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Structural neuroimaging studies have identified a combination of shared and disorder-specific patterns of gray matter (GM) deficits across psychiatric disorders. Pooling large data allows for examination of a possible common neuroanatomical basis that may identify a certain vulnerability for mental illness. Large-scale collaborative research is already facilitated by data repositories, institutionally supported databases, and data archives. However, these data-sharing methodologies can suffer from significant barriers. Federated approaches augment these approaches by enabling access or more sophisticated, shareable and scaled-up analyses of large-scale data. We examined GM alterations using Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation, an open-source, decentralized analysis application. Through federated analysis of eight sites, we identified significant overlap in the GM patterns (n = 4,102) of individuals with schizophrenia, major depressive disorder, and autism spectrum disorder. These results show cortical and subcortical regions that may indicate a shared vulnerability to psychiatric disorders.
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OBJECTIVES: The rate of mental health services provided to children and young people is increasing worldwide, including in Australia. The aim of this study was to describe patterns of hospital and ambulatory mental health service use among a large population cohort of adolescents followed from birth, with consideration of variation by age, sex and diagnosis. METHODS: Characteristics of services provided for children with mental disorder diagnoses between birth and age 17.5 years were ascertained for a population cohort of 85,642 children (52.0% male) born between 2002 and 2005, from 'Admitted Patients', 'Emergency Department' and 'Mental Health Ambulatory' records provided by the New South Wales and Australian Capital Territory Health Departments. RESULTS: A total of 11,205 (~13.1%) children received at least one hospital or ambulatory health occasion of service for a mental health condition in the observation period. More than two-fifths of children with mental disorders had diagnoses spanning multiple categories of disorder over time. Ambulatory services were the most heavily used and the most common point of first contact. The rate of mental health service contact increased with age across all services, and for most categories of mental disorder. Girls were more likely to receive services for mental disorders than boys, but boys generally had an earlier age of first service contact. Finally, 3.1% of children presenting to mental health services experienced involuntary psychiatric inpatient admission. CONCLUSIONS: The extent of hospital and ambulatory-based mental healthcare service among children emphasises the need for primary prevention and early intervention.
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Desarrollo Infantil , Humanos , Niño , Femenino , Masculino , Adolescente , Nueva Gales del Sur/epidemiología , Preescolar , Estudios de CohortesRESUMEN
The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.
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Estudio de Asociación del Genoma Completo , Cabeza , Neoplasias , Humanos , Cabeza/anatomía & histología , Neoplasias/genética , Neoplasias/patología , Femenino , Masculino , Polimorfismo de Nucleótido Simple/genética , Variación Genética , Tamaño de los Órganos/genética , Transducción de Señal/genética , Adulto , Predisposición Genética a la EnfermedadRESUMEN
Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.
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Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.
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Conectoma , Imagen por Resonancia Magnética , Esquizofrenia , Humanos , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Conectoma/métodos , Adulto , Femenino , Masculino , Imagen por Resonancia Magnética/métodos , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Persona de Mediana Edad , Vías Nerviosas/fisiopatología , Vías Nerviosas/patología , Adulto JovenRESUMEN
IMPORTANCE: There are currently 55 million adults living with declining functional cognition-altered perception, thoughts, mood, or behavior-as the result of Alzheimer's disease (AD) and related neurocognitive disorders (NCDs). These changes affect functional performance and meaningful engagement in occupations. Given the growth in demand for services, occupational therapy practitioners benefit from consolidated evidence of effective interventions to support adults living with AD and related NCDs and their care partners. OBJECTIVE: These Practice Guidelines outline effective occupational therapy interventions for adults living with AD and related NCDs and interventions to support their care partners. METHOD: We synthesized the clinical recommendations from a review of recent systematic reviews. RESULTS: Twelve systematic reviews published between 2018 and 2021 served as the foundation for the practice recommendations. CONCLUSION AND RECOMMENDATIONS: Reminiscence, exercise, nonpharmacological behavioral interventions, cognitive therapy, sensory interventions, and care partner education and training were found to be most effective to support adults living with AD and related NCDs. Plain-Language Summary: These Practice Guidelines provide strong and moderate evidence for occupational therapy practitioners to support adults living with Alzheimer's disease (AD) and related neurocognitive disorders (NCDs) and their care partners. They provide specific guidance for addressing the decline in cognition, behavioral and psychological symptoms of dementia, and pain experience of adults living with AD and related NCDs. The guidelines also describe interventions to support care partners. With support from the evidence, occupational therapy practitioners are better equipped to address the unique needs of adults living with AD and related NCDs and their care partners.
