Risk factors for developmental vulnerability: Insight from population-level surveillance using the Early Development Instrument.

Objectives: Population-level studies may elucidate the most promising intervention targets to prevent negative outcomes of developmental vulnerability in children. This study aims to bridge the current literature gap on identifying population-level developmental vulnerability risk factors using combined social and biological/health information. Methods: This study assessed developmental vulnerability among kindergarten children using the 2016 Early Development Instrument (EDI) and identified risk factors of developmental vulnerability using EDI data cross-linked to a population-wide administrative health dataset. A total number of 23,494 children aged 5-6 were included (48% female). Prenatal, neonatal, and early childhood risk factors for developmental vulnerability were investigated, highlighting the most important ones contributing to early development. Results: The main risk factors for developmental vulnerability were children with a history of mental health diagnosis (risk ratio = 1.46), biological sex-male (risk ratio = 1.51), and poor socioeconomic status (risk ratio = 1.58). Conclusion: Our study encompasses both social and health information in a populational-level representative sample of Alberta, Canada. The results confirm evidence established in other geographic regions and jurisdictions and demonstrate the association between perinatal risk factors and developmental vulnerability. Based on these results, we argue that the health system should adopt a multilevel prevention and intervention strategy, targeting individual, family, and community together.

Synchronous Web-Based Psychotherapy for Mental Disorders From a Health Quality Perspective: Scoping Review.

BACKGROUND: The COVID-19 pandemic necessitated rapid changes to health care delivery, including a shift from in-person to digitally delivered psychotherapy. While these changes helped ensure timely psychotherapy provision, many concerns exist, including clinical, cultural, practical, privacy, and security issues. OBJECTIVE: This scoping review systematically mapped existing peer-reviewed research on synchronous, therapist-delivered web-based psychotherapy for individuals with a diagnosed mental illness. Data were analyzed through the lens of the Alberta Quality Matrix for Health (AQMH) to assess to what degree this literature addresses key indicators of health care quality. This analysis aided in the identification and organization of knowledge gaps with regard to web-based psychotherapies, highlighting potential disparities between previously prioritized dimensions of care and those requiring further attention. METHODS: This review adhered to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines. We included peer-reviewed primary research studies in the English language investigating synchronous, therapist-delivered remote psychotherapy delivered to adults (aged 18 years and older) with a Diagnostic and Statistical Manual of Mental Disorders or International Statistical Classification of Diseases diagnosed mental illness. All other citations were excluded. Relevant studies were identified through MEDLINE, APA PsycINFO, Embase (OVID), Web of Science: Core Collection (Clarivate), Cochrane Library (Wiley), and Scopus (Elsevier) databases. Databases were searched on March 18, 2021. For every publication that was taken into consideration, the data were charted independently by 2 reviewers, and in the event of a discrepancy, the principal investigator validated the choice of either extractor. Results were thematically described according to the 6 AQMH dimensions: acceptability, accessibility, appropriateness, effectiveness, efficiency, and safety. RESULTS: From 13,209 publications, 48 articles were included, largely from North American studies. Most studies measured treatment effectiveness (n=48, 100%) and acceptability (n=29, 60%) health quality dimensions. Over 80% (40/48) of studies investigated either a cognitive or exposure intervention for either posttraumatic stress disorder or a mood or anxiety disorder, generally indicating comparable results to in-person therapy. Safety (n=5, 10%) was measured in fewer studies, while treatment accessibility, appropriateness, and efficiency were not explicitly measured in any study, although these dimensions were mentioned as a future direction, hypothesis, or potential outcome. CONCLUSIONS: In relation to web-based therapist-delivered psychotherapies for those with a diagnosed mental illness, important aspects of health care quality (accessibility, appropriateness, efficiency, and safety) have received little scientific examination, underscoring a need to address these gaps. There are also significant issues related to the generalizability of this literature, including the underrepresentation of many geographic regions, cultures, populations, clinical contexts, and psychotherapy modalities. Qualitative research in underrepresented populations and settings may uncover important patient and contextual factors important for the future implementation of quality web-based psychotherapy.

