RESUMEN
BACKGROUND: Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder overlap with regard to symptoms, structural and functional brain abnormalities, and genetic risk factors. Neurobiological pathways connecting genes to clinical phenotypes across the spectrum from schizophrenia to psychotic bipolar disorder remain largely unknown. METHODS: We examined the relationship between structural brain changes and risk alleles across the psychosis spectrum in the multi-site Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) cohort. Regional MRI brain volumes were examined in 389 subjects with a psychotic disorder (139 schizophrenia, 90 schizoaffective disorder, and 160 psychotic bipolar disorder) and 123 healthy controls. 451,701 single-nucleotide polymorphisms were screened and processed using parallel independent component analysis (para-ICA) to assess associations between genes and structural brain abnormalities in probands. RESULTS: 482 subjects were included after quality control (364 individuals with psychotic disorder and 118 healthy controls). Para-ICA identified four genetic components including several risk genes already known to contribute to schizophrenia and bipolar disorder and revealed three structural components that showed overlapping relationships with the disease risk genes across the three psychotic disorders. Functional ontologies representing these gene clusters included physiological pathways involved in brain development, synaptic transmission, and ion channel activity. CONCLUSIONS: Heritable brain structural findings such as reduced cortical thickness and surface area in probands across the psychosis spectrum were associated with somewhat distinct genes related to putative disease pathways implicated in psychotic disorders. This suggests that brain structural alterations might represent discrete psychosis intermediate phenotypes along common neurobiological pathways underlying disease expression across the psychosis spectrum.
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Encéfalo/patología , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Trastornos Psicóticos/genética , Trastornos Psicóticos/patología , Encéfalo/diagnóstico por imagen , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Trastornos Psicóticos/diagnóstico por imagenRESUMEN
BACKGROUND: Existing models of the pathophysiology of bipolar disorder posit disruption in neural circuits of emotion regulation and reward processing. However, few fMRI studies have compared regional brain activity and connectivity in different mood states in bipolar disorder to determine if manic symptomatology is reflected in specific circuit abnormalities. The purpose of this study was to test the hypothesis that bipolar mania is associated with altered connectivity between cortical regions thought to regulate subcortical structures such as the amygdala and striatum. METHODS: 28 subjects with bipolar disorder in a manic state, 24 different bipolar subjects in a euthymic state, and 23 matched healthy comparison subjects underwent resting state fMRI scans. Several cortical and sub-cortical structures implicated in the pathogenesis of bipolar disorder were selected for study. We conducted a whole-brain analysis of functional connectivity of these regions. RESULTS: Bipolar mania was differentiated from euthymia by decreased functional connectivity between the amygdala and anterior cingulate cortex (ACC). Mania was also characterized by increased connectivity between amygdala and dorsal frontal cortical structures that are normally anti-correlated in emotion regulation tasks. LIMITATIONS: Both groups of bipolar subjects were prescribed medications. The study was not longitudinal in design. CONCLUSIONS: Compared to bipolar subjects in a euthymic state, subjects in the manic state demonstrate disrupted functional connectivity between brain regions involved in the regulation of emotion and the amygdala. This disruption of activity in neural circuits involved in emotion may underlie the emotional dysregulation inherent to a bipolar manic episode.
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Amígdala del Cerebelo/fisiopatología , Trastorno Bipolar/fisiopatología , Lóbulo Frontal/fisiopatología , Imagen por Resonancia Magnética/métodos , Adulto , Trastorno Bipolar/psicología , Mapeo Encefálico/métodos , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects. METHODS: We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale. RESULTS: Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality. CONCLUSIONS: The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially.
