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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.
Am J Hum Genet ; 106(1): 26-40, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870554

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/patologia , Humanos , Desequilíbrio de Ligação , Masculino , Fenótipo , Duplicações Segmentares Genômicas
3.
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.

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.
Am J Med Genet A ; 176(10): 2172-2181, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30289625

RESUMO

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicologia , Adolescente , Adulto , Criança , Feminino , Humanos , Deficiência Intelectual/genética , Testes de Inteligência , Masculino
8.
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
9.
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.

10.
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
11.
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
12.
Hum Mol Genet ; 27(7): 1150-1163, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361080

RESUMO

Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.


Assuntos
Alelos , Mapeamento Cromossômico , Síndrome de DiGeorge/genética , Meiose , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Masculino
13.
Dev Sci ; 21(2)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28032434

RESUMO

The attentional blink (AB) is thought to help the visual system parse and categorize rapidly changing information by segmenting it into temporal chunks, and is elicited using Rapid Serial Visual Presentation. It is reflected in a decrease in accuracy at detecting the second of two targets presented within 200-500 ms of the first, and its development appears to be protracted on tasks that require set-shifting. Here, younger (M = 8.5 years) and older (M = 12.8 years) children and adults (M = 19.13 years) completed a simple AB task with no set-shift requirement in which participants detected two letters in a stream of numbers presented at a rate of 135 ms/item. In addition to assessing the developmental course of the AB on this simple task, we also assessed temporal order errors, or swaps. The AB and its associated characteristics are present in both groups but developmental differences were noted in the depth of the AB, and the presence or absence of lag-1 sparing. These developmental changes were explained by changes in a single parameter, inhibition, using the eTST model, which suggests that the AB is an adaptive function of the visual system.


Assuntos
Intermitência na Atenção Visual/fisiologia , Fatores Etários , Criança , Desenvolvimento Infantil , Feminino , Humanos , Masculino , Memória , Adulto Jovem
14.
Early Interv Psychiatry ; 12(4): 686-693, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-27629273

RESUMO

AIM: Schizophrenia and 22q11.2 deletion syndrome (22q11DS) share similar patterns of cognitive deficits. Up to 30% of those with 22q11DS develop schizophrenia during early adulthood. As cognitive decline has recently been found to predict onset of psychosis in adolescents with 22q11DS, early interventions such as cognitive remediation (CR) during adolescence are warranted. This paper investigates the durability of a remote, computerized, CR programme for youth with 22q11DS. Our aim was to determine if the positive effects of CR persisted 6 months beyond intervention completion. METHODS: A longitudinal design with 21 participants serving as their own controls was used. Youth were seen for neurocognitive assessments at pre-treatment, after the targeted 8-month intervention, at post-treatment, and 6 months after for follow-up. During the intervention, cognitive coaches met remotely with participants for CR via video conferencing three times a week, and offered task-specific strategies. To determine if intervention improvements held across the 6-month follow-up period, neurocognitive measures were statistically examined with repeated measures analysis of variances from pre-treatment through follow-up. RESULTS: Our CR intervention proved durable. Post-treatment improvements comprising cognitive flexibility, executive function, reaction time and working memory were maintained over the follow-up period. CONCLUSIONS: Results confirm previous research regarding the durability of CR treatment and extend these findings to youth with 22q11DS. The present study may serve to inform early intervention efforts focused on cognitive and functionally relevant rehabilitation goals for youth with 22q11DS and suggests that 22q11DS can potentially serve as a suitable model for examining the trajectory preceding psychosis.


Assuntos
Cognição , Remediação Cognitiva/métodos , Síndrome de DiGeorge/psicologia , Síndrome de DiGeorge/terapia , Terapia Assistida por Computador/métodos , Adolescente , Feminino , Humanos , Masculino , Comunicação por Videoconferência
15.
Childs Nerv Syst ; 33(12): 2215, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29032517

RESUMO

AbstractThe published version of this article unfortunately contained an error. Author "E. Mark Mahone" has been published incorrectly by capturing "Mark Mahone" as family name when it should only be "Mahone". Given in this article is the corrected name.

16.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29025761

RESUMO

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. METHODS AND RESULTS: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. CONCLUSIONS: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.


