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

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, charac...

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Autores principales:	Johanna Seitz-Holland, Monica Lyons, Leila Kushan, Amy Lin, Julio E. Villalon-Reina, Kang Ik Kevin Cho, Fan Zhang, Tashrif Billah, Sylvain Bouix, Marek Kubicki, Carrie E. Bearden, Ofer Pasternak
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/db82ab623713474fa5a3e198e5514566
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spelling	oai:doaj.org-article:db82ab623713474fa5a3e198e55145662021-11-14T12:11:26ZOpposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers10.1038/s41398-021-01703-12158-3188https://doaj.org/article/db82ab623713474fa5a3e198e55145662021-11-01T00:00:00Zhttps://doi.org/10.1038/s41398-021-01703-1https://doaj.org/toc/2158-3188Abstract 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.Johanna Seitz-HollandMonica LyonsLeila KushanAmy LinJulio E. Villalon-ReinaKang Ik Kevin ChoFan ZhangTashrif BillahSylvain BouixMarek KubickiCarrie E. BeardenOfer PasternakNature Publishing GrouparticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENTranslational Psychiatry, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Johanna Seitz-Holland Monica Lyons Leila Kushan Amy Lin Julio E. Villalon-Reina Kang Ik Kevin Cho Fan Zhang Tashrif Billah Sylvain Bouix Marek Kubicki Carrie E. Bearden Ofer Pasternak Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
description	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.
format	article
author	Johanna Seitz-Holland Monica Lyons Leila Kushan Amy Lin Julio E. Villalon-Reina Kang Ik Kevin Cho Fan Zhang Tashrif Billah Sylvain Bouix Marek Kubicki Carrie E. Bearden Ofer Pasternak
author_facet	Johanna Seitz-Holland Monica Lyons Leila Kushan Amy Lin Julio E. Villalon-Reina Kang Ik Kevin Cho Fan Zhang Tashrif Billah Sylvain Bouix Marek Kubicki Carrie E. Bearden Ofer Pasternak
author_sort	Johanna Seitz-Holland
title	Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
title_short	Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
title_full	Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
title_fullStr	Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
title_full_unstemmed	Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
title_sort	opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/db82ab623713474fa5a3e198e5514566
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Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers

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