Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

was found, with a reduction of about 3 micron per decade.21 Sanchis-Gimeno and others have analyzed the changes of central corneal thickness values of Caucasian emmetropic subjects in accordance with their age—Caucasian emmetropic aged subjects have reduced corneal thickness values when compared to young emmetropic subjects.22

In conclusion, it seems there is no substantial change in corneal thickness during aging—nevertheless, there is evidence suggesting a significant age-dependent decrease in corneal thickness later in life for some ethnic groups.

Corneal Aberration

Normally, the cornea has positive spherical aberrations that compensate for the negative aberrations attributed to the lens. Around 20 years of age, ocular spherical aberration is almost zero, and it gradually increases with age (positive values). This change in total spherical aberration with aging is because of aberration changes in the lens, which may be induced by the age-related changes of anterior and posterior lens radius.23,24,25 There is wide individual variability in anterior corneal aberrations, and little of this is attributable to age-related changes.

Analyzing data from different studies, it is possible to see that while corneal spherical aberrations do not show change with aging, there is a positive correlation between corneal coma aberration with age and evidence that the increase of ocular coma with aging is mainly because of the increase of corneal coma.26 Because coma-like aberrations consist of tilt and/or asymmetry, the corneas become less symmetric with aging. Increases in corneal coma-like aberrations in elderly do not directly indicate the deterioration of visual function in their eyes for different rea- sons—one of these is that pupils of older subjects tend to be more miotic, thus with smaller influence of the corneal wavefront aberrations on visual performance.

Structure

Epithelium

The corneal epithelium acts as barrier from environmental agents and contributes to movement of water and molecules through the cornea. With age, this function seems to undergo some deterioration resulting in a breakdown of epithelial barrier function. This can be quantified by fluorophotometric determination of corneal epithelial permeability to fluorescein.27 A breakdown of epithelial barrier function28 and the increased tear contact time29 may explain the increase in epithelial permeability with age that renders the aging cornea more susceptible to infection. Changes in distribution of integrin subunits in the epithelium could also reduce the epithelial

barrier function. The α6 subunit and the β4 subunit—components of hemidesmo- somes—become discontinuous with age.30 A reduced ability of corneal cells to upregulate adhesion molecules, and a reduced phagocytic ability of reactive polymorphonucleocytes in response to infection, also occur with aging.31 This could impair the ability to eliminate a bacterial infection.

Bowman’s Membrane

Bowman’s membrane (epithelial basement membrane) is the layer that separates the epithelium from the stroma. It is about 10-16 µm thick and is acellular, except for the nerves that perforate it. Taylor and Kimsey studied the basal membranes of corneas in 12 diabetic patients by transmission electron microscopy (TEM). They found no clear relation between the corneal epithelial basement membrane thickness and age.32 Alvarado et al. published an ultrastructural evaluation and morphometric analysis of the basement membrane on a large number of specimens from subjects ranging in age from 17 weeks of gestation to 93 years of age. They found that structural changes occur with aging in the basement membranes. There is a progressive thickening of the corneal epithelial basement membrane that is caused by two different processes—membrane deposition (forming unilaminar membranes) and membrane reduplication (forming multilaminar membranes). Membrane deposition appears to be the only process involved in membrane thickening in the prenatal and early postnatal period. Later in life, the process of membrane reduplication plays a more prominent role than thickening by deposition. In middle-aged individuals, areas of reduplication are focal (mixed membrane type). With increasing age, a greater proportion of the basement membrane becomes multilaminar.33

Subbasal Nerve Plexus

The cornea is one of the most innervated tissues in the body. Its innervation is provided by the ophthalmic and maxillary branches of the trigeminal nerve. The nerve bundles enter the peripheral cornea at the limbus in the anterior third of the stroma, and then penetrate the Bowman’s layer where they form the subbasal nerve plexus. The fibers run parallel to the cornea’s surface between the Bowman’s layer and the basal epithelial layer, and then terminate in the superficial epithelium as free nerve endings. Because of the fast degeneration of nerve fibers after death, the morphology of the corneal nerve based on histological and microscopic studies is limited and unclear. In vivo confocal microscopy is able to visualize and measure subbasal nerve fibers. Confocal microscopy studies have shown that the human subbasal nerve plexus is primarily oriented in a superior-to-inferior direction at the central corneal apex.34

