34
With the advancement of age, both the thickness and
complexity of Bruch’s membrane increase primarily due
to extracellular matrix remodelling and accumulation of
inclusions in this region
(10)
. Bruch’s membrane calcifies
and doubles in thickness between the ages of 10 and 90
years
(10)
. There is a linear thickening due to deposits of
collagen, lipids and debris. After the 30’s its lipid concen-
tration increases during life and consequently the fluid
permeability and nutrient transport across the membrane
decreases
(11)
. In normal conditions Bruch’s membrane acts
as an intercellular matrix regulating survival of adjacent
RPE and choriocapillaris cells. Its diminished function
results in apoptosis of these cells from incorrect cell adhe-
sion
(12)
. On the other hand extracellular deposits around
Bruch’s membrane instigate chronic inflammation, inva-
sion by dendritic cells and release of inflammatory cy-
tokines, angiogenic factors and immune complexes
(13,14)
.
The RPE is a monolayer of regularly arranged hexago-
nal cells that spans the retina from the margins of the
optic disc anteriorly to the ora serrata. The number of
RPE cells diminishes with age. Macular RPE cells be-
come wider, flatter and increase in height with advanc-
ing age
(4,15)
. In each RPE cell there is a progressive accu-
mulation of lipofuscin during life and in people over 80
years of age, the debris can occupy more than one fifth
of the total volume of an RPE cell
(16)
. RPE cells have a
brown color in young eyes but with age, they become
increasingly more golden colored, owing to the accumu-
lation of lipofuscin pigment granules
(17)
. Lipofuscin in
the RPE is the source of fundus autofluorescence. The
major component of lipofuscin is N-retinylidene-N-reti-
nylethanol-amine (A2E) a retinoid product of the visual
cycle
(18)
. The A2E produced interferes with the function
of RPE cells, leading to its apoptosis and subsequent
geographic atrophy
(19)
. Age-related changes also include
a decrease in the number of melanin granules, loss of
basal digitations and irregularity in shape. The RPE cells,
become separated from their basal membrane by mem-
branous debris and abnormal secretory products and,
subsequently occurs deposition of collagen and fibro-
nectin and latter formation of basal laminar deposits
(20)
.
Basal laminar deposits are composed of basement mem-
brane protein and long-spacing collagen located between
the RPE plasma and basement membranes
(21)
. Basal lam-
inar deposits are considered the precursors of age-related
macular degeneration and can appear around the age of
40 years
(22)
.
Basal linear deposits consist of granular, vesicular or
membranous lipid-rich material located external to the
basement membrane of the RPE, in the inner collage-
nous layer of Bruch’s membrane, and represent a specific
marker of AMD
(23)
.
These two types of deposits can only be shown on patho-
logical specimens and not by clinical evaluation
(19)
.
The combination of the deposits with secondary changes
in the RPE results in the formation of drusen. Drusen are
localized deposits of extracellular material lying between the
basement membrane of the RPE and the inner collagen
layer of Bruch’s membrane
(20,24)
. Drusen often have a core of
glycoproteins but they also contain fragments of RPE cells,
crystallins, apolipoproteins B and E, and proteins related
to inflammation such as amyloid P and ß, C5 and C5b-9
complement complex
(25-28)
.
Drusen change in size, shape, color, distribu-
tion and consistency with the passing years
(29)
.
Small drusen are defined as being less than 63μm
in diameter
(30)
. The presence of small, hard dru-
sen alone is not sufficient to diagnose early AMD.
These deposits are ubiquitous and the new develop-
ment of small drusen in an adult eye without prior
evidence of hard drusen is not age dependent
(31)
.
Hard drusen are discrete nodules or deposits composed
of hyaline-like material. During fluorescein angiography
hard drusen behave as pin-point window defects
(32)
.
Soft drusen are larger and associated with pigment epi-
thelium detachment and diffuse abnormal Bruch’s mem-
brane alterations
(33,34)
. Soft drusen have a tendency to
cluster and merge with one another demonstrating con-
fluence
(32)
. During fluorescein angiography soft drusen
hyperfluoresce early and either fade or stain in the late
phase
(5)
.
Drusen can be visible in ophthalmoscopy when their di-
ameter exceeds 25μm as dots ranging in color from white
to yellow
(6)
. However soft drusen are clinically identified
whenever there is sufficient RPE hypopigmentation or
atrophy overlying diffuse Bruch’s membrane thickening,
or, when there are focal detachments within this mate-
rial. These findings suggest that the clinical identification
of soft drusen identifies an eye with diffuse changes at the
RPE-Bruch’s membrane complex
(32)
. When they become
larger (>125μm), and greater the area that they cover, the
risk of late AMD becomes higher
(35)
.
The RPE degeneration and non-geographic atrophy of the
RPE are characterized by pigment mottling and stippled
hypopigmentation with thinning of the neurosensory
retina
(36)
. Histopathology shows mottled areas of RPE hy-
popigmentation or atrophy overlying diffuse basal linear
and basal laminar deposits
(33)
. Incidence and prevalence
rates of RPE depigmentation are age dependent
(31)
. Focal
hyperpigmentation of the RPE, clinically evident as pig-
