Age-related maculopathy – Linking aetiology and pathophysiological changes to the ischaemia hypothesis

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Abstract

Age-related maculopathy (ARM) has remained a challenging topic with respect to its aetiology, pathomechanisms, early detection and treatment since the late 19th century when it was first described as its own entity. ARM was previously considered an inflammatory disease, a degenerative disease, a tumor and as the result of choroidal hemodynamic disturbances and ischaemia. The latter processes have been repeatedly suggested to have a key role in its development and progression. In vivo experiments under hypoxic conditions could be models for the ischaemic deficits in ARM. Recent research has also linked ARM with gene polymorphisms. It is however unclear what triggers a person's gene susceptibility. In this manuscript, a linking hypothesis between aetiological factors including ischaemia and genetics and the development of early clinicopathological changes in ARM is proposed.

New clinical psychophysical and electrophysiological tests are introduced that can detect ARM at an early stage. Models of early ARM based upon hemodynamic, photoreceptor and post-receptoral deficits are described and the mechanisms by which ischaemia may be involved as a final common pathway are considered. In neovascular age-related macular degeneration (neovascular AMD), ischaemia is thought to promote release of vascular endothelial growth factor (VEGF) which induces chorioretinal neovascularisation. VEGF is critical in the maintenance of the healthy choriocapillaris. In the final section of the manuscript the documentation of the effect of new anti-VEGF treatments on retinal function in neovascular AMD is critically viewed.

Introduction

A manuscript on age-related maculopathy (ARM) often starts with the statement “ARM is the most common cause of blindness in people over 60 years of age in the Western world.” While writing this, an author may admit that there is no better introductory sentence. However, research in the late 19th century also recognized that ARM is one of the most challenging entities regarding its aetiology, pathomechanisms and treatment. This manuscript combines different research views on ARM in the light of ischaemia. The role of hemodynamic changes, ischaemia and oxidative stress in ARM has been long recognized (Fuchs, 1893, Kornzweig, 1977, Friedman et al., 1995, Grunwald et al., 1998, Beatty et al., 2000, Schlingemann, 2004). More recently, exciting advances have been made in genetic research (Edwards et al., 2005, Hageman et al., 2005, Haines et al., 2005, Klein et al., 2005, Zareparsi et al., 2005) and in the development and application of diagnostic functional tests that detect ARM at an early stage (Phipps et al., 2004, Feigl et al., 2005a; Dimitrov et al., 2007).

Section snippets

Terminology: is it ARM or AMD?

There is controversy in the literature regarding the use of the terms age-related maculopathy (ARM) and age-related macular degeneration (AMD). Gass (1967) used the term AMD and divided the condition into (1) a predisciform stage with drusen, (2) an occult choroidal neovascularisation where new vessels grow from the choroid into the subretinal pigment epithelium (RPE) space and (3) a disciform detachment stage where there is subretinal neovascularisation with serous or hemorrhagic detachment of

Histopathology

Several distinct clinical features can be identified in ARM: drusen (formerly called colloid bodies), pigmentary changes, atrophic areas as well as serous and haemorrhagic pigment epithelial and retinal detachment due to choroidal neovascularisation. The underlying histopathological mechanisms resulting in these changes are only partly understood. It is known that histopathological changes involve the choroid and choriocapillaris, the RPE, Bruch's membrane (Ruysch's complex) as well as the cone

Aetiology

A large number of reviews on ARM and its aetiology have been published (Young, 1987, Ambati et al., 2003, de Jong, 2006, Jager et al., 2008). Theories of the aetiology of ARM include primary hydrodynamic changes in Bruch's membrane and the senescence of the RPE. The decline in the hydraulic conductivity of Bruch's membrane is caused by a progressive accumulation of extracellular material containing lipid. The extracellular material is thought to be derived from the RPE (Hogan, 1972,

Linking hypothesis in ARM

The current data support the proposal that ARM might be an ocular manifestation of a systemic response. It has been suggested that a genetic susceptibility might cause an overactive immune and inflammatory response which leads to the formation of drusen (Hageman et al., 2001, Donoso et al., 2006). The primary insult or trigger is not known, however. While an infectious agent such as Chlamydia pneumoniae has been suggested (Kalayoglu et al., 2003, Baird et al., 2008), this result was not

Electrophysiological and psychophysical assessment of early age-related maculopathy

Identifying the association between risk genes and outcomes on clinical tests will be central for identifying early stages and subtypes of the condition before its manifestation (for a review of clinical tests in ARM, see Hogg and Chakravarthy, 2006). One of these test batteries might involve studies with dark adaptometry and electrophysiology. Recent dark adaptometry studies have revealed different patterns of rod and cone dynamics in ARM patient (Dimitrov et al., 2008), and suggest that

Models in early ARM

It is not clear whether functional deficits in early ARM as measured with psychophysical and electrophysiological tests are primarily caused by abnormalities of the photoreceptors (Smith et al., 1988, Elsner et al., 2002, Zele et al., 2006) or by post-receptoral damage (Phipps et al., 2003, Feigl et al., 2007a). Knowing the primary site affected in early ARM and having a psychophysiological measure of this site would assist in the early detection of the disease, in monitoring progression and

Treatments targeting ischaemia in neovascular AMD

The growth of new vessels is closely controlled by pro-angiogenic and anti-angiogenic factors with VEGF as prime regulator of angiogenesis (Ferrara, 1999). Pro-angiogenic factors include VEFG, fibroblast growth factor, angiopoietins, transforming growth factor alpha and beta, hepatocyte growth factor, connective tissue growth factor and interleukin-8. Anti-angiogenic factors include thrombospondin, angiostatin, endostatin and pigment epithelium derived factor (for review, see Lee et al., 1998,

Future directions

Future directions in ARM will be diverse and perhaps controversial. They will be diverse in so far as better electrophysiological and psychophysical diagnostic methods may allow functional documentation of the retina that will be incorporated into routine clinical examinations. Better diagnostic methods can help detecting the disease earlier than commonly used functional tests such as visual acuity but will also be critical for monitoring treatment outcomes and especially for clinical trials.

Acknowledgements

My special thanks go to Shirley Sarks, Amanda Greaves, Jan Lovie-Kitchin, Anton Haas and Andrew J. Zele for their valuable discussions.

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