Retinal degeneration and ionizing radiation hypersensitivity in a mouse model for Cockayne syndrome.

Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but hardly clarifies the other CS symptoms. Many of these, including retinopathy, are associated with premature aging. We studied eye pathology in a mouse model for CS. Csb(m/m) mice were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, which underscores the importance of transcription-coupled repair of photolesions in the mouse. In addition, we observed a spontaneous loss of retinal photoreceptor cells with age in the Csb(m/m) retina, resulting in a 60% decrease in the number of rods by the age of 18 months. Importantly, when Csb(m/m) mice (as well as Csa(-/-) mice) were exposed to 10 Gy of ionizing radiation, we noticed an increase in apoptotic photoreceptor cells, which was not observed in wild-type animals. This finding, together with our observation that the expression of established oxidative stress marker genes is upregulated in the Csb(m/m) retina, suggests that (endogenous) oxidative DNA lesions play a role in this CS-specific premature-aging feature and supports the oxidative DNA damage theory of aging.

Foveal cone photoreceptor involvement in primary open-angle glaucoma.

BACKGROUND: To test whether foveal cone photoreceptors are impaired in primary open-angle glaucoma (POAG). METHODS: Nineteen POAG eyes with central glaucomatous visual field defects, and 34 age-matched control eyes were included. Fundus reflectometry, together with a model fit procedure, provided information on a set of parameters: lens optical density, macular pigment optical density, melanin, blood, the directional cone reflectance (Rd), a measure for foveal cone photoreceptor integrity, and RILM, the reflectance at the inner limiting membrane. Optical coherence tomography (OCT) was performed to assess macular thickness. A Kolmogorov-Smirnov Z-test was used to compare parameters between the two groups. RESULTS: Median age (range) was 55.1 (24.7-73.3) years in the control subjects, and 60.1 (20.7-77.0) years in the POAG patients (P = 0.24). Of all eight model parameters, only Rd and RILM were significantly lower in POAG. Median Rd (range) was 2.21 (0.64-4.93) % in the control subjects and 1.19 (0.08-3.60) % in the POAG patients (P = 0.003). Median RILM (range) was 0.15 (0.00-1.08) % in the control subjects, and 0.08 (0.01-0.29) % in the POAG patients (P < 0.001). Rd showed no linear relationship with central retinal sensitivity on Visual Field test in POAG patients. Retinal thickness of the inner 1-3 mm ring and the outer 3-6 mm ring on OCT, centered on the fovea, was significantly lower in POAG patients than in control subjects. CONCLUSIONS: The integrity of the foveal cone outer segments, and the reflectance of the central ILM were impaired in POAG with advanced central visual field defects.

Foveal cone-photoreceptor integrity in aging macula disorder.

PURPOSE: To establish the relation between AMD stage and a quantitative measure for the integrity of foveal cone photoreceptors related to the optical Stiles-Crawford effect. METHODS: Fifty-six AMD eyes and 57 control eyes were included in the final analysis. AMD was graded in accordance with the International Classification System into five mutually exclusive stages. Stages 0 to 1 were labeled no AMD, stages 2 to 3 were labeled early AMD, and stage 4 was labeled late AMD. Fundus reflectometry, together with a model-fit procedure, provided information on directional cone reflectance (Rd), a quantitative measure for the integrity of foveal cone photoreceptors. Optical densities of macular pigment (MPOD) and melanin (MOD) were also obtained. A general linear model analysis was used to compare Rd, MPOD, and MOD among the AMD stages. RESULTS: Mean Rd was lower in early AMD (0.92%, P < 0.001) and late AMD (0.86%, P < 0.001) compared with mean Rd in the no-AMD stage (1.76%). Mean MPOD was not different in early AMD (0.53, P = 0.05), but it was lower in late AMD (0.19, P < 0.001) compared with mean MPOD in the no-AMD stage (0.42). Mean MOD was lower in early (1.09, P = 0.001) and late (1.01, P = 0.004) AMD compared with mean MOD in the no-AMD stage (1.23). CONCLUSIONS: Foveal cones show signs of misalignment and/or outer segment deterioration in early AMD. Melanin rather than macular pigment may play a protective role against AMD, although loss of these ocular pigments can also be caused by AMD.

Directional and nondirectional spectral reflection from the human fovea.

