Manganese-enhanced MRI of the DBA/2J mouse model of hereditary glaucoma.

Preventing vision loss in glaucoma has been limited by the inability of currently available methods, such as electroretinography (ERG) and ocular coherence tomography (OCT), to assess regional prehistologic retinal changes leading to irreversible degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve.1-3 In other words, interventions based on irreversible structural changes are likely to be applied late in the degenerative process and so may, at best, be expected only to minimize additional losses. Methods that are more sensitive to glaucoma-related changes in retinal physiology may allow for earlier intervention and thus could be more effective in improving therapeutic outcome. The pathophysiology of glaucoma is not well understood, although current evidence strongly supports the concept that abnormal regulation of ionic activity leading to calcium overload is an apoptotic triggering event linked with retinal ganglion cell demise4-7 and optic nerve degeneration.8,9 Studies of pressure-related ischemic injury at the nerve head indicate that influx of extracellular Ca2+ into the RGC axoplasm is critical to disease from ischemic insult.10 In indirect support of this idea, drugs used to lower IOP or reduce vasoconstriction in glaucoma also have a secondary action on RGCs by modulating accumulation of intracellular Ca2+.11 For example, nonselective β-adrenoceptor antagonists blunt the influx of both Na+ and Ca2+ into RGCs.5 Also, betaxolol, a β1-antagonist, is highly effective at reducing Ca2+ influx to RGCs induced by glutamate receptor agonism.12 These data suggest that monitoring ion flux may be a promising diagnostic and/or prognostic parameter in glaucoma. Manganese-enhanced MRI (MEMRI) allows for noninvasive and simultaneous measurement of ocular anatomy, including structures expected to be targets of glaucomatous damage (e.g., ciliary body area, iridocorneal angle, ocular perimeter, and retinal thickness). It also allows for assessment of structure-specific uptake of the manganese (Mn2+) ion after systemic MnCl2 injection.13-16 The Mn2+ ion is an MRI contrast agent and analogue of, for example, Ca2+; readily accumulates intracellularly as a function of membrane integrity and cellular activity; and is relatively slowly removed.17-21 We have shown that intraretinal manganese uptake reflects dysfunctional retinal ion activity before and during retinopathy in experimental rat models, including two models of retinal degeneration.13-16 These data also suggest a possible role of intraretinal ion dysregulation in the formation of retinal histopathology. The potential value of applying MEMRI to glaucoma has only begun to be explored.9 In this study, we tested the hypothesis that MEMRI can be useful for addressing the knowledge gaps by evaluating in young and aged C57BL/6 and DBA/2J mice the differences in ocular anatomy and intraretinal ion activity. The DBA/2J mouse is a model of hereditary glaucoma in which RGC axonal degeneration in the optic nerve is associated with age-dependent elevations in IOP that are normally absent in other mouse strains.22-26 These elevations arise from closure of the drainage canals in the anterior segment induced by iris atrophy and pigment dispersion that are caused by mutations in the Tyrp1 and Gpnmb genes, respectively.26-28 This ocular phenotype presents prominently in many DBA/2J mice by 4 to 6 months and increases in probability of occurrence with increasing age.25,26,29 However, at each age, even in older animals, there is considerable variability in the degree of ocular and nerve disease.25