Introduction

Age-related maculopathy (ARM) has become a major public health issue in developed countries, as it is the leading cause of blindness in people aged over 65 years.1 The management and treatment of ARM remain an ongoing challenge.2, 3, 4 Its pathogenesis is still unclear and a genetic background together with environmental factors have been discussed.5, 6, 7 Photoreceptor death and vision loss result from subretinal choroidal neovascularization (CNV), from retinal pigment epithelium (RPE) detachment, or from central geographic atrophy in late ARM. These appear to occur in response to deposition of abnormal material within Bruch's membrane, which accumulate during the early course of ARM.8, 9, 10, 11, 12, 13 Current treatment options for ARM are limited, but they can be effective at slowing progression of the disease if applied early.14, 15, 16, 17, 18 It is important to investigate the early stage of ARM as defined by drusen and RPE abnormalities,19 where there is hardly any subjective vision function loss to better understand the pathogenesis and the mechanisms underlying ARM.

It is still not clear whether functional deficits in early ARM measured with various psychophysical tests are primarily caused by reduced sensitivity of photoreceptors,20, 21, 22, 23 by postreceptoral damage21, 24, 25 or by damage to other tissues involved in ARM such as the RPE/Bruch's membrane complex10, 11, 26 or the choroid.27, 28, 29, 30, 31 Knowledge of the primary retinal site affected by ARM would be helpful in targeting the application of future treatments, such as pharmaceuticals, retinal transplants, or computer chips. Earlier detection and diagnosis of retinal changes would improve the efficient implementation of treatments and reduce the number of years individuals live with visual disability and subsequent costs to society, and perhaps lead to preventative treatments.

Psychophysical and electrophysiological function tests in ARM

An extensive overview of the subjective and objective cone- and rod-mediated function tests has been published recently.32, 33 The functional results of these tests cannot be given in detail but all show an impairment of cone- or rod-mediated function (or both) in early ARM. In addition, there is preferential vulnerability of the S-cone34, 35 and rod pathway36, 37, 38, 39, 40, 41, 42 in early ARM over the L- and M-cone pathway. Curcio43 has demonstrated that parafoveal rods were the first to die in early ARM and the last surviving photoreceptor in late ARM was a cone. Most studies have explained their functional findings as being due to an alteration at the photoreceptor level (abnormal orientation or shape or photoreceptor loss) and/or by the kinetic model.21, 25, 34, 41, 44, 45 In contrast to a structural abnormality or loss of photoreceptors that might result in decreased photopigment and photosensitivity, the kinetic model suggests slowed regeneration of photopigment owing to slowed transfer of vitamin A to the retinoid cycle through a thickened Bruch's membrane. The kinetic model proposes that cones and rods have abnormal adaptation and therefore altered recovery dynamics caused by the dysfunction in the photopigment regenerative capacity. This hypothesis would suggest that the amount of abnormal deposits and thus drusen would correlate with poorer recovery dynamics. In fact, the contrary has been shown in a number of studies which report poor correlations between drusen and kinetic measures such as dark-adaptation or glare recovery.46, 47, 48 Elsner and Burns20 hypothesized that decreased photosensitivity did not imply primary damage to Bruch's membrane. They used colour match techniques and demonstrated that decreased photosensitivity of the cone photopigment was not correlated with slowed regeneration kinetics in early ARM. They suggested that the kinetic model does not explain all functional deficits in ARM and that there must be other factors possibly relating to microenvironmental alterations.

Another approach to explain the functional deficits might be related to perfusion abnormalities and ischaemia. Arterial hypertension, atherosclerosis, and hypercholesterinaemia that increase vascular rigidity and their effects on the ocular circulation and Bruch's membrane have been hypothesized to increase the risk for developing ARM.49 Vascular deficits have been identified in early and late ARM using fluorescein and indocyanine green angiography, laser Doppler flowmetry, and colour Doppler imaging.31, 50 Pauleikhoff et al51 demonstrated that prolonged choroidal filling seen on fluorescein and indocyanine green angiography is a clinical marker for diffuse deposits in Bruch's membrane. Grunwald et al50 found that eyes with more advanced ARM fundus features such as drusen, RPE abnormalities, and CNV in the fellow eye tended to show more pronounced decrease in choroidal blood flow. Together with other authors52, 53 they hypothesized that thickening of the RPE/Bruch's membrane complex would increase the distance that oxygen must travel from the choriocapillaris to the retina and that this would reduce the availability of oxygen and important metabolites to the outer retina. A haemodynamic model of ARM has been proposed by Friedman et al27 who hypothesized a progressive decrease in the compliance of the sclera and choroidal vessels, which is initiated by the deposition of lipid in the sclera and Bruch's membrane. This might result in a higher intravascular pressure with decreased ocular perfusion.

The perfusion abnormalities and the haemodynamic model together with the kinetic model suggest that the primary insult causing functional deficits in ARM is caused by lipid deposition within Bruch's membrane. However, we hypothesize a new mechanism in ARM that includes these previous models, but is driven by ischaemia and might explain most of the functional findings; we describe it in a new model (Figure 1a–e).