Associations between Differential Aging and Lifestyle, Environment, Current, and Future Health Conditions: Findings from Canadian Longitudinal Study on Aging.

INTRODUCTION: An aging population will bring a pressing challenge for the healthcare system. Insights into promoting healthy longevity can be gained by quantifying the biological aging process and understanding the roles of modifiable lifestyle and environmental factors, and chronic disease conditions. METHODS: We developed a biological age (BioAge) index by applying multiple state-of-art machine learning models based on easily accessible blood test data from the Canadian Longitudinal Study of Aging (CLSA). The BioAge gap, which is the difference between BioAge index and chronological age, was used to quantify the differential aging, i.e., the difference between biological and chronological age, of the CLSA participants. We further investigated the associations between the BioAge gap and lifestyle, environmental factors, and current and future health conditions. RESULTS: BioAge gap had strong associations with existing adverse health conditions (e.g., cancers, cardiovascular diseases, diabetes, and kidney diseases) and future disease onset (e.g., Parkinson's disease, diabetes, and kidney diseases). We identified that frequent consumption of processed meat, pork, beef, and chicken, poor outcomes in nutritional risk screening, cigarette smoking, exposure to passive smoking are associated with positive BioAge gap ("older" BioAge than expected). We also identified several modifiable factors, including eating fruits, legumes, vegetables, related to negative BioAge gap ("younger" BioAge than expected). CONCLUSIONS: Our study shows that a BioAge index based on easily accessible blood tests has the potential to quantify the differential biological aging process that can be associated with current and future adverse health events. The identified risk and protective factors for differential aging indicated by BioAge gap are informative for future research and guidelines to promote healthy longevity.

Individualized Prospective Prediction of Opioid Use Disorder.

OBJECTIVE: Opioid use disorder (OUD) is a chronic relapsing disorder with a problematic pattern of opioid use, affecting nearly 27 million people worldwide. Machine learning (ML)-based prediction of OUD may lead to early detection and intervention. However, most ML prediction studies were not based on representative data sources and prospective validations, limiting their potential to predict future new cases. In the current study, we aimed to develop and prospectively validate an ML model that could predict individual OUD cases based on representative large-scale health data. METHOD: We present an ensemble machine-learning model trained on a cross-linked Canadian administrative health data set from 2014 to 2018 (n = 699,164), with validation of model-predicted OUD cases on a hold-out sample from 2014 to 2018 (n = 174,791) and prospective prediction of OUD cases on a non-overlapping sample from 2019 (n = 316,039). We used administrative records of OUD diagnosis for each subject based on International Classification of Diseases (ICD) codes. RESULTS: With 6409 OUD cases in 2019 (mean [SD], 45.34 [14.28], 3400 males), our model prospectively predicted OUD cases at a high accuracy (balanced accuracy, 86%, sensitivity, 93%; specificity 79%). In accord with prior findings, the top risk factors for OUD in this model were opioid use indicators and a history of other substance use disorders. CONCLUSION: Our study presents an individualized prospective prediction of OUD cases by applying ML to large administrative health datasets. Such prospective predictions based on ML would be essential for potential future clinical applications in the early detection of OUD.

Systematic Review of Psychiatric Adverse Effects Induced by Chloroquine and Hydroxychloroquine: Case Reports and Population Studies.