Assuntos
Síndrome de DiGeorge/genética , Estudo de Associação Genômica Ampla , Receptores Acoplados a Proteínas-G/genética , Tetralogia de Fallot/genética , Cromatina/metabolismo , Cromossomos Humanos Par 5 , Síndrome de DiGeorge/complicações , Loci Gênicos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Desequilíbrio de Ligação , Fatores de Transcrição MEF2/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/metabolismo , Análise de Sequência de DNA , Tetralogia de Fallot/complicações
17.
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
18.
J Exp Child Psychol ; 164: 32-44, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28779698

RESUMO

The ability to select targets from an ongoing stream of visual information is critical to the successful management of visual attention. The attentional blink (AB), a phenomenon elicited using rapid serial visual presentation, allows for the assessment of the limits of the temporal visual system, and is reflected in a decrease in accuracy in the detection of the second of two targets when it occurs within 200-500ms of a first target. Evidence regarding the development of the AB is mixed and appears to be dependent on the task demands. Here we present data examining the AB across middle childhood, early adolescence, and adulthood using a feature binding task. Participants were asked to detect and report the identity of two purple letters presented in a stream of black letters at a rate of 135ms/item. On this feature binding task, the depth of the AB was invariant across development but AB recovery occurred earlier with increasing age. Furthermore, the error data suggested important developments in temporal binding that were reflected both in a decrease in the number of swaps (where participants reverse the order of the targets but identify them correctly) and in the spread of temporal binding errors with age. These findings suggest that the characteristics of the AB and its development are task dependent and also suggest that the development of binding abilities in visual search tasks mirrors the time course of multisensory binding effects, perhaps suggesting a common mechanism.


Assuntos
Envelhecimento/fisiologia , Atenção/fisiologia , Intermitência na Atenção Visual/fisiologia , Percepção Visual/fisiologia , Adolescente , Criança , Feminino , Humanos , Masculino , Adulto Jovem
19.
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
20.
Childs Nerv Syst ; 33(6): 965-972, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28455540

RESUMO

PURPOSE/OBJECTIVE(S): Cranial radiation therapy (CRT) may disrupt the corpus callosum (CC), which plays an important role in basic motor and cognitive functions. The aim of this prospective longitudinal study was to assess changes in CC mid-sagittal areas, CC volumes, and performance on neuropsychological (NP) tests related to the CC in children following CRT. MATERIALS/METHODS: Twelve pediatric patients were treated with CRT for primary brain malignancies. Thirteen age-matched healthy volunteers served as controls. Brain MRIs and NP assessment emphasizing motor dexterity, processing speed, visuomotor integration, and working memory (visual and verbal) were performed at baseline and at 6, 15, and 27 months following completion of CRT. Linear mixed effects (LME) analyses were used to evaluate patient NP performance and changes in regional CC volumes (genu, anterior body, mid-body, posterior body, and splenium) and mid-sagittal areas over time and with radiation doses, correcting for age at CRT start. RESULTS: The mean age at CRT was 9.41 (range 1.2-15.7) years. The median prescription dose was 54 (range 18-59.4) Gy. LME analysis revealed a significant decrease in overall CC volumes over time (p < 0.00001), with no overall effect of radiation dose. Analysis of individual CC regions demonstrated a significant decrease in all regional volumes over time (p < 0.00001) in patients, with no effect of radiation dose. Only in the splenium was there a trend toward a dose-dependent effect (p = 0.093). Patients had significantly reduced NP performance across visits-most notably in motor dexterity and visual working memory (both p < 0.0001). CONCLUSIONS: These prospective data demonstrate a significant decrease in CC regional volumes after CRT, with associated decline in neurocognitive function, most notably in manual dexterity, attention, and working memory. Further prospective study of larger cohorts of patients is needed to establish the relationship between CRT dose, neuroanatomical, and functional changes in the CC.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Disfunção Cognitiva/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Irradiação Craniana/efeitos adversos , Testes Neuropsicológicos , Adolescente , Neoplasias Encefálicas/psicologia , Criança , Pré-Escolar , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Irradiação Craniana/tendências , Feminino , Humanos , Lactente , Masculino , Tamanho do Órgão , Estudos Prospectivos , Resultado do Tratamento
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