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Title Senescence of the human cone photoreceptor pathways

Permalink https://escholarship.org/uc/item/6jq7c5km

Journal VISION SCIENCE AND ITS APPLICATIONS, PROCEEDINGS, 35

ISSN 1094-5695

Authors Knau, H Werner, JS

Publication Date 2000

Peer reviewed

eScholarship.org Powered by the California Digital Library University of California Senescence of the human cone photoreceptor pathways

Holger Knau and John S. Werner University of California, Davis Medical Center, Department of Ophthalmology Sectionand ofNeurobiology, Physiology Behavior,and 4860 Street,Y Sacramento 95817CA [email protected], [email protected]

Abstract: mechanisms dominate sensitivite th y db f short-yo , middle longd an - - wave cones have been isolated in individuals from infancy to old age. Losses in sensitivity occul threal n ei r cone mechanisms beginnin adolescencn gi continuind ean g through later life. Thes boteo t changee h opticadu e neurad sar an l l factors. Quantitative modeling of threshold vs. intensity functions indicates that much of the neural loss occurs at early stage f retinao s l processing associated with senescent change n quantai s l efficiency rather than increases in neural noise (dark ). Intrinsic compensation mechanisms appear to normalize the balance of cone sensitivities across the life span. OCIS codes: (330.1720) ; (330.5310) Photoreceptors; (330.5510) Psychophysics; (999.9999) Aging

Introduction

The proportion of the world s population that is elderly is higher now than at any other point in history. Every month, another one million people enter the sixth decade of life. The consequences of these demographic change r visuafo s l healt e profoundhar . Age-correlated change visuan i s l detection, discriminatio perceptiod nan n greatly affec qualitye elderlye th t th liff r t theso efo bu , e change stile sar l t welno l understood purpose Th . thif eo s pape revieo t s i r w evidence concernin cone sitee th gth en si pathways responsibl age-relater efo d change sensitivityn si . Human photopic visio normalls ni y trichromatic presence th o t f three eo du ,e classe f cono s e photoreceptors, characterized by the wavelength of their peak sensitivity. Studies with the preferential- looking technique have demonstrated that infant discriminatn ca s e various pair f spectrao s l bands, implying that the lease yar t dichromatic (1). However e spectrath , l identit photoreceptore th f yo s mediating discrimination e determineb coul t dno d from these studies. Action spectra have been obtaine wee5 4- kn di infant measuriny b s visually-evokee gth d cortical potential under conditionf o s chromatic adaptatio r short-wave-sensitivnfo e (SWS )d silen conean ) t s(2 substitutio r middlefo n - (MWS longd an ) - (LWS) wave-sensitive cones (3). These studies reveal that when sensitivits yi specifie retinae th t da , infant cone mechanisms have similar relative spectral sensitivity t reducebu , d absolute sensitivity thao t ,f adults o t . Absolute sensitivity increases after continueinfancd an ) y(4 s through adolescence (5). Beyond the teenage years, several studies have demonstrated S-cone sensitivity decreases with age (5-10), and some (5,8,10), but not all (9), studies have shown similar losses in the sensitivity of MWS- and LWS-cone mechanisms. Thus, what we call normal changes continuousl whad ycale an wit tw e l aginghag begin least sa adolescencey tb .

Senescent sensitivitlossee th n si conf yo e pathways

Several studies have attempte measuro dt e age-related change sensitivite th n si individuaf yo l classef so cone receptors and/or cone pathways (5-10) mosn I .f thes o t e studies, sensitivit measures ywa y db increasing the intensity of a monochromatic light superimposed on a chromatic adapting field until the test stimulus reached threshold. The purpose of the adapting field was to suppress the sensitivity of two

