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Abstract Background and Hypothesis Individuals with schizophrenia have less priors than controls, meaning they rely less upon their prior experiences to interpret the current stimuli. These differences in priors are expected to show as higher alternation rates in bistable perception tasks like the Structure-from-Motion (SfM) paradigm. In this paradigm, continuously moving dots in two dimensions are perceived subjectively as traveling along a three-dimensional sphere, which results in a direction of motion (left or right) that shifts approximately every few seconds. Study Design Here, we tested healthy controls, patients with schizophrenia, siblings of patients with schizophrenia, and patients with depression with both the intermittent and continuous variants of the SfM paradigm. Study Results In the intermittent variant of the SfM paradigm, depressive patients exhibited the lowest alternation rate, followed by unaffected controls. In contrast, patients with schizophrenia and their unaffected siblings displayed significantly higher alternation rates. In the continuous variant of the SfM paradigm, patients with schizophrenia showed the lowest mean percept durations, while there were no differences between the other three groups. Conclusions The intermittent SfM paradigm is a candidate endophenotype for schizophrenia. The aberrant processing in the patients may stem from alterations in adaptation and/or cross-inhibition mechanisms leading to changes in priors, as suggested by current models in the field. The intermittent SfM paradigm is, hence, a trait marker that offers the great opportunity to investigate perceptual abnormalities across the psychiatry spectrum, ranging from depression to psychosis.

More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ 42 ), tau, and phosphorylated tau (ptau 181 ) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau 181 , including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ 42 near GLIS1 on 1p32.3 ( β  = −0.059, P  = 2.08 × 10 −8 ) and within SERPINB1 on 6p25 ( β  = −0.025, P  = 1.72 × 10 −8 ) were also associated with AD risk ( GLIS1 : OR = 1.105, P  = 3.43 × 10 −2 ), disease progression ( GLIS1 : β  = 0.277, P  = 1.92 × 10 −2 ), and age at onset ( SERPINB1 : β  = 0.043, P  = 4.62 × 10 −3 ). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ 42 ( P  = 0.001 and P  = 0.009, respectively) and the INPP5D locus may affect ptau 181 levels (P  = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Patients with anorexia nervosa (AN) show impaired decision-making ability, but it is still unclear if this is a trait marker (i.e., being associated with AN at any stage of the disease) or a state parameter of the disease (i.e., being present only in acutely ill patients), and if it has endophenotypic characteristics. The aim of this study was to determine the endophenotypic, and state- or trait-associated nature of decision-making impairment in AN.BACKGROUNDPatients with anorexia nervosa (AN) show impaired decision-making ability, but it is still unclear if this is a trait marker (i.e., being associated with AN at any stage of the disease) or a state parameter of the disease (i.e., being present only in acutely ill patients), and if it has endophenotypic characteristics. The aim of this study was to determine the endophenotypic, and state- or trait-associated nature of decision-making impairment in AN.Ninety-one patients with acute AN (A-AN), 90 unaffected relatives (UR), 23 patients remitted from AN (R-AN), and 204 healthy controls (HC) carried out the Iowa gambling task (IGT). Prospective valence learning (PVL) model was employed to distinguish the cognitive dimensions underlying the decision-making process, that is, learning, consistency, feedback sensitivity, and loss aversion. IGT performance and decision-making dimensions were compared among groups to assess whether they had endophenotypic (i.e., being present in A-AN, UR, and R-AN, but not in HC) and/or trait-associated features (i.e., present in A-AN and R-AN but not in HC).METHODSNinety-one patients with acute AN (A-AN), 90 unaffected relatives (UR), 23 patients remitted from AN (R-AN), and 204 healthy controls (HC) carried out the Iowa gambling task (IGT). Prospective valence learning (PVL) model was employed to distinguish the cognitive dimensions underlying the decision-making process, that is, learning, consistency, feedback sensitivity, and loss aversion. IGT performance and decision-making dimensions were compared among groups to assess whether they had endophenotypic (i.e., being present in A-AN, UR, and R-AN, but not in HC) and/or trait-associated features (i.e., present in A-AN and R-AN but not in HC).Patients with A-AN had lower performance at the IGT (p < 0.01), while UR, R-AN, and HC had comparable results. PVL-feedback sensitivity was lower in patients with R-AN and A-AN than in HC (p < 0.01).RESULTSPatients with A-AN had lower performance at the IGT (p < 0.01), while UR, R-AN, and HC had comparable results. PVL-feedback sensitivity was lower in patients with R-AN and A-AN than in HC (p < 0.01).Alteration of decision-making ability did not show endophenotypic features. Impaired decision-making seems a state-associated characteristic of AN, resulting from the interplay between trait-associated low feedback sensitivity and state-associated features of the disease.CONCLUSIONSAlteration of decision-making ability did not show endophenotypic features. Impaired decision-making seems a state-associated characteristic of AN, resulting from the interplay between trait-associated low feedback sensitivity and state-associated features of the disease.

