BritishJournal ofOphthalmology, 1992,76, 11-16 11

A primate model for age related macular drusen Br J Ophthalmol: first published as 10.1136/bjo.76.1.11 on 1 January 1992. Downloaded from

G M Hope, WW Dawson, H M Engel, R J Ulshafer, M J Kessler, M B Sherwood

Abstract are allowed on the island except during annual A closed colony of semi-free-ranging rhesus medical examinations, when limited, non-in- monkeys maintained in isolation since 1938 by vasive, biomedical research is possible. Animals the Caribbean Primate Research Center removed to reduce the colony's size are housed, (CPRC) is being studied as a model for age with a number of non-colony animals, in large, related macular drusen. Of examined colony outdoor corrals at a second facility (Sabana Seca) animals 57*7% of the monkeys and 47*3% of on the Puerto Rican mainland. The CPRC their eyes have drusen. The prevalence and maintains over 2000 monkeys, the majority severity of drusen are linearly related to in- being derived from original Cayo Santiago creasing age and are significantly higher in matriarchs. specific maternal lineages (matrilines). An We conducted 315 eye examinations on 246 electrophysiological estimate indicates loss of monkeys from the Cayo Santiago matrilines. function associated with drusen. Prevalence of Sixty-one ofthese were repeat examinations after drusen in CPRC females is almost twice that of one to three years, and eight were accidental males, while the prevalence among CPRC duplicates (after one to two days). Examinations animals in general appears to be several times were conducted at Sabana Seca and on Cayo that ofmonkeys from continental US facilities. Santiago. Only data from animals with traceable Evidence suggests that the frequency of end- Cayo Santiago lineages are included in this stage lesions is also similar to that in human report. populations. The CPRC matriline monkeys All monkeys were anaesthetised by initial appear to provide the best model yet reported intramuscular injection of ketamine hydro- for human age related macular drusen. chloride (12 mg/kg, Vetalar), with supplementa- tion (6-12 mg/kg) as necessary to maintain an effective level ofanaesthesia. Pupils were dilated Age related (AMD) is a with phenylephrine (10%, Neo-Synephrine) major cause of severe vision loss in the United and tropicamide (1%, Mydriacil). Corneas were States and the major cause in persons over 50.12 kept moist with artificial tears (Tears Naturale) The initial clinical manifestation of AMD,3 and and anaesthetised with propacaine (0-5%, one of the most important,4 is drusen. These are Alcaine). http://bjo.bmj.com/ visible ophthalmoscopically as yellow-white Eye examinations consisted of notation of spots in the retinal pigment epithelium (RPE) abnormalities of the externae and anterior seg- and are seen histologically as depositions of ments, intraocular pressure measurement, in- pleomorphic material beneath the RPE.-6 Given direct and direct ophthalmoscopy, and, for some the significance ofdrusen in AMD and failure to affected monkeys, and, induce them in normal eyes, it would be valuable rarely, fluorescein angiography. The animals to identify an animal species in which drusen were not refracted but extreme refractive errors on September 27, 2021 by guest. Protected copyright. occur spontaneously. There have been several were noted when detected under direct oph- reports of drusen and macular lesions in aging thalmoscopy. monkeys,6-'5 but the condition appears rare in In the retinal examinations gross abnormalities animals in US facilities. We have been investigat- were noted, cup/disc ratios estimated, and detect- ing the incidence of macular signs associated able macular drusen were counted, under direct Department of with this disease in a closed colony of free- ophthalmoscopy, up to 15. The drusen counts , University ofFlorida, ranging rhesus macaques (Macaca mulatta) at the were recorded either directly or in quantitative Box J-284, JHMHC, Caribbean Primate Research Center (CPRC) of increments offive, as 0, <5 . . . '15, >15. The Gainesville, Florida the University of Puerto Rico. While samples counts were later used to categorise each eye on a 32610, USA from " we G M Hope this population have been described, five point drusen category scale (O to 4) based W W Dawson report new relationships between drusen and purely on the numbers of drusen, as: 0=0 R J Ulshafer aging, resolution loss, sex, and colony drusen, 1= 5 drusen, 2=>5 and .0 drusen, M B Sherwood matriarchal lineages. 3=>10 and <15 drusen, and 4=>15 drusen. Department of Drusen counts were conducted by two or more Ophthalmology, of three examiners. Initially, the drusen count Montefiore Medical Material and methods for each eye was reached consensus but more Center by H M Engel The colony was established on Cayo Santiago, a recently was taken as the mean of independently small island off the east coast of Puerto Rico, in conducted and recorded counts by each of the Caribbean Primate 1938 and no new animals have been introduced three examiners. Multiple correlation analysis of Research Center, Medical Sciences since.16 Since 1956 all monkeys have been indivi- these data indicate that the agreement among Campus, dually identified and daily census records main- examiners is very close (r=0 89) with a standard University of Puerto Rico tained. The social history and matriarchal error of estimate of less than two drusen (1-84). M J Kessler lineages (matrilines) for eight to 10 generations This correlation is statistically significant Correspondence to: Dr G M Hope. are known for each animal. Commercial monkey (p