OSA TOPS Vol. Vision35 Science and ApplicationsIts Vasudevan Lakshminarayanan, (ed.) 3 82 ©2000 Optical Society of America Vision Science and Its Applications of the three classes of cones and the rods, leaving the third cone type isolated to mediate sensitivity (11,12) r exampleFo . intensn a , e adapting backgroun conesS d wilLW ,ld suppresan S sMW rendering the SWS cones relatively more sensitive. Under these conditions of chromatic adaptation, a SWS-cone pathway can be isolated for wavelengths below about 510 nm, depending on the intensity of the background. At longer wavelengths, sensitivity is mediated by MWS- and or LWS-cone pathways. Although univariant cone mechanism t isolateno e ar sd completely with these methods (13,14)s i t i , nevertheless possibl measuro t e e cone sensitivit gooda o yt first approximation overe partth f o s spectrum. The quality of mechanism isolation can be improved by judicious choice of temporal parameter tese th t f stimulso i owinnormalle th o gt y slower respons f SWS-coneo e mechanisms (15. cf , 16). For mechanism isolation at longer wavelengths, brief test flashe more sar e likele b o yt determined by the quantum catch of a single class of cone (17), whereas longer test flash durations e morar e e detectelikelb o t y d througa h chromatically-opponent pathway (18). Eisne measure) t al(6 e r sensitivite dth f yo a SWS-cone mechanism in individuals above 60 years of age and found a significant decline with "(75 increasing age. Johnson et al. (7) and Werner and CD C/D Steele (8) sampled evenly over the age range of about 12 to 88 years and found continuous changes c 03 conn i e sensitivities from aboue year2 ag 1 t f o s o3 throughou e remaininth t g life span. Figur1 e CD summarizes the sensitivities of isolated cone mechanisms reporte Werney db d Steelan r e (8). CD Each datum represents average sensitivity across DC o wavelength whicn i s e conhon e class dominated 6) sensitivity; SWS cones (440, 460, 500 nm); MWS O coneS LW s d (500 an nm)0 , 62 530 . d ,an 5600 59 , o o1 The declin sensitivitn i e y with advancins i e gag O O o°<9 cPo significant for each of the three cone classes. §( Indeed, the slopes of the regression lines shown in figure th e were similal threal r e fo rcon e typed san impl ydeclina 0.1f eo 3 ±0.0 unitg decader 1lo pe , . Results consistent with these have recently been reported by Knoblauch et al. (5) based on a 25 50 75 100 different task, detection of chromatic stimuli fallin dichromatin o g c confusion lines that were Age (years) embedded in a spatio-temporal achromatic noise field. Fig.lrelativg Lo . e sensitivity (quanta deliveree th o dt cornea r s plottemechanismi ) fo functioa e s da ag f o n s dominate y eitheb d r SWS- (unfilled squares), MWS- Sites of senescent cone sensitivity loss (filled circles), or LWS- (unfilled circles) cone mechanisms dat e normalizee Th aar . d arbitrarily along In all phases of the life span, neural changes in the sensitivity axis for each cone mechanism. Least- relativ absolutd ean e sensitivitie underlyine th f so g squares linear regression lines are shown for each cone type. Each datum represent subjece son averags t e across receptor e difficular s o quantift t y becausf o e numbea wavelengthf o r s dominate sensitivite th y db f yo correlated developmental change oculan si r media e conon e type texe r detailsse ;fo t . [Data from Werner density (19-21) and individual variation in macular and Steele (8).] pigment (22,23) density. In addition, stimuli

