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B. A. Berkowitz, M. Gradianu, S. Schafer, Y. Jin, A. Porchia, A. Kennedy, R. Iezzi, R. Roberts; Prognostic Phenotyping of Retinal Degeneration With Manganese-Enhanced MRI. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2042.
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Manganese-enhanced MRI (MEMRI) is a powerful non-invasive approach for studying intraretinal ionic regulation in models of ocular injury, diabetic retinopathy, retinopathy of prematurity, or choroidal melanoma. In this study, we tested the hypothesis that intraretinal ion dysregulation precedes pathologic retinal thinning and predicts efficacy of a neuroprotective therapy
Four hours post 44 mg/Kg MnCl2 injection i.p., high resolution MEMRI data were collected from over-night dark-adapted male control Sprague Dawley and albino RCS rats before (P17) and during degeneration (P36 and P57). In separate experiments, control rats, with and without repetitive hypoxic preconditioning, were subjected to high intraocular pressure (100 mm Hg) for 60 min followed by 24 hr or 7 days of reperfusion (e.g., ischemia/reperfusion or I/R). Central retinal thickness and intraretinal ion activity were measured from the MEMRI data. Histology examination was also performed to confirm retinal thickness changes.
In both control and RCS rats, developmental retinal thinning (P < 0.05) was readily detected. As expected, by P57 RCS rat retinas were relatively thinner (P < 0.05) than those of the age-matched controls. In control rats, intraretinal manganese uptake remained constant from P17 - P57. In contrast, in RCS rats, post-receptor and photoreceptor uptake of manganese were subnormal (P < 0.05) at P17, and increased (P < 0.05) to control levels by P57. In addition, on the MEMRI exam, only P17 RCS rats were partially light-adapted (P < 0.05) relative to controls. After I/R, significant reductions in MEMRI-retinal thickness were found only at 7 days of reperfusion. After 24 hours of reperfusion, intraretinal manganese uptake was subnormal but returned to control levels (P < 0.05) at 7 days of reperfusion. Preconditioning muted (P < 0.05) manganese uptake in controls, and, following I/R, muted uptake was also associated with significant reductions (P < 0.05) in retinal thinning relative to the I/R-only group.
First time evidence was found, using MEMRI and a non-toxic dose of systemically administered MnCl2, for ionic dysregulation prior to pathologic, but not developmental, retinal thinning, and which could be beneficially altered by repetitive hypoxic preconditioning. These results highlight MEMRI as a powerful approach for the study of neurodegeneration progression and rescue efficacy.
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