Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

rods helps to closely regulate the synaptic threshold for neurotransmitter release, to provide maximal gain for transmitting the tiny single-photon signal. Corroborating evidence for this role exists in recordings from ganglion cells at scotopic backgrounds where the antagonistic receptive field surround has been reported as hidden (summing nonlinearly with the receptive field center) and is only evident when a light stimulus is also applied to the center. This would be expected in the case where negative feedback from the HBat to the rod must pass through the rod synapse’s nonlinear threshold to be sensed by the rod bipolar pathway.

Conclusion

The rod functions both at night and in twilight, but is specialized to transduce signals over the scotopic range of illuminance from starlight to moonlight where photons are rare. The single-photon signal is tiny and would be swamped by the dark continuous noise present in a large array of rods, but the rod ribbon synapse contains several mechanisms to reduce the noise and amplify the singlephoton signal. Horizontal cells are thought to provide negative feedback at the rod synapse, and may provide a means to regulate the presynaptic release of neurotransmitter to optimize the single-photon signal. The balance between signal and noise in the rod’s signal processing mechanisms is delicate. However, the rod’s striking ability to capture and transmit single-photon signals suggests that each of its components has a specific function, and that biology has found for each a nearly optimal solution.

Acknowledgment

This work was supported by NEI grant EY016607.

See also: The Physiology of Photoreceptor Synapses and Other Ribbon Synapses; Rod and Cone Photoreceptor Cells: Inner and Outer Segments.

Further Reading

Berntson, A., Smith, R. G., and Taylor, W. R. (2004). Postsynaptic calcium feedback between rods and rod bipolar cells in the mouse retina. Visual Neuroscience 21: 913–924.

Berntson, A., Smith, R. G., and Taylor, W. R. (2004). Transmission of single photon signals through a binary synapse in the mammalian retina. Visual Neuroscience 21: 693–702.

Field, G. D., Sampath, A. P., and Rieke, F. (2005). Retinal processing near absolute threshold: From behavior to mechanism. Annual Review of Physiology 67: 491–514.

Hagins, W. A., Penn, R. D., and Yoshikami, S. (1970). Dark current and photocurrent in retinal rods. Biophysical Journal 10: 380–412.

Heidelberger, R., Thoreson, W. B., and Witkovsky, P. (2005). Synaptic transmission at retinal ribbon synapses. Progress in Retinal and Eye Research 24: 682–720.

Hsu, A., Tsukamoto, Y., Smith, R. G., and Sterling, P. (1998). Functional architecture of primate cone and rod axons. Vision Research 38: 2539–2549.

MacLeish, P. R. and Nurse, C. A. (2007). Ion channel compartments in photoreceptors: Evidence from salamander rods with intact and ablated terminals. Journal of Neurophysiology 98: 86–95.

Migdale, K., Herr, S., Klug, K., et al. (2003). Two ribbon synaptic units in rod photoreceptors of macaque, human, and cat. Journal of Comparative Neurology 455: 100–112.

Okawa, H. and Sampath, A. P. (2007). Optimization of single-photon response transmission at the rod-to-rod bipolar synapse. Physiology (Bethesda) 22: 279–286.

Rodieck, R. W. (1998). The First Steps in Seeing. Sunderland, MA: Sinauer Associates.

Smith, R. G., Freed, M. A., and Sterling, P. (1986). Microcircuitry of the dark-adapted cat retina: Functional architecture of the rod–cone network. Journal of Neuroscience 6: 3505–3517.

Sterling, P. and Matthews, G. (2005). Structure and function of ribbon synapses. Trends in Neuroscience 28: 20–29.

Taylor, W. R. and Smith, R. G. (2004). Transmission of scotopic signals from the rod to rod bipolar cell in the mammalian retina. Vision Research 44: 3269–3276.