383 Vision Science and Its Applications presented in Newtonian view require a correction for age-related changes in pupillary area. Only a few studies have obtained individual measure correco st t sensitivitie conf so e mechanism ocular sfo r media and macular pigment density, although many have included estimates preretinaf o l factors. resulte Th s presente Figuren di refe1 sensitivito t r y specifie e somcornee o s th th f d t eo da a an loss must be attributable to an age-related reduction in retinal illuminance. When these data were correcte r estimatedfo d ocular media density changes, SWS-cone sensitivit retinae th t ya decliney sb about 0.08 log unit per decade. This is in agreement with the results of Johnson et al. (7) using a similar approach and a more recent study by Werner et al. (10) in which ocular media and macular pigment density were measured in separately for each subject. Thus, in these investigations about 40% or more age-correlatee oth f d losconeS sensitivitn si SW s e (defineth f yo termn di f lighso t deliveree th o dt cornea at 440 nm) is attributable to light-losses in the ocular media, with the remaining loss ascribable to receptoral and/or postreceptoral changes. To the extent that the changes in sensitivity for all three cone pathways are similar, relatively greater neural changes would be implied for MWS and LWS mechanisms perhapy t thibu ,ma s s reflect some gain changes supporting constanc f relativyo e cone sensitivity as discussed below. Histological data have so far provided only a few constraints on hypotheses about the neural loci that may be responsible for functional changes in human cone mechanisms inasmuch as age-correlated anatomical changes are nearly ubiquitous in human visual pathways (but see ref. 24). Candidate sites for age-correlated losse sensitivitn si neuraa t ya l level include change morphologe th n si conf yo e outer segments (25), density of cones outside the central (26,27), displaced nuclei in the outer plexiform layer (29), ganglion cell density (29), and cell loss in the visual cortex (30). Psychophysical studies have provided more specific information about the sites of senescent losses of sensitivity of cone pathways based upon quantitative modeling of threshold vs. intensity (tvi) functions. Schefrin et al. have shown that age-related changes in detection (31) and discrimination (32) thresholds mediate S-conn a y db e pathway were dependen levee th lighf o ln o t t adaptation. Similart bu , less extensive, results were reporte LWS/MWS-conn a r dfo e pathway. Figur show2 e s meai ntv functions for groups of younger and older E 10 observers under conditions that isolated an SWS- cone mechanism o detect e s e tasth tTh wa k . , tespresenctnm spo 0 1;a 44 tf , eo superimpose d on 470 nm adapting fields and a 570 nm auxiliary o grouptw f e observerfieldo s Th . s differed C/3 CD primaril intensitiew lo t ya s (the platea absolutr uo e threshold of the mechanism) and then converged at higher intensity. year4 2 - s= Mea e nAg The dat n Figuri a wer2 e e analyzen i d a terms of a modified version of a model of the ,,i pathway (14), according to which SWS-cone

1 1 0 1 9 8 signals pass through two serial gain sites. Quantal Field Intensity (47) 0nm Attenuation at the first site is related to quantal efficiency and spontaneous neural noise. In this Fig. 2. Mean increment threshold functions for younger context, intrinsic noise is additive noise, also (open symbols olde)and r observers (filled symbols) under know Eigengraus na darr o k light (33). Dark light conditions in which test flash detection was mediated by an is defined operationally as the intensity of the SWS-cone pathway. The solid curves show theoretical background wher plateae eth risind uan g portions functions using Eq. [1]. In terms of the model, the difference between younge d oldean r r observers i s of the tvi function intersect. Attenuation of the primarily due an age-related reduction in quantal efficiency test signal at the second site in the model is elevatioon a r neuraf no l noise. [Data from Schefri. al t ne monotonically related to the net imbalance (31)-] between antagonistic inputs S conefromSW s

384 Vision Science and Its Applications versus conesS somLW e . d combinatioFollowinan S MW gf n o Pug alt he (34), predicte i functiondtv s were fitted wit followine hth g equation:

LogU44o = log U044o - log Ci [ko SWS(A 0 A)] - log ^2 [ki SWS(A 0 A)]

- [k2 MWS( AA)0 k- ]3 [LWS( AA)0 ] [1]

where Uis the threshold at 440 nm in the presence of the 470 nm adapting field of radiance A and the 0

570 nm 44 auxiliary field of radiance A . (A 0 A ) represents the superposition of the adapting and auxiliary fields. Log Uo44o is the absolute threshold of the SWS-cone mechanism for the 440 nm test light. The variables SWS, MWS and LWS represent the normalized rates of quantal absorption by the cones, adjusted for individual subjects based upon estimates of their ocular media density. The gain functions at the level of the SWS cones and the second (postreceptoral) stage are represented by ^ and ^respectively, and have the form of Stiles' (36) tabulated increment threshold function, tj(x). Parameters k0, and k2 were allowed to vary freely for curve fitting. Following Pugh and Mollon (14), parameters k1? k2, and k3 were constrained to satisfy the following equation:

0 = ki SWS - k2 MWS - k3 LWS [2]

kd = kan . Reliablm whern 0 e50 |Le= l differences between younge olded ran r observers were founr dfo 3

