A multi-centre database for clinical and molecular analysis of age-related macular degeneration

Age-related maculopathy (ARM) represents a group of degenerative disorders of
the macula that are increasingly frequent after 55 years of age. Early ARM is
defined as the presence of (soft) drusen and pigmentary abnormalities of the
retinal pigment epithelium. The late stage of ARM is similar to age-related
macular degeneration (AMD) and includes both geographic atrophy (*dry* AMD) and
neovascular or exudative (*wet*) AMD. Overall, the AMD phenotype is highly
diversive and ranges from minor atrophic changes in the retinal pigment
epithelium and associated neurosensory detachment to subretinal hemorrhages and
large disciform lesions extending beyond the vascular arcades.

The prevalence of AMD is about 1.5% in subjects over the age of 50 and
increases up to 20% in subjects over the age of 80. The prevalence of AMD is
expected to double within the next 15 years. AMD is currently the leading cause
of legal blindness in the Western World, and as such the subject of numerous
studies. Population-based, cross sectional and epidemiologic studies have
provided us with an enormous amount of data concerning incidence, prevalence
and risk factors with regard to AMD. At present, an increasing number of
studies are directed at unravelling the pathophysiology of AMD. Closely related
to this subject are the ongoing molecular genetic studies aimed at identifying
underlying genetic factors. Over the last years, the development of several new
and promising pharmacotherapeutic approaches has culminated in a variety of
therapeutic trials.

For these and future studies, the availability of clinically well-defined,
homogeneous AMD patient groups is crucial. Since AMD most likely represents a
group of disorders sharing phenotypic similarities, study designs that
incorporate clinically homogenous patient groups will have a greater likelihood
of identifying significant correlations. In this, the development of a
multi-centre database with large numbers of AMD patients will be instrumental
in future studies on the pathophysiology, as well as the genetic and
environmental factors of this multifactorial disease. In addition, the
collaboration of various centres in the AMD database enables the quick
evaluation of new therapeutic regimens in large, well-described (sub)groups of
AMD patients.

Our research proposal has several aims:
1) We propose to use large-scale genetic studies to identify allelic variants
that influence the development of AMD, which will enable the development of
diagnostic and prognostic tools in the near future.
2) Knowledge of susceptibility factors for AMD will allow us to identify
cellular pathways that are involved in the development of AMD.
3) The innate immune response, orchestrated by toll-like receptors (TLR) and
mediated by the complement components, is likely to play a crucial role in the
initiation and/or perpetuation of AMD. Since TLR and their intracellular
signaling pathways are currently well-known pharmaceutical targets, we will
decipher the potential role of TLR in AMD.
4) The identification of new cellular pathways and the role of TLR signaling
will help us to understand the pathogenesis of AMD and to develop new leads for
preventive and therapeutic strategies.

Data collection. Participating centres are required to collect a small number
of clinical data as well as blood samples for each AMD patient that will be
included (see Supplement). Most of the data can be obtained with the standard
ophthalmologic examination. In addition to the blood samples, the only
additional discomfort to the patient will be the completion of a questionnaire
concerning their general and medical history and a standard fundus photograph.
The questionnaire will be completed in an interview by a trained person. The
blood samples will be stored at the departments taking part in the study. We
aim to collect overall 3000 - 5000 patients and 500 age-matched control
individuals.

Specific research projects may require additional investigations besides the
minimally required data specified in the supplement. Examples of additional
data that may be collected by participating centres with the proper resources
include (high-speed) fluorescein angiography and/or indocyanine angiography,
OCT, fundus autofluorescence, measurements on macular pigment density and
treatment data.

All study protocols regarding blood samples and DNA extraction, as well as the
various imaging techniques can be found in supplement II and III.

Database structure. The clinical data and the fundus photographs of the AMD
patients will be entered into a specificially designed database. A web based
application would be preferable providing that the safety issues can be solved.

not applicable