Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers

Johanna Seitz-Holland,Kang Ik Kevin Cho,Marek Kubicki,Fan Zhang,Sylvain Bouix,Monica Lyons,Julio E Villalon-Reina,Amy Lin,Tashrif Billah,Leila Kushan,Carrie E Bearden,Ofer Pasternak

doi:10.1038/s41398-021-01703-1

Abstract

Deletions and duplications at the 22q11.2 locus are associated with significant neurodevelopmental and psychiatric morbidity. Previous diffusion-weighted magnetic resonance imaging (MRI) studies in 22q11.2 deletion carriers (22q-del) found nonspecific white matter (WM) abnormalities, characterized by higher fractional anisotropy. Here, utilizing novel imaging and processing methods that allow separation of signal contribution from different tissue properties, we investigate whether higher anisotropy is driven by (1) extracellular changes, (2) selective degeneration of secondary fibers, or (3) volumetric differences. We further, for the first time, investigate WM microstructure in 22q11.2 duplication carriers (22q-dup). Multi-shell diffusion-weighted images were acquired from 26 22q-del, 19 22q-dup, and 18 healthy individuals (HC). Images were fitted with the free-water model to estimate anisotropy following extracellular free-water elimination and with the novel BedpostX model to estimate fractional volumes of primary and secondary fiber populations. Outcome measures were compared between groups, with and without correction for WM and cerebrospinal fluid (CSF) volumes. In 22q-del, anisotropy following free-water elimination remained significantly higher compared with controls. BedpostX did not identify selective secondary fiber degeneration. Higher anisotropy diminished when correcting for the higher CSF and lower WM volumes. In contrast, 22q-dup had lower anisotropy and greater extracellular space than HC, not influenced by macrostructural volumes. Our findings demonstrate opposing effects of reciprocal 22q11.2 copy-number variation on WM, which may arise from distinct pathologies. In 22q-del, microstructural abnormalities may be secondary to enlarged CSF space and more densely packed WM. In 22q-dup, we see evidence for demyelination similar to what is commonly observed in neuropsychiatric disorders.

Highlights

Copy number variation (CNV) at the 22q11.2 locus is associated with significant neurodevelopmental and psychiatric morbidity
Using the BedpostX method, which allows us to differentiate the primary and secondary fiber populations in one voxel, we found a higher proportion of both primary and secondary fibers in 22q-del compared to Healthy controls (HC)
In 22q-del, we identified an association between white matter (WM) microstructure findings and macrostructural volumetric measures, suggesting microstructural abnormalities are directly related to macrostructural features

Summary

Introduction

Copy number variation (CNV) at the 22q11.2 locus is associated with significant neurodevelopmental and psychiatric morbidity. Deletion of the 22q11.2 locus occurs in approximately one in 4000 live births [1]. 22q11.2 deletion carriers (22q-del), have elevated risk for autism spectrum disorder, attention deficit-hyperactivity disorder (ADHD), anxiety, intellectual disability, and up to 25% develop psychosis [5, 6]. Duplication of the 22q11.2 locus is more common than the reciprocal deletion (estimated at one out of 700 live births) [7] but was more recently identified and is less wellcharacterized [8]. 22q-dup can suffer from a range of comorbidities that partially overlap those reported for 22q-del, including increased risk for autism, ADHD, and mild intellectual disability [12, 13]

Methods

Results

Discussion

Conclusion