2 parameters log Uo44o and k, but not for the other curve-fitting parameters of Eq. [1]. This analysis

indicated that, on average, 680 % of the sensitivity loss in elderly subjects is due to age-related changes in effective photon capture (quantal efficiency) elevation a r o , neuran ni l noise. Accountine th r gfo remaining differences in age-related sensitivity losses requires that other neural factors be considered. Whil e datmodelind th e an a g imply tha larga t e proportio e age-relateth f no d los conn i s e sensitivity is ascribable to changes in early stages of processing, the model cannot distinguish between effecte th f quantao s l efficienc dard yan k lightreasoe Th . tha s nrisini e tth g i function portiontv e th f so followed Weber s law, implying a unit slope, or n = 1.0 in Eq. [3]:

] [3 Increment D)Threshol+ p n]/ x (p A [ d= Webee th wher s i r eA fractionfiele th d s proportio e i intensity th darx e , s th i k s p i ligh f d nD o , an t unbleached photopigment (36). Under conditions that follow Weber s law, (n = 1.0), either reductions in photopigment (or mathematically equivalent degradations of quantal efficiency) or increases in dark light affect the shape of the tvi curve in the same manner. Because Weber s law was followed in previous aging studies such as illustrated by Figure 2, these two factors could not be separated from one another; both essentially move curvee th s alon g4a 5 \ lin log-lon ei g coordinates. However, under conditions that are limited by statistical fluctuations in the number of quanta absorbed, following the deVries-Ros (37,38w ela ) wit 0.5= h,n decrease quantan si l efficienc increased yan darn si kt lighno o d t produce equivalen i functiontv t e shiftth n .i s Thi illustrates si Figurey db . Not3A e that photopigment depletion shifts the tvi function such that there is no convergence of the rising portions of the curves. Thus, if tvi functions are measured under conditions in which n «1.0, it may be possible to distinguish between the contributions of dark light and quantal efficiency to age-related elevations in photopic thresholds. Barlow (39) has shown that conditions likely to generate a tvi function conforming to the deVries- law are obtained with test stimuli of small area and short duration detected on backgrounds of moderately low intensity. Tvi functions were measure year8 8 subjects8 4 f ageo r o st fo ,d 0 2 usin, g experimental conditions chose thao ns t thresholds were clos thoso et e limite statisticay db l fluctuation quantun i s m absorption (deVries-Rose law), thereby permittin influencee gth darf o s k ligh quantad an t l efficienco yt senescent elevations in photopic thresholds to be separated (40). Fig. 3B presents results from one older subject. Each subjec dats t a were fitted simultaneously fouy b r straight lines usin gMarquarda t least- squares algorithm. Two lines were constrained to a slope of zero, and two lines were unconstrained in their slope. Goodness of fit was evaluated by R2 (mean = 0.98). Additional tests showed that the

385 Vision Science and Its Applications

O) 11 0) •o . (A) 11 (B) MW (70 yrs) (C) 10 A, = 560 nm = 500 nm 10

03 9 >_ 70 years old

c/) 8 0) Younger '^ 23 years old

D) O 10 0 2 4 6 8 10 10 Log Background (quanta • sec-1 • deg-2)

Fig. 3. The left panel shows modeled tvi functions using Eq. [3]. The lowest curve shows a hypothetical young observer, while the upper curves show the predicted shifts for older observers assuming either a 1.0 log unit increase in dark light (>D) unig lo t 0 reductio1. o ra photopigmenn i t quantal catch (