W/2,142 df). Comparisons based on drusen categories yielded kappas"7 between 0 40 and Br J Ophthalmol: first published as 10.1136/bjo.76.1.11 on 1 January 1992. Downloaded from 0 50 for pairs of examiners. These levels of agreement are significantly (p<0 001) greater than would be expected by chance. In addition the eight animals (16 eyes) accidentally re- examined on successive days provided a useful estimate of the repeatability of the measures. Drusen categories on the initial and repeat examinations were identical for 14 of the 16 eyes (6 at 0, 6 and 1, and 2 at 4) and differed by only one category unit (3 v 4) for two eyes of one animal. The test-retest correlation coefficients were 0-98 for eyes and for animals, both statis- tically significant (p<0 01). The age and paren- tage of the animals were unknown to the examiners until after completion of the examina- tions, when these data were determined from the matriarchal lineages. Fundus photographs and fluore'scein angio- grams were taken with a Kowa hand-held fundus camera which had been modified to carry a 35 mm camera back (Pentax MX) and auto- winder (Pentax). Angiograms were taken with appropriate barrier and exciter filters at 1-second intervals for 20 seconds following fluorescein injection (10 mg/kg, Fluorescite) and after 30 seconds and 3 minutes. Extensive fundus photo- graphy was not feasible under the primitive conditions on the island where over half of these animals were examined. All ophthalmic equip- ment was transported daily by small boat across * VP__Ed open water to Cayo Santiago, then by hand up the island's highest hill. Examinations were Figure I Fundus photographs oftypical category 4 retinas. Numerous drusen are obvious in both the right (OD) and left conducted in an open air shelter with no light (OS)fundi. control and with unregulated electricity from portable generators. Electricity was shared and consequently was frequently inadequate for http://bjo.bmj.com/ fundus camera operation. The adequacy of the the percentages of animals and/or eyes in which photographic records could not be verified until drusen was present; and the relative severity, in- after the opportunity to collect data was lost. dicated by the quantitative drusen category into Finally, small lesions clearly visible through the which each retina fell; and the visual resolution direct ophthalmoscope were undetectable estimate described above. In most cases analyses through the fundus camera or in photographs. are presented for affected monkeys and for on September 27, 2021 by guest. Protected copyright. Under these conditions the certainty, instant affected eyes, consistent with similar human verification, and greater magnification provided studies.'8 Data were evaluated statistically by by the direct ophthalmoscope proved much analysis of variance, t tests, regression/correla- more suitable than fundus photography for tion, and non-parametric x2 analyses for con- determination of quantities ofdrusen. tingency tables. Eight monkeys shipped to our laboratories for electrophysiological estimatesofvisual resolution were anaesthetised and their pupils were dilated (as above). They were maintained on 25% 20 - - SAMPLE oxygen, 75% nitrous oxide, muscle relaxant - POPULATION (pancuronium bromide, Elkins-Sinn), and intra- venous saline. Core temperature, electro- cardiogram and end tidal CO2 were monitored. 0 0 I \ All procedures were approved by the relevant I \ Institutional Animal Care and Use Committees. z I \ Signals in response to counterphased patterns, I projected on to the macula under visual control Lb a- for location and focus via a modified Zeiss fundus - camera, were led to specially designed low-noise \I /- - preamplifiers, then processed and stored by 5 10 15 20 25 30 digital computer (Nicolet Med 80). The root AGE (Years) mean square (RMS) amplitudes were later deter- Figure 2 Age distribution ofCayo Santiago macaques. The mined from the stored signals and provided the left ordinate presents the percentages ofanimals at eachyear of basic data for resolution estimates. age indicated on the abscissa. Distributions ofthe colony (solid line) and our sample (broken line) are presented. The majority Primary dependent variables evaluated in this ofthe animals in the sample distribution were over 10years of report were prevalence of drusen, indicated by age. A primate modelforage related maculardrusen 13