Thoreson, W. B. (2007). Kinetics of synaptic transmission at ribbon synapses of rods and cones. Molecular Neurobiology 36: 205–223.

van Rossum, M. C. W. and Smith, R. G. (1998). Noise removal at the rod synapse. Visual Neuroscience 15: 809–821.

Glossary

Henle’s nerve fiber layer – The inner layer of cones at the fovea lacking overlying nerve fiber or inner nuclear layer cells that have the most attenuated internal limiting membrane covering; could be the most susceptible location for a breach in that layer that might initiate macular hole formation.

Internal limiting membrane – The confluence of inner footplates of Mu¨ller cells of retina that forms a membrane-like structure delimiting inner retinal surface where it contacts the posterior hyaloidal elements.

Macula – The retina that subserves central vision, populated by the most dense distribution of cone photoreceptors to offer the best visual resolution; this term is somewhat imprecisely used among clinicians (broader, perhaps 2 disk diameter zone) and histologists (more narrowly used to central point). Posterior hyaloid – The most posterior elements of the vitreous body; this structure is more complex than previously thought, frequently exists as a multilaminated structure, and composed primarily of type IV collagen, but may be impregnated with cellular components.

Vitreoschisis – A phenomenon that is usually not visible, but could be important pathogenically whereby the vitreous body develops a splitting of some of its layers, most notably just anterior to the posterior hyaloidal attachment to the macula.

The pathogenesis of macular holes has undergone at least one full cycle of thought. Since macular holes were first identified following trauma, it was natural for early clinicians to deduce that a coup–countrecoup force transmitted through the vitreous caused macular hole formation. However, as it became apparent that trauma was only infrequently associated with the finding of a macular hole, other mechanisms were proposed as first summarized by Aaberg. Three principal, possibly coexisting, enhanced mechanisms have been proposed including unroofing or dissolution of the attenuated inner retinal layer of cystoid edema due to a range of etiologies, atrophy or degeneration of the retina, and vitreomacular traction. Advances in imaging have allowed unprecedented resolution which has ratified vitreomacular traction as the most prominent

component, if not the basic underlying mechanism, of macular hole formation.

Undeniably, the vitreoretinal interface is the battlefront of macular hole formation and therapeutics. Some observations do not fully conform to the model of vitreomacular traction as the sole and universal cause of macular hole formation, but these may be consequences of vitreomacular traction or factors contributing to or potentiating vitreous traction. Thus, it is possible that the vitreous may play a prime-mover role, an innocent bystander role, or a collaborative role in the formation of macular holes. This article reviews the evidence and perspective of the role of the vitreous in macular hole formation.

Vitreous Anatomy and Biochemistry

The vitreous body has a much more complex structure and physiology than might initially be apparent from its transparent, paucicellar, predominantly aqueous appearance. It is a nonhomogeneous biochemical complex of collagen and hyaluronan. The physical structure of the vitreous is an extensive cisternal system of cavitated, more liquefied portions lined by extenuated and thickened walls. This seems to be accentuated with age (syneresis) or in certain disease states. Most specifically, the concept of a posterior precortical vitreous pocket and, consequently, a cortical vitreous layer has been defined and to a large degree imaged which, by its proximity to the fovea, mostly likely plays some role in the genesis of vitreous forces at the fovea. Improved optical visualization of the fine structure of the vitreous has allowed clinical detection of this pocket, and its size has been hypothesized to be proportional to the amount of tangential traction generated at the fovea.

The vitreous dual senescent processes of synchesis and syneresis render a posterior vitreous detachment (PVD) to be a much more complex process than the casual observer might suspect.

Vitreous Traction

Peripheral retinal breaks form at the time of a PVD. Thus, it was a natural step to conceive of the PVD as playing a formative role in causing macular holes. Gass’ seminal grading scheme standardized observations of the stages involved in macular hole formation and it remains generally accepted. Its clinical relevance was immediately

seized upon and preventative surgery aimed at inducing the posterior vitreous separation before a macular break could occur led to several surgical investigations that seemed to offer promising results initially, but a randomized trial failed to establish the efficacy of this preemptive strategy. The surgical strategy employed at the time was to remove the cortical vitreous, which itself may reflect an incomplete or overly simplified understanding of the pre-hole dynamics.