Grupcheva et al. found a small age-associated decrease in subbasal nerve density in clinically healthy corneas.35 In a recent study, Erie also demonstrated that the density and orientation of the subbasal nerve plexus do not show changes with age.36 Despite this morphological observation, several studies demonstrated that corneal sensation decreases with age.37,38,39

Corneal sensitivity is important in the maintenance of function and structure of the cornea, and it is also crucial in the healing process after injury or surgery. Roszkowska evaluated central and peripheral corneal sensitivity in a population that ranged from 20 to 90 years of age. In this study, they found that corneal sensitivity is maintained throughout life—corneal sensitivity remains stable in the central zone until the age of 60 when it begins to decrease, while the peripheral sensitivity starts to decrease earlier and progresses at a fast rate.40

Stroma

Transparency of the cornea is due to the uniform size of the constituent collagen fibrils and to the degree of ordering in their packing in the stroma. Changes in the corneal stromal structure occur with aging for both the collagen fibrils and the cellular component. Studies on these stromal changes were obtained from both in vivo and in vitro observations.

Human collagen undergoes progressive changes with age, including a decrease in elasticity. In vitro studies suggest that the physical changes involve progressive crosslinking between collagen molecules. Daxer et al. performed x-ray scattering experiments on corneas of various ages to investigate the three-dimensional structural properties of collagen fibrils in the human corneal stroma. Analyzing fibril diameter, intermolecular Bragg spacing, and axial collagen period, they found that aging is related to a three-dimensional growth of collagen fibrils in the human corneal stroma. The age-related growth of the fibril diameter was mostly a result of an increased number of collagen molecules and, in addition, to some expansion of the intermolecular Bragg spacing, probably resulting from glycationinduced crosslinking.41

The expansion of the collagen intermolecular Bragg spacing within the fibrils suggests that molecules other than collagen are deposited in the fibrils during aging and push the collagen molecules further apart. It confirms recent studies that have demonstrated glycation-induced expansion of the intermolecular spacing and subsequent crosslinking of the molecules with age.42 Advanced glycation end products (AGEs) play a significant role in many age-related disorders. AGEs accumulate in the aging cornea and mediate crosslinking of molecules in the stroma. Such age-related crosslinking occurs largely on the collagen component of the cornea.

Two changes with age were identified by Malik: 1) an increase in the cross-sectional area associated with each molecule in corneal collagen, which may be due to an increase in nonenzymatic crosslinking between collagen molecules, and 2) a decrease in the stroma interfibrillar spacing, which could be related to changes in the proteoglycan

composition of the interfibrillar matrix. The decrease in stromal interfibrillar spacing with age was also found by Kanai and Kaufman using an electron microscopy study.43

These findings related to stromal fibrillar changes can, in part, explain the result obtained by Elsheikh et al. on corneal stiffness. They evaluated the stress-strain behavior of corneal tissue and how the behavior was affected by age. In this study, the cornea demonstrates considerable stiffening with age with the behavior closely fitting an exponential power function typical of collagenous tissue. The increase in stiffness could be related to the additional nonenzymatic crosslinking that affects the stromal collagen fibrils that occurs with age, and to the age-related increase in collagen fibril diameter.44

A new instrument that is starting to be used in clinical practice is the ocular response analyzer that measures the corneal biomechanical response to a rapid indentation obtained by an air jet. This corneal response is called corneal hysteresis (CH), and is a new parameter that can help to better understand the behavior of the cornea on the intraocular pressure measurement obtained by Goldmann applanation.

