Reduced fractional anisotropy and axial diffusivity in white matter in 22q11.2 deletion syndrome: A pilot study

Abstract Background Cognitive decline is considered a fundamental component in schizophrenia. Abnormalities in fronto-striatal-thalamic (FST) sub-circuits are present in schizophrenia and are associated with cognitive impairments. However, it remains unknown whether abnormalities in FST sub-circuits are present before psychosis onset. This may be elucidated by investigating young adults with 22q11.2 deletion syndrome (22q11DS), of whom 30% will develop schizophrenia in adulthood. In 22q11DS, cognitive decline, most pronounced in Verbal IQ (VIQ), precedes the onset of psychosis and those who develop psychosis diverge more strongly from a typical cognitive trajectory. Based on these findings, studies of young adults with 22q11DS without overt psychosis but with prodromal symptoms may increase our understanding of cognitive manifestations and early pathology in FST sub-circuits in schizophrenia. Here we examined white matter (WM) tracts in FST sub-circuits, especially those involving dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), and their associations with VIQ in young adults with 22q11DS with and without prodromal symptoms. Methods We compared Fractional Anisotropy (FA), Axial Diffusivity (AD), and Radial Diffusivity (RD) in tracts of the FST sub-circuits in 21 individuals with 22q11DS with prodromal symptoms (age: M=21.43) and 30 individuals without prodromal symptoms (age: M=20.73) to 30 healthy controls (age: M=20.89). Two-tensor tractography was applied to reconstruct WM fiber tracts of the whole brain, followed by applying the White Matter Query Language (WMQL) method to select tracts between striatum and thalamus, with the rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC. This yielded four tracts of interest: thalamus-rMFG, thalamus-IFG, striatum-rMFG, and striatum-IFG tracts. Additionally, correlations between the dMRI measures and scores on VIQ were performed. Results FA was significantly increased, while RD was significantly decreased in most WM tracts in both 22q11DS groups when compared to healthy controls. In the whole 22q11DS group, VIQ correlated negatively with FA in the right thalamus-IFG tract (r=-0.336, p=.018), while RD correlated positively with VIQ in the right thalamus-IFG tract (r=0.290, p=.043) in individuals with 22q11DS, such that increased FA and decreased RD were associated with a lower VIQ. We followed up on the results in individuals with 22q11DS with prodromal symptoms to determine whether the presence of prodromal symptoms drove the correlations. VIQ correlated significantly with FA (r=-0.491, p=0.024, FDR-adjusted=0.048) and significantly at trend level with RD (r=0.487, p=0.025, FDR-adjusted=0.050) in the right thalamus-IFG tract in individuals with 22q11DS with prodromal symptoms. Discussion Microstructural abnormalities in brain WM tracts connecting the thalamus and the striatum with prefrontal cortices are present in young adults with 22q11DS with and without prodromal symptoms compared to healthy controls. These abnormalities are associated with the individuals’ cognitive performance in VIQ in individuals with 22q11DS with prodromal symptoms and therefore emphasize the potential involvement of the FST sub-circuits in schizophrenia. While changes in FST circuitry have been reported in patients with schizophrenia, we observed that changes in FST circuitry are also present in young adults with 22q11DS at risk for but without psychotic symptoms. Our results suggest that psychosis onset in 22q11DS may be associated with a complex pattern of WM alterations. Furthermore, cognitive abnormalities, especially in VIQ, present an important preclinical risk factor for psychosis in 22q11DS.

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White matter abnormalities in 22q11.2 deletion syndrome patients showing cognitive decline

Psychological Medicine ◽

10.1017/s0033291717003142 ◽

2017 ◽

Vol 48 (10) ◽

pp. 1655-1663 ◽

Cited By ~ 6

Author(s):

Jasper Olivier Nuninga ◽

Marc Marijn Bohlken ◽

Sanne Koops ◽

Ania M. Fiksinski ◽

René C. W. Mandl ◽

...

Keyword(s):

White Matter ◽

Cognitive Decline ◽

Internal Capsule ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Psychotic Episode ◽

