Étude retrospective observationnelle sur l'usage des biomarqueurs du liquide céphalo-rachidien de la maladie d'Alzheimer [Prospective and observational study of use of cerebrospinal fluid biomarkers of Alzheimer's disease]

Objectifs: Le dosage des biomarqueurs du liquide céphalorachidien (LCR) ne fait pas partie des recommandations de la démarche diagnostique de la maladie d'Alzheimer (MA) en France. Nous voulions analyser l'apport de leur dosage en pratique clinique quotidienne. Matériel et méthode: Étude rétrospective observationnelle, portant sur l'ensemble des dosages de biomarqueurs du LCR de la MA effectués entre le 1er novembre 2010 et le 30 septembre 2012 dans l'hôpital de jour (HDJ) et le service de médecine interne gériatrique (SMIG) du centre mémoire de ressources et de recherche (CMRR) des hôpitaux universitaires de Strasbourg (Alsace, France). Résultats: Quatre-vingt-dix-sept patients (femmes : 60,8 % ; âge moyen : 80 ± 6,5 ans) ont été considérés. En HDJ (n = 50), les biomarqueurs étaient utilisés pour le diagnostic positif de MA (64,0 %) ou le diagnostic différentiel entre les démences (36,0 %). Au SMIG (n = 47), leur dosage était effectué afin de confirmer une MA (19,1 %), de rechercher une pathologie cognitive sous-jacente à un syndrome confusionnel (17,0 %) ou pour diagnostiquer une démence chez des patients atteints de pathologies psychiatriques (29,8 %). Si 49,5 % des patients ont eu un diagnostic de MA confirmée, les biomarqueurs ont contribué à infirmer cette étiologie dans 9,2 % des cas. Le doute entre une MA et une autre étiologie persistait cependant encore chez 10 patients. Les analyses comparatives des taux des différents biomarqueurs ont montré que la protéine tau est observée avec un taux significativement plus élevé dans la MA que dans la démence vasculaire (p = 0,003) et à la limite de la significativité pour la maladie de Parkinson (p = 0,06). Le profil observé avec la Ptau est similaire mais avec une significativité atteinte vis-à-vis de la démence de la maladie de Parkinson (p = 0,01). En ce qui concerne l'Aβ1-42, si les taux moyens étaient les plus élevés dans les démences vasculaire et à corps de Lewy, (p < 0,0001 et p < 0,01), ils étaient plus faibles en cas de démence de la maladie de Parkinson mais sans atteindre le seuil de signification (p = 0,12). Conclusion: Cette étude a analysé l'utilisation des biomarqueurs de la MA en pratique courante. Si leur intérêt se positionne actuellement dans le diagnostic de la MA à un stade léger, ces biomarqueurs montrent leur utilité dans les situations où le diagnostic clinique est rendu difficile par un trouble psychiatrique et/ou une confusion, une clinique atypique où lorsque les tests cognitifs sont irréalisables.

Accuracy of cognitive MRI-targeted biopsy in hitting prostate cancer-positive regions of interest.

PURPOSE: Prostate cancer (PCa) diagnosis relies on clinical suspicion leading to systematic transrectal ultrasound-guided biopsy (TRUSGB). Multiparametric magnetic resonance imaging (mpMRI) allows for targeted biopsy of suspicious areas of the prostate instead of random 12-core biopsy. This method has been shown to be more accurate in detecting significant PCa. However, the precise spatial accuracy of cognitive targeting is unknown. METHODS: Consecutive patients undergoing mpMRI-targeted TRUSGB with cognitive registration (MRTB-COG) followed by robot-assisted radical prostatectomy were included in the present analysis. The regions of interest (ROIs) involved by the index lesion reported on mpMRI were subsequently targeted by two experienced urologists using the cognitive approach. The 27 ROIs were used as spatial reference. Mapping on radical prostatectomy specimen was used as reference to determine true-positive mpMRI findings. Per core correlation analysis was performed. RESULTS: Forty patients were included. Overall, 40 index lesions involving 137 ROIs (mean ROIs per index lesion 3.43) were identified on MRI. After correlating these findings with final pathology, 117 ROIs (85 %) were considered as true-positive lesions. A total of 102 biopsy cores directed toward such true-positive ROIs were available for final analysis. Cognitive targeted biopsy hit the target in 82 % of the cases (84/102). The only identified risk factor for missing the target was an anterior situated ROI (p = 0.01). CONCLUSION: In experienced hands, cognitive MRTB-COG allows for an accuracy of 82 % in hitting the correct target, given that it is a true-positive lesion. Anterior tumors are less likely to be successfully targeted.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

BackgroundBipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.AimsWe sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.MethodTo detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.ResultsIntegrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.ConclusionsOur findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.

