Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study

Abstract

Aim-To describe the early formation of drusen and their relation to normal aging changes at the macula and to the development of age related maculopathy (ARM). Method-Histopathological features of 353 eyes without histological evidence of ARM are described and correlated with the clinical appearance. In addition, 45 of these eyes were examined by transmission electron microscopy. Results-Drusen were detected histopathologically in 177 (50%) eyes but were seen clinically in only 34% of these. Drusen were mainly small hard drusen with an occasional soft distinct drusen: no soft indistinct drusen were seen. Only those drusen deposits larger than 25-30 µm in diameter were detectable clinically. Preclinical drusen in eyes with only an occasional drusen were seen on electron microscopy as entrapment sites of coated membrane bound bodies which formed adjacent to the inner collagenous zone of Bruch's membrane. In contrast, preclinical drusen deposits in eyes with many drusen were seen as accumulations of amorphous material which appeared hyalinised by light microscopy. A distinct feature were rows of dense hyalinised microdrusen (1-2 µm in diameter), over which larger globular hyalinised drusen formed. Conclusion-Histological and ultrastructural examination can recognise and distinguish the earliest drusen formed as a result of normal aging from those associated with ARM. In eyes without diVuse deposits, histologically all drusen were of the hard hyalinised variety or their derivatives; no soft drusen composed of membranous debris were found. These findings support and explain those of other authors who do not consider the presence of a few small hard drusen to be a risk factor for the development of ARM. (Br J Ophthalmol 1999;83:358-368)

Age-related changes in human macular Bruch's membrane as seen by quick-freeze/deep-etch

“…In another study, Pauleikhoff et al (1990) indicated the appearance of small membrane-bound vesicles and membrane fragments. Other studies also reported membranous debris (Curcio and Millican 1999;Curcio et al, 2005a), long spacing collagens (Sarks, 1976;van der Schaft et al, 1991), drusen (Green and Enger, 1993;Sarks et al, 1999;Hageman and Mullins, 1999)), and fine granules in BrM (Killingsworth, 1987;Curcio and Millican 1999). In our studies, we found three types of inclusions in QFDE images: LLPs, SGs, and membrane-like structures.…”

“…As only one drusenoid structure was observed in QFDE preparation of our study, its morphological features could not represent all types of drusen described in other studies (Green et al, 1985;Green and Enger, 1993;Sarks et al, 1999;Hageman and Mullins, 1999). Nevertheless it fits the characteristics of "entrapment site", a phenotype of CMBBs described in eyes with clinically undetectable drusen (Sarks et al, 1999).…”

“…Nevertheless it fits the characteristics of "entrapment site", a phenotype of CMBBs described in eyes with clinically undetectable drusen (Sarks et al, 1999). It has been suggested that the formation of the drusen is caused by CMBBs unable to penetrate the tightly woven collagens of the ICL (Sarks et al, 1999).…”

“…Nevertheless it fits the characteristics of "entrapment site", a phenotype of CMBBs described in eyes with clinically undetectable drusen (Sarks et al, 1999). It has been suggested that the formation of the drusen is caused by CMBBs unable to penetrate the tightly woven collagens of the ICL (Sarks et al, 1999). However, our findings of CMBBs in all three middle layers of BrM indicated either the CMBBs were mobile in spite of their relatively large size, or that this type of inclusions was formed locally via some unknown mechanism.…”

Structures and biogenetic analysis of lipofuscin bis-retinoids

“…Time-dependent lipofuscin accumulation in retinal pigment epithelial (RPE) cells has been notoriously deemed as a major risk factor in association with age-related macular degeneration (AMD) (Bressler et al, 1988;Eldred and Katz, 1988;Eldred and Lasky, 1993;Kliffen et al, 1997;Sarks et al, 1999;Delori et al, 2000). AMD, the leading cause of blindness in elderly people, is a degenerative disease of the eye (Bressler et al, 1988;Mata et al, 2000;Telander, 2011), for which there is thus far no remedy.…”