Imaging Data ◽

22Q11.2 Deletion ◽

White Matter Abnormalities ◽

Cingulum Bundle

AbstractBackgroundDecline in cognitive functioning precedes the first psychotic episode in the course of schizophrenia and is considered a hallmark symptom of the disorder. Given the low incidence of schizophrenia, it remains a challenge to investigate whether cognitive decline coincides with disease-related changes in brain structure, such as white matter abnormalities. The 22q11.2 deletion syndrome (22q11DS) is an appealing model in this context, as 25% of patients develop psychosis. Furthermore, we recently showed that cognitive decline also precedes the onset of psychosis in individuals with 22q11DS. Here, we investigate whether the early cognitive decline in patients with 22q11DS is associated with alterations in white matter microstructure.MethodsWe compared the fractional anisotropy (FA) of white matter in 22q11DS patients with cognitive decline [n = 16; −18.34 (15.8) VIQ percentile points over 6.80 (2.39) years] to 22q11DS patients without cognitive decline [n = 18; 17.71 (20.17) VIQ percentile points over 5.27 (2.03) years] by applying an atlas-based approach to diffusion-weighted imaging data.ResultsFA was significantly increased (p < 0.05, FDR) in 22q11DS patients with a cognitive decline in the bilateral superior longitudinal fasciculus, the bilateral cingulum bundle, all subcomponents of the left internal capsule and the left superior frontal-occipital fasciculus as compared with 22q11DS patients without cognitive decline.ConclusionsWithin 22q11DS, the early cognitive decline is associated with microstructural differences in white matter. At the mean age of 17.8 years, these changes are reflected in increased FA in several tracts. We hypothesize that similar brain alterations associated with cognitive decline take place early in the trajectory of schizophrenia.

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

Brain Imaging and Behavior ◽

10.1007/s11682-016-9602-x ◽

2016 ◽

Vol 11 (5) ◽

pp. 1353-1364 ◽

Cited By ~ 11

Author(s):

Zora Kikinis ◽

Kang Ik K. Cho ◽

Ioana L. Coman ◽

Petya D. Radoeva ◽

Sylvain Bouix ◽

...

Keyword(s):

White Matter ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Psychotic Symptoms ◽

22Q11.2 Deletion ◽

Brain White Matter

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M155. RECIPROCAL CHANGES IN WHITE MATTER MICROSTRUCTURE IN 22Q11.2 DELETION AND DUPLICATION SYNDROME

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.467 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S194-S195

Author(s):

Johanna Seitz ◽

Monica Lyons ◽

Leila Kushan ◽

Kang Ik Kevin Cho ◽

Tashrif Billah ◽

...

Keyword(s):

White Matter ◽

Symptom Score ◽

Negative Symptom ◽

Free Water ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Psychotic Symptoms ◽

22Q11.2 Deletion ◽

White Matter Microstructure ◽

Human Connectome Project

Abstract Background The 22q11.2 deletion syndrome is a neurogenetic disorder that is associated with both physical anomalies and neurocognitive impairments. Deletion carriers have a greatly elevated risk of developing schizophrenia (SCZ); as such, it offers a compelling ‘high-penetrance’ model to explore the neuropathology of SCZ risk. Indeed, widespread structural alterations of both gray and white matter have been reported for 22q11.2 deletion carriers. Interestingly, there are also cases of duplications at the same gene locus. While less is known about the phenotype associated with 22q11.2 duplication, carriers also present physical and neurodevelopmental abnormalities, although they may have reduced risk of developing SCZ compared to the general population. The only study to date which looked at brain structure in duplication carriers found reciprocal effects of 22q11.2 deletion and duplication on cortical thickness and surface measurements. In the present study, we apply diffusion magnetic resonance imaging (MRI) to examine the white matter microstructure in both 22q11.2 deletion and duplication carriers. Methods Multi-shell diffusion-weighted images were acquired on a 3 Tesla MRI scanner from 13 healthy control individuals (HC), 25 deletion carriers, and 18 22q11.2 duplication carriers. Images were preprocessed utilizing the Human Connectome Project (HCP) Minimal Preprocessing Pipeline v4.0.0. Free Water imaging was applied, which differentiates the diffusion signal into a free-water compartment and a tissue compartment. The output parameters are the free-water fractional volume (FW) and a free-water corrected diffusion tensor from which fractional anisotropy of the tissue (FAT) is calculated. We compared FAT and FW maps between 1) HC and 22q11.2 deletion carriers and 2) HC and 22q11.2 duplication carriers using Tract-Based Spatial Statistics (TBSS) and voxel-wise, non-parametric statistics (5000 permutations, threshold-free cluster enhancement, corrected for age and sex). Lastly, white matter clusters that displayed significant differences between 22q11.2 deletion or duplication and HC were extracted. We averaged FAT and FW values over these significant clusters for each individual and correlated with the scores of the Structured Interview for Prodromal Syndromes (SIPS). Results 22q11.2 deletion carriers showed significant (p<0.05) FW reductions (72% of white matter skeleton) and FAT increase (8%) when compared to HC. In contrast, 22q11.2 duplication carriers displayed the opposite effect, with significant (p<0.05) widespread FW increase (51%) and FAT decrease (50%) when compared to HC. Both 22q11.2 deletion and duplication carriers scored higher on the SIPS than HC, with negative symptom score differences being the most pronounced (mean for HC= 1.36, mean for 22q11.2 duplication = 7.0, mean for 22q11.2 deletion =9.96, F=6.68, df=2, p<.003). FAT and FW were not associated with SIPS scores in 22q11.2 deletion syndrome. However, FAT was negatively correlated with the negative symptom score in 22q11.2 duplication carriers (Spearman rho=-.61, p<.009). Discussion We observed opposing effects of gene-dosage on FAT and FW. While we did not see an association between WM measurements and psychotic symptoms in 22q11.2 deletion, there was an association of WM structure with negative symptoms in 22q11.2 duplication carriers. These findings highlight the importance of studying the influence of reciprocal chromosomal imbalance on white matter architecture. Ongoing longitudinal studies may help advance understanding of the role of microstructural white matter abnormalities in the emergence of neuropsychiatric symptoms.