OBJECTIVE: To perform a systematic review on the psychiatric adverse effects of chloroquine (CQ) and hydroxychloroquine (HCQ); to summarize what is known about psychiatric adverse effects of these drugs; to compare clinical trials, populational studies, and case report studies; and to increase awareness of the potential psychiatric adverse effects of these drugs. DATA SOURCES: A literature search of PubMed, Scopus, and Web of Science was performed to identify manuscripts published between December 1962 and June 2022. Search terms included CQ, HCQ, psychiatry, psychosis, depression, anxiety, bipolar disorder, delirium, and psychotic disorders. STUDY SELECTION AND DATA EXTRACTION: Relevant studies included reports of adverse effects after CQ or HCQ ingestion. DATA SYNTHESIS: The current literature presents evidence for a risk of short-term psychiatric adverse effects induced by either CQ or HCQ. However, the populational-level studies presented some limitations regarding the voluntary response in survey data, self-report adverse effects, and placebo group reporting similar symptoms to the case group. Thus, populational-level studies addressing the discussed limitations and the nature and extent of possible psychiatric adverse effects are needed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Most of the patients who developed such adverse effects did not report a family history of psychiatric disease. The frequency of psychiatric adverse effects depends on the patient's biological sex, age, and body mass index, but not on the drug dosage. CONCLUSIONS: Based on clinical trials and case reports, the current literature presents evidence for a risk of short-term psychiatric adverse effects induced by either drug.

Systems-Level Analysis of Genetic Variants Reveals Functional and Spatiotemporal Context in Treatment-resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) occurs in one-third of the patients, but the molecular determinants of poor antipsychotic response remain unclear. We compared genetic data of patients with TRS (n = 63) with non-TRS (n = 111) by polygenic risk scores (PRS) calculated by PRSice software using PGC2_SCZ (Psychiatric Genomics Consortium - Schizophrenia) data. TRS criteria followed the International Psychopharmacology Algorithm Project SCZ algorithm. Statistical clustering and functional enrichment analyses of genes harboring TRS-linked variants were performed. Individuals on the top three deciles of schizophrenia PRS distribution exhibited higher odds of being refractory to antipsychotics than those on the bottom three deciles. Clusters of interacting variant-harboring genes were identified among the association signals. They are upregulated in the dorsolateral prefrontal, orbitofrontal, temporal, and inferior parietal areas during adolescence and early adulthood. Similar gene modules were found using transcriptional data from the same brain regions in individuals with schizophrenia. Genes were enriched among markers of cortical interneurons and somatosensory pyramidal cells. Finally, the enrichment of the clustered genes in drug-response expression signatures revealed compounds that could be employed to identify novel antipsychotic targets. In conclusion, we identified variant-harboring genes that may predispose SCZ patients to poor antipsychotic response and found statistically enriched clusters which provided functional and spatiotemporal context for TRS, suggesting that genotypic variation may converge to biological alterations at the interplay between actin dynamics and synaptic organization.

A systematic scoping review of dissociation in borderline personality disorder and implications for research and clinical practice: Exploring the fog.

BACKGROUND: Borderline Personality Disorder (BPD) is frequently complicated by the presence of dissociative symptoms. Pathological dissociation is linked with earlier and more severe trauma exposure, emotional dysregulation and worse treatment outcomes in Posttraumatic Stress Disorder and Dissociative Disorders, with implications for BPD. OBJECTIVE: A systematic scoping review was conducted to assess the extent of current literature regarding the impact of dissociation on BPD and to identify knowledge gaps. METHODS: Four electronic databases (MEDLINE, APA PsycINFO, EMBASE, CINAHL Plus) were searched, and English peer-reviewed studies with adults with BPD were included, following Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) extension for scoping reviews (PRISMA-ScR) 2018 guidelines. RESULTS: Most of the 70 included studies were observational (98%) with first authors from Germany (59%). Overall, dissociation was associated with increased BPD symptom severity, self-harm and reduced psychotherapy treatment response; findings regarding suicide risk were mixed. Dissociation was associated with working memory and cognitive deficits, decreased pain perception, altered body ownership, no substance abuse or the abuse of sedative substances, increased fantasy proneness, personality fragmentation, fearful attachment, dream anxiety, perceived stress and altered stress responses, increased cumulative body mass index, decreased water consumption, several neurological correlates and changes in gene expression. CONCLUSION: BPD with significant dissociative symptoms may constitute a more severe and at-risk subgroup of BPD patients. However, there are significant research gaps and methodological issues in the area, including the possibility of unrecognized Dissociative Disorders in BPD study populations confounding results. Further studies are needed to better understand the impact of dissociation on BPD course and treatment, and to clarify the most appropriate assessment tools for clinical practice. In addition, interventional studies are needed to develop dissociation-specific BPD treatments to determine whether targeting dissociation in BPD can improve treatment outcomes.