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Enfermedad de Alzheimer , Terapia Ocupacional , Adulto , Humanos , Actividades Cotidianas , Trastornos Neurocognitivos , MemoriaRESUMEN
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
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Background: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome. Methods: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale. Results: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10-5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10-7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10-4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control. Conclusions: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.
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There is an established need to translate evidence-based practices into real-world practice. Community pharmacists and their corresponding pharmacies are well-positioned to be effective partners as researchers seek to study and implement practice-based research. Challenges exist when partnering with community pharmacies which can vary based on the study type, the nature of the community pharmacy, and stakeholder groups (i.e., patients, staff, leadership, physicians). This commentary seeks to describe these challenges and provide recommendations that can help mitigate and/or overcome these challenges. Recommendations are provided for team structure, communication, research tools/technology, motivational factors, workflow, and sustainability. These recommendations are based on the authors' experience in partnering with community pharmacy for opioid-related research in a variety of study types, states, and pharmacy environments.
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Servicios Comunitarios de Farmacia , Farmacias , Médicos , Humanos , Analgésicos Opioides/uso terapéutico , FarmacéuticosRESUMEN
The relationship between childhood maltreatment and subsequent offending/victimization is well established. However, the magnitude of this relationship for different levels of child protection services (CPS) involvement is poorly understood, due to measurement issues, lack of longitudinal data, and reliance on reports of substantiated maltreatment, which can underestimate the impact of maltreatment. This study examined associations between CPS involvement during childhood (ages 0 to <11 years) and police services contact (as a victim and/or a person of interest) for criminal incidents in early adolescence (11 to ~14 years), differentiated according to levels of CPS involvement (i.e., no risk of significant harm [non-ROSH], unsubstantiated ROSH, substantiated ROSH, and out-of-home care; each examined relative to no CPS contact). Data for 71,465 children were drawn from the New South Wales Child Development Study, an intergenerational, longitudinal investigation that uses administrative records from CPS and police alongside other health, justice, and education data. Multinomial regression analyses were conducted to determine associations between increasing levels of CPS involvement and police contact as a victim only, a person of interest only, and as both victim and person of interest while accounting for covariates (i.e., child's sex, Aboriginal, and/or Torres Strait Islander background, socioeconomic status, maternal age at child's birth, and parental offending history). Children exposed to any of the four levels of CPS involvement had higher odds of police contact, relative to children with no CPS involvement. Odds ratios were higher for contact with police as both a victim and a person of interest, compared to police contact as a victim or a person of interest only. These findings highlight that children with even unsubstantiated CPS reports (i.e., non-ROSH and unsubstantiated ROSH reports) are at heightened risk of police contact compared to children who are unknown to CPS, underlining the need to support all families in contact with CPS.
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Maltrato a los Niños , Servicios de Protección Infantil , Víctimas de Crimen , Policia , Humanos , Servicios de Protección Infantil/estadística & datos numéricos , Niño , Masculino , Femenino , Adolescente , Víctimas de Crimen/estadística & datos numéricos , Víctimas de Crimen/psicología , Maltrato a los Niños/estadística & datos numéricos , Preescolar , Estudios Longitudinales , Lactante , Nueva Gales del SurRESUMEN
BACKGROUND: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. METHODS: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined. RESULTS: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure. CONCLUSIONS: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.
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Experiencias Adversas de la Infancia , Pruebas Psicológicas , Trastorno de la Personalidad Esquizotípica , Autoinforme , Adulto , Masculino , Femenino , Humanos , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Trastorno de la Personalidad Esquizotípica/diagnóstico por imagen , Trastorno de la Personalidad Esquizotípica/psicología , Encéfalo/diagnóstico por imagen , Sustancia Gris , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND AND HYPOTHESIS: Schizotypy provides a framework for understanding the developmental nature of psychotic disorders and a means of identifying "at-risk" individuals early in the lifespan. However, there is a lack of prospective longitudinal research examining the relationship between schizotypy in childhood and later psychotic and other mental disorders. We hypothesized that distinct profiles of schizotypy in childhood would be differentially associated with psychotic and other mental disorders emerging later in adolescence. STUDY DESIGN: In a large population cohort of Australian young people (n = 26 837), we prospectively examined the relationship between person-centered profiles of schizotypy identified in middle childhood (age ~11 years) and adolescent diagnoses (age ~13-18 years) across 7 types of mental disorders using multinomial logistic regression. RESULTS: Membership in any of 3 childhood schizotypy profiles (true schizotypy, affective schizotypy, or introverted schizotypy) was associated with an increased likelihood of being diagnosed with any type of mental disorder in adolescence; effects were strongest for the true schizotypy group (aOR = 3.07, 95% CI = 2.64, 3.57), followed by the introverted (aOR = 1.94, 95% CI = 1.75, 2.15) and affective (aOR = 1.29, 95% CI = 1.13, 1.47) schizotypy groups. Six of the 7 types of mental disorders measured (including psychotic disorders) were associated with at least 1 schizotypy group. CONCLUSIONS: Schizotypy in middle childhood is an important correlate of mental disorders in adolescence; however, it does not appear to be specifically associated with psychotic disorders in this age group.