A model of the directional and nondirectional reflection spectrum of the human fovea is developed, incorporating reflectors, absorbers, and a wavelength-dependent optical Stiles-Crawford effect (OSCE). Data from 102 healthy subjects between 18 and 75 years obtained with the fundus reflection analyzer (FRA), an imaging spectrograph that measures the directional reflection profile of the human fovea in the pupil plane from 400 to 950 nm, were analyzed. Subgroups of young (<40 years) and old (>50 years) observers were defined. Mean results of the young group defined a template for directionality versus wavelength. For the whole group, mean reflection at 550 nm from the cones was 2.12%, from the retinal pigment epithelium 0.56%, and from the choroid 7.92%. Lens density, cone disc reflection, and blood layer thickness showed significant trends versus age. The model for the first time simultaneously describes the spectra of the directional and nondirectional reflection of the human fovea. Rayleigh scatter losses of the media and in preretinal layers were assumed zero in the nondirectional pathway. Mean density of the macular pigment of a subgroup (53 subjects, 19 to 75 years) correlated significantly with independent data from reflectance and autoflourescence images obtained by scanning laser ophthalmoscope (SLO) and data from flicker photometry.

Spectral transmission of intraocular lenses expressed as a virtual age.

AIM: Currently available intraocular lenses (IOL) have widely different spectral filters. This study aimed to calculate the virtual age of IOL with regard to photoprotection and photoreception, i.e. the age of the natural lens that has similar effects on these aspects. METHODS: With diffuse solar radiation as a light source blue light damage was calculated for natural lenses at all ages, commercially available IOL and Schott steep cut-off filters in the wavelength range 300-600 nm. Similarly, the input to the short wavelength sensitive cone system was calculated for the range 380-600 nm. RESULTS: The virtual age for photoprotection of IOL and steep cut-off filters varied from under 0 to 66 years. Most IOL had similar ages for photoreception, and thus show a reasonable resemblance to the spectral properties of the natural lens. Two IOL and all steep cut-off filters had a lower age for photoreception than for photoprotection, and thus outperformed the natural lens. CONCLUSION: The virtual age of an IOL relates its spectral filtering properties to what happens in the healthy crystalline lens. Many older IOL types offer less protection than the lens of a newborn. Middle age seems a reasonable choice for an IOL.

Sharp cutoff filters in intraocular lenses optimize the balance between light reception and light protection.

PURPOSE: To facilitate the selection of the spectral filter in intraocular lenses (IOLs). SETTING: Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands. METHODS: The spectral transmission of commercially available IOLs was measured, and information from manufacturer data sheets and the literature was gathered. Illumination with sunlight filtered by the natural eye media (aged 20 and 70 years) and artificial eye media resulted in calculated values for the blue-light damage and the signals from the sensory systems (rods, cones, melatonin suppression, and melanopsin). Results were presented as log differences with respect to the 20-year-old human lens. A single rating value for each lens was calculated to facilitate the selection. RESULTS: The 70-year-old lens showed a reduction in blue-light damage of 0.45 log units compared to the 20-year-old lens, although a similar reduction occurred in the signal from the short-wave-sensitive cones. Intraocular lenses showed a range of nearly 1 log unit in blue-light damage protection. A change in dioptric power in blue-filtering IOLs, with a corresponding change in thickness, strongly influenced behavior. Dioptric power was less of a factor in IOLs with sharp cutoff filters. CONCLUSIONS: Blue-filtering IOLs sometimes showed density spectra very different from those of the natural lens; however, their filtering generally caused only mild sensory losses. Nearly none of the IOLs offered an optimum tradeoff between protection and signal reduction. Sharp cutoff filtering near 445 nm provided better performance, removing limitations in optical design.

Macular pigment shows ringlike structures.

PURPOSE: The spatial distribution of macular pigment is generally assumed to monotonously decrease to very low values in the periphery. However, there are indications that this picture may be too simple. The purpose of this study was to examine the spatial distribution of the macular pigment optical density. METHODS: Fundus reflectance and autofluorescence maps at 488 and 514 nm Argon laser wavelengths were acquired in 53 healthy subjects with a custom-built scanning laser ophthalmoscope. Because the lens and the macular pigment are the only absorbers in this wavelength region, digital subtraction of log reflectance and log autofluorescence at the two wavelengths provides density maps of the sum of both absorbers. RESULTS: In approximately half of the subjects, we observed a distinct ring pattern at a mean distance of 0.7 degrees of the fovea. In a few subjects, the ring had an even larger optical density than did the central peak. A simple model with an exponentially decaying density as a function of eccentricity, in combination with a Gaussian-distributed ring pattern, yielded a good description of the data for both methods. The widths of the central peak and the Gaussian ring, and also the eccentricity at which the ring peaks, were similar for both methods. The prominence of the ring did not depend on age and gender. CONCLUSIONS: Both reflectance and autofluorescence maps showed ring patterns in the distribution of the macular pigment, which probably follow the inner plexiform layer.

