Overall, the blood flow findings combined with the blue fERGs provided compelling evidence that ChBF must have been shifted away from the subfovea, likely toward retinal regions with the highest metabolic activity, in this case toward eccentric rods because the stimulus wavelength was selected to match the spectral sensitivity of rhodopsin that is found exclusively in rods. Confirmation that blood moves from the subfoveal choroid to the peripheral choroid during a similar series of blue flashes would require simultaneous ChBF measurements in the periphery and the subfovea, which is technically very challenging. The decrease in subfoveal ChBF during the blue flash stimuli that increased activity in rod photoreceptors parallels the progressive reduction in subfoveal ChBF measured during physiological dark adaptation of the retina where the site of increasing metabolic activity was increasingly far from the fovea, in the rod-domi- nated zone of the far macula.

10.8Aging

10.8.1 Structure

Normal aging is accompanied by a reduction in the number of arterioles and venules and an associated neural loss such as a dropout in retinal ganglion cells [85]. Along with this reduction in retinal vessels, there is a modification in the geometry of arterial bifurcations that likely alters blood flow and leads to blood rarefaction of the microvasculature [86]. In addition to these changes in retinal vessels, the density and caliber of the vessels forming the choriocapillaris in the human macula also decrease, thereby causing a thinning of the choroid [87]. There is also a significant reduction in the sympathetic innervation to the choroid [88] and a loss of endothelial cells in the choriocapillaris [89]. With normal aging, a thickening of Bruch’s membrane is known to occur [87, 89] and is subject to accumulation of cholesterol, particularly in the macular region [90], thereby impairing normal diffusion of blood between the RPE and the choroid [91, 92]. All of these histological findings are compatible with an alteration in ocular hemodynamics in senescence.

10.8.2 Blood Flow

Recent technological advances such as the RVA have led to noninvasive measurements of realtime changes in retinal vessel diameter during flicker. Using this technology, Polak et al. [93] recently reported that retinal vessels dilate in response to flicker between 1 and 60 Hz. Shortly afterward, Nagel and Vilser [94] reported on a clinically usable procedure for quantifying the degree of vasodilation in retinal arteries and veins during a 12.5-Hz flicker. These latter studies formed the basis of a study that compared the timing and amplitude of change in retinal vessel caliber in healthy volunteers 20–80 years of age. In order to compare the degree of dilation between arteries and veins within and across subjects in different age groups, the data sorted by decade of life were normalized such that the prestimulus vessel diameter was designated as 100%, and subsequent changes in caliber were expressed as a percentage of that value.

The group-averaged maximal dilation for an artery and vein in response to 60 s of flicker presented at 12.5 Hz was ~6% and ~8%, respectively. This difference in the degree of vasodilation between arteries and veins was maintained across all age groups from 20 to 80 years of age. However, the overall dilation measured in arteries and veins was less for the subjects in the 60and 70-year age groups. A sample comparison of the vasodilation/vasoconstriction response profiles to flicker for a young and an elderly subject are presented in Fig. 10.20. The outstanding difference in these response profiles was the delayed and slower vasoconstriction of both artery and vein during the recovery phase for the elderly subject. Consequently, neither vessel returned to baseline within the 60-s recovery phase.

The vasodilation to flicker has been interpreted as a response to increased metabolic demand of the retina and hence a need for increased blood flow for more oxygen and metabolites needed to sustain neural activity. The failure of retinal arterioles to dilate as much as the younger subjects may be attributed to a reduction in the amount of circulating substances such as NO with age or a dropout of muscle fibers, thereby affecting the reactivity of the

Fig. 10.20 Representative retinal vessel dilation and recovery profiles in response to a 12.5-Hz flicker in young (Frame a) vs. elderly subjects (Frame b). Results from an ongoing study have revealed that retinal veins dilate biphasically as do arteries during flicker, but veins dilate to a greater degree than arteries in both young and elderly subjects. Furthermore, both arteries and veins tend to

dilate more in younger subjects than in the elderly. Interestingly, retinal arteries in younger subjects overshoot baseline diameter during the vasoconstriction recorded in the recovery phase, but arteries in elderly subjects do not show such an overshoot in recovery. In fact, neither arteries nor veins in elderly subjects regain baseline vessel diameter in the recovery interval

vessels and its ability to vasodilate. Alternatively, because there is an attrition of photoreceptors with age, it is possible that the neural retinal response to standardized flicker luminance was less in subjects over 60 years of age compared to younger subjects, thereby requiring a smaller increase in blood flow. Further studies are needed to determine the precise cause of these new findings on retinal hemodynamics in senescence. Whatever the reason for reduced arterial dilation, this vasomotor deficit may be projected to blood flow in the brain and may also indicate subtle subclinical cardiovascular deficits in senescence.

At the structural level, retinal vessel diameters were also measured in the same group of subjects in an effort to determine structural changes with age and to determine the correlation between retinal hemodynamics and structure. The retinal vessel diameter was quantified over a ~2,700-mm length to provide a more precise measure of age-related changes in vessel caliber because previous studies of vessel size were based on very narrow cross-sectional values. For the data presented in Fig. 10.21, highresolution digital fundus images were first taken with the Imedos Visualis system and then vessel diameters were quantified with their VesselMap

Fig. 10.21 A: optic nerve head, B: white rectangle identifies the location where the first measurement of the vessel caliber was made in the course of determining the taper of the target vessel over a 2700 µm distance from the optic nerve head toward the retinal periphery. C: white line through the retinal vessel identifies the most peripheral site where the measurement of vessel caliber was made. The two solid white arrows highlight the 2700 µm length of vessel along which changes in vessel caliber were determined

software. The group-averaged vessel diameter for paired arteries and veins for each age group in this study are presented in Fig. 10.21. Overall, there is a trend for a reduction in diameter in

both arteries and veins for subjects between 20 and 80 years of age. This narrowing of retinal vessels may be an adaptation for the concomitant increase in the systemic BP and hence an increase in the OPP, although still within normal range. Inasmuch as all subjects were free of systemic and ocular diseases, it was presumed that the decrease in vessel diameter was a response to increased OPP [95].

and abnormalities in the systemic vasculature that directly affect ocular blood flow. The work described above represents some of the first initiatives to define changes in vascular perfusion at different levels within the retina and their effect on neural function in the aging eye. Additional studies are required for a complete description of changes in neurovascular coupling as a function of age.

10.8.3 Retinal Function

The normal aging process is accompanied by physiological decline in many organs, thereby decreasing the functional reserves and increasing their susceptibility to disease. However, the boundary between the functional decline linked with aging and the development of pathology is not well described in a variety of ocular diseases.

Recent studies have concluded that aging per se is associated with a variety of significant nonpathological changes in neural structure and function in the eye of healthy subjects. Specifically, the function of all major retinal neurons, including rod and cone photoreceptors, bipolar/ Mueller cells, amacrine cells [96], ganglion cells [97], the retinal nerve fiber layer [98], and the retinal ganglion cell axons within the ONH [99], is compromised in senescence. These findings allow a distinction between the effects of normal aging and the onset of ocular pathology that occurs more frequently in the elderly.

While these findings have defined the anatomical and physiological changes in the aging eye, changes in the ocular blood flow associated with aging per se are yet to be quantified. This identifies an area of fundamental and clinical research that is essential for correctly diagnosing subclinical ocular pathology related to vascular dysfunction or impaired blood flow that occurs more frequently in the aging population. ARMD is a prime example of a prominent ocular disease thought to have a vascular origin. However, a correct diagnosis of the onset of any vascular disease of the eye must rule out any effects of normal aging on retinal or choroidal perfusion

Abbreviations