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Trastornos Mentales , Trastornos Psicóticos , Trastorno de la Personalidad Esquizotípica , Niño , Adolescente , Humanos , Trastorno de la Personalidad Esquizotípica/diagnóstico , Australia/epidemiología , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/psicología , Trastornos Mentales/epidemiología , PersonalidadRESUMEN
Efforts to identify and prevent childhood exposure to physical violence within domestic and family relationships must be underpinned by reliable prevalence estimates to ensure the appropriate allocation of resources and benchmarks for assessing intervention efficacy. We conducted a systematic review and meta-analysis of the global prevalence of childhood exposure to physical domestic and family violence separately as a victim or witness. Searches were conducted in Criminal Justice Abstracts, Embase, Scopus, PubMed, PsychInfo, and Google Scholar. Studies were included if they were peer-reviewed, published in English, had a representative sample, unweighted estimates, and were published between January 2010 and December 2022. One-hundred-and-sixteen studies comprising 56 independent samples were retained. Proportional meta-analysis was conducted to calculate the pooled prevalence for each exposure. Pooled prevalence estimates were also stratified by region and sex. The global pooled prevalence of childhood exposure to physical domestic and family violence as a victim or witness was 17.3% and 16.5%, respectively. Prevalence estimates were highest in West Asia and Africa (victim = 42.8%; witness = 38.3%) and lowest for the Developed Asia Pacific region (victim = 3.7%; witness = 5.4%). Males were 25% more likely than females to be the victim of physical domestic and family violence during childhood, while both were equally likely to have witnessed it. These findings suggest that childhood exposure to domestic and family violence is relatively common, affecting around one-in-six people by 18 years of age globally. Regional variations in prevalence estimates may reflect underlying economic conditions, cultural norms, and service availability.
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Experiencias Adversas de la Infancia , Violencia Doméstica , Violencia de Pareja , Humanos , África , Relaciones Familiares , Abuso Físico , PrevalenciaRESUMEN
BACKGROUND: Unpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored. METHODS: We comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank. Epigenetic changes were investigated in association with cognitive status, age of onset, treatment resistance, Global Assessment of Functioning scores, and common variant polygenic risk scores for schizophrenia. We subsequently explored alterations within genes previously associated with psychiatric illness, phenome-wide epigenetic covariance, and epigenetic scores. RESULTS: Epigenome-wide association studies of the 5 primary traits identified 662 suggestively significant (p < 6.72 × 10-5) differentially methylated probes, with a further 432 revealed after controlling for schizophrenia polygenic risk on the remaining 4 traits. Interestingly, we uncovered many probes within genes associated with a variety of psychiatric conditions as well as significant epigenetic covariance with phenotypes and exposures including acute myocardial infarction, C-reactive protein, and lung cancer. Epigenetic scores for treatment-resistant schizophrenia strikingly exhibited association with clozapine administration, while epigenetic proxies of plasma protein expression, such as CCL17, MMP10, and PRG2, were associated with several features of schizophrenia. CONCLUSIONS: Our findings collectively provide novel evidence suggesting that several features of schizophrenia are associated with alteration of DNA methylation, which may contribute to interindividual phenotypic variation in affected individuals.