Kotecha et al. investigated the association between CH and both age and central corneal thickness, as well as the agreement between ocular response analyzer and Goldmann applanation tonometer IOP measurements. Analyzing the data, they found a correction factor that describes a biomechanical property of the cornea that is independent from the intraocular pressure and that increases with thicker cornea and decreases with age. This factor is a measure of the corneal material properties, which include both stiffness and viscoelasticity. The observed negative association between corneal viscoelastic properties with advancing age may be further evidence of an increase in crosslinkage of collagen fibrils within the cornea, making it a stiffer and less viscoelastic structure.45

Keraticytes are the principal cellular components of corneal stroma—they are fibroblast-like cells that produce, degrade, and remodel the stroma, and are therefore important in corneal wound healing. Keraticyte density in a normal human anterior corneal stroma has been reported to be around 20.000–24.000 cells/mm3, being highest posterior to the Bowman’s layer and then decreasing towards posterior stroma (see Fig. 4.3).46,47

Using biochemical measurements of the stromal DNA/ mass content within the central 7-mm diameter zone, Møller-Pedersen48 found a direct correlation between keratocyte density and donor age, with a physiologic decline of 0.3 percent per year throughout life. Møller-Pedersen and Ehlers49 describe a 30 percent decrease in cell density in the subendothelial region. The DNA method is invasive and cannot be used to study keratocyte density in vivo.

Recent use of Confocal microscopy in vivo allowed quantification of stromal cell density without the need of tissue processing that can alter the tissue. In their work, Patel and coworkers found that full-thickness central keratocyte density was negatively correlated with age and decreased 0.45 percent per year. Keratocyte densities in all anteroposterior regions were negatively correlated with age, except the posterior 67 to 90 percent region of the stroma. The number of keratocytes in

Fig. 4.3 Confocal images of stroma: A) anterior stroma, and B) posterior stroma with different keratocyte density

the full-thickness stroma was also negatively correlated with age and decreased 0.43 percent per year.47 Using same modality with confocal microscopy, Berlau et al. found that keratocyte density was lower in patients older than 50 years than in those younger than 50 years.50

Descemet’s Membrane

Changes in Descemet’s membrane with aging are well-characterized in humans. Before birth it is a very thin basement membrane and different in appearance from the adult Descemet’s membrane. It grows by deposition of a series of similar “membrane units,” which are stacked to form a lamellar structure consisting of at least 30 layers by the end of gestation.

At birth, it has an average thickness of 3 m and exhibits an electron-dense, banding pattern with 110 nm periodicity.51,52

This portion of Descemet’s membrane is referred to as the anterior banded zone. Over the ensuing decades of life, the anterior banded zone remains well-demarcated and stable in thickness and appearance. In postnatal life the membrane continues to grow in thickness by deposition of a non-striated, non-lamellar material posterior to the striated prenatal layer. This posterior portion of the membrane directly subjacent to the endothelium progressively thickens as a non-banded, homogeneous substance referred to as the posterior non-banded zone. Thickening of the posterior

annual reduction found by Murphy et al. averages approximately 0.56 percent per year.57,58,59 Blatt et al. found with the clinical specular microscope that cell density decreases significantly with age when the endothelial cells are regular in size, but that if the endothelial cells are irregular in size and arrangement, the endothelial cell densities do not correlate with age.60

The topographical distribution of the corneal endothelial cell density in different age ranges has been studied by Roszkowska et al. They evaluated 300 eyes of 204 healthy subjects aged from 20 to 83 years. Age-related changes involve both center and periphery. In particular, they observed a higher peripheral decrement in the ancient subjects resulting in a topographical disparity in the elderly. They concluded that the central density evaluation is sufficient to provide the exact information about an entire endothelial surface, but only in the young subjects. It did not work with elderly patients where a topographical disparity might occur and the only central density determination could provide insufficient results.61

The reason why a gradual loss of endothelial cells occurs with age remains unclear. Green hypothesizes that aging processes in the eye occur as a consequence of degradation of enzymes that normally metabolize and detoxify hydrogen peroxide and other free radicals. The loss of enzyme activity allows hydrogen peroxide—which normally occurs within eye fluids—and free radicals to induce irreversible deleterious effects on different eye tissues. These processes may lead to cataract formation in the lens, as well as loss of corneal endothelial cells.

This hypothesis is partially supported by the results obtained by Cejkova et al.62 from the analysis of the activities of superoxide dismutase, glutathione peroxidase, and catalase (the enzymatic scavengers of reactive oxygen species) in rabbit corneas. They found that in aged corneas, the activities of all antioxidant enzymes were dramatically decreased, suggesting that the cornea of aged rabbits are more susceptible to oxidative injury in comparison to the corneas of young adult animals.63

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