100 Results o % ANIMALS W/ DRUSEN , - / Br J Ophthalmol: first published as 10.1136/bjo.76.1.11 on 1 January 1992. Downloaded from Figure 1 presents right and left eyes of monkey Y = 3.17(X) + 22.19 * *0 ° ,' / z no. 909, an 11 YO (at examination) female from 80 - r =0.858 0 ' matriline 091. Both eyes of this animal fell into 0 60 o ,- drusen category 4 (>15 drusen). The lesions I seen here are typical of those seen in the eyes of 3I , ,0 , / z 40 CPRC monkeys. Note that drusen in OS appear LiJ -I o0 ° % EYES w/ DRUSEN to be larger, confluent and more foveal than in LiJ a. 20 /* * Y = 3.12(X) + 13.65 OD. r = 0.861 Age distributions (Fig 2) show that our sample was selective for older animals, while the colony D5 10 15 20 25 30 distribution washeavily skewed bylarge numbers of very young monkeys.'9 The majority of our AGE (Years) sample were over 10 years of age. Ordy and Figure 3 Relationship between age and percentage ofeyes Brizzee'0 have estimated that one monkey year is and monkeys having drusen. Abscissa is age inyears, ordinate indicates percentages (monkeys and eyes) ofeach age which equal to about 3-3.5 human years. By this have drusen. Relationshipsfrom linear regression and estimate our sample ranges up to the human correlation coefficients are provided in the upper left and lower equivalent ofabout 85-100 years ofage. right corners ofthe graph. A total of490 fundi from the 246 animals from the Cayo Santiago matrilines were examined (cataracts obscured two fundi). Drusen were graphs in this figure. Several matrilines appeared found in 142 of246 animals (57-7%) and in 232 of notable for relatively high percentages of eyes the 490 retinas (47 3%). Ages of animals whose with drusen and higher mean drusen categories. retinas contained drusen ranged from 3 to 29 Between 60% and 85% of the monkeys sampled years, or 9-10 to 85-100 human years.20 Per- from matrilines AC, 031, 076, and 091 had centages of affected animals and eyes increased drusen (Fig 6a). The percentages of eyes with linearly with increasing age (Fig 3). The correla- drusen (6a) and mean drusen categories (6b) in tions, r=0-858 and r=0-861, are significant these matrilines were also higher than those of (p<001) and suggest that 74% of the variability other matrilines. Matrilines AC, 031, 076, and in prevalence can be accounted for by age. 091 were significantly (p<0-001) different from Figure 4 shows a similar relationship between the others in all three measures of drusen. mean drusen category and age. The correlation These four high prevalence matrilines did not coefficient (r=0-83, p<0-01) by this measure differ statistically (p<030) in mean age from the indicates that 69% of the variability in drusen five low prevalence matrilines (Fig 6c). Extra- category (severity) is accounted for by age in our polation from regression equations (Figs 3 and cross-sectional sample. 4), based on mean ages ofthe high (mean= 11- 13) Longitudinal evidence indicates progression and low (mean= 10-75) prevalence matrilines ofthe disease in 57 matriline animals re-examined yielded expected differences of 1-25% in preva- http://bjo.bmj.com/ after one to three years. Thirty (52 6%) of these lence (animals or eyes) and 0 04 in drusen monkeys and 59 of the 114 (51-7%) eyes showed category between the two groups, as compared quantitative increases in drusen. The quantity of with differences of 25% and 0 5, respectively, in drusen decreased in 10 eyes of six animals over the data. The only notable difference in sample the same period. Most changes involved less than size (Fig 6d) was the much larger sample from five drusen, though some monkeys went through matriline 091. We had access to numerous 091 several drusen categories. The observed propor- animals when the troop for which this was the on September 27, 2021 by guest. Protected copyright. tions were significantly different (p<0-001) from dominant matriline was removed from the island. those expected under the assumptions of no Figure 7 presents RMS amplitudes of pattern increase or ofrandom variability. evoked retinal responses to gratings in two eyes Of the 246 individual animals comprising the (two animals) differing in drusen size and loca- sample 114 were males and 132 were females. In tion. The eye producing the upper curve in this Table 1 females can be seen to be significantly figure had numerous (>15) small drusen scat- higher than males in every category of drusen tered throughout the macula. The eye in the prevalence or severity, for animals or eyes. Only differences in ages and numbers of males and females in the sample were not statistically 4.00 Y = 0.099(X)-0.204 . r = 0.834 > 3.50 significant. Regression analyses for prevalence - p ( 0.01 among males and females against age (Fig 5) ° 3.00 hi show that the slopes are very similar but the < I 0 2.50 0 intercepts differ by about 20%, indicating that z 0 increased prevalence among females was main- Li 2.00 0 0 a- 1.50 tained across all ages. 0 Figure 6a-d presents distributions of percent- M 1.00' 0 0 m age of affected monkeys and eyes (6a), mean 0.50- 0 0 drusen mean and number 0 category (6b), age (6c), 0.00 of monkeys sampled (6d) for nine matrilines. 5 i'o 1'5 io A 30 Seven additional matrilines were excluded owing to sample sizes of fewer than 10 animals. The AGE (Years) abscissa of the first is matri- Figure 4 Relationships between age and drusen category. graph organised by Abscissa is age inyears, ordinate indicates mean drusen lines with decreasing prevalence, and, to aid category. Relationshipsfrom linear regression and correlation comparison, this order is maintained in the other coefficients are provided in the upper left corner ofthe graph. 14 Hope, Dawson, Engel, Ulshafer, Kessler, Sherwood

