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1.
Am J Psychiatry ; : appiajp201919060583, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046535

RESUMO

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. METHODS: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female). RESULTS: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. CONCLUSIONS: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

2.
Mol Psychiatry ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358905

RESUMO

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

3.
Psychol Med ; 49(16): 2801-2807, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30636648

RESUMO

BACKGROUND: The Research Domain Criteria initiative was launched by the US National Institute of Mental Health to establish a multi-level framework for understanding psychological constructs relevant to human psychiatric disorders, and identified 'effort valuation/willingness to work' as a clinically useful construct worthy of further study. This construct encompasses the processes by which the cost(s) of obtaining an outcome are calculated, and the tendency to overcome response costs to obtain a reinforcer. The current study aims to examine effort valuation as a correlate of psychopathology in children and adults, and the moderating effects of sex on this relationship. METHODS: Participants were 1215 children aged 6-12 and their parents (n = 1044). All participants completed the Effort Expenditure for Rewards Task as a measure of effort expenditure. Child psychopathology was measured via the Child Behavior Checklist, while adult psychopathology was measured via the Adult Self Report. Additionally, the Social Adjustment Inventory for Children and Adolescents and Injury Behavior Checklist were used to examine child social impairments/problem behaviors. RESULTS: In children, significant interactions between reward sensitivity and sex were observed in association with anxiety and thought problems, specifically at low reward sensitivity levels. In adults, main effects of effort expenditure were seen in drug and alcohol abuse, where higher effort was associated with higher degrees of abuse. CONCLUSIONS: These results establish effort valuation as a relevant psychological construct for understanding psychopathology, but with different profiles of associated psychopathology across sex in children and adults.

4.
Psychol Med ; 49(11): 1914-1922, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30226117

RESUMO

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with high rates of psychiatric disorders, including schizophrenia in up to 30% of individuals with the syndrome. Despite this, we know relatively little about trajectories and predictors of persistence of psychiatric disorders from middle childhood to early adulthood. Accordingly, we followed youth over four timepoints, every 3 years, to assess long-term trajectories of attention-deficit hyperactivity disorder (ADHD), anxiety, mood, and psychosis-spectrum disorders (PSDs), as well as medication usage. METHODS: Eighty-seven youth with 22q11DS and 65 controls between the ages of 9 and 15 years at the first timepoint (T1; mean age 11.88 ± 2.1) were followed for 9 years (mean age of 21.22 ± 2.01 years at T4). Baseline cognitive, clinical, and familial predictors of persistence were identified for each class of psychiatric disorders. RESULTS: Baseline age and parent-rated hyperactivity scores predicted ADHD persistence [area under curve (AUC) = 0.81]. The presence of family conflict predicted persistence of anxiety disorders (ADs) whereas parent ratings of child internalizing symptoms predicted persistence of both anxiety and mood disorders (MDs) (AUC = 0.84 and 0.83, respectively). Baseline prodromal symptoms predicted persistent and emergent PSDs (AUC = 0.83). Parent-reported use of anti-depressants/anxiolytics increased significantly from T1 to T4. CONCLUSIONS: Psychiatric, behavioral, and cognitive functioning during late childhood and early adolescence successfully predicted children with 22q11DS who were at highest risk for persistent psychiatric illness in young adulthood. These findings emphasize the critical importance of early assessments and interventions in youth with 22q11DS.