Various clinical studies identified a lack of PVD to be associated with a higher risk of macular hole formation in the fellow eyes of patients with macular holes compared to fellow eyes with incident posterior vitreous separations. Histopathologic series not only established that posterior vitreous separation was more common among patients with full-thickness macular holes, but also made the observation that persistent attachments of the vitreous and associated cystic changes may imply a more complex mechanism than simple posterior vitreous separation.

The earliest imaging studies included ultrasound tests which also seem to establish the strong association of vitreous separation with macular hole formation. Subsequently, imaging with optical coherence tomography (OCT) depicted a compelling role for vitreous traction.

However, other observations have suggested that while traction at the time of posterior vitreous separation may well be important, it may be part of a more complex scenario. The fellow eyes of patients develop macular holes much more frequently than in the general populations, suggesting a constitutional susceptibility to macular hole formation, presumably at the time of posterior vitreous separation.

Vitreoretinal Interface

The second iteration of the vitreous separation at the fovea has focused on the nature and actions that occur at the vitreofoveal interface. Formerly, a vitreous separation was simplistically thought of as a clean, total separation of the hyaloid from the internal limiting membrane (ILM). However, the concept of an anomalous posterior vitreous separation at the fovea is what is probably most consistent with both the clinical behavior and the imaging appearances. Vitreous cortex remnants have been identified at the fovea and perifoveal area after apparent spontaneous posterior vitreous separation. In this way, the vitreous may be a necessary substrate for action at the fovea. Histopathologic studies have also suggested or have identified numerous other possible substrates that might mediate traction, but more of a delayed or tangential nature than the expected anterior-to-posterior traction of the simplified posterior vitreous separation. Anatomic features at the fovea are unique and may also account for what are

incidental vitreoretinal forces elsewhere. For example, the fovea is thin centrally and the ILM as well as the basal lamina of the vitreous are extremely thin at the fovea. At the fovea, the outer plexiform layer and the photoreceptor layer (Henle’s nerve fiber layer) are more exposed and the ILM is even more attenuated in this area. The tangential orientation of the fibers, their delicate nature, and the thin overlying ILM may make this layer more susceptible to incidental trauma at the time of vitreous separation at the fovea.

These anatomic and theoretic features seem to be consistent with other clinical observations, including the apparent predecessor lesion as a cyst. Thus, the question of the pathogenic role of the vitreous becomes open to its possible chronic role in inducing an inner cystic change, or its subsequent action on the weakened inner cystic layers to precipitate the full-thickness hole. Careful biomicroscopic study of the vitreous at the fovea can demonstrate vitreous separation or, more importantly, a partial vitreous separation at the fovea. Other imaging modalities besides OCT, including laser biomicroscopy kinetic ultrasound and retinal thickness analysis, also demonstrate these findings. The most convincing evidence for this role comes from the more newly advanced and available optical coherence tomography images which have corroborated the apparent impact of the vitreous at the fovea (Figure 1). This concept is demonstrated by cases with spontaneous closure of a macular hole after release of the persistent vitreofoveal attachment, whether in traumatically induced or in idiopathic cases. Applying this observation therapeutically, others have performed vitrectomy relieving the traction with peeling of the posterior hyaloid, vitrectomy with removal of the ILM, or even vitreolysis of its persistent attachment without a larger vitrectomy with resolution of a macular hole as well. However, the indication for intervention is not well established, and occasionally, the apparent vitreofoveal traction will spontaneously release (Figure 2).

