M155. RECIPROCAL CHANGES IN WHITE MATTER MICROSTRUCTURE IN 22Q11.2 DELETION AND DUPLICATION SYNDROME
Authors: Seitz Johanna , Lyons Monica , Kushan Leila , Ik Kevin Cho Kang , Billah Tashrif , Bouix Sylvain , Kubicki Marek , Bearden Carrie , Pasternak Ofer 
Published: May 2020

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&lt;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&lt;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&lt;.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&lt;.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.