Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings

Abstract

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.

Identifying 22q11.2 Deletion Syndrome and Psychosis Using Resting-State Connectivity Patterns

“…Although these discriminative connections were widespread, functional connectivity of the frontal lobe played an important role in classification. Several studies using DTI have already identified a widespread alteration of the structural brain network in 22q11DS (Barnea-Goraly et al 2003;Simon et al 2005;Sundram et al 2010;Radoeva et al 2012) that also affect tracts originating from the frontal lobe (Simon et al 2008;Barnea-Goraly et al 2003;Radoeva et al 2012). This has been further confirmed by a recent tractographic study showing alterations in the number of reconstructed fibers in several brain lobes, including the frontal lobes (Ottet et al 2013a).…”

“…Apart from the somatic consequences of this deletion, the disorder is characterized by a high incidence of cognitive and psychiatric disabilities (Baker and Vorstman 2012), including notably a mild decrease in IQ (Antshel et al 2008a) and a high prevalence of psychotic symptoms (Baker and Skuse 2005) and schizophrenia (Murphy et al 1999). In this disorder, structural alterations of the brain networks are sustained by white matter alterations including a well described 11-16 % loss of volume (Simon et al 2005;Eliez et al 2000) and widespread microstructural defects (Sundram et al 2010;Barnea-Goraly et al 2003;da Silva et al 2011;Simon et al 2008) that have furthermore been associated to various cognitive deficiencies (Radoeva et al 2012;Barnea-Goraly et al 2005;Simon et al 2008) and psychiatric symptoms (Radoeva et al 2012) including schizotypal traits (Sundram et al 2010). The alteration of the structural wiring of the brain in 22q11DS has recently been confirmed using tractography (Ottet et al 2013a).…”

Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome

“…First, based on prior work (Sundram et al, 2010; Radoeva et al, 2012), we expected to find lower FA in long-range fiber tracts in 22q11DS relative to controls, including the SLF and uncinate fasciculus, which would be driven by abnormal AD (Kikinis et al, 2012; Radoeva et al, 2012). Based on previous literature in CHR youth and 22q11DS (Karlsgodt et al, 2009; Ottet et al, 2013a), we hypothesized that 22q11DS youth would fail to show the typical age-associated increases in FA observed in typically developing controls (Simmonds et al, 2014).…”

Large-scale functional network reorganization in 22q11.2 deletion syndrome revealed by modularity analysis

“…Neuroimaging studies have shown associations between brain connectivity alterations and the clinical and cognitive phenotype in 22q11DS. Indeed, diffusion tensor imaging (DTI) studies [reviewed in (Gothelf, Schaer, & Eliez, 2008)] have reported relationships between microstructural irregularities of the white matter tracts and cognitive symptoms including arithmetic difficulties, and deficits in attention and social capacities (Barnea-Goraly, Eliez, Menon, Bammer, & Reiss, 2005;Radoeva et al, 2012;Simon et al, 2008). Similar alterations have been associated with the intensity of schizotypal traits (Sundram et al, 2010) and psychotic symptoms (Jalbrzikowski et al, 2014;Radoeva et al, 2012).…”