Polyenvironmental and polygenic risk scores and the emergence of psychotic experiences in adolescents.

Psychotic experiences (PE) are forms of hallucinations and delusions neither reaching the intensity and functional impairment required to be regarded as full psychotic symptoms nor a psychotic disorder. Here we investigated the ability to predict PE using multiple models (regressions, mediation and moderation) using polygenic risk score for psychotic experiences (PE-PRS), polygenic risk score for schizophrenia (SCZ-PRS), and polyenvironmental risk score (PERS) in youth from a Brazilian sample. The scores were not able to predict outcome, either when both scores were combined (PERS + PE-PRS and PERS + SCZ-PRS) or separately. Our results show that there is no association between PE and PRS or PERS among adolescents in our Brazilian sample. The lack of association may be a result of the absence of better representativeness regarding genetic and environmental factors of our population.

Aging biological markers in a cohort of antipsychotic-naïve first-episode psychosis patients.

Schizophrenia is a severe and multifactorial disorder with an unknown causative pathophysiology. Abnormalities in neurodevelopmental and aging processes have been reported. Relative telomere length (RTL) and DNA methylation age (DMA), well-known biomarkers for estimating biological age, are both commonly altered in patients with schizophrenia compared to healthy controls. However, few studies investigated these aging biomarkers in first-episode psychosis (FEP) and in antipsychotic-naïve patients. To cover the existing gap regarding DMA and RTL in FEP and antipsychotic treatment, we aimed to verify whether those aging markers could be associated with psychosis and treatment response. Thus, we evaluated these measures in the blood of FEP antipsychotic-naïve patients and healthy controls (HC), as well as the response to antipsychotics after 10 weeks of treatment with risperidone. RTL was measured in 392 subjects, being 80 FEP and 312 HC using qPCR, while DMA was analyzed in a subset of 60 HC, 60 FEP patients (antipsychotic-naïve) and 59 FEP-10W (after treatment) using the "Multi-tissue Predictor"and the Infinium HumanMethylation450 BeadChip Kit. We observed diminished DMA and longer RTL in FEP patients before treatment compared to healthy controls, indicating a decelerated aging process in those patients. We found no statistical difference between responder and non-responder patients at baseline for both markers. An increased DMA was observed in patients after 10 weeks of treatment, however, after adjusting for blood cell composition, no significant association remained. Our findings indicate a decelerated aging process in the early phases of the disease.

Variability may limit the translation of neuroimaging findings comment on "Variability in the analysis of a single neuroimaging dataset by many teams".

Variability in fMRI data analysis from different research teams on the same data set makes the scientific findings of similar studies using fMRI less persuasive. We want to comment that this reproductivity issue is associated with the hypothesis testing paradigm, which can be potentially mitigated by a machine learning based predictive modeling approach. Furthermore, such an approach also opens new possibilities in detecting subtle spatial patterns across the brain and in estimating more useful individual effects in neurology and psychiatry.

LINE-1 hypomethylation is associated with poor risperidone response in a first episode of psychosis cohort.

Aim: We investigated the DNA methylation profile over LINE-1 in antipsychotic-naive, first-episode psychosis-patients (n = 69) before and after 2 months of risperidone treatment and in healthy controls (n = 62). Materials & methods: Patients were evaluated using standardized scales and classified as responders and nonresponders. DNA from blood was bisulfite converted and LINE-1 fragments were amplified and pyrosequencing was performed. Results: Lower LINE-1 methylation was observed in antipsychotic-naive first-episode psychosis patients than in healthy controls. Lower DNA methylation levels before treatment were associated with poor risperidone responses. A positive correlation was observed between LINE-1 methylation levels and positive symptoms response. Conclusion: Our study brings new insight regarding how epigenomic studies and clinical correlation studies can supplement psychosis treatment.

Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths.

BACKGROUND: Psychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time. METHODS: We selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n = 48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature. RESULTS: We identified 663 differentially methylated positions (DMPs) and 90 differentially methylated regions (DMRs) associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood; among these, we found a correlation between the DNA methylation and mRNA levels of RB1CC1 and a correlation between the CBCL and mRNA levels of KMT2E. Of the DMRs, three genes were differentially expressed: ASCL2, which is involved in neurogenesis; HLA-E, which is mapped to the MHC loci; and RPS6KB1, the gene expression of which was correlated with an increase in the CBCL between the time points. CONCLUSIONS: We observed that changes in DNA methylation and, consequently, in gene expression in the peripheral blood occurred concurrently with the emergence of dimensional psychopathology in youths. Therefore, epigenomic modulations might be involved in the regulation of an individual's development of psychopathology.

Genetic risk for Alzheimer's disease and functional brain connectivity in children and adolescents.

Research suggested accumulation of tau proteins might lead to the degeneration of functional networks. Studies investigating the impact of genetic risk for Alzheimer's disease (AD) on early brain connections might shed light on mechanisms leading to AD development later in life. Here, we aim to investigate whether the polygenic risk score for Alzheimer's disease (AD-PRS) influences the connectivity among regions susceptible to tau pathology during childhood and adolescence. Participants were youth, aged 6-14 years, and recruited in Porto Alegre (discovery sample, n = 332) and São Paulo (replication sample, n = 304), Brazil. Subjects underwent genotyping and 6-min resting state funcional magnetic resonance imaging. Connections between the local maxima of tau pathology networks were used as dependent variables. The AD-PRS was associated with the connectivity between the right precuneus and the right superior temporal gyrus (discovery sample: ß = 0.180, padjusted = 0.036; replication sample: ß = 0.202, p = 0.031). This connectivity was also associated with inhibitory control (ß = 0.157, padjusted = 0.035) and moderated the association between the AD-PRS and both immediate and delayed recall. These findings suggest the AD-PRS may affect brain connectivity in youth, which might impact memory performance and inhibitory control in early life.

Gene expression over the course of schizophrenia: from clinical high-risk for psychosis to chronic stages.

The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. We investigated 12 genes in 394 individuals (27 individuals with CHR, 70 antipsychotic-naive individuals with FEP, 157 CSZ patients, and 140 healthy controls (HCs)). For a subsample, genotype data were also available, and we extracted SNPs that were previously associated with the expression of selected genes in whole blood or brain tissue. We generated a mediation model in which a putative cause (SNP) is related to a presumed effect (disorder) via an intermediate variable (gene expression). MBP and NDEL1 were upregulated in FEP compared to all other groups; DGCR8 was downregulated in FEP compared to HC and CHR; DGCR2 was downregulated in CSZ compared to FEP and HCs; DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression; and UFD1 was upregulated in CSZ and CHR compared to FEP and HC. Our results indicated changes in gene expression profiles throughout the different clinical stages of SZ, reinforcing the need for staging approaches to better capture SZ heterogeneity.

Heterotypic trajectories of dimensional psychopathology across the lifespan: the case of youth-onset attention deficit/hyperactivity disorder.