Numerous case reports of macular hole formation associated with seemingly unrelated diseases share themes of vitreous traction in the setting of intravitreal injection, fungal endophthalmitis, and laser-assisted in situ keratomileusis (LASIK) associated with formation of full-thickness macular holes. A corollary of the role of the vitreous attachment at the fovea is that other case reports have suggested a sort of accomplice role that the vitreous may play in transmitting tractional effects from seemingly unassociated conditions as they burst as hemorrhage from a retinal microaneurysm, LASIK, transpupillary thermal therapy, yttrium aluminum garnet (YAG) laser injury, and subhyaloid hemorrhage. The possible contractilepotent quality of tissue in the vitreous is demonstrated by the ultrastructural analyses of removed tissue specimen from patients with impending macular holes which

demonstrate glial-type tissue that might cause such a secondary tractional effect.

Confounding Observations

However, some macular holes have been observed under circumstances that do not seem to follow the mold of a direct or secondary, tractionally induced macular hole formation via active vitreous traction. These include macular hole cases that seemed to have been observed distantly after a documented short-term or long-term PVD, following the repair of retinal detachment repair or even after a vitrectomy for seemingly unrelated disorders. In addition, macular holes have been found to reopen clearly in the absence of any vitreous which would have been systematically removed at the time of previous surgery.

These observations have caused some to consider other possible mechanisms that may cause macular hole formation or may influence the vitreous role in macular hole formation. A leading mechanism besides vitreous traction as a primary element is the possible role of cystoid foveal changes. The finding of cystoid changes may represent a confounding of previously, undetected vitreous traction that might have been released, but may play a prominent

role in the circumstances apparently leading to the macular hole by compromising the integrity of the already-delicate foveal elements. Unroofing of cystoid changes has been implicated in a variety of again, seemingly unrelated associations of macular hole formation with conditions including idiopathic juxtafoveal telangiectasis following uncomplicated phacoemulsification surgery and the presumed pseudophakic cystoid edema, macular edema for a branch vein occlusion, eyes with retinitis pigmentosa, and eyes as part of the Alport syndrome. The reopening of macular holes has been demonstrated to be preempted by some cystoid changes that seem to have no relationship to the vitreous since the vitreous was previously removed. Another case report of a formation of a macular hole after an OCT documented release of the posterior cortical remnant had been demonstrated a year and a half previously further brings into question the tractional induced role. The cystic changes observed might possibly be secondary to small breaks in the ILM or Henle’s nerve fiber layer, which subsequently lead to hydration with secondary stiffening of the retina and extension of a separation into the deeper layers of the retina.

There are numerous elements that have been delineated above that may persist in the foveal area that could have contractile potential and lead to the separation of the foveal layers.

Summary

The pathogenesis of macular holes has been widely reviewed. Undoubtedly, the vitreous plays a pivotal role in the formation of most, if not all, macular holes. Its actual role could vary from being the prime initiator and executor of traction at the fovea to being a sort of accomplice by transmitting traction generated elsewhere to being an innocent bystander to some other anatomic circumstances.

Cystoid changes seem to occur at least after a macular hole has occurred and very possibly before a macular hole is actually apparent. This could be because of hydration from a discontinuity in the Henle’s nerve fiber layer or ILM break, or it could be a reflection of some other biochemical process that is occurring, possibly as a response to persistent vitreous traction. The formation of a macular hole in at least many cases is probably not simply from the vitreous separating, but rather from some abnormal features that are consummated by otherwise inconsequential persistent vitreous traction.

See also: Acuity; Adaptive Optics; Histogenesis: Cell Fate: Signaling Factors.

Further Reading

Aaberg, T. M. (1970). Macular holes. A review. Survey of Ophthalmology 15: 139–162.

de Bustros, S. (1994). Vitrectomy for prevention of macular holes. Results of a randomized multicenter clinical trial. Vitrectomy for Prevention of Macular Hole Study Group. Ophthalmology 101: 1055–1059 discussion 1060.

