Postoperative cognitive dysfunction POCD, serum anticholinergic activity and intraoperative cerebral perfusion in geriatric patients

Background: Inadequate intraoperative cerebral perfusion and increased serum anticholinergic activity (SAA) have been suggested as possible causes of postoperative cognitive dysfunction (POCD). Methods: 53 patients aged >65 yrs undergoing elective major surgical procedures under standardized general anaesthesia. Cerebral perfusion was monitored with transcranial Doppler and near-infrared spectroscopy. Mx, an index of cerebral autoregulation was calculated based on the correlation of spontaneous changes inmean arterial blood pressure (MAP) and cerebral blood flow velocity. Cognitive function was measured preoperatively and 7 days postoperatively using the CERAD-Neuropsychological Battery. A postoperative decline >1 z-score in at least 2 cognitive variables was defined as POCD. SAA was measured preoperatively and 7 days postoperatively (data available for 38 patients). CRP was measured at the same time points and 2 days postoperatively. Results: Age was 75_7 yrs (mean_SD). 23 patients (43%) developed POCD. There were no statistical significant differences between patients with POCD and without POCD in age (77_7 vs 73_6 yrs), MAP (74_12 vs 78_11 mmHg), cerebral tissue oxygenation indices (67_6 vs 69_4 %) SAA preoperatively (1.74_1.52 vs 1.74_1.21) and 7 days postoperatively (1.90_1.63 vs 1.84_1.39) and CRP preoperatively (32_72 vs 7_9), 2 days postoperatively (176_129 vs 111_69) and 7days postoperatively (53_43 vs 48_25). Patients with POCD had less efficient autoregulation than patients without POCD (Mx 0.55_0.15 vs 0.45_0.20, p = 0.046). However, the percentage of patients with clearly impaired autoregulation (ie, Mx>0.5) was statistically not different between groups (with POCD: 65%; without POCD: 38%; p = 0.06) but there seems to be a trend. Conclusions: Our data on the association between cerebral perfusion and POCD in elderly patients are inconclusive and more patients need to be investigated. In this small group of patients SAA seems not to be associated with POCD.

Translating cognitive neuroscience to fitness to drive using a neuroergonomic approach

Non-pathological or normal ageing is accompanied by brain alterations that are the result of natural changes occurring with age and our ability to compensate for them. Compared to younger adults, older adults have reduced vision, more difficulties in detecting relevant information they are not intending to and require more time to process sensorial information. Little is known on how these changes affect behaviour in a natural environment. Relying on a translational approach at the frontiers between neurobiology, psychophysics, neuropsychology and epidemiology, we were able to: explore the needs for innovative instrumentations to detect cerebral decline in clinical settings; develop and validate a new computed neuropsychological instrument designed to measure cerebral decline in healthy older adults; explore the link between processing speed and on-road driving performance; and investigate the effects of being able to anticipate on visual processing speed.

Detection of cognitive impairment with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in adolescents with psychotic symptomatology.

Cognitive impairment has been identified in the early phase of schizophrenia spectrum disorders, and is a major contributor to disease-related disability. While screening tools assessing cognitive impairment have been validated for adult schizophrenic populations, there is a need for brief, easily administered, standardized instruments that provide clinically relevant information for adolescents. This study examines the utility of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in identifying and quantifying neurocognitive impairment in adolescents with schizophrenia spectrum disorders and other serious psychiatric illnesses. 112 adolescents, including 32 healthy subjects and 80 patients, were administered the RBANS. Patients with psychotic disorders demonstrated significant impairment on the RBANS total score compared to patients with other disorders and healthy controls, but this impairment appeared somewhat less severe than is typically reported for in adult patients with schizophrenia on this measure. The RBANS appears to be sensitive in the detection of neurocognitive impairment in a psychiatric population of adolescents with psychotic symptomatology, and may therefore have utility as a clinical screening instrument and/or neurocognitive outcome measure in this population.

Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators.

Glutamate was previously shown to enhance aerobic glycolysis i.e. increase glucose utilization and lactate production with no change in oxygen levels, in mouse cortical astrocytes by a mechanism involving glutamate uptake. It is reported here that a similar response is produced in both hippocampal and cerebellar astrocytes. Application of the cognitive-enhancing drug CX546 promoted further enhancement of glucose utilization by astrocytes from each brain area following glutamate exposure. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent the purported molecular target of cognitive-enhancing drugs such as CX546, and the presence of AMPA receptor subunits GluR1-4 was evidenced in astrocytes from all three regions by immunocytochemistry. AMPA itself did not stimulate aerobic glycolysis, but in the presence of CX546, a strong enhancement of glucose utilization and lactate production was obtained in cortical, hippocampal and cerebellar astrocytes. The effect of CX546 was concentration-dependent, with an EC(50) of 93.2 microm in cortical astrocytes. AMPA-induced glucose utilization in the presence of CX546 was prevented by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the negative modulator GYKI 52466. In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide. Our data suggest that astrocyte energetics represents a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators.

Task-dependent influence of genetic architecture and mating frequency on division of labour in social insect societies.