BACKGROUND: Recent studies have demonstrated the existence of a distinct late-onset attention deficit/hyperactivity disorder (ADHD) trajectory. Our objective is to test if there are distinct ADHD trajectories regarding age of onset from childhood to adolescence and to compare clinical manifestations, cognitive functions and genetic risk for ADHD among distinct longitudinal groups. METHOD: Nine hundred and twenty four children and adolescents from the community participated in the study. We compared clinical, cognitive features and genetic risk among four groups of participants: (a) childhood-limited, (b) youth-onset, (c) childhood-onset with youth persistence, and (d) community comparisons without ADHD. Symptomatic and diagnostic assessments were performed using the Development and Well-Being Behavior Assessment, the Strengths and Difficulties Questionnaire, and the Child Behavior Checklist. Cognitive functions were measured using a battery of standardized tests. Genetic risk for ADHD was calculating using summary statistics from the Psychiatric Genomics Consortium. RESULTS: Half of the adolescents (52%) with ADHD had their symptom onset in adolescence. The impairment level of this group in adolescence is similar to the persistent group. Despite not having ADHD, the youth-onset group already presented in childhood more symptoms from other domains of psychopathology, higher shared variance in psychiatric symptomatology (p-factor), school impairment, and executive dysfunctions than community comparisons. Furthermore, the youth-onset group presented lower levels of genetic risk for ADHD compared to other cases. CONCLUSIONS: A significant proportion of adolescents with ADHD were youth-onset cases and presented similar impairment levels as those cases with early-onset ADHD. The presence of cognitive impairments and higher levels of clinical symptoms in the youth-onset group already at childhood speaks in favor of a heterotypic trajectory of psychopathology suggesting that youth-onset ADHD might be an artificial consequence of categorizing dimensional psychopathology into discrete diagnostic groups.

Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort.

In this study, we aimed to test if the schizophrenia (SCZ) polygenic risk score (PRS) was associated with clinical symptoms in (a) the first episode of psychosis pre-treatment (FEP), (b) at nine weeks after initiation of risperidone treatment (FEP-9W) and (c) with the response to risperidone. We performed a detailed clinical assessment of 60 FEP patients who were antipsychotic-naive and, again, after nine weeks of standardized treatment with risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS, we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered a p-value < 0.0014 (Bonferroni correction) as significant. First, we verified that the schizophrenia PRS was also able to distinguish cases from controls in this south-eastern Brazilian sample, with a similar variance explained to that seen in Northern European populations. In addition, within-cases analyses, we found that PRS is significantly correlated with baseline (pre-treatment) symptoms, as measured by lower clinical global assessment of functioning (-GAF), higher depressive symptoms and higher scores on a derived excitement factor. After standardized treatment for nine weeks, the correlation with GAF and the excitement factor disappeared while depressive symptoms became negatively associated with PRS. We conclude that drug (and other treatments) may confound attempts to understand the aetiological influence on symptomatology of polygenic risk scores. These results highlight the importance of studying schizophrenia, and other disorders, pre-treatment to understand the relationship between polygenic risk and phenotypic features.

Polygenic Risk Score for Alzheimer's Disease: Implications for Memory Performance and Hippocampal Volumes in Early Life.

OBJECTIVE: Alzheimer's disease is a heritable neurodegenerative disorder in which early-life precursors may manifest in cognition and brain structure. The authors evaluate this possibility by examining, in youths, associations among polygenic risk score for Alzheimer's disease, cognitive abilities, and hippocampal volume. METHOD: Participants were children 6-14 years of age in two Brazilian cities, constituting the discovery (N=364) and replication samples (N=352). As an additional replication, data from a Canadian sample (N=1,029), with distinct tasks, MRI protocol, and genetic risk, were included. Cognitive tests quantified memory and executive function. Reading and writing abilities were assessed by standardized tests. Hippocampal volumes were derived from the Multiple Automatically Generated Templates (MAGeT) multi-atlas segmentation brain algorithm. Genetic risk for Alzheimer's disease was quantified using summary statistics from the International Genomics of Alzheimer's Project. RESULTS: Analyses showed that for the Brazilian discovery sample, each one-unit increase in z-score for Alzheimer's polygenic risk score significantly predicted a 0.185 decrement in z-score for immediate recall and a 0.282 decrement for delayed recall. Findings were similar for the Brazilian replication sample (immediate and delayed recall, ß=-0.259 and ß=-0.232, both significant). Quantile regressions showed lower hippocampal volumes bilaterally for individuals with high polygenic risk scores. Associations fell short of significance for the Canadian sample. CONCLUSIONS: Genetic risk for Alzheimer's disease may affect early-life cognition and hippocampal volumes, as shown in two independent samples. These data support previous evidence that some forms of late-life dementia may represent developmental conditions with roots in childhood. This result may vary depending on a sample's genetic risk and may be specific to some types of memory tasks.