Fast assessment of the central macular pigment density with natural pupil using the macular pigment reflectometer.

We built a new macular pigment reflectometer (MPR) for fast and objective measuring of the optical density of macular pigment in the human eye, using the undilated eye. The design is based on the spectral reflectance from a spot of white light at the fovea. To evaluate its performance, we measured the macular pigment of 20 healthy subjects, ages 18 to 79 years, under four conditions: (1) natural pupil in the dark, (2) natural pupil with dim room light, (3) dilated pupil in the dark, and for comparison with a different technique, (4) heterochromatic flicker photometry (HFP) in dim room light with natural pupil. Condition 1 was repeated in a subset of 10 subjects after an interval of at least 3 days. Data analysis with a model of reflectors and absorbers in the eye provided the density of the macular pigment in conditions 1 to 3. Dim room light and pupil dilatation had no influence on measured density. Mean within subjects variation was typically 7%. Mean difference between test and retest after at least 3 days was 1%. Correlation between MPR and HFP was r=0.56 (p=0.012). Mean within subjects variation with HFP was 19%. The new instrument holds promise for specific applications such as epidemiological research.

Fundus reflectance--historical and present ideas.

In 1851 Helmholtz introduced the ophthalmoscope. The instrument allowed the observation of light reflected at the fundus. The development of this device was one of the major advancements in ophthalmology. Yet ophthalmoscopy allows only qualitative observation of the eye. Since 1950 attempts were made to address the challenging, quantitative assessment of the amount of light reflected by the fundus. At first, only comparative measurements were possible, applied in the study of macular and visual pigments. With improvements in light detecting techniques, and with the advent of microprocessors, the measurement of spectral and spatial distribution of the reflectance became feasible. This led to the development of models that explained the observed wavelength dependence and the directional behavior of light reflected from the fovea. The models allowed a quantitative assessment of many parameters on absorption and reflection by structures in the human eye. This paper provides a review of both the experimental and theoretical progress, and summarizes the results of fundamental and clinical research using fundus reflectometry.

A yellow ring-shaped macular reflection.

PURPOSE: To describe a yellow ring-shaped reflection in the macula of healthy subjects observed with a common indirect ophthalmoscope. DESIGN: Observational case series. METHODS: Fundus photographs of the macula were acquired with a slit lamp and 90-diopter lens in 5 healthy subjects (age range, 23-50 years) at a perpendicular angle and at an oblique angle to the retina. RESULTS: The perpendicular fundus photographs showed a yellow ring-shaped reflection with a diameter of approximately 5 degrees. The oblique photographs had a dark red spot in the center. CONCLUSIONS: To our knowledge, this phenomenon has hitherto escaped attention in the literature. We conclude that the shape, size, and location of the yellow reflection are consistent with a cone origin. This observation may be used for diagnostic purposes.

Spectral and directional reflectance of the fovea in diabetes mellitus: photoreceptor integrity, macular pigment and lens.

Our aim was to assess the integrity of the photoreceptors in the fovea, and to measure the optical density of the macular pigment and the eye lens in patients with diabetes mellitus, and to compare the results with those of a group of healthy subjects. The directional and spectral properties of the light reflected from a 1.9 deg field centered on the fovea were measured simultaneously, in a single one second flash, with the Foveal Reflection Analyzer. The directional characteristics, i.e., the optical Stiles-Crawford effect, provided information on the integrity of the foveal photoreceptors. Model analysis of the spectral reflectance yielded optical densities of the macular pigment and the lens. The amplitude of the directional reflectance in diabetic eyes was significantly lower compared to controls (P<0.001). This indicates that the integrity of the photoreceptors in the fovea was altered in diabetics. Surprisingly, the directionality (a measure for the peakedness) was similar in diabetics and controls (P=0.3). The density of macular pigment was not different from that in controls (P=0.3). The optical density of the lens increased with age in both groups, but the rate of increase was larger in the diabetics (P<0.05). Possibly, the lens optical density increasing at a higher rate with age reflects changes preceding cataract formation.

Macular pigment and melanin in age-related maculopathy in a general population.