5.
Neuroimage Clin ; 21: 101611, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30522971

RESUMO

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic, neurodevelopmental disorder characterized by a chromosomal deletion and a distinct cognitive profile. Although abnormalities in the macrostructure of the cortex have been identified in individuals with 22q11DS, it is not known if there are additional microstructural changes in gray matter regions in this syndrome, and/or if such microstructural changes are associated with cognitive functioning. METHODS: This study employed a novel diffusion MRI measure, the Heterogeneity of Fractional Anisotropy (HFA), to examine variability in the microstructural organization of the cortex in healthy young adults (N = 30) and those with 22q11DS (N = 56). Diffusion MRI, structural MRI, clinical and cognitive data were acquired. RESULTS: Compared to controls, individuals with 22q11DS evinced increased HFA in cortical association (p = .003, d = 0.86) and paralimbic (p < .0001, d = 1.2) brain areas, whereas no significant differences were found between the two groups in primary cortical brain areas. Additionally, increased HFA of the right paralimbic area was associated with poorer performance on tests of response inhibition, i.e., the Stroop Test (rho = -0.37 p = .005) and the Gordon Diagnostic System Vigilance Commission (rho = -0.41 p = .002) in the 22q11DS group. No significant correlations were found between HFA and cognitive abilities in the healthy control group. CONCLUSIONS: These findings suggest that cortical microstructural disorganization may be a neural correlate of response inhibition in individuals with 22q11DS. Given that the migration pattern of neural crest cells is disrupted at the time of early brain development in 22q11DS, we hypothesize that these neural alterations may be neurodevelopmental in origin, and reflect cortical dysfunction associated with cognitive deficits.


Assuntos
Síndrome da Deleção 22q11/patologia , Encéfalo/patologia , Substância Cinzenta/patologia , Síndrome da Deleção 22q11/diagnóstico por imagem , Síndrome da Deleção 22q11/psicologia , Adolescente , Adulto , Anisotropia , Encéfalo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Teste de Stroop , Adulto Jovem
6.
J Int Neuropsychol Soc ; 24(9): 905-916, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30375321

RESUMO

OBJECTIVE: While individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for a variety of functional impairments and psychiatric disorders, including psychosis, not all individuals with 22q11DS experience negative outcomes. Efforts to further understand which childhood variables best predict adult functional outcomes are needed, especially those that investigate childhood executive functioning abilities. METHODS: This longitudinal study followed 63 individuals with 22q11DS and 43 control participants over 9 years. Childhood executive functioning ability was assessed using both rater-based and performance-based measures and tested as predictors of young adult outcomes. RESULTS: Childhood global executive functioning abilities and parent report of child executive functioning abilities were the most consistent predictors of young adult outcomes. The study group moderated the relationship between child executive functioning and young adult outcomes for several outcomes such that the relationships were stronger in the 22q11DS sample. CONCLUSION: Rater-based and performance-based measures of childhood executive functioning abilities predicted young adult outcomes in individuals with and without 22q11DS. Executive functioning could be a valuable target for treatment in children with 22q11DS for improving not only childhood functioning but also adult outcomes. (JINS, 2018, 24, 905-916).

7.
Cortex ; 108: 67-79, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30130634

RESUMO

Chromosome 22q11.2 Deletion Syndrome (22q11DS) is a genetic syndrome characterized by a variety of cognitive impairments, including difficulty with attention. 22q11DS is the strongest known genetic risk factor for developing schizophrenia, a disorder characterized by impairments in visual attention and temporal binding processes. Here we examine a specific temporal visual attention phenomenon (the attentional blink; AB) within two rapid serial visual presentation tasks, and compare those with 22q11DS to groups of typically developing individuals matched on chronological (CA) and mental age (MA). Performance of individuals with 22q11DS was sensitive to differing task demands. On a Category Task, individuals with 22q11DS performed similarly to control groups on all measures of the AB, with the exception of lower detection accuracy of the first of two targets. In contrast, on a feature-based Color Task which required temporal binding of stimulus features, individuals with 22q11DS differed from CA and MA matched control groups on all AB performance measures, exhibiting lower target accuracy, more temporal binding errors, and a deeper, more protracted AB. Temporal binding in the visual domain is thought to be dependent on a serial attention mechanism that facilitates simultaneous firing of neurons in multiple areas of the visual cortex, activating short-term working memory for storage of bound features. Given the discrepancy between these two tasks, results suggest that temporal binding processes may be significantly affected in individuals with 22q11DS, a finding that importantly, has been previously demonstrated among individuals with schizophrenia.


