Intrinsically photosensitive retinal ganglion cell function in relation to age: a pupillometric study in humans with special reference to the age-related optic properties of the lens

Abstract

Background: The activity of melanopsin containing intrinsically photosensitive ganglion retinal cells (ipRGC) can be assessed by a means of pupil responses to bright blue (appr.480 nm) light. Due to age related factors in the eye, particularly, structural changes of the lens, less light reaches retina. The aim of this study was to examine how age and in vivo measured lens transmission of blue light might affect pupil light responses, in particular, mediated by the ipRGC.

Methods: Consensual pupil responses were explored in 44 healthy subjects aged between 26 and 68 years. A pupil response was recorded to a continuous 20 s light stimulus of 660 nm (red) or 470 nm (blue) both at 300 cd/m2 intensity (14.9 and 14.8 log photons/cm2/s, respectively). Additional recordings were performed using four 470 nm stimulus intensities of 3, 30, 100 and 300 cd/m2. The baseline pupil size was measured in darkness and results were adjusted for the baseline pupil and gender. The main outcome parameters were maximal and sustained pupil contraction amplitudes and the postillumination response assessed as area under the curve (AUC) over two time-windows: early (0-10 s after light termination) and late (10-30 s after light termination). Lens transmission was measured with an ocular fluorometer.

Results: The sustained pupil contraction and the early poststimulus AUC correlated positively with age (p=0.02, p=0.0014, respectively) for the blue light stimulus condition only.The maximal pupil contraction amplitude did not correlate to age either for bright blue or red light stimulus conditions.Lens transmission decreased linearly with age (p<0.0001). The pupil response was stable or increased with decreasing transmission, though only significantly for the early poststimulus AUC to 300 cd/m2 light (p=0.02).

Conclusions: Age did not reduce, but rather enhance pupil responses mediated by ipRGC. The age related decrease of blue light transmission led to similar results, however, the effect of age was greater on these pupil responses than that of the lens transmission. Thus there must be other age related factors such as lens scatter and/or adaptive processes influencing the ipRGC mediated pupil response enhancement observed with advancing age.

Figure 1

Graphic representation of the pupil response to blue light in one normal subject. The dotted line at the top is an extrapolation from baseline pupil size (BS) and corresponds to 1.0 on the Y-axis. Y-axis represents values of the normalized pupil size (NPS). Time −10 is the start of video recording of the pupil while in darkness.. Time 0 is the onset of a 300 cd/m² continuous blue light stimulus having duration of 20 seconds (vertical bars at the bottom). The arrow at point 1 shows where the maximal contraction occurs (the maximal CA). The arrow at point 2 is the 20^th second of light stimulation and represents the sustained CA. The third parameter, 3, is the early poststimulus AUC (grey shaded area in the pupillogram) which is the summed pupil response during the first 10 s after light termination. The late poststimulus AUC, 4 (black shaded area), another summed post-illumination response parameter is taken from the 10^th to 30^th second after light termination. For definitions, see Methods.

Figure 2

Lens autofluorescence scan. Lens autofluorescence of a 28 year old subject (A) and a 61 year old subject (B). The fluorescence intensity is given as ng/ml. The x-axis represents a visual axis in mm. Ppost is a peak fluorescence of the lens posterior pole, and Pant is a peak fluorescence of the lens anterior pole. In the older subject values of the peaks appear higher and the difference between posterior and anterior peaks is greater than that of the young subject. Due to the accumulation of denaturated lens proteins in the advanced age lens, light absorption increases, and the back emitted fluorescent light from the posterior peak appears less intense than the light from the anterior peak.

Figure 3

The correlation between age and early poststimulus pupil response (AUC) at 300 cd/m²blue light conditions. The linear correlation of age to the summed poststimulus pupil response within the first 10 seconds after light termination (early AUC 0–10) was highly significant (Pearson correlation coefficient r = 0.43), with increasing age corresponding to a larger pupil contraction (solid line is regression line, the dashed lines represent the 95% CI).

Figure 4

The relation between age and lens transmission of blue light. Lens transmission correlated negatively to age, with lens transmission decreasing significantly with increasing age. The rate of change was approximately 1% per year of age (Pearson coefficient r = −0.91). Lens transmission of 1.0 corresponds to a totally clear lens in a young healthy subject (solid line is regression line, the dashed lines represent the 95% CI).

Figure 5

The relation between early poststimulus pupil response and blue light intensity. Early poststimulus response (AUC) versus 470 nm light intensity (cd/m²). The pupil response increases as intensity increases, but levels off at intensities approaching 300 cd/m² (solid line represents an exponential fitted curve, the dashed lines is 95% CI).

Figure 6

The relation between early poststimulus pupil response at 300 cd/m²and lens transmission of blue light. The early poststimulus pupil response (AUC) increased significantly when lens transmission decreased (Pearson correlation coefficient r = − 0.38), i.e., the greater poststimulus pupil response was observed in advanced age subjects with denser lenses (solid line is regression line, the dashed lines represent the 95% CI).