386 Vision Science and Its Applications However, studies measuring differences in the Rayleigh equation for fields of various sizes, the color- match area effect, revea calculatea l d decreas photopigmenn ei t optical density between 0.00.0d 1an 2 log unit per decade with a more pronounced effect in the fovea and less so in the parafovea (48). Reduction photopigmenn si t optical densit thue yar s likel explaio yt portiona senescene th f no t changes in cone sensitivity, but they are insufficient to explain completely the elevations in the plateau of the tvi function as shown in Figure 3C. Additional factors producing mathematically equivalent photodegradations mus consideree tb explaio dt n these results. Finally addition i , factoro nt s influencing quantal efficiency, age-related degradations not tested in this study may exist such as additive and multiplicative internal noise (49), central inefficiency (50), or intrinsic uncertainty (51). However, other studies have examined senescence of internal noise and have generally not found significant changes (52,53). Environmental Factors: The Role of Ocular Media and Macular Pigment The current literature suggests that important site f age-relateo s d lossee sensitivitth n i s f conyo e pathways are early in retinal processing, most likely within the photoreceptors themselves. It is unclear from these studies, however, why such changes occur in the first place. One view is that light itself may contribute to changes in cone pathways (54). High energy photons from the UV and short-wave visible regions of the spectrum can initiate destructive chain reactions through lipid peroxidation and the formation of singlet-state oxygen and oxygen free radicals. The photoreceptors, which have a high polyunsaturate t contentparticularle dfa b y ma , y vulnerable because visual transduction occurn a n i s environment that requires high oxygen levels numbeA . f antioxidano r t defense presene e ar s th n i t retina (e.g., a-tocopherol, glutathione, melanin, selenium and ascorbic acid), which help to protect from lipid peroxidation. The relevance of studies on light damage by brief, intense exposures to age-related changes under chronic, less intense, exposure s basei s d partl evidencn yo e that retinal damagy eb photochemical processes is additive over time and intensity (55). This additivity is not complete, though, because rods and cones are capable of molecular renewal (56). Rods can replace the entire lengt theif ho r outer segment aboun s i weeks o ttw . Renewa conf o l e outer segments involves piecemeal replacement of molecular constituents and is considerably slower than molecular renewal in rods. Cones may, therefore, be less resilient in their recovery following actinic insult. That light might contribute to foveal sensitivity losses was demonstrated (57) with eight patients undergond ha o wh e bilateral cataract surger implantatiod yan intra-oculaf no r lenses (lOLs) same Th .e surgeo techniqud nan e were containeuseL botr IO d fo e h eyeson d t UV-absorbinbu , g chromophored san the other did not. Hence, the latter lens did not prevent UV radiation (between 320 and 400 nm) from reachin retinae gth . After five year f differentiaso l ligh tretinaeo exposurtw foveae e S th th , f eo SW l cones of the eye receiving more UV exposure were about 1.7 times less sensitive than the SWS cones of the other eye. These results are consistent with the hypothesis that light itself may contribute to senescence of the photoreceptors. radiatioV U Muce th nf h o inciden normae absorbes i th e n o t ey l d beforreacn retinaca e t hth ei ; the amount depends on the age of the observer (21). This may provide a natural defense against the most hazardous radiatio naturan i n l light sources n additionI . e maculath , r pigment a yello, w photostabile pigment that lies in the receptor fiber layer and inner plexiform layer (58), may act as an additional defense by absorbing some of the high-energy photons contained in short wavelengths from visible th e spectrum maculae Th . r pigment might also provid activn ea e photochemical defense th r efo comprises i fovet i s a f carotinoido d pigments that ten neutralizo dt e photosensitized molecules (59) inhibid an t free radical reactions (60)relatione Th . s between normal aging, age-related diseased an , light-induced retinal damag complexe ear thert some ,bu ear e remarkable parallels among them (61-64). Haegerstrom-Portnoy (65) suggested tha maculae th t r pigmen protecy ma tfove e th t a from some hazardous effects of light. She reported that sensitivity losses in a SWS-cone mechanism of an older