Division of labour is one of the most prominent features of social insects. The efficient allocation of individuals to different tasks requires dynamic adjustment in response to environmental perturbations. Theoretical models suggest that the colony-level flexibility in responding to external changes and internal perturbation may depend on the within-colony genetic diversity, which is affected by the number of breeding individuals. However, these models have not considered the genetic architecture underlying the propensity of workers to perform the various tasks. Here, we investigated how both within-colony genetic variability (stemming from variation in the number of matings by queens) and the number of genes influencing the stimulus (threshold) for a given task at which workers begin to perform that task jointly influence task allocation efficiency. We used a numerical agent-based model to investigate the situation where workers had to perform either a regulatory task or a foraging task. One hundred generations of artificial selection in populations consisting of 500 colonies revealed that an increased number of matings always improved colony performance, whatever the number of loci encoding the thresholds of the regulatory and foraging tasks. However, the beneficial effect of additional matings was particularly important when the genetic architecture of queens comprised one or a few genes for the foraging task's threshold. By contrast, a higher number of genes encoding the foraging task reduced colony performance with the detrimental effect being stronger when queens had mated with several males. Finally, the number of genes encoding the threshold for the regulatory task only had a minor effect on colony performance. Overall, our numerical experiments support the importance of mating frequency on efficiency of division of labour and also reveal complex interactions between the number of matings and genetic architecture.

The fine-scale architecture of structural variants in 17 mouse genomes.

BACKGROUND: Accurate catalogs of structural variants (SVs) in mammalian genomes are necessary to elucidate the potential mechanisms that drive SV formation and to assess their functional impact. Next generation sequencing methods for SV detection are an advance on array-based methods, but are almost exclusively limited to four basic types: deletions, insertions, inversions and copy number gains. RESULTS: By visual inspection of 100 Mbp of genome to which next generation sequence data from 17 inbred mouse strains had been aligned, we identify and interpret 21 paired-end mapping patterns, which we validate by PCR. These paired-end mapping patterns reveal a greater diversity and complexity in SVs than previously recognized. In addition, Sanger-based sequence analysis of 4,176 breakpoints at 261 SV sites reveal additional complexity at approximately a quarter of structural variants analyzed. We find micro-deletions and micro-insertions at SV breakpoints, ranging from 1 to 107 bp, and SNPs that extend breakpoint micro-homology and may catalyze SV formation. CONCLUSIONS: An integrative approach using experimental analyses to train computational SV calling is essential for the accurate resolution of the architecture of SVs. We find considerable complexity in SV formation; about a quarter of SVs in the mouse are composed of a complex mixture of deletion, insertion, inversion and copy number gain. Computational methods can be adapted to identify most paired-end mapping patterns.

The cognitive errors and coping patterns of child molesters as assessed by external observers: a pilot study

Cognitive errors (CE) and coping strategies (CS) are the focus of most cognitive-behavioral treatments for incarcerated child molesters. Several studies have reported differences in CEs and CSs between child molesters and controls. However, the vast majority of these studies assessed cognitive errors and coping using questionnaires, which are known to present a number of important limitations. This pilot study aimed to compare the CEs and CSs of N = 17 incarcerated child abusers and N = 12 controls using observer-rated methods, namely the Cognitive Error Rating Scale (CERS; Drapeau et al., 2005) and the Coping Action Pattern Rating Scale (CAPRS; Perry, Drapeau, & Dunkley, 2005). Results showed that child molesters presented more cognitive errors, in particular positive selective abstraction, and lower coping functioning, such as escape strategies. Treatment and research implications, including the use of observer-rated methods, are discussed.

Change in cognitive errors and coping over the course of brief psychodynamic intervention.

OBJECTIVE: Cognitive change over the course of psychodynamic psychotherapy has been postulated by several models, but has rarely been studied. Based on the adaptive skills model (Badgio, Halperin, & Barber, 1999), it is reasonable to expect that very brief dynamic psychotherapy may be associated with change in coping patterns and cognitive errors (also known as cognitive distortions) y. METHOD: N = 50 outpatients presenting with various psychiatric disorders and undergoing 4 sessions of Brief Psychodynamic Intervention (BPI; Despland, Drapeau, & de Roten, 2005; Despland, Michel, & de Roten, 2010) were included in this naturalistic study (mean age: 31 years; 56% female; all Caucasian). Cognitive errors and coping strategies were assessed using the Cognitive Errors Rating Scale (Drapeau et al., 2008) and Coping Patterns Rating Scale (Perry et al., 2005). These observer rated methods were applied to the verbatim transcriptions of all 4 therapy sessions completed by each patient. RESULTS: Results indicate change in both cognitive errors and coping patterns over the course of BPI, including an increase in the Overall Coping Functioning and a decrease in unhelpful coping processes, such as isolation, which reflects a shift in participant appraisal towards stress appraised as a challenge at the end of treatment. These changes predicted symptom change at the end of treatment. While cognitive errors also changed over the course of BPI, no predictive effect was found with regard to symptom change. CONCLUSIONS: These results are interpreted within the framework of common change principles in psychotherapy. Implications and future research are discussed.

Demyelination in mild cognitive impairment suggests progression path to Alzheimer's disease.

The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.

The heterotetrameric architecture of the epithelial sodium channel (ENaC).

The epithelial sodium channel (ENaC) is a key element for the maintenance of sodium balance and the regulation of blood pressure. Three homologous ENaC subunits (alpha, beta and gamma) assemble to form a highly Na+-selective channel. However, the subunit stoichiometry of ENaC has not yet been solved. Quantitative analysis of cell surface expression of ENaC alpha, beta and gamma subunits shows that they assemble according to a fixed stoichiometry, with alpha ENaC as the most abundant subunit. Functional assays based on differential sensitivities to channel blockers elicited by mutations tagging each alpha, beta and gamma subunit are consistent with a four subunit stoichiometry composed of two alpha, one beta and one gamma. Expression of concatameric cDNA constructs made of different combinations of ENaC subunits confirmed the four subunit channel stoichiometry and showed that the arrangement of the subunits around the channel pore consists of two alpha subunits separated by beta and gamma subunits.

The shared allelic architecture of adiponectin levels and coronary artery disease.

OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.