Diffusion tensor imaging of optic nerve integrity in mouse models of E50K optineurin mutation and optineurin deficiency

Abstract

Purpose : Mutations in optineurin (OPTN) are associated with familial normal tension glaucoma and other neurodegenerative diseases, yet their contribution to visual impairments remain unclear. Recently, in vivo longitudinal assessments on transgenic mouse models revealed that E50K OPTN was associated with differential age-dependent vision loss, whereas knocking out OPTN appeared to preserve visual function [IOVS 2021; 62(8):2385]. Here, we aimed to determine the role of E50K OPTN on underlying structural integrity in the mouse visual pathway using diffusion tensor imaging (DTI).

Methods : Twenty-eight 24-month-old mice with C57BL/6 background were used: wildtype (WT; n=9), homozygous OPTN knock-out (mOPTN-KO; n=8), hemizygous mouse E50K OPTN knock-in (mE50K het; n=3), homozygous mouse E50K OPTN knock-in (mE50K homoz; n=5), and human E50K OPTN bacterial artificial chromosome overexpression (hE50K BAC; n=3) (PMID: 31076632, 25818176). Ex vivo whole-brain DTI was acquired in 60 directions in a 7-Tesla MRI scanner. DTI parametric maps including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) maps were derived, and bilateral regions-of-interests (ROIs) were manually delineated for the optic nerve (ON) and anterior commissure (AC) on each map (Fig. 1). Results were analyzed using ANOVA and post-hoc tests.

Results : Significant group differences were observed in FA, RD, and MD but not AD for ON (ANOVA, p<0.05). No significant group difference was observed in either DTI map for AC (p>0.05). As shown in Fig. 2, Bonferroni-corrected post-hoc tests for ON revealed significantly lower FA in mE50K het and mE50K homoz relative to WT, along with significantly higher RD and MD in the same mE50K groups. Post-hoc analyses also revealed higher RD in mE50K het relative to hE50K BAC for ON.

Conclusions : The significant DTI differences in ON but not AC between WT and mE50K groups suggest the preferential disruption of structural integrity in the visual pathway upon a toxic gain of function mechanism from E50K OPTN. Such overall integrity loss as indicated by reduced FA appeared to be driven by increases in RD and MD, which are sensitive to glial activity and neuroinflammation. The non-significant differences between mOPTN-KO and WT suggest that suppression of OPTN might help preserve white matter structures from glaucomatous neurodegeneration.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.