Assuntos
Intermitência na Atenção Visual/fisiologia , Síndrome de DiGeorge/fisiopatologia , Percepção Visual/fisiologia , Adolescente , Atenção/fisiologia , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Adulto Jovem
8.
Mol Psychiatry ; 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29895892

RESUMO

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

9.
J Pediatr Psychol ; 43(6): 636-644, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29378061

RESUMO

Background: 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a variety of negative health, cognitive, emotional, and behavioral outcomes. 22q11DS is comorbid with many psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The current study aimed to investigate the cognitive, behavioral, and functional outcomes that a childhood ADHD diagnosis predicts to in adulthood. Methods: This longitudinal study followed 52 individuals with 22q11DS over 9 years. Childhood ADHD was operationalized both categorically (Diagnostic and statistical manual - 4th edition (DSM-IV) ADHD diagnoses) and dimensionally (inattentive and hyperactive-impulsive symptoms) and was tested as predictors of young adult outcomes. Results: As young adults, children with 22q11DS + baseline ADHD had more parent-reported executive dysfunction and lower levels of clinician-rated overall functioning than those with 22q11DS yet without ADHD. Dimensional symptoms of ADHD in childhood did not predict young adult outcomes. No self-report differences emerged between those with and without baseline ADHD. The majority (82.4%) of individuals with 22q11DS + baseline ADHD were never treated with an ADHD medication. Conclusions: A categorical diagnosis of ADHD in childhood predicted a greater variety of worse outcomes than dimensional levels of ADHD symptoms. Despite the significant impact of comorbid ADHD in 22q11DS, evidence-based treatment rates were low.


Assuntos
Síndrome da Deleção 22q11/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Síndrome da Deleção 22q11/diagnóstico , Síndrome da Deleção 22q11/epidemiologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Comorbidade , Progressão da Doença , Função Executiva , Feminino , Humanos , Estudos Longitudinais , Masculino , Prognóstico , Estados Unidos/epidemiologia , Adulto Jovem
10.
Behav Brain Funct ; 14(1): 2, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29352808

RESUMO

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental syndrome associated with deficits in cognitive and emotional processing. This syndrome represents one of the highest risk factors for the development of schizophrenia. Previous studies of functional connectivity (FC) in 22q11DS report aberrant connectivity patterns in large-scale networks that are associated with the development of psychotic symptoms. METHODS: In this study, we performed a functional connectivity analysis using the CONN toolbox to test for differential connectivity patterns between 54 individuals with 22q11DS and 30 healthy controls, between the ages of 17-25 years old. We mapped resting-state fMRI data onto 68 atlas-based regions of interest (ROIs) generated by the Desikan-Killany atlas in FreeSurfer, resulting in 2278 ROI-to-ROI connections for which we determined total linear temporal associations between each. Within the group with 22q11DS only, we further tested the association between prodromal symptoms of psychosis and FC. RESULTS: We observed that relative to controls, individuals with 22q11DS displayed increased FC in lobar networks involving the frontal-frontal, frontal-parietal, and frontal-occipital ROIs. In contrast, FC between ROIs in the parietal-temporal and occipital lobes was reduced in the 22q11DS group relative to healthy controls. Moreover, positive psychotic symptoms were positively associated with increased functional connections between the left precuneus and right superior frontal gyrus, as well as reduced functional connectivity between the bilateral pericalcarine. Positive symptoms were negatively associated with increased functional connectivity between the right pericalcarine and right postcentral gyrus. CONCLUSIONS: Our results suggest that functional organization may be altered in 22q11DS, leading to disruption in connectivity between frontal and other lobar substructures, and potentially increasing risk for prodromal psychosis.


Assuntos
Atlas como Assunto , Mapeamento Encefálico/métodos , Síndrome de DiGeorge/diagnóstico por imagem , Lobo Frontal/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Adolescente , Adulto , Síndrome de DiGeorge/genética , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Masculino , Adulto Jovem
11.
Neuroimage Clin ; 15: 832-842, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28761808

RESUMO

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental syndrome that has been studied intensively in order to understand relationships between the genetic microdeletion, brain development, cognitive function, and the emergence of psychiatric symptoms. White matter microstructural abnormalities identified using diffusion tensor imaging methods have been reported to affect a variety of neuroanatomical tracts in 22q11.2DS. In the present study, we sought to combine two discovery-based approaches: (1) white matter query language was used to parcellate the brain's white matter into tracts connecting pairs of 34, bilateral cortical regions and (2) the diffusion imaging characteristics of the resulting tracts were analyzed using a machine-learning method called support vector machine in order to optimize the selection of a set of imaging features that maximally discriminated 22q11.2DS and comparison subjects. With this unique approach, we both confirmed previously-recognized 22q11.2DS-related abnormalities in the inferior longitudinal fasciculus (ILF), and identified, for the first time, 22q11.2DS-related anomalies in the middle longitudinal fascicle and the extreme capsule, which may have been overlooked in previous, hypothesis-guided studies. We further observed that, in participants with 22q11.2DS, ILF metrics were significantly associated with positive prodromal symptoms of psychosis.