Figure 1
figure 1

(a–e) Schematic representation of ischaemia postreceptoral model in early ARM.

Full size image

Ischaemia is defined as an imbalance between perfusion and demand for oxygenated blood.54 It is characterized not only by insufficiency of oxygen, but also reduced availability of nutrients and inadequate removal of metabolites.54 We propose that the primary insult causing functional deficits in early ARM is reduced ocular blood flow27, 31 (Figure 1a) resulting in chronic ischaemia of the overlying tissues.50, 52 Reduced ocular blood flow might cause imbalance of vascular growth factors such as vascular endothelial growth factor (VEGF) with diminution of VEGF from the RPE. An extensive review of growth factors involved in ARM has been given elsewhere.53, 55 VEGFs have important roles in vascular permeability angiogenesis, and lymphangiogenesis and have neurotrophic and proinflammatory functions.55 VEGF depletion induces choroidal atrophy55, 56, 57 that might cause a further delay in perfusion. Impaired perfusion might also result in impaired function of the RPE with decreased degradation of photoreceptor disc membranes, reduced antioxidant capacity, and deposition of abnormal extracellular matrix58 and abnormal debris, the basal linear and basal laminar deposits59 possibly triggering an inflammatory response.60 Consequently, increased resistance of the choroid to blood flow by deposition of lipids in the sclera and in Bruch's membrane as hypothesized in the haemodynamic model27 might occur (Figure 1b). The postulation of Bruch's membrane being a barrier has not only been demonstrated morphologically61, 62 but also functionally in early ARM.63 A thickened Bruch's membrane61, 62 may lead not only to reduced diffusion of oxygen50, 53 and thus pronounced ischaemia distal to the membrane but also to an impaired transport capacity of important metabolites to the retinoid cycle (such as vitamin A, trans-retinol). Therefore, the photoreceptor circulation current is altered as synthesis of 11-cis retinal is slowed in the RPE as proposed in the kinetic model43 (Figure 1b). It is likely that the photoreceptors (Figure 1c) are more resistant to ischaemic insults than postreceptoral sites64, 65, 66 (Figure 1d) owing to their proximity to metabolic reserves available in the RPE and the choriocapillaris,66 and this is reflected in less functional alteration. The postreceptoral region is proposed to be particularly vulnerable to ischaemia as it is at the watershed zone between two sources of blood supply; the choroid and the central retinal artery (Figure 1e). It is likely that L- and M-cone pathways are more resistant to hypoxia than S-cone and rod-pathways.67, 68, 69, 70, 71

Discussion

We suggest that in early ARM, the cone- and rod-mediated postreceptoral pathways are primarily affected by chronic ischaemia, before the photoreceptors. Ischaemia might have an effect at the postreceptoral levels as photoreceptors and especially rods act as an oxygen sink66, 71 and the postreceptor region is the watershed zone between two sources of blood supply (choroid and central retinal artery).

Sarks et al (unpublished data) demonstrated that delayed choroidal perfusion on fluorescein angiography corresponded to focal loss and attenuation of the choroidal capillaries. In addition, regions of choroidal capillary dropout relate to diffuse deposits beneath the RPE histologically.72 Sarks and Sarks59 have shown (using electron microscopy) that the RPE cannot exist without the choriocapillaris, and when the RPE degenerates, the first retinal layers affected are the outer plexiform layers and the inner nuclear layer.73

The choroid supplies the overlying retina to a depth of 130 μm including the outer parts the inner nuclear layer (and thus bipolar cells),74 is very susceptible to hypoxia and is thought to regulate oxygen tension poorly.75, 76 It has been suggested that during hypoxia a compensatory increase in choroidal blood flow does not occur and a deficit on the choroidal site is not made up by increased supply from the retinal circulation.77 Yu and Cringle65 and Cringle et al66 showed that there is a high rate of oxygen consumption in the outer and inner plexiform layers where there is high synaptic activity (Figure 1d, e) in animal models. A study involving the rat retina has indicated that there is higher oxygen uptake under light adapted conditions in the inner plexiform layer whereas dark adapted conditions increase oxygen consumption in the outer retina leaving the inner retina unaffected.66 Although there is reduced blood flow in the central retinal artery in ARM27 the inner retinal oxygen tension is better regulated during hypoxia76 with compensatory vasodilatation and increase in blood flow.78 This might be the reason why ganglion cells are better preserved in early ARM.79 However, in more advanced stages of ARM a loss can be also found (Figure 29, p. 571 in Sarks et al73).