Ezra, E., Wells, J. A., Gray, R. H., et al. (1998). Incidence of idiopathic full-thickness macular holes in fellow eyes: A 5-year prospective natural history study. Ophthalmology 105: 353–359.

Gass, J. D. M. (1988). Idiopathic senile macular hole: Its early stages and pathogenesis. Archives of Ophthalmology 106: 629–639.

Gass, J. D. M. (1995). Reappraisal of biomicroscopic classification of stages of development of a macular hole. American Journal of Ophthalmology 119: 752–759.

Green, W. R. (2006). The macular hole. Histopathologic studies.

Archives of Ophthalmology 124: 317–321.

Hee, M. R., Puliafito, C. A., Wong, C., et al. (1995). Optical coherence tomography of macular holes. Ophthalmology 102: 748–756.

Kiry, J., Ogura, Y., Shahidi, M., et al. (1993). Enhanced visualization of vitreoretinal interface by laser biomicroscopy. Ophthalmology 100: 1040–1043.

Kishi, S., Demaria, C., and Shimizu, K. (1986). Vitreous cortex remnants at the fovea after spontaneous vitreous detachment. International Ophthalmology 9: 253–260.

Lipham, W. J. and Smiddy, W. E. (1997). Idiopathic macular hole following vitrectomy: Implications for pathogenesis. Ophthalmic Surgery and Lasers 28: 633–639.

McDonnell, P. J., Fine, S. L., and Hillis, A. I. (1982). Clinical features of idiopathic macular cysts and holes. American Journal of Ophthalmology 93: 777–786.

Sebag, J. (1998). Macromolecular structure of vitreous. Progress in Polymer Science 23: 415–446.

Sebag, J. (2004). Anomalous posterior vitreous detachment:

A unifying concept in vitreo-retinal disease. Graefe’s Archive for Clinical and Experimental Ophthalmology 242: 690–698.

Smiddy, W. E. and Flynn, H. W., Jr. (2004). Pathogenesis of macular holes and therapeutic implications. American Journal of Ophthalmology 137: 525–537.

Smiddy, W. E., Michels, R. G., Glaser, B. M., and deBustros, S. (1988). Vitrectomy for impending idiopathic macular holes. American Journal of Ophthalmology 105: 371–376.

Worst, J. G. F. (1977). Cisternal systems of the fully developed vitreous body in the young adult. Transactions of the Ophthalmological Societies of the United Kingdom 97: 550–554.

Glossary

Drusen – The abnormal deposits containing cellular debris and inflammatory molecules that form beneath the retinal pigmented epithelium (RPE) and are associated with the development of age-related macular degeneration.

Macula – The portion of the retina that is responsible for fine acuity vision in the central visual field. It is a small ( 6 mm diameter) area located at the posterior pole of the eye near the optic nerve that is structurally unique and contains the highest concentration of cone photoreceptor cells in the retina. Photoreceptor – The cells of the retina responsible for the absorption of light and its conversion to electrical signals that are transmitted to the brain.

In humans, there are two types of photoreceptor cells: rods and cones. Rod photoreceptor cells are very sensitive in dim light situations but do not provide high resolution or color vision. Cone photoreceptor cells are less sensitive than rods but in bright light distinguish colors and provide for high-acuity vision owing to their concentration in the macula.

Retina – The light-sensitive part of the eye that lines its inner surface. It is a multilayered tissue that collects light, processes electronic signals produced by the light, and transmits those signals to the brain.

Retinal pigmented epithelium(RPE) –

A pigmented monolayer of cells lying directly adjacent to the retina that provides support for the photoreceptor cells. Its functions include absorption of excess light; processing of molecules required for transduction of light into electrical signals; removal of cellular debris shed by photoreceptor cells; and transport of nutrients, waste products, and ions.

