Modeling the Chronic Loss of Optic Nerve Axons and the Effects on the Retinal Nerve Fiber Layer Structure in Primary Disorder of Myelin

Abstract

PurposeWe determined whether the chronic lack of optic nerve myelination and subsequent axon loss is associated with optical coherence tomography (OCT) changes in the retinal nerve fiber layer (RNFL), and whether this models what occurs in multiple sclerosis (MS) and confers its use as a surrogate marker for axon degeneration.MethodsUsing an animal model of Pelizaeus-Merzbacher disease (shp) bilateral longitudinal measurements of the peripapillary RNFL (spectral-domain OCT), electroretinograms (ERG), and visual evoked potentials (VEP) were performed in affected and control animals from 5 months to 2 years and in individual animals at single time points. Light and electron microscopy of the optic nerve and retina and histomorphometric measurements of the RNFL were compared to OCT data.ResultsOf the shp animals, 17% had an average reduction of OCT RNFL thickness on the superior retinal quadrant compared to controls (P < 0.05). Electroretinograms showed normal photopic A- and B-waves but flash VEPs were disorganized in shp animals. Morphologically, the shp retinas and optic nerves revealed significant RNFL thinning (P < 0.001) without retinal ganglion cell (RGC) loss, decrease total and relative retinal axonal area, and loss of optic nerve axons. There was strong positive correlation between OCT and morphometric RNFL thickness measurements (r = 0.878, P = 0.004).ConclusionThe loss of optic nerve axons demonstrated in the shp model resulted in moderate thinning of the RNFL confirmed by OCT and histology. These results indicate that OCT-derived RNFL measurement can be a useful surrogate biomarker of optic nerve axon loss and potentially disease progression in demyelinating diseases.

Diffusion tensor imaging of the visual pathway in dogs with primary angle‐closure glaucoma

“…Diffusion weighted imaging provides an alternative approach to early evaluation of glaucoma, a group of diseases characterized by the loss of RGCs and their axons. The technique we describe does overcome a major limitation associated with OCT, which is increasingly reported in the veterinary literature for assessment of the retina and ONH 46‐63 . Canine glaucoma is commonly associated with corneal opacities and drug‐induced miosis which both preclude reliable OCT assessment, but do not affect measurements of the white matter tracts using DTI.…”

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

“…These processes are impaired in HET mice and almost absent in KOs , suggesting a key role for Nr2f1 in the maturation of oligodendrocytes and in the myelination process, consistently with a previous report (Yamaguchi et al, 2004 ). Hypomyelination could in turn exacerbate the loss of ON axonal fibers by affecting RGC survival (Teixeira et al, 2016 ). It would be interesting to investigate whether this is a common mechanism happening in other structures, for example in the neocortical white matter, since MRI scans have revealed impaired myelination in some BBSOAS patients (Chen et al, 2016 ; Rech et al, 2020 ).…”

Optical coherence tomography of the retina, nerve fiber layer, and optic nerve head in dogs with glaucoma

“…[23][24][25][26] Despite widespread use of OCT in clinical ophthalmic and optometry settings for people, the use of OCT for assessment of the canine posterior segment remains limited, although its use has been increasingly reported over the last decade. Veterinary use of OCT for assessment of the posterior segment is reported in normal Beagles, 27,28 dogs with Sudden Acquired Retinal Degeneration Syndrome (SARDS), [29][30][31] in research settings investigating diseased retinas, [32][33][34][35][36] in cats, 37,38 and in case reports describing a variety of retinal conditions. 39- 42 Grozdanic et al 43 reported thinning of the inferior retina as measured by OCT following induction of an acute elevation in IOP in normal Beagles.…”