Abnormalities in brain white matter in adolescents with 22q11.2 deletion syndrome and psychotic symptoms

Kikinis, Zora; Cho, Kang Ik K.; Coman, Ioana L.; Radoeva, Petya D.; Bouix, Sylvain; Tang, Yingying; Eckbo, Ryan; Makris, Nikos; Kwon, Jun Soo; Kubicki, Marek; Antshel, Kevin M.; Fremont, Wanda; Shenton, Martha E.; Kates, Wendy R.

doi:10.1007/s11682-016-9602-x

Cited by 20 publications

(16 citation statements)

References 58 publications

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“…WM differences associated with psychosis are of interest in 22q11DS. Psychotic symptoms in 22q11DS have been associated with higher FA and lower WM diffusivities, but not always in the same regions across studies [22,25,30,31,33,34]. In addition, there is variability in deletion breakpoints; 85-90% of individuals with the deletion have a~3 Mb (A-D) deletion, containing 46 protein-coding genes, whereas~10% of cases have a nested 1.5 Mb (A-B) deletion [1].…”

Section: Introductionmentioning

confidence: 99%

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study

Villalon‐Reina

Martínez

et al. 2019

Mol Psychiatry

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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 dMRIderived 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.

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Section: Introductionmentioning

confidence: 99%

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study

Villalon‐Reina

Martínez

et al. 2019

Mol Psychiatry

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“…For instance, in a recent review article, we concluded that higher symptoms severity is associated with altered long-range frontal connections ( 13 ). Fewer studies specifically investigated brain morphology and connectivity in 22q11DS patients with high psychotic symptoms compared to less symptomatic patients ( 14 – 21 ). The aim of this manuscript is to review evidence of specific alterations at the level of brain morphology and connectivity in patients with 22q11DS with a higher clinical risk to develop psychosis.…”

Section: Introductionmentioning

confidence: 99%

A Mini Review on the Contribution of the Anterior Cingulate Cortex in the Risk of Psychosis in 22q11.2 Deletion Syndrome

et al. 2018

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22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that causes a high risk of developing schizophrenia, thus representing a unique model for the investigation of biomarkers of psychosis. Cognitive and clinical risk factors have been identified as reliable predictors of schizophrenia in patients with 22q11DS and are currently used in the clinical practice. However, biomarkers based on neuroimaging are still lacking, mainly because of the analytic approaches adopted so far, which are almost uniquely based on the comparison of 22q11DS patients with healthy controls. Such comparisons do not take into account the heterogeneity within patients with 22q11DS, who indeed show various clinical manifestations. More recently, a number of studies compared measures of brain morphology and connectivity between patients with 22q11DS with different symptomatic profiles. The aim of this short review is to highlight the brain alterations found in patients with 22q11DS fulfilling ultra-high risk (UHR) criteria. Findings point to alterations in brain morphology and connectivity in frontal brain regions, and in particular in the anterior cingulate cortex, in patients with 22q11DS presenting UHR symptoms. These alterations may represent valuable biomarkers of psychosis in 22q11DS.

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“…In order to disentangle which brain connectivity alterations are associated to psychosis, it is essential to compare patients with 22q11DS with different levels of symptoms severity. To date, only one study investigated structural connectivity differences in subgroups of patients with 22q11DS ( Kikinis et al, 2016 ). The authors compared adolescent patients with 22q11DS with high and low psychotic symptoms scores and showed altered white matter diffusivity in the most symptomatic patients ( Kikinis et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…To date, only one study investigated structural connectivity differences in subgroups of patients with 22q11DS ( Kikinis et al, 2016 ). The authors compared adolescent patients with 22q11DS with high and low psychotic symptoms scores and showed altered white matter diffusivity in the most symptomatic patients ( Kikinis et al, 2016 ). However, this investigation was limited by the low number of patients included ( N = 9 patients with high symptoms severity).…”

Section: Introductionmentioning

confidence: 99%

Altered structural network architecture is predictive of the presence of psychotic symptoms in patients with 22q11.2 deletion syndrome

Padula

Scariati

Schaer

et al. 2017

NeuroImage: Clinical

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22q11.2 deletion syndrome (22q11DS) represents a homogeneous model of schizophrenia particularly suitable for the search of neural biomarkers of psychosis. Impairments in structural connectivity related to the presence of psychotic symptoms have been reported in patients with 22q11DS. However, the relationships between connectivity changes in patients with different symptomatic profiles are still largely unknown and warrant further investigations.In this study, we used structural connectivity to discriminate patients with 22q11DS with (N = 31) and without (N = 31) attenuated positive psychotic symptoms. Different structural connectivity measures were used, including the number of streamlines connecting pairs of brain regions, graph theoretical measures, and diffusion measures. We used univariate group comparisons as well as predictive multivariate approaches.The univariate comparison of connectivity measures between patients with or without attenuated positive psychotic symptoms did not give significant results. However, the multivariate prediction revealed that altered structural network architecture discriminates patient subtypes (accuracy = 67.7%). Among the regions contributing to the classification we found the anterior cingulate cortex, which is known to be associated to the presence of psychotic symptoms in patients with 22q11DS. Furthermore, a significant discrimination (accuracy = 64%) was obtained with fractional anisotropy and radial diffusivity in the left inferior longitudinal fasciculus and the right cingulate gyrus.Our results point to alterations in structural network architecture and white matter microstructure in patients with 22q11DS with attenuated positive symptoms, mainly involving connections of the limbic system. These alterations may therefore represent a potential biomarker for an increased risk of psychosis that should be further tested in longitudinal studies.

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Abnormalities in brain white matter in adolescents with 22q11.2 deletion syndrome and psychotic symptoms

Cited by 20 publications

References 58 publications

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study

A Mini Review on the Contribution of the Anterior Cingulate Cortex in the Risk of Psychosis in 22q11.2 Deletion Syndrome

Altered structural network architecture is predictive of the presence of psychotic symptoms in patients with 22q11.2 deletion syndrome

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