are based on changes of coarse-scale quantities rather than on fine-scale quantities, as it is routinely done before in the adaptive MsFV method. By means of a complexity analysis we show that the adaptive approach gives a noticeable speed-up with respect to the standard MsFV algorithm. In particular, it is efficient in case of large upscaling factors, which is important for multiphysics problems. Based on the observation that local time stepping acts as a smoother, we devise a self-correcting algorithm which incorporates the information from previous times to improve the quality of the multiscale approximation. We present results of multiphase flow simulations both for Darcy-scale and multiphysics (hybrid) problems, in which a local pore-scale description is combined with a global Darcy-like description. The novel spatiotemporal-adaptive multiscale method based on the local-global splitting is not limited to porous media flow problems, but it can be extended to any system described by a set of conservation equations.

Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas.

Canonical Wnt signaling plays a critical role in stem cell maintenance in epithelial homeostasis and carcinogenesis. Here, we show that in the mouse this role is critically mediated by Bcl9/Bcl9l, the mammalian homologues of Legless, which in Drosophila is required for Armadillo/beta-catenin signaling. Conditional ablation of Bcl9/Bcl9l in the intestinal epithelium, where the essential role of Wnt signaling in epithelial homeostasis and stem cell maintenance is well documented, resulted in decreased expression of intestinal stem cell markers and impaired regeneration of ulcerated colon epithelium. Adenocarcinomas with aberrant Wnt signaling arose with similar incidence in wild-type and mutant mice. However, transcriptional profiles were vastly different: Whereas wild-type tumors displayed characteristics of epithelial-mesenchymal transition (EMT) and stem cell-like properties, these properties were largely abrogated in mutant tumors. These findings reveal an essential role for Bcl9/Bcl9l in regulating a subset of Wnt target genes involved in controlling EMT and stem cell-related features and suggest that targeting the Bcl9/Bcl9l arm of Wnt signaling in Wnt-activated cancers might attenuate these traits, which are associated with tumor invasion, metastasis, and resistance to therapy.