100 0 0 05 0 0 0 -0.0 0 0 Table I Comparisons ofdrusen in retinas ofmale and 90- female monkeys Br J Ophthalmol: first published as 10.1136/bjo.76.1.11 on 1 January 1992. Downloaded from P

80- . ooo ,-0 , o *,-. Males Females Total x 70- , 60- oO Monkeys o 0 z Number 114 132 246 50. o 0 0 0 % Total sample 46-3 53 7 100 z 40. Mean age (yrs) 10-98 11-4 11-2 ^ 30- Number with drusen** 53 89 142 0 -M MALES % of same sex** 46 5 67-4 20 o -- FEMALES % ofall with drusen*** 37-3 62-7 100 % total sample* 21-5 36-2 57.7 10 Eyes Number 226 264 490 0 5 10 15 20 25 30 % total sample 46-1 53 9 100 Number with drusen*** 81 151 232 AGE (Years) %ofsamesex** 35 8 57-1 % ofall with drusen*** 34-9 65-1 100 Figure 5 Relationships between age and prevalencefor % total sample* 16-5 30-8 47-3 males andfemales. Abscissa is age inyears, ordinate indicates Mean drusen category*** 0-52 1-02 0-79 prevalence in percent. Relationshipsfrom linear regression are provided in the lower right corner ofthe graph. ***p

lower curve had similar quantities of drusen but of humans. While there is no general agreement one large, coalesced druse was centred directly on which human signs and symptoms are neces- over the fovea. The difference in pattern resolu- sary to diagnose age related macular degenera- tion due to these two drusen distributions is tion,' some of the more frequently used are: (a) evident. A summary is presented in Table 2 presence of drusen, the typical early lesion; (b) which shows averaged areas (with SD and n) relationship of drusen to aging; (c) vision loss under similar curves for retina and cortex in accompanying drusen; (d) late occurrence of response to patterns covering 15° and 300 for exudative or dry disciform lesions. retinas having >10 and -10 drusen. Drusen in In addition a number ofsecondary characteris- most of these eyes were small, scattered, and tics have been associated with AMD in humans, non-foveal. Retinas with more than 10 drusen including consistently greater prevalence in performed significantly worse (p=0 044) in females than males and relationships between response to 30° patterns, while marginal familial (especially maternal) and individual (p=0-64) differences were seen with 150 fields. occurrence of the disease. I 2 1821-23 The case for a Cortical results, however, were not different. model would be strengthened if all features (including secondary ones) of the human disease could be demonstrated in the animal population. Discussion Results from the CPRC rhesus macaque colony In order to identify an animal model for any suggest that this population has all of the impor- http://bjo.bmj.com/ disease the signs in animals should mimic those tant, drusen related features as well as several of

900 X a EZ21 ANIMALS b wZ 80 on September 27, 2021 by guest. Protected copyright.

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AC 031 076 )91 073 DI ,4 RB 116 092 MATRIUNE MATRIUNE Figure 6 Variation ofsample characteristics with matriline. Levels ofeach ordinal variable are presented versus matriarchal lineages on the abscissa. The matrilines are ordered by decreasing percentage ofeyes having drusen in 6a and this order is maintained in 6b-d. A primate modelforage related maculardrusen 15