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Magnitude and heterogeneity of brain structural abnormalities in 22q11.2 deletion syndrome: a meta-analysis

Molecular Psychiatry ◽

10.1038/s41380-019-0638-3 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1704-1717 ◽

Cited By ~ 4

Author(s):

Maria Rogdaki ◽

Maria Gudbrandsen ◽

Robert A McCutcheon ◽

Charlotte E Blackmore ◽

Stefan Brugger ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

White Matter ◽

Brain Volume ◽

Meta Analysis ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Structural Abnormalities

AbstractThe 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case–control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = −0.96; p < 0.001); total grey matter (g = −0.81, p < 0.001); and total white matter (g = −0.81; p < 0.001). There was also a significant overall reduction of mean volume in 22q11.2DS subjects compared with controls in frontal lobe (g = −0.47; p < 0.001), temporal lobe (g = −0.84; p < 0.001), parietal lobe (g = −0.73; p = 0.053), cerebellum (g = −1.25; p < 0.001) and hippocampus (g = −0.90; p < 0.001). Significantly increased variability in 22q11.2DS individuals compared with controls was found only for the hippocampus (VR, 1.14; p = 0.036; CVR, 1.30; p < 0.001), and lateral ventricles (VR, 1.56; p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.

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

Schizophrenia Research ◽

10.1016/j.schres.2013.11.015 ◽

2014 ◽

Vol 152 (1) ◽

pp. 117-123 ◽

Cited By ~ 32

Author(s):

Matthew D. Perlstein ◽

Moeed R. Chohan ◽

Ioana L. Coman ◽

Kevin M. Antshel ◽

Wanda P. Fremont ◽

...

Keyword(s):

White Matter ◽

Receptor Gene ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

White Matter Abnormalities

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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

Schizophrenia Research ◽

10.1016/j.schres.2014.07.010 ◽

2015 ◽

Vol 161 (1) ◽

pp. 76-84 ◽

Cited By ~ 30

Author(s):

Wendy R. Kates ◽

Amy K. Olszewski ◽

Matthew H. Gnirke ◽

Zora Kikinis ◽

Joshua Nelson ◽

...

Keyword(s):

White Matter ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Neuropsychological Function ◽

22Q11.2 Deletion ◽

Prodromal Symptoms ◽

Cingulum Bundle

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In vivo evidence of microstructural hypo-connectivity of brain white matter in 22q11.2 deletion syndrome

10.21203/rs.3.rs-80221/v1 ◽

2020 ◽

Author(s):

Erika Raven ◽

Jelle Veraart ◽

Rogier Kievit ◽

Sila Genc ◽

Isobel Ward ◽

...

Keyword(s):

White Matter ◽

Large Scale ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Typically Developing ◽

22Q11.2 Deletion ◽

Genetic Syndrome ◽

Brain White Matter ◽

Axonal Morphology

Abstract 22q11.2 Deletion Syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia, autism, and attention deficit hyperactivity disorder, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterisation of white matter microstructure in both typically-developing children and children with 22q11.2DS using a dedicated magnetic resonance imaging scanner which is sensitive to axonal morphology. By extracting a rich array of diffusion metrics, we present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences between typically-developing and 22q11.2DS children. A recent, large-scale consortium study identified higher diffusion anisotropy and reduced overall mobility of water as hallmark microstructural alterations of white matter in 22q11.2DS, in particular for commissural fibers. We observed similar findings across all white matter tracts in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that microstructural connectivity in 22q11.2DS is mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo mechanistic features of 22q11.2DS, and promote further investigation of shared features in neurodevelopmental and psychiatric disorders.

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