Introduction

Age-related macular degeneration (AMD) is a disease of the eye that causes loss of vision in the center of the visual field. Central vision is mediated by a region of the retina, known as the macula that is specialized for fine acuity vision such as that used for reading and other tasks that require fine focus and high resolution. While the macula

comprises only 4% of the retina (it is only 6 mm in diameter), it is responsible for essentially all scotopic (bright light) vision and almost 10% of our visual field. In AMD, the light-sensitive photoreceptor cells in this critical region of the retina become dysfunctional and die resulting in symptoms ranging from slight visual distortions to complete loss of central vision.

Incidence

As the name implies, AMD is most common in the elderly, its incidence being highest in those over 50 years of age. It is the most common cause of irreversible blindness in elderly individuals worldwide and its clinical symptoms are recognized in more than onethird of persons over the age of 75 in industrialized societies. In 2004, it was estimated that over 9 million persons were affected by some form of AMD in the United States alone. It is expected that this number will reach almost 15 million by the year 2020. There are other diseases that affect the macula in younger individuals, but the frequencies of these are significantly less than for AMD and many of these are known to be monogenic diseases, that is, caused by single gene mutations (e.g., vitelliform macular dystrophy, Sorsby’s fundus dystrophy, and malattia leventinese).

The Macula

It is not yet clear why the macula is preferentially affected in AMD. The term macula is derived from the Latin macula lutea (yellow spot) that describes the appearance of the macula in life due to the accumulation of two carotenoid pigments, lutein and zeaxanthin, in the macular retina. Lutein and zeaxanthin are thought to function as antioxidants and filters of high-energy blue light, and thus protect the macula from light-induced oxidative damage. The fovea is the centermost 2 mm of the macula and is the region of the retina where cone photoreceptor density is highest (up to 200 000 cells mm2) and visual acuity is maximal. One factor that may contribute to macular sensitivity is its relative lack of vasculature compared to the rest of the retina. Despite the fact that photoreceptor cell density is highest in this region of the retina and photoreceptor cells consume oxygen at a higher rate than any other cells in the body, the inner

retina here is thinned and avascular. As a consequence, macular photoreceptors appear to rely on the choroidal capillary bed, the choriocapillaris, as their primary source for oxygen and nutrients. Age-related decreases in choroidal vascular volume and flow could thus compromise macular photoreceptor cells. Age-related changes in Bruch’s membrane that are more pronounced in the macular region than elsewhere in the eye may also contribute to the macula’s particular susceptibility to pathogenic changes leading to AMD.

Clinical Symptoms

AMD is typically classified into early and late forms. Early AMD (dry or atrophic AMD) is characterized by the appearance of abnormal extracellular deposits known as drusen that form below the retinal pigmented epithelium (RPE) and by focal areas of increased or decreased pigmentation in the RPE and choroid. Drusen are classified as hard (small, distinct, and hemispherical) or soft (large, diffuse, and amorphous) based on their fundoscopic and histologic appearance. Late AMD has two forms: neovascular AMD (wet or exudative AMD) and

geographic atrophy, the end stage of dry AMD when neovascularization does not occur (Figure 1).

Neovascular AMD is typified by the growth of blood vessels from the choroid into the RPE and the subretinal space (choroidal neovascularization or CNV) and subretinal hemorrhage that cause severe damage to the retina, leading to precipitous vision loss. Physicians often use a procedure known as fluorescein angiography to assess the extent of CNV in patients suspected of having neovascular AMD. If untreated, neovascular AMD can lead to the development of a disk-shaped fibrovascular scar underlying the macula and severe loss of central vision (central scotoma). Individuals who develop neovascular AMD in one eye are likely to have it develop in the other (contralateral) eye and thus the risk of bilateral vision loss is high in neovascular AMD. Geographic atrophy is characterized by widespread areas of depigmentation that represent areas of degeneration of the RPE and adjacent photoreceptor cells of the retina. Atrophy of the capillary bed (choriocapillaris) of the choroid is also commonly associated with geographic atrophy. Ultimately, these areas coalesce to form a large distinct area of degeneration that encompasses the macula and causes loss of central vision.