3000* Table 2 Effects ofdrusen on electrophysiological indices of *-* Small Scattered Drusen Br J Ophthalmol: first published as 10.1136/bjo.76.1.11 on 1 January 1992. Downloaded from In z visualfunction 5200 Total root mean square signal size 0o 2000 0 Field t test c size >lO drusen < =lO drusen p In Retina Retina V) 10ooo 300 3822 (745) (n=7) 6220 (2712) (n=8) 0 044 < _ o~~~~-- - -o 150 1433 (666) (n=6) 2337 (703) (n=7) 0-064 z / - Cortex Cortex cn -0- Large Foveal Drusen 300 1675 (264) (n=7) 1553 (703) (n=8) 0-968 150 945 (302) (n=6) 1154 (842) (n=7) 0-576 1 2 3 STIMULUS SIZE (Log Min Arc) Figure 7 Relationships between resolution and drusen. electroretinograms (ERGs) in affected animals. Comparison ofeffects ofsmall scattered drusen (solid line, Bellhorn et al26 found no drusen associated filled symbols) and largefoveal drusen (dashed line, open degradation in signals from the eyes or cortices of symbols). Data are root mean square amplitudesfrom retinas on which patterned stimuli subtending the visual angles on the US animals, with conventional, cone selective, abscissa are projected under visual control. and patterned stimuli. Thus, while loss ofretinal resolution capacity is associated with drusen in our small sample of tested CPRC monkeys, the the epidemiological characteristics ofthe disease. nature of this relationship and of differences The presence of drusen in the eyes of CPRC between CPRC and mainland monkeys are un- monkeys and the histopathological similarity of resolved. drusen in monkey eyes to drusen in human eyes A question raised - explicitly or implicitly - in have been firmly established.`-"'3-'5 24 However, several macaque AMD studies involves the rela- in monkey eyes, vacuolated or lipid filled pig- tive paucity of neovascular lesions in mented epithelial (PE) cells can appear virtually monkeys.'°026 Stafford et al identified seven eyes identical to drusen.'2 1425 Stafford et all4 noted the in four animals among their 574 elderly monkeys difficulty in distinguishing between the two, but (mostly rhesus) having probable choroidal neo- Fine and Kwapein'2 speculated that it might be vascular lesions.4 These animals were 8-15 possible to differentiate by the small size and dioptres myopic.'4 Myopia has been linked to solitary nature of the lipid laden PE cells. We macular lesions, as these authors note,'4 while have used the term 'drusen' to refer to the AMD correlates with hyperopia in humans.2"-23 ophthalmoscopic yellowish-white figures in We have reported one monkey with a disciform these monkey fundi, which is consistent with its macular lesion ophthalmoscopically identical to application in clinical medicine. While a small those seen in human AMD.8 The prevalence of portion ofthe drusen in our animals have proved severe macular serous and exudative lesions in to on was 0-78% of be abnormal PE cells microscopic examina- the Framingham Eye Study (29 http://bjo.bmj.com/ tion, a demonstrated increase with age and 5253).18 This compares favourably with 0-7% of frequent confluence argue that most are the Stafford and coworkers,'4 monkeys and 0 4% of 'true' drusen we have described at both electron our sample. These lesions therefore appear to and light microscopic levels.6 have been encountered in monkeys at about the El-Mofty et al'° found an increase in macular same relative frequency as reported in humans. drusen across five increasing age groups ofCPRC The infrequent observation of end-stage or neo- animals. Bellhorn et al26 found that macular score vascular lesions in monkeys is probably a func- on September 27, 2021 by guest. Protected copyright. increased with age among the five age groups into tion of the relatively few very old monkeys which they divided their sample, but in grades 3 examined. and 4 alone (dependent on drusen) the preva- El-Mofty et aP '0 found that 25% of the non- lence appeared to peak at 11-15 years, then selected CPRC monkeys they examined had decrease in both older and younger animals. Our drusen, which is consistent with our observa- results establish firm, linear relationships be- tions on several matrilines (note Fig 4a-b). tween drusen and aging. The high correlations Comparison of CPRC monkeys with random associated with these relationships, significant source monkeys from US mainland facilities is intraanimal increases in drusen over one to three more interesting. Bellhorn et a126 and Stafford et years, and previous observations'0 firmly estab- al'4 studied relatively large samples (n=500-600) lish that drusen progression in CPRC animals is and found that only about 6% showed druse-like age related. lesions. If all category 1 (1-5 drusen) CPRC Relationships between pattern evoked poten- animals are eliminated, comparison with tials and visual acuity and dependence ofcortical Stafford and coworkers"4 older monkeys having signals on foveal integrity have been established five or more drusen indicates that 21% of the previously.27-29 The reduced effect of drusen on CPRC monkeys are affected, compared with 6% signals from smaller stimulation fields (greater of their sample of US animals. Bellhorn and foveal influence) and unaffected foveally coworkers'26 minimum criterion (<10 drusen) dominated cortical responses is to be expected in appears to indicate that some 6-1% of their these animals whose foveas were mostly intact. animals had drusen, compared with 57-7% ofthe We have previously described a non-matriline CPRC monkeys. Apparently, therefore, the pre- CPRC monkey whose pattern evoked responses valence of monkeys with lesions in the CPRC indicated resolution of about 220 minutes of arc colony is up to nine times that ofmonkeys on the in an affected eye compared with about 30 US mainland. minutes in the unaffected companion.78 El- CPRC animals differ from those in US facili- Mofty et al '0 reported reduction in cone related ties in many respects. The CPRC animals are 16 Hope, Dawson, Engel, Ulshafer, Kessler, Shervood