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Trastorno Bipolar/patología , Cuerpo Calloso/patología , Fenotipo , Trastornos Psicóticos/patología , Esquizofrenia/patología , Adolescente , Adulto , Anciano , Envejecimiento/patología , Atrofia/patología , Trastorno Bipolar/psicología , Estudios de Casos y Controles , Cognición , Endofenotipos , Familia/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Trastornos Psicóticos/psicología , Esquizofrenia/diagnóstico , Adulto JovenRESUMEN
Patients with psychotic disorders appear to exhibit greater impulsivity-related behaviors relative to healthy controls. However, the neural underpinning of this impulsivity remains uncertain. Furthermore, it remains unclear how impulsivity might differ or be conserved between psychotic disorder diagnoses in mechanism and manifestation. In this study, self-reported impulsivity, measured by Barratt Impulsiveness Scale (BIS), was compared between 305 controls (HC), 139 patients with schizophrenia (SZ), 100 with schizoaffective disorder (SZA), and 125 with psychotic bipolar disorder (PBP). In each proband group, impulsivity was associated with regional cortical volumes (using FreeSurfer analysis of T1 MRI scans), suicide attempt history, Global Assessment of Functioning (GAF), and Social Functioning Scale (SFS). BIS scores were found to differ significantly between participant groups, with SZA and PBP exhibiting significantly higher impulsivity than SZ, which exhibited significantly higher impulsivity than HC. BIS scores were significantly related to suicide attempt history, and they were inversely associated with GAF, SFS, and bilateral orbitofrontal cortex (OFC) volume in both SZA and PBP, but not SZ. These findings indicate that psychotic disorders, particularly those with prominent affective symptoms, are characterized by elevated self-reported impulsivity measures. Impulsivity's correlations with suicide attempt history, GAF, and SFS suggest that impulsivity may be a mediator of clinical outcome. The observed impulsivity-OFC correlations corroborate the importance of OFC deficits in impulsivity. These correlations' presence in SZA and PBP but not in SZ suggests that impulsivity may have different underlying mechanisms in affective and non-affective psychotic disorders.
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Corteza Cerebral/patología , Conducta Impulsiva , Trastornos Psicóticos/patología , Trastornos Psicóticos/psicología , Intento de Suicidio/psicología , Adulto , Trastorno Bipolar/patología , Trastorno Bipolar/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Escalas de Valoración Psiquiátrica , Esquizofrenia/patología , Psicología del Esquizofrénico , AutoinformeRESUMEN
Schizophrenia (SZ) is a heterogeneous disorder that presents in adolescence, persists into adulthood, and has many clinical features. Recent evidence suggests that abnormalities in inflammatory, neurotrophic, and angiogenic processes may play a role in the etiology of SZ. The identification of molecular biomarkers early in the course of disease is crucial to transforming diagnostic and therapeutic avenues. We investigated 14 molecular analytes focusing on inflammatory, neurotrophic and angiogenic pathways from the plasma of antipsychotic-naïve familial high risk for SZ (FHR; n=35) and first-episode psychosis (FEP; n=45) subjects, in comparison to healthy controls (HC, n=39). We identified distinct alterations in molecular signatures in young relatives at FHR for SZ prior to psychosis onset and FEP subjects. Firstly, the expression of soluble fms-like tyrosine kinase (sFlt-1), an anti-angiogenic factor that binds vascular endothelial growth factor (VEGF), was significantly increased in the FHR group compared to HC, but not in FEP. Secondly, interferon gamma (IFNγ) was significantly reduced in the FEP group compared to HC. Thirdly, network analysis revealed a positive correlation between sFlt-1 and VEGF, suggesting an activation of the angiogenic cascade in the FHR group, which persists in FEP. Our results indicate an angiogenesis and immunological dysfunction early in the course of disease, shifting the balance towards anti-angiogenesis and inflammation.
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Predisposición Genética a la Enfermedad , Interferón gamma/sangre , Trastornos Psicóticos/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Enfermedad Aguda , Adolescente , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Familia , Femenino , Humanos , Interleucina-10/sangre , Masculino , Síntomas Prodrómicos , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
INTRODUCTION: Elevated prevalence of comorbid cardio-vascular and metabolic dysfunction (CMD) is consistently reported in patients with severe psychotic disorders such as schizophrenia (SZ), schizoaffective (SZA) and bipolar disorder (BP-P). Since both psychosis and CMD are substantively heritable in nature, we attempted to investigate the occurrence of CMD disorders in first-degree relatives of probands with psychosis. METHODS: Our sample included 861 probands with a diagnosis of SZ (n=354), SZA (n=212) and BP-P (n=295), 776 first-degree relatives of probands and 416 healthy controls. Logistic regression was used to compare prevalence of any CMD disorders (diabetes, hypertension, hyperlipidemia or coronary artery disease) across groups. Post hoc tests of independence checked for CMD prevalence across psychosis diagnosis (SZ, SZA and BP-P), both in relatives of probands and within probands themselves. RESULTS: After controlling for potential confounders, first-degree relatives with (p<0.001) and without (p=0.03) Axis I non-psychotic or Axis- II cluster disorders were at a significant risk for CMD compared to controls. No significant difference (p=0.42) was observed in prevalence of CMD between relatives of SZ, SZA and BP-P, or between psychosis diagnoses for probands (p=0.25). DISCUSSION: Prevalence of CMD was increased in the first-degree relatives of psychosis subjects. This finding suggests the possibility of overlapping genetic contributions to CMD and psychosis. Increased somatic disease burden in relatives of psychotic disorder probands points to need for early detection and preventive efforts in this population.