Acute and Chronic Altitude-Induced Cognitive Dysfunction in Children and Adolescents.

OBJECTIVE: To assess whether exposure to high altitude induces cognitive dysfunction in young healthy European children and adolescents during acute, short-term exposure to an altitude of 3450 m and in an age-matched European population permanently living at this altitude. STUDY DESIGN: We tested executive function (inhibition, shifting, and working memory), memory (verbal, short-term visuospatial, and verbal episodic memory), and speed processing ability in: (1) 48 healthy nonacclimatized European children and adolescents, 24 hours after arrival at high altitude and 3 months after return to low altitude; (2) 21 matched European subjects permanently living at high altitude; and (3) a matched control group tested twice at low altitude. RESULTS: Short-term hypoxia significantly impaired all but 2 (visuospatial memory and processing speed) of the neuropsychological abilities that were tested. These impairments were even more severe in the children permanently living at high altitude. Three months after return to low altitude, the neuropsychological performances significantly improved and were comparable with those observed in the control group tested only at low altitude. CONCLUSIONS: Acute short-term exposure to an altitude at which major tourist destinations are located induces marked executive and memory deficits in healthy children. These deficits are equally marked or more severe in children permanently living at high altitude and are expected to impair their learning abilities.

Patients' understanding of blood tests and attitudes to HIV screening in the emergency department of a Swiss teaching hospital: a cross-sectional observational study.

BACKGROUND: In Switzerland, patients may undergo "blood tests" without being informed what these are screening for. Inadequate doctor-patient communication may result in patient misunderstanding. We examined what patients in the emergency department (ED) believed they had been screened for and explored their attitudes to routine (non-targeted) human immunodeficiency virus (HIV) screening. METHODS: Between 1st October 2012 and 28th February 2013, a questionnaire-based survey was conducted among patients aged 16-70 years old presenting to the ED of Lausanne University Hospital. Patients were asked: (1) if they believed they had been screened for HIV; (2) if they agreed in principle to routine HIV screening and (3) if they agreed to be HIV tested during their current ED visit. RESULTS: Of 466 eligible patients, 411 (88%) agreed to participate. Mean age was 46 ± 16 years; 192 patients (47%) were women; 366 (89%) were Swiss or European; 113 (27%) believed they had been screened for HIV, the proportion increasing with age (p ≤0.01), 297 (72%) agreed in principle with routine HIV testing in the ED, and 138 patients (34%) agreed to be HIV tested during their current ED visit. CONCLUSION: In this ED population, 27% believed incorrectly they had been screened for HIV. Over 70% agreed in principle with routine HIV testing and 34% agreed to be tested during their current visit. These results demonstrate willingness among patients concerning routine HIV testing in the ED and highlight a need for improved doctor-patient communication about what a blood test specifically screens for.

A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: A 12-month follow-up study.

BACKGROUND: Cognitive deficits have been reported during the early stages of bipolar disorder; however, the role of medication on such deficits remains unclear. The aim of this study was to compare the effects of lithium and quetiapine monotherapy on cognitive performance in people following first episode mania. METHODS: The design was a single-blind, randomised controlled trial on a cohort of 61 participants following first episode mania. Participants received either lithium or quetiapine monotherapy as maintenance treatment over a 12-month follow-up period. The groups were compared on performance outcomes using an extensive cognitive assessment battery conducted at baseline, month 3 and month 12 follow-up time-points. RESULTS: There was a significant interaction between group and time in phonemic fluency at the 3-month and 12-month endpoints, reflecting greater improvements in performance in lithium-treated participants relative to quetiapine-treated participants. After controlling for multiple comparisons, there were no other significant interactions between group and time for other measures of cognition. CONCLUSION: Although the effects of lithium and quetiapine treatment were similar for most cognitive domains, the findings imply that early initiation of lithium treatment may benefit the trajectory of cognition, specifically verbal fluency in young people with bipolar disorder. Given that cognition is a major symptomatic domain of bipolar disorder and has substantive effects on general functioning, the ability to influence the trajectory of cognitive change is of considerable clinical importance.

