Graphical analysis and simplified quantification of striatal and extrastriatal dopamine D2 receptor binding with [123I]epidepride SPECT.

The purpose of this study was to extend the graphical analysis of reversible tracer binding to account for labeled lipophilic metabolites (metabolites) in quantifying [123I]epidepride binding to striatal and extrastriatal D2 receptors and, additionally, to evaluate the feasibility of simplified analysis to measure the specific volume of distribution (V3') using single-sample blood data because the tissue ratio (RT) may be a less reliable measure of D2 binding in the presence of metabolites. METHODS: Multilinear regression analysis (MLRA) and graphical analysis (GA) using plasma parent (P) plus metabolite (M) activities as input and time activities of receptor-free (RF, cerebellum) and receptor-containing regions (RR, striatum and temporal cortex) derived V3' = (alpha(RR)(P) - alpha(RF)(P)), V3' = (1 + delta) (alpha(RR) - alpha(RF)) and RT = V3'/(V2P' + deltaV2M'), where alpha is a regression coefficient, delta is the equilibrium area ratio of M and P, and (V2P'/V2M') are the corresponding nondisplaceable distribution volumes. V3' by simplified analysis (SA) was calculated from RT determined without blood data and (V2P' + deltaV2M') with single-blood sample data. The accuracy of these three V3' values was assessed relative to the metabolite-accounted kinetic analysis (KA) for [123I]epidepride SPECT studies of 11 healthy volunteers, in which each participant had 27 scans and 30 plasma samples drawn during the 14 h after injection. RESULTS: All three V3' values (mL/g) significantly correlated with those by KA (r > or = 0.90) (striatum/temporal cortex: MLRA, 77.8 +/- 36.6/2.35 +/- 1.16; GA, 98.8 +/- 34.2/4.61 +/- 1.77; SA, 83.9 +/- 24.8/4.26 +/- 1.74; KA, 107.6 +/- 34.4/5.61 +/- 1.84). However, the correlation between RT and V3' was only moderate (r < or = 0.65) because of significant intersubject variability (23%) in (V2P' + deltaV2M'). CONCLUSION: The graphical analysis can be extended to account for metabolites in measuring D2 binding with [123I]epidepride SPECT for both high and low D2 density regions. Additionally, simplified V3' measurements with single blood sampling are feasible and may be a practical alternative to the tissue ratio RT because RT suffers as a measure of D2 binding from significant intersubject variability in the metabolite-contributed distribution volume of the nondisplaceable compartment.     

Functional connectivity and alterations in baseline brain state in humans

This work examines the influence of changes in baseline activity on the intrinsic functional connectivity fMRI (fc-fMRI) in humans. Baseline brain activity was altered by inducing anesthesia (sevoflurane end-tidal concentration 1%) in human volunteers and fc-fMRI maps between the pre-anesthetized and anesthetized conditions were compared across different brain networks. We particularly focused on low-level sensory areas (primary somatosensory, visual, and auditory cortices), the thalamus, and pain (insula), memory (hippocampus) circuits, and the default mode network (DMN), the latter three to examine higher-order brain regions. The results indicate that, while fc-fMRI patterns did not significantly differ (p < 0.005; 20-voxel cluster threshold) in sensory cortex and in the DMN between the pre- and anesthetized conditions, fc-fMRI in high-order cognitive regions (i.e. memory and pain circuits) was significantly altered by anesthesia. These findings provide further evidence that fc-fMRI reflects intrinsic brain properties, while also demonstrating that 0.5 MAC sevoflurane anesthesia preferentially modulates higher-order connections.     

Flower-bud formation in explants of photoperiodic and day-neutral Nicotiana biotypes and its bearing on the regulation of flower formation

The capacity to form flower buds in thin-layer explants was studied in flowering plants of several species, cultivars, and lines of Nicotiana differing in their response to photoperiod. This capacity was found in all biotypes examined and could extend into sepals and corolla. It varied greatly, depending on genotype, source tissue and its developmental stage, and composition of the culture medium, particularly the levels of glucose, auxin, and cytokinin. It was greatest in the two day-neutral plants examined, Samsun tobacco and Nicotiana rustica, where it extended from the inflorescence region down the vegetative stem, in a basipetally decreasing gradient; it was least in the two qualitative photoperiodic plants studied, the long-day plant Nicotiana silvestris and the short-day plant Maryland Mammoth tobacco, the quantitative long-day plant Nicotiana alata and the quantitative short-day plant Nicotiana otophora line 38-G-81, where it was limited to the pedicels (and, in some cases, the sepals). Regardless of the photoperiodic response of the source plants, the response was the same in explants cultured under long and short days. The finding that capacity to form flower buds in explants is present in all Nicotiana biotypes studied supports the idea that it is regulated by the same mechanism(s), regardless of the plant's photoperiodic character. However, the source plants were all in the flowering stage, and no flower-bud formation can be obtained in explants from strictly vegetative Nicotiana plants. Hence, flower formation in the explants is not identical with de novo flower formation in a hitherto vegetative plant: it is rather the expression of a floral state already established in the plant, although it can vary widely in extent and spatial distribution. Culture conditions that permit flower-bud formation in an explant are conditions that maintain the floral state and encourage its expression; conditions under which no flower buds are formed reduce this state and/or prevent its expression.     

Genome‐wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome‐wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome‐wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition‐related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.     

Application of six IrisPlex SNPs and comparison of two eye color prediction systems in diverse Eurasia populations

DNA-based prediction for externally visible characteristics such as eye color is already a useful tool in forensic criminal investigations. The IrisPlex system, consisting of six single nucleotide polymorphisms (SNPs) and a prediction model, was developed based on individuals from several European populations. Other recent studies have developed a different prediction model, also based on European populations. In this study, we compared two prediction models using the data for the six IrisPlex SNPs genotyped on 905 individuals from 12 different Eurasian populations. All SNPs showed significant differences in allele frequencies among three groups of populations: European, genetically intermediate (Khanty, Uygur, and Yakut), and East Asian. The two prediction models, the FROG-kb calculation based on the formula of Walsh et al. (2011) and the Snipper calculation from Ruiz et al. (2013), gave identical predictions of brown eye color for the four East Asian populations with complete data but did not give concordant predictions for many individuals in the seven intermediate and European populations. Inconsistencies were mainly conclusive prediction by one model but not the other. Of the 714 individuals with complete 6-locus genotypes, the two models gave 22 % inconsistent predictions. Eliminating the 306 individuals in the Korean and three Chinese populations, in which the predictions were always consistent for brown eye color, the inconsistencies (among the remaining 408 individuals) were 38.7 %. We conclude that more attention should be paid to predictive uncertainty/error. Implementation of both prediction models in future forensic casework is one immediate way to highlight uncertainty.