Petya D. Radoeva

Atlas-Based White Matter Analysis in Individuals With Velo-Cardio-Facial Syndrome (22q11.2 Deletion Syndrome) and Unaffected Siblings

BackgroundVelo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning.MethodsThirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (pFDR < 0.05), we assessed the correlations between DTI and neuropsychological measures.ResultsIn VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of the internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD with measures of executive function, IQ, working memory, and/or social cognition.ConclusionsOur results suggest that individuals with VCFS display abnormal WM connectivity in a widespread cerebro-anatomical network, involving tracts from/to all cerebral lobes and the cerebellum. Future studies could focus on the WM developmental trajectory in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate 22q11.2 genes on WM anomalies.

Deficits in mental state attributions in individuals with 22q11.2 deletion syndrome (velo-cardio-facial syndrome).

Velo‐cardio‐facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video‐based task to assess mentalizing at two sites University of California, Los Angeles (UCLA) and State University of New York (SUNY) Upstate Medical University. The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e. mentalizing) and Appropriateness. Using Repeated Measures analysis of variance (ANOVA), we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real‐life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions. Autism Res 2012, 5: 407–418.

White matter abnormalities in 22q11.2 deletion syndrome: Preliminary associations with the Nogo-66 receptor gene and symptoms of psychosis

BACKGROUND This study utilized diffusion tensor imaging (DTI) to analyze white matter tractography in the anterior limb of the internal capsule (ALIC), fornix, and uncinate fasciculus (UF) of individuals with 22q11.2 deletion syndrome and controls. Aberrations in these tracts have been previously associated with schizophrenia. With up to 25% of individuals with 22q11.2DS developing schizophrenia in adulthood, we hypothesized reduction in structural integrity of these tracts, including an association with prodromal symptoms of psychosis. We further predicted an association between allelic variation in a functional polymorphism of the Nogo-66 receptor gene and 22q11.2DS white matter integrity. METHODS Tractography was conducted using fiber assignment by streamline tracking algorithm in DTI Studio. Subjects were genotyped for the rs701428 SNP of the Nogo-66 receptor gene, and assessed for presence of prodromal symptoms. RESULTS We found significant group differences between 22q11.2DS and controls in DTI metrics for all three tracts. DTI metrics of ALIC and UF were associated with prodromal symptoms in 22q11.2DS. Further, ALIC DTI metrics were associated with allelic variation of the rs701428 SNP of the Nogo-66 receptor gene in 22q11.2DS. CONCLUSIONS Alterations in DTI metrics suggest white matter microstructural anomalies of the ALIC, fornix, and UF in 22q11.2DS. Structural differences in ALIC appear to be associated with the Nogo-66 receptor gene, which has been linked to myelin-mediated axonal growth inhibition. Moreover, the association between psychosis symptoms and ALIC and UF metrics suggests that the Nogo-66 receptor gene may represent a susceptibility gene for psychosis through its disruption of white matter microstructure and myelin-associated axonal growth.

White matter microstructural abnormalities of the cingulum bundle in youths with 22q11.2 deletion syndrome: associations with medication, neuropsychological function, and prodromal symptoms of psychosis.

BACKGROUND The 22q11.2 deletion syndrome (22q11.2DS) is regarded as an etiologically homogenous model for understanding neuroanatomic disruptions associated with a high risk for schizophrenia. This study utilized diffusion tensor imaging (DTI) to analyze white matter microstructure in individuals with 22q11.2DS. We focused on the cingulum bundle (CB), previously shown to be disrupted in patients with schizophrenia and associated with symptoms of psychosis. METHODS White matter microstructure was assessed in the anterior, superior, and posterior CB using the tractography algorithm in DTIStudio. Neuropsychological function, presence of prodromal symptoms of psychosis, and medication history were assessed in all participants. RESULTS Relative to controls, young adults with 22q11.2DS showed alterations in most DTI metrics of the CB. Alterations were associated with positive prodromal symptoms of psychosis. However, when individuals with 22q11.2DS were divided by usage of antipsychotics/mood stabilizers, the medicated and non-medicated groups differed significantly in axial diffusivity of the anterior CB and in fractional anisotropy of the superior CB. DTI metrics did not differ between the medicated group and the control group. CONCLUSIONS Results suggest that the microstructure of the CB is altered in individuals with 22q11.2DS, and that those alterations may underlie positive prodromal symptoms of psychosis. Our findings further provide preliminary evidence that antipsychotic/mood stabilizer usage may have a reparative effect on white matter microstructure in prodromal 22q11.2DS, independent of the potential effects of psychosis. Future studies of white matter pathology in individuals with 22q11.2DS should test for potential effects of medication on white matter microstructure.

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27–28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS.

Is child intelligence associated with parent and sibling intelligence in individuals with developmental disorders? An investigation in youth with 22q11.2 deletion (velo-cardio-facial) syndrome.

Children with 22q11.2 deletion syndrome (22q11DS), a copy-number variation (CNV) genetic disorder, demonstrate a great deal of variability in IQ scores and are at particular risk for cognitive difficulties, with up to 45% experiencing intellectual disability. This study explored the IQ relationship between individuals with 22q11DS, their parents and their siblings. Participants included individuals with 22q11DS, unaffected siblings and community controls, who participated in a longitudinal study of 22q11DS. Significant associations between proband and relative (parent, sibling) IQ scores were found. Results suggest that the cognitive functioning of first-degree relatives could be a useful marker of general genetic background and/or environmental effects, and can explain some of the large phenotypic variability in 22q11DS. These findings underscore the importance of including siblings and parents in studies of 22q11DS whenever possible.

Longitudinal study of cerebral surface morphology in youth with 22q11.2 deletion syndrome, and association with positive symptoms of psychosis

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.

Longitudinal study of premorbid adjustment in 22q11.2 deletion (velocardiofacial) syndrome and association with psychosis

Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome (22q11DS), is associated with an increased risk of major psychiatric disorders, including schizophrenia. The emergence of psychotic symptoms in individuals with schizophrenia in the general population is often preceded by a premorbid period of poor or worsening social and/or academic functioning. Our current study evaluated premorbid adjustment (via the Cannon-Spoor Premorbid Adjustment Scale [PAS]) and psychotic symptoms (via the Structured Interview for Prodromal Symptoms and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) in youth with 22q11DS (N = 96), unaffected siblings (N = 40), and community controls (N = 50). The PAS scores indicated greater maladjustment during all developmental periods in individuals with 22q11DS compared to the controls. Many participants with 22q11DS had chronically poor (n = 33) or deteriorating (n = 6) PAS scores. In 22q11DS, chronically poor PAS trajectories and poor childhood and early adolescence academic domain and total PAS scores significantly increased the risk of prodromal symptoms or overt psychosis. Taking into account the catechol-O-methyltransferase (COMT) genotype, the best predictor of (prodromal) psychosis was the early adolescence academic domain score, which yielded higher sensitivity and specificity in the subgroup of youth with 22q11DS and the high-activity (valine) allele. PAS scores may help identify individuals at higher risk for psychosis.

Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome

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.

Developmental abnormalities in brain white matter in prodromes with 22q11.2 Deletion Syndrome: A tract based spatial statistics study

the molecular mechanism by which QKI regulates the expression of SIRT2 in OLs during development. Two quaking response elements (QREs) were identified in the 3′UTR of Sirt2 mRNA and RNA co-immunoprecipitation experiments confirmed that all three transcripts of Sirt2 were bound and stabilized by QKI protein. Together, these findings suggest that the expression of Sirt2 is regulated by QKI protein for proper OL development and the loss of Sirt2 contributes to dysmyelination (Funded by CIHR).