In early, dry AMD, vision loss is gradual and progresses over many years. As such, individuals with early AMD are often unaware of their visual dysfunction. More rapid and severe vision loss is seen in individuals where early AMD progresses to geographic atrophy or neovascular AMD; this occurs in 10–15% of individuals in each case.

Histopathology

Numerous studies show that the earliest pathologic changes associated with AMD occur in the RPE and the adjacent extracellular matrix complex known as Bruch’s membrane, which undergoes a substantial number of changes in association with aging and AMD. These include thickening, accumulation of lipids and cholesterol, decreased permeability, and development of deposits of extracellular debris between Bruch’s membrane and the RPE. The most prominent of these deposits are known as drusen (German for geodes, because of their glittering appearance when first described) (Figure 2).

Large numbers and extensive areas of drusen deposits in the macula (especially soft drusen) are potent risk factors for the development of AMD. It is thought that drusen diminish access to vital nutrients and oxygen diffusing from the choroidal vessels, leading to the compromise of overlying RPE cells and secondarily to the dysfunction and death of the photoreceptor cells in the adjacent neural retina.

The process of drusen formation is poorly characterized. Drusen are comprised of protein and lipid molecules, many of which are known to be involved in inflammatory processes. These include activators of the complement system, activated complement components, and complement regulatory molecules. As such, it has been proposed that drusen formation is the byproduct of chronic local inflammatory processes. Many drusen components are normal constituents of circulating plasma

and it has been suggested that reduced choroidal blood flow associated with AMD leads to increased hydrostatic pressure in the choroidal capillaries forcing plasma proteins extravascularly into the sub-RPE space. However, some drusen-associated molecules are known to be biosynthetic products of RPE cells and cellular debris, likely of RPE origin, is frequently observed in drusen. It is thus likely that RPE-derived molecules also contribute to drusen biogenesis; however, causative conditions and precise mechanisms remain to be identified. It has also been noted that some molecular constituents of drusen have been oxidatively modified, consistent with the idea that oxidative damage may be an important component of drusen formation and AMD pathogenesis.

Risk Factors

The two most significant risk factors for AMD are age and heredity. As noted above, the disease is most commonly diagnosed in individuals over 50 years of age. There is a significant increase in AMD risk if close family members are afflicted with the disease. Individuals who have a first-degree relative (parent or sibling) with the disease are more than twice as likely to be afflicted as those without afflicted relatives. They also tend to be affected at an earlier age. These results indicate that specific genetic attributes are likely to be involved in influencing an individual’s susceptibility to AMD (see the section titled ‘Genetics’).

Of environmental risk factors, smoking is the most significant modifiable risk factor for AMD. One study indicates that approximately 25% of AMD cases in individuals over 70 may be attributable to risk conferred by smoking. The preponderance of epidemiological data shows that smokers have a twoto threefold increased risk of having late AMD, neovascular AMD, or geographic atrophy, compared to individuals who have never smoked. There is a dose–response effect in that the risk of

developing AMD increases in relation to the duration and intensity of smoking history. It also appears that the average age of onset of AMD symptoms is earlier in smokers compared to nonsmokers, as is the likelihood of disease in both eyes. Stopping smoking, however, can have beneficial effects. While ex-smokers still have an increased AMD risk compared to never-smokers, it is significantly lower than for current smokers. It has been suggested that the increased AMD risk conferred by smoking is related to oxidative damage in the retina, induction of proinflammatory mediators, reduced choroidal blood flow, and decreased levels of protective carotenoid pigments (lutein, zeaxanthin) in the macular retina.