387 Vision Science and Its Applications group of observers, relative to young controls, were less in the fovea where the density of the macular pigmen highests i t parafovea,e thath n ni . Consistent with this study, Hammon alt de (66) showed that older individuals with high macular pigment densit highed yha r SWS-cone sensitivity (specifiee th t da retina) than individual same havine th f eag so g lower macular pigment density. However formee th , r t includstudno d yedi direct measure maculaf so r pigment lattedensite th t d rcompar studyan no d ydi e cone sensitivitie a parafoveae fove d th an n ai s l location with little macular pigment. These methodological considerations are important in view of an alternative hypothesis. It might be that long- term adaptation or gain changes in the foveal SWS cones results in higher sensitivity that is directly related to the reduction in short-wave light due to macular pigment screening. The macular pigment protection hypothesi compensatioe th d an s n hypothesis both predic positiva t e correlation between macular pigment densit fovead yan l SWS-cone sensitivity compare parafoveao dt l SWS-cone sensitivity (specifie retina)e th t t onlda forme e ,bu yth r predicts that this correlation shouldependente ag e db . To evaluate these hypotheses about the role of macular pigment in long-term regulation of the sensitivity of cone pathways, sensitivity of SWS-, MWS- and LWS-cone mechanisms was measured at three retinal loci (fovea, 4; and 8; temporal retina) that differ in their pre-receptoral screening by macular pigment dependence vien th I .f wo f age-relateeo d losse sensitivitn si levee th f ligh o n l yo t adaptation (31; Figure 2), foveal and parafoveal increment thresholds were measured on the plateau of the threshold vs. intensity function of each isolated mechanism, and were referred to the retina using individual measurements of ocular media and macular pigment density. Linear age-related increases in foveal thresholds, specified at the retina, were found for all three cone mechanisms. Parallel sensitivity losses for each cone mechanism were also obtained at 4\ and 8j in the temporal retina. No significant relation was found between macular pigment density and the age-related change in absolute thresholds obtained from these healthy observers under condition f foveaso l S-cone isolation illustrates A . y db Figure significana , 4 t positive correlatio founs nwa d between foveal macular pigment densite th d yan coneS LW , d sensitivitan S yMW t differenc coneno S t SW bu , e (Oj-8j) specifie retinae th t da . This relation is consistent with previous evidence that 03 _C maculae th r pigment protect photoreceptore th s s "-I—• 0) from senescent changes (65,66). In this study, DC 1.0 SWS-cone 0) however e relatioth , n between macular pigment e Oj-8th d j differencan SWS-conn i e e sensitivity was not age dependent, and can be interpreted as due to local gain changes resulting from 9 0.5 o differential macular pigment screening between the fovea and parafovea. Thus, while there is evidence thae maculath t r pigmen y afforma t d some protectioS coneSW s r durinfo n g senescence, 0.0 evaluatio f thino s effec s complicatei t gaiy db n changes that may compensate for lower stimulatio orden ni maintaio rt balancna f coneo e sensitivities across the retina, and across the life -0.5 span.

oD) Conclusion d Implicationan s r Colofo s r 0.0 0.5 10 Appearance Macular Pigment Density (fovea, 460 nm) Significant age-related losses in cone pathways Fig. 4. Log sensitivity difference (Oj-8j) for a SWS- begin around the time of adolescence and continue cone mechanism is plotted as a function of peak ove e remaininth r g life span. These sensitivity macular pigment density. [Data from Werner et al. losses have been demonstrate l threal r ed fo con e (10).]

388 Vision Science and Its Applications mechanisms and in parafoveal as well as foveal locations. The ocular media and macular pigment selectively screen UV- and short-wave-visible radiation, respectively, and, therefore, alter the spectral sensitivity of cone mechanisms specified at the cornea. Although the shapes of the spectral sensitivity functions canno compensatee b t univariany db t cone mechanisms, their overall sensitivitiee b n ca s rescaled by mechanisms of adaptation. Evidence for this kind of adaptation is provided by the relation between macular pigment density and the threshold difference between two retinal areas differing in macular pigment screening. Mechanisms that compensate for age-related changes in ocular media density or variations in the spatial distributio f maculano r pigment would promote constanc f coloyo r appearance acros life sth e span. A number of studies, using different methods or probing different regions of , have demonstrate dsubstantiaa l degre stabilitf eo colon yi r appearance acros life seth span. (67-69) Analyses of these data indicates that such stability would be possible only if the visual system actively recalibrates itself (68,70). Renormalizatio f sensitivitieno f cono s e pathways woul consistene db t wit date hth a presented her would ean d also support perceptual stability acros life seth span.

Acknowledgements

The authors research is supported by the National Institute on Aging (AG04058), National Eye Institute Core Grant (EY12576 Julea Dorid d san )an s SteiProfessorshipB nRP .

References

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