mostly free ranging and are geophagous.30 They 7 Dawson WW, Ulshafer RJ, Engel HM, Hope GM, Kessler

MJ. Macular disease in related rhesus monkeys. Br J Ophthalmol: first published as 10.1136/bjo.76.1.11 on 1 January 1992. Downloaded from thus may differ from monkeys in US facilities in Doc Ophthalmol 1989; 71: 253-64. content of, and/or access to, soil. Several 8 Dawson WW, Engel HM, Hope GM, Kessler MJ, Ulshafer RJ. Age onset macular degeneration. Puerto Rico Health elements have been found to occur in abnormal SciJ 1989; 8:111-5. concentrations in the blood and, notably, drusen 9 El-Mofty AAM, Gouras P, Eisner G, Balaz EA. Macular degeneration in rhesus monkey Macaca mulatta. Exp Eye of AMD patients.3'-34 CPRC animals are also Res 1978; 27: 499-502. subjected to lifelong exposure to more direct 10 El-Mofty AAM, Eisner G, Balaz EA, Denlinger JL, Gouras P. Retinal degeneration in rhesus monkeys Macaca mulana. Caribbean sunlight. A solar irradiation contribu- Survey of three seminatural free-breeding colonies. Exp Eye tion to human AMD, while generally suspected, Res1980; 31:147-66. 11 Engel HM, Dawson WW, Ulshafer RJ, Hines MW, Kessler has been unsupported or supported only in- MJ. Degenerative changes in maculas of rhesus monkeys. directly."37 However, recently presented Ophthalmologica 1988; 196:143-50. 12 Fine BS, Kwapien RP. Pigment epithelial windows, drusen: epidemiological evidence implicates exposure to animal model. Invest Ophthalmol VisSci 1978; 17: 1059-68. the blue portion of the visible spectrum late in 13 Stafford TJ. in an elderly sub-human primate. Mod Probl Ophthalmol 1974; 12: 214-9. life as a possible risk factor in AMD.35 Influences 14 Stafford TJ, Anness SH, Fine BS. Spontaneous degenerative *due to differences in ingested minerals and maculopathy in the monkey. Ophthalmology 1984; 91: 513-21. elements and differential solar irradiation offer 15 Ishibashi T, Sorgente N, Patterson R, Ryan S. Pathogenesis of interesting, though speculative possibilities for drusen in the primate. Invest Ophthalmol Vis Sci 1986; 27: 184-93. exploration. 16 Rawlins RG, Kessler MJ. (1986) The history of theCayo Finally, since no animals have been added to Santiago colony. In: Rawlins RG, Kessler MJ, eds. The Cayo Santiago Macaques. Albany: State University of New York the colony since 1938,16 all current inhabitants of Press, 1986: 13-45. the island are the progeny of the breeding 17 Dawson WW, Maida TW. Relations between the human retinal cone and ganglion cell distribution. Ophthalmologica females surviving the original introduction. 1984; 188: 216-21. While males tend to migrate among social groups, 18 Leibowitz H, Krueger D, Maunder L, Milton R, Kini M, Kahn H, etal. The Framingham eye study monograph. Surv females tend to remain in the group into which Ophthalmol 1980; 24 (suppl): 335-610. they are born.39 Early introduction of a genetic 19 Kessler M, Berard J. A brief description of theCayo Santiago rhesus monkey colony. Puerto Rico Health Sci J 1989; 8: propensity to develop drusen could, in the 55-9. succeeding eight to 10 generations, have been 20 Ordy JM, Brizzee KR. Visual acuity and foveal cone density in the retina of the aged rhesus monkey. NeurobiolAging 1980; transmitted through the closed colony by males 1: 133-40. yet be more heavily represented in a few primarily 21 Delaney WV Jr, Oates RP. Senile macular degeneration: a preliminary study. Ann Ophthalmol 1982; 14: 21-4. affected matrilines. Relationships between 22 Hymen LG, Lilienfeld AM, Ferris FL III, Fine SL. Senile maternal lineage and drusen development macular degeneration: a case-control study. AmJ Epidemiol 1983; 118: 213-27. demonstrated here and the familial - especially 23 Maltzman BA, Mulvihill MN, Greenbaum A. Senile macular maternal - associations observed in AMD in degeneration and risk factors: a case-control study. Ann Ophthalmol 1979; 14:1197-201. humans22 implicate this as a potentially impor- 24 UlshaferRJ,AllenCB, Nicolaissen D, Rubin ML. Scanning tant factor in explaining the dramatic difference electron microscopy of human drusen. Invest Ophthalmol Vis Sci1987; 28:683-9. between drusen prevalence in CPRC monkeys 25 Feeney-Burns L, Malinow MR, Klein ML, Neuringer M. and their US counterparts. Maculopathy in cynomolgus monkeys. A correlated fluore- scein angiographic and ultrastructural study. Arch Ophthal- http://bjo.bmj.com/ The evidence indicates that all features mol 1981;99: 664-72. associated with age related macular drusen in 26Bellhorn RW, KingCD, Aguirre GD, Ripps H, SiegelIM, TsaiHC. Pigmentary abnormalities of the macula in rhesus humans can be found in the CPRC rhesus monkeys: clinical observations. Invest Ophthalmol Vis Sci population. Comparisons of these monkeys with 1981; 17: 771-81. 27 Odum J, Dawson W, Maida T. Human pattern-evoked retinal those from other populations suggest that this and cortical potentials.II. The second international evoked colony is uniquely predisposed to develop drusen. potentials symposium. Boston: Butterworths, 1984: 536-42. 28 Odum J, Bromberg N, Dawson W.Canine visual acuity: While environmental factors may have a role, the retinal and cortical field potentials evoked by pattern associations between drusen development and stimulation. Am JPhysiol 1983; 245: 637-41. on September 27, 2021 by guest. Protected copyright. 29 Dawson WW, Stratton RD, Hope GM, Parmer R, Engel HM, matriline shown above suggest that a major KesslerMJ. Tissue responses of the monkey retina:tuning difference between this closed colony and others and dependence on inner layer integrity. Invest Ophthalmol VisSci 1986; 27:734-45. surveyed is probably genetic, hence their 30 Marriott BM, RoemerJ, SultanaG. An overview of food intake uniqueness. It appears therefore that CPRC patterns of the Gayo Santiago rhesus monkeys (Macaca mulatta): report of a pilot study. Puerto Rico Health Sci J matriline monkeys offer the best human substi- 1989;88:87-94. tute reported so far for the study of spontaneous 31 UlshaferRJ, Allen GB, Rubin ML. Distribution of elements in human retinal pigment epithelium. Arch Ophthalmol (in development of age related drusen, the principal press). precursor to age related macular degeneration. 32 Ulshafer RJ. Zinc content in melanosomes of degenerating RPE as measured by x ray mapping. In: LaVail M, Anderson RE, Hollyfield JG, eds. Inherited and environ- mentally induced retinal degenerations. New York: Lisa, 1989: This work was supported by NIH Grant1 P40 RR3640 to the 131-9. Carribbean Primate ResearchCenter; NEI Grant2R01 EY04460 33 Miller ED, Schwartz M, Leone NG, Bennecoff TA, Newsome to W W Dawson; and an unrestricted grant from Research to DA. Serum zinc concentration in macular degeneration. 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