Obesity (or elevated body mass index) has also been linked to an increased risk of progression to late-stage AMD. It has been proposed that this relationship is due to increased oxidative stress, reduced antioxidant defense mechanisms, and/or increased incidence of chronic lowgrade inflammation in obese individuals. Low-grade systemic inflammation may contribute to AMD pathogenesis directly through inflammatory damage at the level of the RPE and Bruch’s membrane, or secondarily by reducing systemic availability of the macular pigments, lutein and zeaxanthin (increased body fat is associated with decreased serum and macular levels of carotenoids).

Reduced progression of early AMD and reduced risk for neovascular AMD is associated with dietary supplementation with antioxidant vitamins and minerals (the Age-Related Eye Disease Study (AREDS) supplement: 500 mg vitamin C, 50 mg vitamin E, 15 mg beta carotene, 80 mg zinc, and 2 mg copper daily). Diets high in foods that are good sources of the macular carotenoid pigments (e.g., certain green leafy vegetables) and omega-3 fatty acids (e.g., fatty fish and flaxseed) are also associated with decreased incidence of AMD. Interestingly, some epidemiological studies have noted a decreased risk of AMD in individuals who regularly use antacids or anti-inflammatory medications.

Genetics

Genes in two chromosomal regions, one on chromosome 1 (1q32) and one on chromosome 10 (10q26), have now been linked to a significant proportion of AMD cases. In both cases, certain single-base differences in DNA sequence (single-nucleotide polymorphisms or SNPs) in specific genes have been shown to be present at higher frequency in individuals with AMD than in those not afflicted with the disease. Together, genetic variants in these two chromosomal loci confer significant risk for AMD and can account for over half of AMD cases. The implicated gene on chromosome 1 is that for complement factor H (CFH ), which lies within an area of

the chromosome known as the regulator of complement activation (RCA) locus that is known to be involved in modulating activity of the complement system. The involvement of the complement system in AMD that is implied by these observations is consistent with pathological evidence suggesting that chronic inflammation has a primary role in the AMD disease process (see the section titled ‘Histopathology’). The AMD-associated genes on chromosome 10 are tightly linked and include PLEKHA1, ARMS2 (LOC387715), and HTRA1. The functions of the proteins encoded by these genes and their potential relationship to AMD pathogenesis are less well defined than for CFH. HTRA1 encodes a serine protease and PLEKHA1 a plekstrin-homology-domain-containing protein; the product of the ARMS2 gene has not been completely characterized but may be a mitochondrial protein. Polymorphisms in the genes in these two chromosomal loci, especially CFH and ARMS2/HTRA1 (see below), can account for a substantial number of AMD cases. Several additional genes, including those encoding complement component C3, complement factor B, the adenosine triphosphate (ATP)-binding cassette transporter (ABCA4), fibulin-5, apolipoprotein E, human leukocyte antigens, and others have been associated with smaller percentages of AMD cases.

CFH

A SNP (rs1061170 ) in the gene for CFH has been shown in numerous studies to be associated with increased risk for both forms of late AMD. The CFH gene is located on human chromosome 1 (1q32) in an area often linked to AMD in familial and population-based studies. The risk-conferring polymorphism in CFH results in a thymidine (T) to cytosine (C) substitution at nucleotide position 1277 in exon 9 of the gene. Individuals carrying one copy of the C allele (heterozygotes) are 2–5 times more likely to be afflicted with AMD and carriers of two copies (homozygotes) are 3–7 times more likely to be afflicted. The T ! C nucleotide change leads to a tyrosine to histidine shift at amino acid position 402 (Y402H) of the CFH protein. At the time of writing, the functional implications of this amino acid change have not been fully characterized but the affected site in the protein is one that is known to contribute to a number of CFH functions, including the binding of heparin and C-reactive protein. CFH is an important negative regulator of the alternative pathway of complement activation and it is hypothesized that the 402H variant of the molecule may have reduced inhibitory activity. Compromised regulation of the complement system could lead to inflammation and complement-mediated damage to the RPE, and secondary damage to the retina. Combined analyses of polymorphisms in CFH and genes encoding some other members of the complement system (complement factor