PURPOSE: It has been suggested that macular pigment (MP) and melanin may protect against age-related maculopathy (ARM). To check this, MP and melanin optical density were measured in a random population-based sample of subjects 55 years of age or older. METHODS: Spectral fundus reflectance of the fovea was measured in one eye per subject in a 2.3 degrees detection field with a fundus reflectometer. The sample consisted of 199 men and 236 women. Analysis with a fundus reflectance model yielded individual estimates for the MP and melanin optical density. Diagnosis of ARM was based on grading of standardized fundus transparencies. Eyes were stratified in four exclusive stages of ARM. RESULTS: MP optical density (at 460 nm) was 0.33 +/- 0.15 in eyes without ARM (n = 289) and 0.33 +/- 0.16 in eyes at any stage of ARM (n = 146). Melanin optical density (at 500 nm) was 1.18 +/- 0.19 in eyes without ARM and 1.20 +/- 0.21 in eyes at any stage of ARM. We found no gender differences for either MP or melanin optical density. CONCLUSIONS: No differences in MP and melanin optical density were found between eyes with and without ARM or between the various ARM stages.

Lens aging in relation to nutritional determinants and possible risk factors for age-related cataract.

OBJECTIVE: To investigate whether nutritional factors and possible risk factors for cataract influence the lens optical density (LOD). DESIGN: Three hundred seventy-six subjects, aged 18 to 75 years, were recruited. In a cross-sectional design, serum was analyzed for lutein, zeaxanthin, vitamin C, alpha-tocopherol, and cholesterol levels. Adipose tissue (n = 187) was analyzed for lutein level. The LOD and the macular pigment optical density (MPOD) were measured by spectral fundus reflectance. RESULTS: The mean +/- SD LOD at 420 nm was 0.52 +/- 0.17. It showed a significant association with age (beta =.008, P<001) and MPOD (beta = -.096, P =.02). For subjects 50 years and younger (mean +/- SD LOD, 0.45 +/- 0.11), we found only a single significant beta coefficient, for age (beta =.006, P<.001). For subjects older than 50 years (mean +/- SD LOD, 0.68 +/- 0.16), we found significant beta coefficients for age (beta =.011, P<.001) and MPOD (beta = -.240, P =.005). Controlling for age, we found no associations between LOD and other possible risk factors for age-related cataract or serum or adipose tissue concentrations of carotenoids, vitamin C, and alpha-tocopherol. CONCLUSIONS: Macular pigment is composed of lutein and zeaxanthin, the only carotenoids found in human lenses. The inverse relationship between LOD and MPOD suggests that lutein and zeaxanthin may retard aging of the lens.

Thermal cataract, from furnaces to lasers.

BACKGROUND: Thermal cataract has long been known as an occupational disease in furnace workers. This affliction has virtually disappeared in western countries due to improved working conditions. However, new light sources have appeared on the scene, in particular lasers, which might also be capable of producing thermal cataract. The aim of this survey is to review the history and describe the present state of knowledge. METHODS: Experimental work, mainly on rabbits, was reviewed and complemented with the results of calculations on the thermal changes in the ocular media. RESULTS: Safe exposure limits were derived over the optical spectrum from the near ultraviolet to the far infrared. CONCLUSIONS: Lasers may be a cause of thermal cataract only in the near ultraviolet. Moreover, in this field of research too, it is concluded that science may be regarded as the present state of misunderstanding.

The action spectrum of photochemical damage to the retina: a review of monochromatic threshold data.

Photochemical damage to the retina occurs for prolonged exposures of intense light. Two action spectra exist for this phenomenon. In rat an action spectrum matching the absorption spectrum of rhodopsin was found. In macaque, the susceptibility for photochemical damage decreased continuously from the UV to long visible wavelengths. Later, such a spectrum was also found in rat. In search for critical parameters that determine the shape of the spectrum we gathered all available data on the damage threshold dose for monochromatic radiation and noted the experimental conditions. The rhodopsin action spectrum was found in two sources; the other 16 sources adhered to the short wavelength spectrum. Comparing the conditions we conclude that the critical parameters for the generation of either action spectrum remain elusive. Experiments are suggested to resolve this issue and fill a few gaps in our knowledge.

Directional model analysis of the spectral reflection from the fovea and para-fovea.

Directional and nondirectional spectral reflection data from 0, 1, 2, 4, and 8 deg eccentricity, and the optic disk, were analyzed from 400 to 950 nm with an existing optical reflection model. The optical model, developed for the fovea, appeared to be also suitable for more eccentric locations. The optical densities of melanin and of the macular pigments zeaxanthin and lutein peaked in the fovea, in correspondence with literature data. The amplitude of the directional component, originating in the cone photoreceptors, had its maximum at 1 deg. The maximum of the directionality (peakedness) occurred at a slightly higher eccentricity.

In vivo quantification of the retinal reflectance spectral composition in elderly subjects before and after cataract surgery: Implications for the non-visual effects of light.