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Enfermedades Cardiovasculares , Familia , Enfermedades Metabólicas , Trastornos Psicóticos/complicaciones , Adolescente , Adulto , Anciano , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/genética , Femenino , Humanos , Modelos Logísticos , Masculino , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/genética , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Trastornos Psicóticos/clasificación , Adulto JovenRESUMEN
INTRODUCTION: Structural alterations may correlate with symptom severity in psychotic disorders, but the existing literature on this issue is heterogeneous. In addition, it is not known how cortical thickness and cortical surface area correlate with symptom dimensions of psychosis. METHODS: Subjects included 455 individuals with schizophrenia, schizoaffective, or bipolar I disorders. Data were obtained as part of the Bipolar Schizophrenia Network for Intermediate Phenotypes study. Diagnosis was made through the Structured Clinical Interview for DSM-IV. Positive and negative symptom subscales were assessed using the Positive and Negative Syndrome Scale. Structural brain measurements were extracted from T1-weight structural MRIs using FreeSurfer v5.1 and were correlated with symptom subscales using partial correlations. Exploratory factor analysis was also used to identify factors among those regions correlating with symptom subscales. RESULTS: The positive symptom subscale correlated inversely with gray matter volume (GMV) and cortical thickness in frontal and temporal regions, whereas the negative symptom subscale correlated inversely with right frontal cortical surface area. Among regions correlating with the positive subscale, factor analysis identified four factors, including a temporal cortical thickness factor and frontal GMV factor. Among regions correlating with the negative subscale, factor analysis identified a frontal GMV-cortical surface area factor. There was no significant diagnosis by structure interactions with symptom severity. CONCLUSIONS: Structural measures correlate with positive and negative symptom severity in psychotic disorders. Cortical thickness demonstrated more associations with psychopathology than cortical surface area.
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Trastorno Bipolar/patología , Lóbulo Frontal/patología , Sustancia Gris/patología , Trastornos Psicóticos/patología , Esquizofrenia/patología , Psicología del Esquizofrénico , Lóbulo Temporal/patología , Adulto , Trastorno Bipolar/psicología , Encéfalo/patología , Análisis Factorial , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Trastornos Psicóticos/psicología , Adulto JovenRESUMEN
BACKGROUND: Psychotic disorders are characterized by aberrant neural connectivity. Alterations in gyrification, the pattern and degree of cortical folding, may be related to the early development of connectivity. Past gyrification studies have relatively small sample sizes, yield mixed results for schizophrenia, and are scant for psychotic bipolar and schizoaffective (SZA) disorders and for relatives of these conditions. Here, we examine gyrification in psychotic disorder patients and their first-degree relatives as a possible endophenotype. METHODS: Regional local gyrification index (LGI) values, as measured by FreeSurfer software, were compared between 243 control subjects, 388 psychotic disorder probands, and 300 of their first-degree relatives. For patients, LGI values were examined grouped across psychotic diagnoses and then separately for schizophrenia, SZA, and bipolar disorder. Familiality (heritability) values and correlations with clinical measures were also calculated for regional LGI values. RESULTS: Probands exhibited significant hypogyria compared with control subjects in three brain regions and relatives with Axis II cluster A disorders showed nearly significant hypogyria in these same regions. Local gyrification index values in these locations were significantly heritable and uncorrelated with any clinical measure. Observations of significant hypogyria were most widespread in SZA. CONCLUSIONS: Psychotic disorders appear to be characterized by significant regionally localized hypogyria, particularly in cingulate cortex. This abnormality may be a structural endophenotype marking risk for psychotic illness and it may help elucidate etiological underpinnings of psychotic disorders.