Brain Connections Associated With Socio-Cognitive Skills in Preterm and Low Birth Weight School Age Children

Identification of neuroimaging biomarkers following extreme prematurity (EP) and intrauterine growth restriction (IUGR) is crucial for understanding their cognitive and behavioral impairments at school age

Workgroup climates and employees' counterproductive work behaviors: A social-cognitive perspective

This research examines employees' anticipation of social and self-sanctions as a self-regulatory mechanism linking workgroup climates and counterproductive work behaviors (CWBs) and personality as a limit to these effects. A cross-level study with 158 employees from 26 workgroups demonstrated that in groups with a high compliance climate-a climate emphasizing the importance of complying with organizational rules-employees anticipate more social and self-sanctions, leading those low in conscientiousness and low in agreeableness to engage less frequently in CWBs. In contrast, a high relational climate-a climate emphasizing the importance of positive social relations over self-interest-indirectly unbridles the CWBs of these employees by alleviating the social and self-sanctions they anticipate for CWBs. Climates did not have indirect effects for employees high in agreeableness and high in conscientiousness. These findings elucidate why workgroup climates do not affect the CWBs of all members in the same way.

A cognitive hierarchy model of behavior in the action commitment game

We apply the cognitive hierarchy model of Camerer et al. (Q J Econ 119(3):861-898, 2004)-where players have different levels of reasoning-to Huck et al. (Games Econ Behav 38:240-264, 2002) discrete version of Hamilton and Slutsky (Games Econ Behav 2:29-46, 1990) action commitment game-a duopoly with endogenous timing of entry. We show that, for an empirically reasonable average number of thinking steps, the model rules out Stackelberg equilibria, generates Cournot outcomes including delay, and outcomes where the first mover commits to a quantity higher than Cournot but lower than Stackelberg leader. We show that a cognitive hierarchy model with quantal responses can explain the most important features of the experimental data on the action commitment game in (2002). In order to gauge the success of the model in fitting the data, we compare it to a noisy Nash model. We find that the cognitive hierarchy model with quantal responses fits the data better than the noisy Nash model.

Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment

BACKGROUND: Despite a low positive predictive value, diagnostic tests such as complete blood count (CBC) and C-reactive protein (CRP) are commonly used to evaluate whether infants with risk factors for early-onset neonatal sepsis (EOS) should be treated with antibiotics. STUDY DESIGN: We investigated the impact of imple- menting a protocol aiming at reducing the number of dia- gnostic tests in infants with risk factors for EOS in order to compare the diagnostic performance of repeated clinical examination with CBC and CRP measurement. The primary outcome was the time between birth and the first dose of antibiotics in infants treated for suspected EOS. RESULTS: Among the 11,503 infants born at 35 weeks during the study period, 222 were treated with antibiotics for suspected EOS. The proportion of infants receiving an- tibiotics for suspected EOS was 2.1% and 1.7% before and after the change of protocol (p = 0.09). Reduction of dia- gnostic tests was associated with earlier antibiotic treat- ment in infants treated for suspected EOS (hazard ratio 1.58; 95% confidence interval [CI] 1.20-2.07; p <0.001), and in infants with neonatal infection (hazard ratio 2.20; 95% CI 1.19-4.06; p = 0.01). There was no difference in the duration of hospital stay nor in the proportion of infants requiring respiratory or cardiovascular support before and after the change of protocol. CONCLUSION: Reduction of diagnostic tests such as CBC and CRP does not delay initiation of antibiotic treat- ment in infants with suspected EOS. The importance of clinical examination in infants with risk factors for EOS should be emphasised.

Mycobacterium tuberculosis Infection in Young Children: Analyzing the Performance of the Diagnostic Tests

This study evaluated the performance of the Tuberculin Skin Test (TST) and Quantiferon-TB Gold in-Tube (QFT) and the possible association of factors which may modify their results in young children (0-6 years) with recent contact with an index tuberculosis case. Materials and Methods: A cross-sectional study including 135 children was conducted in Manaus, Amazonas-Brazil. The TST and QFT were performed and the tests results were analyzed in relation to the personal characteristics of the children studied and their relationship with the index case. Results: The rates of positivity were 34.8% (TST) and 26.7% (QFT), with 14.1% of indeterminations by the QFT. Concordance between tests was fair (Kappa = 0.35 P<0.001). Both the TST and QFT were associated with the intensity of exposure (Linear OR = 1.286, P = 0.005; Linear OR = 1.161, P = 0.035 respectively) with only the TST being associated with the time of exposure (Linear OR = 1.149, P = 0.009). The presence of intestinal helminths in the TST+ group was associated with negative QFT results (OR = 0.064, P = 0.049). In the TST- group lower levels of ferritin were associated with QFT+ results (Linear OR = 0.956, P = 0.036). Conclusions: Concordance between the TST and QFT was lower than expected. The factors associated with the discordant results were intestinal helminths, ferritin levels and exposure time to the index tuberculosis case. In TST+ group, helminths were associated with negative QFT results suggesting impaired cell-mediated immunity. The TST-&QFT+ group had a shorter exposure time and lower ferritin levels, suggesting that QFT is faster and ferritin may be a potential biomarker of early stages of tuberculosis infection.