Assuntos
Síndrome de DiGeorge/diagnóstico por imagem , Fibras Nervosas Mielinizadas/patologia , Adulto , Síndrome de DiGeorge/genética , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Aprendizado de Máquina , Masculino , Rede Nervosa/patologia , Testes Neuropsicológicos , Substância Branca/patologia , Adulto Jovem
12.
Am J Psychiatry ; 174(11): 1054-1063, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28750581

RESUMO

OBJECTIVE: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. METHOD: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. RESULTS: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. CONCLUSIONS: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Síndrome de DiGeorge/genética , Deficiência Intelectual/genética , Esquizofrenia/genética , Adulto , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/psicologia , Deleção Cromossômica , Transtornos Cromossômicos/psicologia , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/psicologia , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Pessoa de Meia-Idade
13.
J Autism Dev Disord ; 47(8): 2480-2501, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28527096

RESUMO

The primary objectives of the current prospective longitudinal study were to (a) describe social functioning outcomes and (b) identify childhood predictors of social functioning in young adults with 22q11.2 deletion syndrome (22q11.2DS). Childhood predictors of young adult social functioning were examined. Family environment and parental stress in adolescence were investigated as potential mediators between childhood variables and adult social functioning. Parent rated childhood internalizing symptoms significantly predicted young adult social functioning in 22q11.2DS, even after controlling for concurrent positive symptoms of psychosis, and problem behaviors contributing to parenting stress in adolescence partially mediated this relationship. These findings highlight child internalizing symptoms and adolescent problem behaviors as potential targets for social functioning interventions in 22q11.2DS.


Assuntos
Síndrome de DiGeorge/diagnóstico , Comportamento Problema , Comportamento Social , Adolescente , Criança , Feminino , Humanos , Masculino
14.
Schizophr Bull ; 43(5): 1079-1089, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28204757

RESUMO

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.


Assuntos
Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Disfunção Cognitiva/epidemiologia , Síndrome de DiGeorge/epidemiologia , Transtornos Psicóticos/epidemiologia , Adolescente , Adulto , Transtornos de Ansiedade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Disfunção Cognitiva/diagnóstico , Comorbidade , Síndrome de DiGeorge/diagnóstico , Humanos , Pessoa de Meia-Idade , Sintomas Prodrômicos , Transtornos Psicóticos/diagnóstico , Adulto Jovem
15.
Am J Med Genet B Neuropsychiatr Genet ; 174(3): 295-314, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28139055

RESUMO

22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicologia , Receptor Nogo 1/genética , Transtornos Psicóticos/genética , Adolescente , Alelos , Catecol O-Metiltransferase/genética , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Substância Cinzenta , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroanatomia , Transtornos do Neurodesenvolvimento/genética , Receptor Nogo 1/fisiologia , Lobo Occipital , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/psicologia , Fatores de Risco , Esquizofrenia/genética , Adulto Jovem
16.
Behav Brain Funct ; 13(1): 4, 2017 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-28209179

RESUMO

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder that is associated with a 25-fold increase in schizophrenia. Both individuals with 22q11.2DS and those with schizophrenia present with social cognitive deficits, which are putatively subserved by a network of brain regions that are involved in the processing of social cognitive information. This study used two-tensor tractography to examine the white matter tracts believed to underlie the social brain network in a group of 57 young adults with 22q11.2DS compared to 30 unaffected controls. RESULTS: Results indicated that relative to controls, participants with 22q11.2DS showed significant differences in several DTI metrics within the inferior fronto-occipital fasciculus, cingulum bundle, thalamo-frontal tract, and inferior longitudinal fasciculus. In addition, participants with 22q11.2DS showed significant differences in scores on measures of social cognition, including the Social Responsiveness Scale and Trait Emotional Intelligence Questionnaire. Further analyses among individuals with 22q11.2DS demonstrated an association between DTI metrics and positive and negative symptoms of psychosis, as well as differentiation between individuals with 22q11.2DS and overt psychosis, relative to those with positive prodromal symptoms or no psychosis. CONCLUSIONS: Findings suggest that white matter disruption, specifically disrupted axonal coherence in the right inferior fronto-occipital fasciculus, may be a biomarker for social cognitive difficulties and psychosis in individuals with 22q11.2DS.