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Metilación de ADN , Esquizofrenia , Humanos , Esquizofrenia/genética , Australia , Epigénesis Genética , Epigenoma , Estudio de Asociación del Genoma CompletoRESUMEN
BACKGROUND: Air pollution has been linked to a variety of childhood mental health problems, but results are inconsistent across studies and the effect of exposure timing is unclear. We examined the associations between air pollution exposure at two time-points in early development and psychotic-like experiences (PLEs), and emotional and conduct symptoms, assessed in middle childhood (mean age 11.5 years). METHODS: Participants were 19,932 children selected from the NSW Child Development Study (NSW-CDS) with available linked multi-agency data from birth, and self-reported psychotic-like experiences (PLEs) and psychopathology at age 11-12 years (middle childhood). We used binomial logistic regression to examine associations between exposure to nitrogen dioxide (NO2) and particulate matter less than 2.5 µm (PM2.5) at two time-points (birth and middle childhood) and middle childhood PLEs, and emotional and conduct symptoms, with consideration of socioeconomic status and other potential confounding factors in adjusted models. RESULTS: In fully adjusted models, NO2 exposure in middle childhood was associated with concurrent PLEs (OR = 1.10, 95% CI = 1.02-1.20). Similar associations with PLEs were found for middle childhood exposure to PM2.5 (OR = 1.05, 95% CI = 1.01-1.09). Neither NO2 nor PM2.5 exposure was associated with emotional symptoms or conduct problems in this study. CONCLUSIONS: This study highlights the need for a better understanding of potential mechanisms of action of NO2 in the brain during childhood.
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Contaminantes Atmosféricos , Contaminación del Aire , Trastornos Mentales , Humanos , Niño , Contaminantes Atmosféricos/análisis , Dióxido de Nitrógeno/efectos adversos , Dióxido de Nitrógeno/análisis , Exposición a Riesgos Ambientales/efectos adversos , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Material Particulado/efectos adversos , Material Particulado/análisisRESUMEN
BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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Anomalías Múltiples , Deleción Cromosómica , Humanos , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Cromosomas Humanos Par 15 , Variaciones en el Número de Copia de ADNRESUMEN
Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3'-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016-1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology.
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Epigénesis Genética , Proteínas del Tejido Nervioso , Esquizofrenia , Sustancia Blanca , Humanos , Encéfalo/metabolismo , Estudios de Casos y Controles , Cognición , Imagen por Resonancia Magnética , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genética , Esquizofrenia/metabolismo , Sustancia Blanca/patología , Proteínas del Tejido Nervioso/genéticaRESUMEN
While RNA expression appears to be altered in several brain disorders, the constraints of postmortem analysis make it impractical for well-powered population studies and biomarker development. Given that the unique molecular composition of neurons are reflected in their extracellular vesicles (EVs), we hypothesized that the fractionation of neuron derived EVs provides an opportunity to specifically profile their encapsulated contents noninvasively from blood. To investigate this hypothesis, we determined miRNA expression in microtubule associated protein 1B (MAP1B)-enriched serum EVs derived from neurons from a large cohort of individuals with schizophrenia and nonpsychiatric comparison participants. We observed dysregulation of miRNA in schizophrenia subjects, in particular those with treatment-resistance and severe cognitive deficits. These data support the hypothesis that schizophrenia is associated with alterations in posttranscriptional regulation of synaptic gene expression and provides an example of the potential utility of tissue-specific EV analysis in brain disorders.
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Encefalopatías , Vesículas Extracelulares , MicroARNs , Esquizofrenia , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Neuronas/metabolismo , Vesículas Extracelulares/metabolismoRESUMEN
Assessment practices in Higher Education remain beholden to the twin pillars of neoliberal economic orthodoxy and White supremacy. The former has given rise to the modularization and commodification of education, wherein student performance is measured according to narrow and often meaningless metrics that foster and maintain ineffective assessment mechanisms. The latter imbues those metrics with a deference to, and valorization of, "Whiteness" as a marker of success, and this manifests in persistent awarding gaps across the sector. Critical Race Theory elucidates the ways in which the "banking model" of education and assessment is implicated in a history of colonial oppression that underpins contemporary experiences of marginalization for racially minoritized students. Furthermore, the rapid proliferation of Artificial Intelligence programs is now throwing into sharp relief the fact that traditional forms of assessment are no longer functional even on their own flawed terms. The authors argue that, at this critical juncture, Anti-Racist assessment, which not only exposes and problematizes racism itself but also embeds formative feedback, drafting, collaboration, and creativity into assessment practices, offers a practical solution that can reconceptualize 'academic excellence' and help to identify and support a different kind of 'good student', reshaping the employability agenda as a force for good and reclaiming the democratizing potential of Higher Education.