Accessing Gene Expression in Treatment-Resistant Schizophrenia.

Schizophrenia (SCZ) is a mental disorder arising from a complex interaction of genetic and environmental factors. It has been suggested that treatment-resistant schizophrenia (TRS) is a distinct, more severe, and homogenous subgroup of schizophrenia that could present specific biological markers. Our aim was to characterize expression of target genes in blood of TRS patients compared with non-TRS (NTRS) patients and healthy controls (HC). TRS has been defined using failure to respond to two previous antipsychotic trials. We hypothesized that genes involved in neurodevelopment, myelination, neuroplasticity, neurotransmission, and miRNA processing could be involved in treatment resistance; then, we investigated 13 genes related to those processes in 256 subjects, being 94 healthy controls and 162 schizophrenia patients treated with antipsychotics. Of those, 78 were TRS patients and 84 were NTRS patients. Peripheral blood samples were collected from all subjects and RNA was isolated. Gene expression analysis was performed using the TaqMan low-density array (TLDA) technology. To verify the influence of expression quantitative trait loci (eQTLs), we evaluated single-nucleotide polymorphism (SNP) of all genes using data from GTEx Project. SNP genotypes were obtained from HumanOmniExpress BeadChip. We did not detect gene expression differences between TRS and NTRS subjects, indicating candidate genes specific to treatment resistance. We detected an upregulation of CNR1 and UFD1L gene expression in patients (TRS and NTRS groups) when compared to controls, that may be associated with the release of neurotransmitters, which can influence neuronal plasticity, or with a stress response-activating protein degradation. DICER1 and AKT1 expression increased slightly across the groups and could differentiate only the extreme opposite groups, HC and TRS. Both genes act in heterogeneous pathways, such as cell signaling and miRNA processing, and seem to have an increased demand in the TRS group. We did not detect any eQTLs in our sample that could explain differences in mRNA levels, suggesting a possible regulation by other mechanism, not driven by genotypes. Our data strengthen the importance of several biological pathways involved in the schizophrenia refractoriness and severity, adding knowledge to develop more effective treatments in the future.

Gene expression analysis in blood of ultra-high risk subjects compared to first-episode of psychosis patients and controls.

OBJECTIVES: This study aimed to investigate peripheral blood gene expression in ultra-high-risk subjects (UHR) compared to first-episode psychosis individuals (FEP) and healthy controls (HC). METHODS: We enrolled 22 UHR, 66 FEP and 67 HC and investigated the expression of 12 genes using Taqman assays. We used the Univariate General Linear Model, as well as Bonferroni correction for multiple comparisons. RESULTS: We found that UFD1L (ubiquitin fusion degradation 1 like (yeast)) gene was upregulated in UHR group compared to HC and FEP (P = 3.44 × 10-6 ; P = 9.41 × 10-6). MBP (myelin basic protein) was downregulated in UHR compared to FEP (P = 6.07 × 10-6). DISC1 (disrupted in schizophrenia 1) was also upregulated in UHR compared to FEP but lost statistical significance when corrected for age. CONCLUSIONS: These genes are directly related to neurodevelopmental processes and have been associated to schizophrenia. Recent findings described that DISC1 overexpression can disrupt MBP expression, thus, we think that these alterations in UHR individuals could be associated with a common process. UFD1L showed a different pattern of expression only for UHR group, suggesting that they can be under an acute endoplasmatic reticulum stress, demanding elevated levels of Ufd1. Further studies can improve knowledge on disease progression and putative targets to preventive strategies.