Assuntos
Encéfalo/diagnóstico por imagem , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/psicologia , Imagem de Tensor de Difusão , Rede Nervosa/diagnóstico por imagem , Transtornos do Comportamento Social/diagnóstico por imagem , Transtornos do Comportamento Social/psicologia , Adolescente , Estudos Transversais , Síndrome de DiGeorge/epidemiologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos do Comportamento Social/epidemiologia , Adulto Jovem
17.
Schizophr Bull ; 43(4): 833-842, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27798222

RESUMO

OBJECTIVE: To assess the extent to which the trajectories of intellectual, academic achievement, executive functioning, attention, working memory, and emotion recognition tests will be predictive of psychosis in young adults with 22q11.2 deletion syndrome (22q11DS). METHODS: Eighty-two participants with 22q11DS were assessed for psychiatric disorders and neuropsychological functioning with validated instruments. Siblings and community controls were employed as comparison groups. RESULTS: Individuals with 22q11DS differed significantly from siblings and controls in longitudinal trajectories of visual and auditory working memory as well as academic achievement. Longitudinal trajectories of cognitive set shifting, reading decoding, and emotion recognition predicted the presence of positive symptoms of psychosis in early adulthood. Cognitive set shifting improved at a slower rate for individuals with 22q11DS + psychosis than those without psychosis. Emotion recognition increased steadily in individuals without psychosis, whereas for those with psychosis, scores increased until approximately 15 years of age, at which point they began to decrease rapidly. A similar, but more subtle effect, was seen for reading decoding. CONCLUSIONS: Our data are the first to go beyond IQ assessments in assessing longitudinal neuropsychological outcomes and risk for psychosis in 22q11DS. Individuals with 22q11DS who developed psychotic symptoms improved less appreciably and continued to demonstrate difficulties with cognitive flexibility relative to individuals with 22q11DS who did not have psychotic symptoms. Individuals with 22q11DS who developed psychosis had weaker reading skills in childhood and, after an initial improvement into adolescence, these individuals with psychosis had a decline in reading skills. In 22q11DS, cognitive deficits are both (a) traits that are preexisting and raise the risk for psychosis and (b) associated with the onset of psychotic symptoms. Future research should consider the extent to which cognitive set shifting and reading decoding are related to the Verbal IQ declines observed in the 22q11DS population.


Assuntos
Disfunção Cognitiva/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Progressão da Doença , Transtornos Psicóticos/fisiopatologia , Adolescente , Adulto , Criança , Disfunção Cognitiva/etiologia , Síndrome de DiGeorge/complicações , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos Psicóticos/etiologia , Risco , Irmãos , Adulto Jovem
18.
J Child Psychol Psychiatry ; 58(3): 305-314, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27786353

RESUMO

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is a genetic disorder that greatly increases risk of developing schizophrenia. We previously characterized cerebral surface morphology trajectories from late childhood to mid adolescence in a cohort of youth with 22q11DS. Herein, we extend the study period into early adulthood, and describe further the trajectories associated with severe psychiatric symptoms in this cohort. METHODS: Participants included 76 youth with 22q11DS and 30 unaffected siblings, assessed at three timepoints, during which high resolution, anatomic magnetic resonance images were acquired. High-dimensional, nonlinear warping algorithms were applied to images in order to derive characteristics of cerebral surface morphology for each participant at each timepoint. Repeated-measures, linear regressions using a mixed model were conducted, while covarying for age and sex. RESULTS: Alterations in cerebral surface morphology during late adolescence/early adulthood in individuals with 22q11DS were observed in the lateral frontal, orbitofrontal, temporal, parietal, occipital, and cerebellar regions. An Age x Diagnosis interaction revealed that relative to unaffected siblings, individuals with 22q11DS showed age-related surface protrusions in the prefrontal cortex (which remained stable or increased during early adulthood), and surface indentations in posterior regions (which seemed to level off during late adolescence). Symptoms of psychosis were associated with a trajectory of surface indentations in the orbitofrontal and parietal regions. CONCLUSIONS: These results advance our understanding of cerebral maturation in individuals with 22q11DS, and provide clinically relevant information about the psychiatric phenotype associated with the longitudinal trajectory of cortical surface morphology in youth with this genetic syndrome.


