MAPPING NEUROANATOMICAL AND MICROSTRUCTURAL PHENOTYPES OF A MOUSE MODEL OF 22Q11.2 DELETION SYNDROME USING VOLUMETRIC AND DIFFUSION MRI

22q11.2 Deletion Syndrome (22q11.2DS) is associated with volumetric and structural abnormalities in several human brain regions. Ex-vivo mouse MRI data can be acquired at higher resolution than in humans, enabling detection of subtler effects, aiding interpretation of results from human studies, and supporting design of additional investigations. 22 C57BL/6-Del(16Dgcr2-Hira)1Tac and 26 wild-type mice (26 female, 22 male, aged 48 – 150 days) were perfused using established protocols. Brains were kept in-skull to preserve morphology and imaged with 60μm isotropic resolution T2w anatomical and 100μm isotropic 2-shell (30 directions, b=2500 and b=10000) diffusion scans. Anatomical data was processed and registered using Pydpiper tools. Diffusion data was processed with custom FSL pipelines. Data was analysed with custom R code and RMINC to identify regions with significant volumetric or microstructural changes. Multiple comparisons were FDR controlled using the Benjamini-Yekutieli procedure. Compared to wild-type, C57BL/6-Del(16Dgcr2-Hira)1Tac mice show significant volumetric reductions in cerebellar cortex, nuclei and fibre tracts, and parts of accessory olfactory bulb, pontine and cuneate nuclei. Prominent volumetric increases were found in parts of the hypothalamus, frontal pole, striatum, and pallidum. No significant changes were seen in fractional anisotropy or mean diffusivity. Neuroanatomical results recapitulate several hallmark effects seen in human 22q11.2DS and replicate phenotypes seen in another mouse model, supporting anatomical face validity of the C57BL/6-Del(16Dgcr2-Hira)1Tac mouse model. Altered microstructure is widely reported in human 22q11.2DS studies; lack of significant diffusion results was therefore surprising but may reflect the simpler architecture of mouse white matter.

Regional volumetric changes between C57BL/6-Del(16Dgcr2-Hira)1Tac versus wild-type mice.