Light is the signal that entrains the biological clock in humans to the 24-hour external time. Recently, it has been shown that short wavelengths play a key role in this process. In the present study, we describe a procedure to measure, objectively and in a quick way, the spectral composition of the light reaching the retina in vivo. The instruments involved are the foveal reflection analyzer (FRA) and the macular pigment reflectometer (MPR). By making use of these reflectometers, we show quantitatively that in subjects with cataracts, the light input is especially reduced in the short wavelength range. After cataract surgery during which the crystalline lens is replaced by a transparent artificial lens, the transmittance of the short wavelengths (between 420-500 nm) improved on average by a factor of 4. We conclude that this technique holds great promises for the chronobiological field because it allows for quantification of the spectral composition and light levels reaching the retina in vivo.

Lutein and zeaxanthin measured separately in the living human retina with fundus reflectometry.

PURPOSE: To separately measure the optical densities of lutein (L) and zeaxanthin (Z) in the human retina in vivo. L and Z are the basic constituents of the macular pigment (MP). METHODS: Spectral fundus reflectance was measured in 23 subjects (group 1) at 0 degrees , 1 degrees , 2 degrees , 4 degrees , and 8 degrees eccentricity with a modified macular pigment reflectometer. A model generated the optical densities of L (LOD) and Z (ZOD), using their slightly different absorption spectra. Three other subjects (group 2) took 20 mg/d zeaxanthin for 6 months; they were measured approximately monthly for 18 months. RESULTS: Mean LOD for group 1 at the central fovea was 0.200 +/- 0.061 (range, 0.085-0.305), mean ZOD was 0.494 +/- 0.169 (range, 0.169-0.806), resulting in a mean Z fraction [ZOD/(LOD + ZOD)] of 0.71. ZOD dropped faster toward the periphery than LOD, measuring 0.044 and 0.010 (Z fraction 0.18) at 8 degrees , respectively. Zeaxanthin supplementation in group 2 caused a significant increase in ZOD, and no or minor changes in LOD. ZOD further increased over a 10-month period after supplementation in all subjects. CONCLUSIONS: LOD and ZOD had different spatial profiles that, apart from scaling factors, showed similarity to in vitro literature data. Supplementation with Z caused LOD to decrease and ZOD to increase. These results strongly suggest that the optical densities of L and Z can be assessed in vivo by fundus reflectometry, opening new ways of investigating the putative protective roles of L and Z in retinal disease.

Optical density of the aging human ocular media in the visible and the UV.

We analyzed the literature on the absorption in the young and aging human eye media. Five templates were derived to provide an adequate description of the spectra from 300 to 700 nm for the lens, cornea, aqueous, and vitreous. Two templates were found in all media. They stand for Rayleigh scatter and the absorbance of tryptophan. Three additional templates for the lens represent absorbance in kynurenine derivatives, such as 3-hydroxykynurenine glucoside (3HKG), and absorbance in two substances found at older age. Except for Rayleigh scatter, all templates have a Gaussian shape. Aging-trend functions were derived that show a linear slope on an age-squared scale. The result can be used to correct for media losses in visual perception tasks, in fundus reflectometry, and in studies on light damage.

Influence of macular pigment and melanin on incident early AMD in a white population.

BACKGROUND: The protective effect of macular pigment (MP) and melanin against age-related macular degeneration (AMD) is still controversial from cross-sectional studies. In an attempt to clarify this issue, we performed a population-based longitudinal study. METHODS: MP optical density (MPOD) and melanin optical density (MOD) data were collected during the second follow-up phase of the Rotterdam Study in 1999 in a random subset of 435 participants. Data from 419 participants (98% white) was available for analysis. AMD diagnosis was based on standardized fundus photographs according to the International Classification System, and AMD cases were subdivided into five mutually exclusive stages. In the three follow-up phases, incident AMD (iAMD), defined as absence of any AMD at baseline and the presence of stage 2 or higher at follow-up, was determined. We used Cox regression analysis to study the effect of an assumedly stable MPOD and MOD on early iAMD. RESULTS: During a mean follow-up of 9.82 years, 13 male and 17 female participants developed early iAMD and two male participants late iAMD. Because only two participants developed late iAMD, we had to restrict our analyses to early iAMD. Cox regression analysis adjusted for age and gender showed no significant effect of MPOD [hazard ratio (HR) 0.37; 95% confidence interval (CI) 0.04, 3.57] and MOD (HR 0.56; 95% CI 0.09, 3.60) on early iAMD. Additional adjustment for smoking did not change these associations. CONCLUSIONS: This unique but quantitatively limited material leads to the conclusion that no major protective effect of MPOD or MOD was seen on early iAMD.