CONTRAST ENHANCED MRI OF EXPERIMENTAL UVEITIS

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The long-term objective of this proposal is to demonstrate that contrast- enhanced proton magnetic resonance imaging (1H MRI) can be used as a quantitative, non-invasive method for the study of normal and abnormal ocular processes. We have chosen experimental anterior uveitis as the condition through which to demonstrate this. Contrast in MR images results from the tissue variations of the inherent relaxation times (T1 and T2) of the protons in water molecules. The development of contrast agents, compounds that alter these protons' inherent relaxation rates (T1-1 and T2-1) has led to new types of studies; most recently contrast agents have been used to study dynamic ocular processes such as aqueous humor flow, molecular diffusion between the ciliary processes and the anterior chamber and permeability of the blood-retinal barrier. MRI allows the three-dimensional localization of such dynamic ocular processes, even in structures, such as the posterior chamber, unobservable by other in vivo methodologies. Idiopathic anterior uveitis (AU) is a sterile, non-suppurative inflammation of the anterior uvea. AU reflects a breakdown of the blood- aqueous barrier (BAB) that is characteristically acute and often recurrent. Currently available objective measures of severity provide little information regarding the dynamics of the inflammatory process, especially the process of BAB repair during resolution. Knowledge of these processes depends on a thorough understanding of protein diffusional mechanics in the normal and inflamed eye. To achieve our goals, contrast agents of protein-like molecular weights will be synthesized. The concentration dependence of their T1- or T2- relaxivities and MR image intensity enhancements will be determined. We will complete sequential contrast-enhanced MRI studies to monitor BAB permeability at several stages during the resolution phase of untreated and treated (using representative steroidal and non-steroidal anti- inflammatory agents) endotoxin-induced AU in rabbits. We will use our MRI data, combined with aqueous fluorophotometry and morphology data, and with computational models for the anterior diffusional pathway to assess the extent and location of disruption of the BAB by AU. We will determine if medications alter the mechanics of BAB repair or merely shorten its time course, and whether differences exist between the permeability of treated versus untreated eyes after clinical resolution of anterior uveitis. Using MRI for these studies affords us the unique opportunity to estimate whether these anti- inflammatory agents affect primarily vascular endothelia or ciliary epithelium by discerning whether leakage relents in the posterior chamber before or after it relents in the anterior chamber.