The pathogenesis of age-related macular degeneration (AMD) is unknown, but clinical evidence strongly suggests that the lesion resides in the retinal pigment epithelium (RPE). The onset of the disease occurs when, and where, the RPE cells have high intracellular deposits of a fluorescent 'age pigment' called lipofuscin, and it has been hypothesized that high levels of lipofuscin contribute to the pathogenesis of AMD. Clinical study of early AMD has been limited by the inability to detect either lipofuscin or the deposits in Bruch's membrane that are eventually visible as drusen (the earliest clinical sign of the disease). The role of lipofuscin is under active biochemical and morphological investigations; the recent development of noninvasive measurement of lipofuscin has made it feasible to extend these efforts to clinical studies. Noninvasive studies in normal subjects have demonstrated that lipofuscin accumulates with age and that its variability is greater in older subjects, supporting the possibility that high lipofuscin could be an indicator of risk for AMD. Studies in AMD patients demonstrate that lipofuscin falls significantly as disease progresses. Preliminary studies on the fluorescence of drusen suggests they can be measured clinically. Noninvasive estimates of lipofuscin and drusen may prove powerful in early diagnosis, prognosis, and the evaluation of treatments intended to prevent or slow the progression of AMD.
The specific aims of the proposed research are: (1) Further characterize the green fluorescence associated with drusen in AMD, compare this fluorescence with that of drusen in donor eyes, and identify optimal conditions for specific measurement of drusen. (2) Determine the contributions of fluorophores (Bruch's membrane, FAD) and absorbers (macular pigment, RPE melanin) to the lipofuscin measurement at the fovea and perifovea, thus facilitating detailed mapping of lipofuscin in the retinal region at greatest risk for early AMD. (3) Evaluate, in a cross- sectional study of normal volunteers, the association of several factors (Vitamin supplementation, antioxidants, ocular pigmentation, smoking, macular pigment concentration) with the accumulation of lipofuscin. Acquire preliminary data on the expected longitudinal change in lipofuscin, including data on intra-subject variability over extended time periods. (4) Evaluate, in a cross sectional study of patients with AMD, the association of disease characteristics and severity with the fluorescence of lipofuscin and/or that of drusen deposits. Measure detailed fluorescence profiles across drusen and at the edges of areas with atrophy. (5) Complete a pilot study of lipofuscin in Stargardt's disease. Study the fluorescence and reflectance characteristics in patients with/without dark choroid and on/off flecks to better understand their nature.
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