Assuntos
Córtex Cerebral/patologia , Síndrome de DiGeorge/patologia , Transtornos Psicóticos/patologia , Transtornos Psicóticos/fisiopatologia , Adolescente , Adulto , Criança , Humanos , Estudos Longitudinais , Irmãos , Adulto Jovem
19.
Brain Imaging Behav ; 11(5): 1353-1364, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27730479

RESUMO

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is considered to be a promising cohort to explore biomarkers of schizophrenia risk based on a 30 % probability of developing schizophrenia in adulthood. In this study, we investigated abnormalities in the microstructure of white matter in adolescents with 22q11DS and their specificity to prodromal symptoms of schizophrenia. METHODS: Diffusion Magnetic Resonance Imaging (dMRI) data were acquired from 50 subjects with 22q11DS (9 with and 41 without prodromal psychotic symptoms), and 47 matched healthy controls (mean age 18 +/-2 years). DMRI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and compared between groups using the Tract Based Spatial Statistics (TBSS) method. Additionally, correlations between dMRI measures and scores on positive symptoms were performed. RESULTS: Reductions in MD, AD and RD (but not FA) were found in the corpus callosum (CC), left and right superior longitudinal fasciculus (SLF), and left and right corona radiata in the entire 22q11DS group. In addition, the 22q11DS subgroup with prodromal symptoms showed reductions in AD and MD, but no changes in RD when compared to the non-prodromal subgroup, in CC, right SLF, right corona radiata and right internal capsule. Finally, AD values in these tracts correlated with the scores on the psychosis subscale. CONCLUSION: Microstructural abnormalities in brain white matter are present in adolescent subjects with prodromal psychotic symptoms.


Assuntos
Encéfalo/diagnóstico por imagem , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/psicologia , Transtornos Psicóticos/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Encéfalo/patologia , Estudos de Coortes , Síndrome de DiGeorge/tratamento farmacológico , Síndrome de DiGeorge/patologia , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Sintomas Prodrômicos , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Substância Branca/patologia , Adulto Jovem
20.
Psychiatry Res Neuroimaging ; 259: 10-15, 2017 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-27918911

RESUMO

Dysfunction of cortical circuitry involving prefrontal cortex, cingulate gyrus and mesial temporal lobe has been implicated in the pathophysiology of psychotic symptoms. 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that comports a 25-fold increased risk of developing psychosis. Morphological changes in the neuroanatomy of this syndrome may represent a biological risk factor for the development of psychosis. The present study explored ratios between cortical volumes and the amygdala. We also explored relationships between these ratios and the eventual development of psychosis in youth with 22q11DS. A group of 73 individuals with 22q11DS, 32 community controls, and 27 unaffected siblings were followed every three years, at four timepoints. We analyzed baseline ratios between 34 bilateral FreeSurfer-generated cortical volumes and amygdala, and examined whether baseline cortical ratios predicted positive symptoms of psychosis 12 years later, at the 4th timepoint. Youth with 22q11DS demonstrated significantly smaller cortical volume-to-amygdala ratios in left anterior cingulate, occipital and parietal cortices. An increased risk of developing psychotic episodes in individuals with 22q11DS was associated with a lower cortical volume- to-amygdala ratio, suggesting that cortico-limbic circuitry may play an important role in emotional modulation and may underlie the pathophysiology of positive symptoms of psychosis.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Síndrome de DiGeorge/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Adolescente , Tonsila do Cerebelo/patologia , Córtex Cerebral/patologia , Criança , Síndrome de DiGeorge/patologia , Síndrome de DiGeorge/psicologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão/fisiologia , Transtornos Psicóticos/patologia , Transtornos Psicóticos/psicologia
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