Bui et al64 have investigated acute hypoxia with electrophysiological measures such as the full field electroretinogram (ERG) and found an immediate postischaemic postreceptoral b-wave loss, whereas photoreceptor responses were more gradually affected. They suggested that the acute selective postreceptoral loss was due to impaired glutamatergic neurotransmission or failure of glutamate recycling.64 It is known that acute ischaemia causes massive damage to the entire retina histopathologically.80 This is reflected in a postreceptoral-mediated b-wave amplitude loss and possibly amacrine cell-mediated reduction in oscillatory potentials electrophysiologically.80, 81, 82, 83 Chronic (as opposed to acute) ischaemia is less likely to cause massive damage to retinal tissue and a delay in implicit times has been reported.64, 80 For example in diabetes, a chronic ischaemic disease, delayed multifocal electroretinogram (mfERG) peak implicit times but no amplitude loss are seen; these findings predict the onset of diabetic retinopathy before ophthalmoscopically visible changes in subjects with diabetes.84 Sandberg et al85 found delayed implicit times in the focal ERG associated with prolonged choroidal perfusion in ARM eyes at risk, where the fellow eye had developed chorioretinal neovascularization. The authors suggested that delayed implicit times rather than amplitudes reflected chronic retinal ischaemia.85

A postreceptoral involvement of rod pathways as found in studies with the mfERG in early ARM38, 39, 40 is supported by Hood et al86 who compared the rod-mediated mfERG with the full-field rod ERG. They suggested that the rod-mediated mfERG responses are like the full-field rod ERG with mainly bipolar cell responses and a very small photoreceptor contribution.86 The blue–yellow functional loss in early ARM might also reflect ischaemic conditions at postreceptoral levels.69 A selective early loss of S-cone postreceptoral pathways has been shown in other ischaemic diseases such as, for example, in diabetes with69, 87 or without retinopathy.87, 88 Additional evidence of primary postreceptoral involvement might be reflected by impaired high contrast-, low contrast-, low luminance (SKILL) visual acuity and contrast sensitivity as demonstrated in other studies in early ARM.21, 89 Although these are mainly L- and M-photoreceptor properties, a loss of these functions is thought to relate to decreased efficiency in lateral inhibitory mechanisms that are mediated by horizontal and amacrine cells at the postreceptoral level (Figure 1d and e).90, 91

Most recently Arden et al71 have proposed a hypothesis based on a similar vicious cycle caused by ischaemia in ARM but mainly driven by the high oxygen consumption of the rods. The preferential vulnerability of rod pathways in ARM is supported by various psychophysical and electrophysiological studies.36, 38, 39, 44, 92 Arden et al71 suggested a primary defect in the RPE causes diminution of VEGF to the choriocapillaris which results in its atrophy. Also, Schlingemann53 suggested a disturbance of the paracrine relationship between the RPE and choriocapillaris. However, it is unclear which event occurs first, a primary defect at the RPE level53, 71 or reduced ocular blood flow as suggested in our model. Nevertheless they all suggest an inevitable cycle driven by ischaemia. In the longer term chronic ischaemia that is caused by reduced oxygen supply to the choroid and reduced oxygen delivery to the retina might result in an upregulation of VEGF93 and well known consequences causing late ARM with chorioretinal neovascularization.94 Expression of some growth factors is stimulated by hypoxia, and their localization within choroidal neovascular membranes suggests that hypoxia may be an aetiologic factor for CNV. In studies of autopsy eyes, VEGF levels were found to be elevated in the RPE and choroidal blood vessels of maculae with age-related macular degeneration.95, 96 Most recent and promising clinical trials with anti-VEGF aptamer97 and anti-VEGF antibody98, 99 show improvement of vision and therefore demonsterate that there is a strong link to ischaemia in ARM.

Recent work suggests that a chronic inflammatory response and complement factor H (a major regulator of the alternative complement pathway and defence system against inflammation) play important roles in the pathogenesis of ARM.7, 100, 101, 102 It has been demonstrated that a polymorphism in the complement factor H gene makes a substantial contribution to ARM susceptibility. Cigarette smoke influences the plasma levels of factor H and has been shown to inhibit its activity. The relationship between smoking and ischaemic diseases103, 104 and between smoking and ARM105 is well established. It could be hypothesized that chronic ischaemia in combination with genetic predisposition7, 100, 101, 106 might trigger ARM and chronic inflammation.

We hypothesize that early function changes in ARM are initiated by chronic ischaemia of postreceptoral layers such as inner nuclear and possibly inner plexiform layers. This ischaemia affects primarily S-cone and rod-mediated postreceptoral pathways first owing to their lower resistance to ischaemia compared to L- and M-cone pathways. Although cone- and rod-mediated impairment at photoreceptor level, as speculated from the psychophysical results found in other studies,21, 36, 37, 41, 107, 108 cannot be excluded, our model would suggest that this happens later in the course of the disease, possibly when ischaemia becomes prolonged and insufficient Vitamin A is provided through the thickened RPE/Bruch's membrane complex.

Conclusion

Early detection of impaired postreceptoral function before there is severe photoreceptor involvement and vision loss could lead to early commencement of treatment. However, whether an approach in the treatment of early ARM might include supplemental oxygen still needs to be investigated. There is some support for such an approach; improvement of diabetic cystoid oedema after oxygen therapy, as measured with the optical coherence tomography has recently been demonstrated.109 Use of supplemental oxygen as a treatment for ARM is not new110, 111 but large clinical trials have never been initiated to show its possible beneficial effect.