Threat Simulation- The Function of Dreaming?

Dreaming is a pure form of phenomenality, created by the brain untouched by external stimulation or behavioral activity, yet including a full range of phenomenal contents. Thus, it has been suggested that the dreaming brain could be used as a model system in a biological research program on consciousness (Revonsuo, 2006). In the present thesis, the philosophical view of biological realism is accepted, and thus, dreaming is considered as a natural biological phenomenon, explainable in naturalistic terms. The major theoretical contribution of the present thesis is that it explores dreaming from a multidisciplinary perspective, integrating information from various fields of science, such as dream research, consciousness research, evolutionary psychology, and cognitive neuroscience. Further, it places dreaming into a multilevel framework, and investigates the constitutive, etiological, and contextual explanations for dreaming. Currently, the only theory offering a full multilevel explanation for dreaming, that is, a theory including constitutive, etiological, and contextual level explanations, is the Threat Simulation Theory (TST) (Revonsuo, 2000a; 2000b). The empirical significance of the present thesis lies in the tests conducted to test this specific theory put forth to explain the form, content, and biological function of dreaming. The first step in the empirical testing of the TST was to define exact criteria for what is a ‘threatening event’ in dreams, and then to develop a detailed and reliable content analysis scale with which it is possible to empirically explore and quantify threatening events in dreams. The second step was to seek answers to the following questions derived from the TST: How frequent threatening events are in dreams? What kind of qualities these events have? How threatening events in dreams relate to the most recently encoded or the most salient memory traces of threatening events experienced in waking life? What are the effects of exposure to severe waking life threat on dreams? The results reveal that threatening events are relatively frequent in dreams, and that the simulated threats are realistic. The most common threats include aggression, are targeted mainly against the dream self, and include simulations of relevant and appropriate defensive actions. Further, real threat experiences activate the threat simulation system in a unique manner, and dream content is modulated by the activation of long term episodic memory traces with highest negative saliency. To sum up, most of the predictions of the TST tested in this thesis received considerable support. The TST presents a strong argument that explains the specific design of dreams as threat simulations. The TST also offers a plausible explanation for why dreaming would have been selected for: because dreaming interacted with the environment in such a way that enhanced fitness of ancestral humans. By referring to a single threat simulation mechanism it furthermore manages to explain a wide variety of dream content data that already exists in the literature, and to predict the overall statistical patterns of threat content in different samples of dreams. The TST and the empirical tests conducted to test the theory are a prime example of what a multidisciplinary approach to mental phenomena can accomplish. Thus far, dreaming seems to have always resided in the periphery of science, never regarded worth to be studied by the mainstream. Nevertheless, when brought to the spotlight, the study of dreaming can greatly benefit from ideas in diverse branches of science. Vice versa, knowledge learned from the study of dreaming can be applied in various disciplines. The main contribution of the present thesis lies in putting dreaming back where it belongs, that is, into the spotlight in the cross-road of various disciplines.

Tests of International Asset Pricing Models in Scandinavian Stock Markets

This thesis examines whether global, local and exchange risks are priced in Scandinavian countries’ equity markets by using conditional international asset pricing models. The employed international asset pricing models are the world capital asset pricing model, the international asset pricing model augmented with the currency risk, and the partially segmented model augmented with the currency risk. Moreover, this research traces estimated equity risk premiums for the Scandinavian countries. The empirical part of the study is performed using generalized method of moments approach. Monthly observations from February 1994 to June 2007 are used. Investors’ conditional expectations are modeled using several instrumental variables. In order to keep system parsimonious the prices of risk are assumed to be constant whereas expected returns and conditional covariances vary over time. The empirical findings of this thesis suggest that the prices of global and local market risk are priced in the Scandinavian countries. This indicates that the Scandinavian countries are mildly segmented from the global markets. Furthermore, the results show that the exchange risk is priced in the Danish and Swedish stock markets when the partially segmented model is augmented with the currency risk factor.