Oculomotor characteristics, including accuracy, timing, and sensorimotor processing, are considered sensitive intermediate phenotypes for understanding the etiology of neurodevelopmental conditions, such as autism and ADHD. Oculomotor characteristics have predominantly been studied separately in autism and ADHD. Despite the high rates of co-occurrence between these conditions, only one study has investigated oculomotor processes among those with co-occurring autism + ADHD. Four hundred and five ( n  = 405; 226 males) Australian children and adolescents aged 4 to 18 years (M = 9.64 years; SD  = 3.20 years) with ADHD ( n  = 64), autism ( n  = 66), autism + ADHD ( n  = 146), or neurotypical individuals ( n  = 129) were compared across four different oculomotor tasks: visually guided saccade, anti-saccade, sinusoidal pursuit and step-ramp pursuit. Confirmatory analyses were conducted using separate datasets acquired from the University of Nottingham UK ( n  = 17 autism, n  = 22 ADHD, n  = 32 autism + ADHD, n  = 30 neurotypical) and University of Kansas USA ( n  = 29 autism, n  = 41 neurotypical). Linear mixed effect models controlling for sex, age and family revealed that children and adolescents with autism + ADHD exhibited increased variability in the accuracy of the final saccadic eye position compared to neurotypical children and adolescents. Autistic children and adolescents demonstrated a greater number of catch-up saccades during step-ramp pursuit compared to neurotypical children and adolescents. These findings suggest that select differences in saccadic precision are unique to autistic individuals with co-occurring ADHD, indicating that measuring basic sensorimotor processes may be useful for parsing neurodevelopment and clinical heterogeneity in autism.

Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed. The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27). Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes. Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.

Characterizing neurocognitive endophenotypes of mental illnesses (MIs) could be useful for identifying at-risk individuals, increasing early diagnosis, improving disease subtyping, and proposing therapeutic strategies to reduce the negative effects of the symptoms, in addition to serving as a scientific basis to unravel the physiopathology of the disease. However, a standardized algorithm to determine cognitive endophenotypes has not yet been developed. The main objective of this study was to present a method for the identification of endophenotypes in MI research. For this purpose, a 14-expert working group used a scoping review methodology and designed a method that includes a scoring template with five criteria and indicators, a strategy for their verification, and a decision tree. This work is ongoing since it is necessary to obtain external validation of the applicability of the method in future research.

IntroductionA growing body of evidence in both chronic and first-episode schizophrenia report increased expression of pro-inflammatory substances in the blood and cerebrospinal fluid of patients. However, there is not much data in the literature on immune alterations in unaffected first-degree relatives (FDRs) of the patients.ObjectivesWe aimed to evaluate inflammatory aberrancies in patients with schizophrenia, their unaffected first-degree relatives (FDRs) and healthy controls.Methods50 chronic, stable schizophrenia patients, 42 FDRs and 40 healthy subjects with no family history (HCSs) were recruited to the study. IL-1β, IL-6, TNF-a and CRP levels were measured. Complete blood counts, fasting glucose and lipid levels were analyzed and neutrofil-lymohocyte ratio (NLR) were calculated.ResultsThere was a significant group difference in all cytokine levels after controlling for age, gender, smoking status, comorbid medical diseases, BMI and blood glucose and tyrigliseride levels (p<.001). FDRs showed significantly higher serum levels of cytokines than HCs, in the same way as the corresponding schizophrenia patients but a lower level. Pairwaise comparisions revealed that the differences were significant between each group after controlling for confounders (p<.001 for all comparisons). However, NLR and CRP levels were not different between groups.ConclusionsOur results support the role of inflammatory aberrancies in the pathophysiology of schizophrenia. The finding of abnormal cytokine levels both in schizophrenic patients and FDRs indicates that such immunological alterations are not exclusive to the patients and can be possible endophenotypes for the disorder.DisclosureNo significant relationships.

Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits. Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics. Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58). A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

Functional magnetic resonance imaging of brain responses to biological motion in children with autism spectrum disorder (ASD), unaffected siblings (US) of children with ASD, and typically developing (TD) children has revealed three types of neural signatures: (i) state activity, related to the state of having ASD that characterizes the nature of disruption in brain circuitry; (ii) trait activity, reflecting shared areas of dysfunction in US and children with ASD, thereby providing a promising neuroendophenotype to facilitate efforts to bridge genomic complexity and disorder heterogeneity; and (iii) compensatory activity, unique to US, suggesting a neural system—level mechanism by which US might compensate for an increased genetic risk for developing ASD. The distinct brain responses to biological motion exhibited by TD children and US are striking given the identical behavioral profile of these two groups. These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

Sex differences exist in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We examined brain proteomes profiled from the dorsolateral prefrontal cortex of 770 donors (66.2% female). Proteome-wide differential expression analysis in males and females jointly identified many significant proteins for AD dementia (n = 1228), amyloid beta (n = 1183), tangles (n = 1309), and global cognitive trajectory (n = 2325) at a false discovery rate of <0.05. Sex-stratified analyses also identified many proteins associated with AD or its endophenotypes. Finally, we found 10 proteins with significant sex-by-trait interactions, including one in AD clinical diagnosis (MARCKS), seven in cognitive trajectories (TOGARAM1, PLCD3, SLC22A5, MTFR1L, DCUN1D5, S100A12, and TRIM46), and two in cerebral pathologies (PANK4 and SOS1). The 10 proteins with sex interaction in AD cover a range of functions likely relevant for AD pathogenesis, including estrogen response, inflammation, and mitochondrial biology, and their specific roles in AD ought to be studied. Future work should test their potential as sex-specific AD biomarkers. At the phenotypic level, we found sex differences in baseline cognitive performance, cognitive trajectories, and AD hallmark pathologies. Proteome-wide differential expression analyses identified many brain proteins associated with AD and its endophenotypes in either sex alone or when considered together. We found 10 brain proteins with significant sex interactions in AD and its endophenotypes, which could be investigated as potential sex-specific biomarkers of AD.