Working memory impairment as an endophenotypic marker of a schizophrenia diathesis

AbstractThis review focuses on the viability of working memory impairment as an endophenotypic marker of a schizophrenia diathesis. It begins with an introduction of the construct of working memory. It follows with a consideration of the operational criteria for defining an endophenotype. Research findings regarding the working memory performance of schizophrenia and schizophrenia-spectrum patients, first-degree relatives of schizophrenia patients and healthy controls, are reviewed in terms of the criteria for being considered an endophenotypic marker. Special attention is paid to specific components of the working memory deficit (namely, encoding, maintenance, and manipulation), in terms of which aspects are likely to be the best candidates for endophenotypes. We examine the extant literature regarding working memory performance in bipolar disorder and major depression in order to address the issue of relative specificity to schizophrenia. Despite some unresolved issues, it appears that working memory impairment is a very promising candidate for an endophenotypic marker of a schizophrenia diathesis but not for mood disorders. Throughout this review, we identify future directions for research in this exciting and dynamic area of research and evaluate the contribution of working memory research to our understanding of schizophrenia

Confirmatory factor analysis of the French version of the Anticipatory and Consummatory Interpersonal Pleasure Scale

The Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS), a measure specifically designed to assess hedonic capacity for social and interpersonal pleasure, was used to evaluate the presence of social anhedonia in patients as well as the general population. The first goal of this study was to validate the structure of the French version of the ACIPS. The second objective was to verify whether a one, two or three factor solution is most appropriate for the ACIPS scale. The French version of the ACIPS was tested on 263 French-speaking pre-graduate students or professional volunteers. For the confirmatory factor analysis, data were treated as categorical ordinal and all the models were estimated using a robust weighted least squares estimator with adjustments for the mean and variance. Three models were estimated. A one-factor model representing a general undifferentiated “pleasure” latent construct was first tested on the 17 ACIPS items. A two-factor model distinguishing anticipatory-pleasure and consummatory-pleasure was tested next. Finally, a three-factor model including intimate social interactions, group social interactions and social bonding was tested. The one and two-factor models showed a somewhat poor fit to the data. However, the goodness of fit of the three factor model was adequate. These results suggest that individuals who enjoyed interaction in one of these three sub domains were more likely to enjoy doing so in the two other domains. However, on the basis of the comparison between the one and three factor models, these three types interactions may not be considered as indistinguishable. Rather, they represent distinct and theoretically meaningful dimensions. These results show the French version of the ACIPS is a useful and valid scale to measure the capacity of savoring different kinds of social relationships

Cognition and Brain Function in Schizotypy: A Selective Review

Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. While the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning, and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable interindividual differences that covary with performance on a wide range of perceptual, cognitive, and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterization of a personality constellation known to be associated with real-life impairments, but also in generating hypotheses concerning the aetiology of schizophreni

Associations of Blood Pressure and Cholesterol Levels During Young Adulthood With Later Cardiovascular Events.

BackgroundBlood pressure (BP) and cholesterol are major modifiable risk factors for cardiovascular disease (CVD), but effects of exposures during young adulthood on later life CVD risk have not been well quantified.ObjectiveThe authors sought to evaluate the independent associations between young adult exposures to risk factors and later life CVD risk, accounting for later life exposures.MethodsThe authors pooled data from 6 U.S. cohorts with observations spanning the life course from young adulthood to later life, and imputed risk factor trajectories for low-density lipoprotein (LDL) and high-density lipoprotein cholesterols, systolic and diastolic BP starting from age 18 years for every participant. Time-weighted average exposures to each risk factor during young (age 18 to 39 years) and later adulthood (age ≥40 years) were calculated and linked to subsequent risks of coronary heart disease (CHD), heart failure (HF), or stroke.ResultsA total of 36,030 participants were included. During a median follow-up of 17 years, there were 4,570 CHD, 5,119 HF, and 2,862 stroke events. When young and later adult risk factors were considered jointly in the model, young adult LDL ≥100 mg/dl (compared with <100 mg/dl) was associated with a 64% increased risk for CHD, independent of later adult exposures. Similarly, young adult SBP ≥130 mm Hg (compared with <120 mm Hg) was associated with a 37% increased risk for HF, and young adult DBP ≥80 mm Hg (compared with <80 mm Hg) was associated with a 21% increased risk.ConclusionsCumulative young adult exposures to elevated systolic BP, diastolic BP and LDL were associated with increased CVD risks in later life, independent of later adult exposures

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Evidence for optimal semantic search throughout adulthood

Abstract As people age, they learn and store new knowledge in their semantic memory. Despite learning a tremendous amount of information, people can still recall information relevant to the current situation with ease. To accomplish this, the mind must efficiently organize and search a vast store of information. It also must continue to retrieve information effectively despite changes in cognitive mechanisms due to healthy aging, including a general slowing in information processing and a decline in executive functioning. How effectively does the mind of an individual adjust its search to account for changes due to aging? We tested 746 people ages 25 through 69 on a semantic fluency task (free listing animals) and found that, on average, retrieval follows an optimal path through semantic memory. Participants tended to list a sequence of semantically related animals (e.g., lion, tiger, puma) before switching to a semantically unrelated animal (e.g., whale). We found that the timing of these transitions to semantically unrelated animals was remarkably consistent with an optimal strategy for maximizing the overall rate of retrieval (i.e., the number of animals listed per unit time). Age did not affect an individual’s deviation from the optimal strategy given their general performance, suggesting that people adapt and continue to search memory optimally throughout their lives. We argue that this result is more likely due to compensating for a general slowing than a decline in executive functioning