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Corteza Cerebral/patología , Trastornos Psicóticos/patología , Adulto , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Endofenotipos , Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Psicóticos/genética , Esquizofrenia/genética , Esquizofrenia/patologíaRESUMEN
Suicide represents a major health problem world-wide. Nevertheless, the understanding of the neurobiological underpinnings of suicidal behavior remains far from complete. We compared suicide attempters to non-attempters, and high vs. low lethality attempters, to identify brain regions associated with suicidal behavior in patients with psychotic disorders. 489 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I and 262 healthy controls enrolled in the B-SNIP study were studied. Groups were compared by attempt history and the highest medical lethality of previous suicide attempts. 97 patients had a history of a high lethality attempt, 51 of a low lethality attempt and 341 had no attempt history. Gray matter volumes were obtained from 3T structural MRI scans using FreeSurfer. ANCOVAs were used to examine differences between groups, followed by Hochberg multiple comparison correction. Compared to non-attempters, attempters had significantly less gray matter volume in bilateral inferior temporal and superior temporal cortices, left superior parietal, thalamus and supramarginal regions, right insula, superior frontal and rostral middle frontal regions. Among attempters, a history of high lethality attempts was associated with significantly smaller volumes in the left lingual gyrus and right cuneus. Compared to non-attempters, low lethality attempters had significant decreases in the left supramarginal gyrus, thalamus and the right insula. Structural brain abnormalities may distinguish suicide attempters from non-attempters and high from low lethality attempters among individuals with psychotic disorders. Regions in which differences were observed are part of neural circuitries that mediate inhibition, impulsivity and emotion, visceral, visual and auditory perception.
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Encéfalo/patología , Trastornos Psicóticos/patología , Trastornos Psicóticos/psicología , Suicidio/psicología , Adulto , Trastorno Bipolar/patología , Trastorno Bipolar/psicología , Trastornos del Conocimiento/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Trastornos Psicóticos/complicaciones , Esquizofrenia/patología , Psicología del Esquizofrénico , Suicidio/clasificaciónRESUMEN
BACKGROUND: Proton magnetic resonance spectroscopy ((1)H MRS) enables in-vivo measurement of several relevant brain metabolites and has provided evidence of a range of neurochemical abnormalities in schizophrenia, especially in glutamate and N-acetyl-aspartate (NAA). While individuals at high familial risk for schizophrenia (HR) exhibit some neurobiological findings observed in the disorder, (1)H MRS findings and their clinical correlates are not well characterized in this population. METHODS: We compared 23 adolescent and young adult offspring of schizophrenia patients with 24 age- and sex-matched healthy controls using (1)H MRS. We acquired multi-voxel, short TE (1)H MRS measurements at 1.5T and obtained metabolite concentrations of N-acetyl-aspartate (NAA), combined glutamate and glutamine (Glu+Gln) and choline-containing compounds (GPC+PC) for the left and right thalamus, anterior cingulate gyrus, and caudate. We also assessed the relationship between regional metabolite levels, clinical measures and brain volume in a subset of 16 high-risk and 15 control subjects. RESULTS: Compared to healthy controls, high-risk subjects showed reductions in NAA levels in all three regions (thalamus, caudate, and anterior cingulate cortex), increases in Glu+Gln in the thalamus and caudate, and increases in GPC+PC in the anterior cingulate. In HR, thalamic Glu+Gln concentration was positively correlated and thalamic NAA inversely correlated with measures of schizotypy. Anterior cingulate GPC+PC and caudate Glu+Gln were significantly correlated with attenuated psychotic symptom severity. Anterior cingulate NAA was correlated with executive function. CONCLUSIONS: Our data suggest the occurrence of metabolic alterations in young relatives of schizophrenia patients similar to those seen in patients with established illness. The observed correlations with cognitive deficits and psychosis-related psychopathology suggest that these metabolic measures may have value as biomarkers of risk for schizophrenia.