The accumulation of the age pigment lipofuscin within the retinal pigment epithelium (RPE) is one the most remarkable changes observed in association with age-related macular degeneration (AMD) and Stargardt disease. Both aging and pathological processes lead to the accumulation of melanolipofuscin (MLF) granules, which have been reported to reflect the onset of AMD more accurately than lipofuscin. The underlying mechanism by which MLF forms is still not understood. We investigate the potential role that melanin plays in the degradation of lipofuscin and MLF in pigmented Abca4-/- mice following treatment with several NO generating drugs. Abca4-/- mice are generally used as models for lipofuscin-related eye diseases. We also induced melanogenesis in albino Abca4-/- mice via the over-expression of tyrosinase, the key enzyme involved in melanogenesis. We compared the ultrastructure of lipofuscinogensis in the RPE of pigmented and albino Abca4-/- mice. Fluorescence microscopy was employed for the quantification of lipofuscin. We found high amounts of unique thin (3-4 nm) lamellar membranes (TLMs) that were left over from the degradation of photoreceptor disc membranes by high-resolution electron microscopy. Accumulated TLMs were significantly more frequent in the RPE cells of the albinos than the pigmented mice, indicating that melanin plays a role in removing TLMs. The intravitreal injection of several NO generating drugs was found to reduce the amount of autofluorescent lipofuscin in the cytoplasm of RPE cells, particularly the MLF granules of pigmented Abca4-/- mice. No effect was observed in terms of lipofuscin removal in NO-exposed albino Abca4-/- mice. However, transfection with tyrosinase led to a reduction in the lipofuscin levels of artificially pigmented RPE cells in albino Abca4-/- mice following the formation of melanin. The results show for the first time that melanin plays an important, if not a key, role in the degradation of lipofuscin in RPE cells.

Aims: To analyze ocular fundus characteristics of patients finally diagnosed with fibrinous central serous chorioretinopathy (CSC) using multimodal imaging and compare the characteristics with images of other confusable exudative maculopathies. Methods: We retrospectively reviewed the records from 189 patients with CSC and found records on 16 patients with fibrinous CSC. Some of these 16 patients were misdiagnosed with another exudative maculopathy and were treated inappropriately. Multimodal imaging comprised fundus photography, spectral-domain optical coherence tomography (OCT), fluorescein angiography (FA), indocyanine green angiography (ICGA), and OCT angiography (OCTA), and the results were compared with those of other exudative maculopathy patients from this study. Results: Twenty-one eyes of 16 patients with a mean age of

Age-related macular degeneration, Stargardt disease, and their Abca4 -/- mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O 2 •– ) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O 2 •– or nitric oxide ( • NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O 2 •– plus • NO creates a dioxetane on melanin that excites its electrons to a high-energy state (termed “chemiexcitation”), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.

AIM: To quantitatively analyze the retinal intermediate and deep capillary plexus (ICP and DCP) in patients with retinal deep vascular complex ischemia (RDVCI), using 3D projection artifacts removal (3D PAR) optical coherence tomography angiography (OCTA). METHODS: RDVCI patients and gender- and age-matched healthy controls were assessed and underwent OCTA examinations. The parafoveal vessel density (PFVD) of retinal deep vascular complex (DVC), ICP, and DCP were analyzed, and the percentage of reduction (PR) of PFVD was calculated. RESULTS: Twenty-four eyes in 22 RDVCI patients (20 in acute phase and 4 in chronic phase) and 24 eyes of 22 healthy subjects were enrolled as the control group. Significant reduction of PFVD in DVC, ICP, and DCP was observed in comparison with the controls (DVC: acute: 43.59%±6.58% vs 49.92%±5.49%, PR=12.69%; chronic: 43.50%±3.33% vs 51.20%±3.80%, PR=15.04%. ICP: acute: 40.28%±7.91% vs 46.97%±7.14%, PR=14.23%; chronic: 41.48%±2.87% vs 46.43%±3.29%, PR=10.66%. DCP: acute: 45.44%±8.27% vs 51.51%±9.97%, PR=11.79%; chronic: 37.78%±3.48% vs 51.73%±5.17%, PR=26.97%; all P<0.05). No significant PR difference was found among DVC, ICP, and DCP of RDVCI in acute phase (P=0.812), but significant difference in chronic phase (P=0.006, DVC vs DCP, ICP vs DCP). No significant difference in PR between acute and chronic phases in the DVC (P=0.735) or ICP (P=0.681) was found, but significant difference in the DCP (P=0.041). CONCLUSION: The PFVD of DVC, ICP, and DCP in RDVCI is significantly decreased in both acute and chronic phases. ICP impairment is stabilized from acute to chronic phase in RDVCI, whereas subsequent DCP impairment is uncovered and can be explained by ischemia-reperfusion damage.