Non-invasive Detection of Visual Pathway Abnormalities in Genetic Experimental Models of Glaucoma Using Diffusion Tensor MRI

Abstract

Purpose : Although recent studies in humans and animal models suggest the involvement of the brain's visual system in glaucoma, its extents across different etiopathogeneses are not completely understood. In this study, we used non-invasive diffusion tensor MRI (DTI) to evaluate the visual pathway in 3 genetic animal models of glaucoma.

Methods : Three genetically determined glaucoma models and their controls were employed: (1) LTBP2 feline model of primary congenital glaucoma (n=3) and age-matched normal cats (n=3) at 2-4 years old; (2) DBA/2J mouse model of hereditary pigmentary glaucoma (n=8) and its genetically-matched DBA/2J-Gpnmb+ control strain (n=7) at 7, 9 and 12 months old; and (3) TBK1 transgenic mouse model of normal tension glaucoma (n=4) and its wild-type littermates (n=4) at about 20 months old. Cat DTI was performed using a 3-Tesla GE MRI scanner, whereas mouse DTI was performed using a 9.4-Tesla Agilent MRI scanner. DTI parameters including fractional anisotropy (FA), axial diffusivity (λ_//) and radial diffusivity (λ_⊥) were evaluated along the optic nerves, optic tracts and/or internal capsules, and compared between groups using ANOVA and post-hoc multiple comparisons correction tests.

Results : LTBP2 mutant cats with glaucoma had significantly lower FA and higher λ_⊥ in the optic tracts when compared to the normotensive, age-matched controls, while λ_// exhibited no difference (Figure 1). When compared to the normotensive DBA/2J-Gpnmb+ controls, the DBA/2J mice exhibited significantly lower FA and λ_//, and higher λ_⊥ along the visual pathway (Figure 2) in concurrence with increasing intraocular pressure (IOP) at 7-12 months old. No apparent DTI difference was observed between transgenic TBK1 mice and wild-type littermates along the visual pathway (not shown).

Conclusions : While LTBP2 cats and DBA/2J mice are characterized by significant IOP elevation and retinal ganglion cell (RGC) loss, TBK1 mice have been found to exhibit no apparent IOP change and less RGC loss even in older ages. The current DTI results suggest that animals with LTBP2 mutation or DBA/2J melanosomal protein mutation had compromised structural integrity in the central visual pathway. Future studies will examine the relationships between IOP, RGC loss, visual pathway integrity, and their functional relevance in different forms and stages of glaucoma.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.