BritishJournal ofOphthalmology, 1992,76, 11-16

A primate model for age related macular drusen

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

AbstractA closed colony of semi-free-ranging rhesusmonkeys maintained in isolation since 1938 bythe Caribbean Primate Research Center(CPRC) is being studied as a model for agerelated macular drusen. Of examined colonyanimals 57*7% of the monkeys and 47*3% oftheir eyes have drusen. The prevalence andseverity of drusen are linearly related to in-creasing age and are significantly higher inspecific maternal lineages (matrilines). Anelectrophysiological estimate indicates loss offunction associated with drusen. Prevalence ofdrusen in CPRC females is almost twice that ofmales, while the prevalence among CPRCanimals in general appears to be several timesthat ofmonkeys from continental US facilities.Evidence suggests that the frequency of end-stage lesions is also similar to that in humanpopulations. The CPRC matriline monkeysappear to provide the best model yet reportedfor human age related macular drusen.

Department ofOphthalmology,University of Florida,Box J-284, JHMHC,Gainesville, Florida32610, USAGM HopeWW DawsonR J UlshaferM B Sherwood

Department ofOphthalmology,Montefiore MedicalCenterH M Engel

Caribbean PrimateResearch Center,Medical SciencesCampus,University of Puerto RicoM J KesslerCorrespondence to:Dr GM Hope.Accepted for publication30 May 1991

Age related macular degeneration (AMD) is amajor cause of severe vision loss in the UnitedStates and the major cause in persons over 50.12The initial clinical manifestation of AMD,3 andone of the most important,4 is drusen. These arevisible ophthalmoscopically as yellow-whitespots in the retinal pigment epithelium (RPE)and are seen histologically as depositions ofpleomorphic material beneath the RPE.-6 Giventhe significance of drusen in AMD and failure toinduce them in normal eyes, it would be valuableto identify an animal species in which drusenoccur spontaneously. There have been severalreports of drusen and macular lesions in agingmonkeys,6-'5 but the condition appears rare inanimals in US facilities. We have been investigat-ing the incidence of macular signs associatedwith this disease in a closed colony of free-ranging rhesus macaques (Macaca mulatta) at theCaribbean Primate Research Center (CPRC) ofthe University of Puerto Rico. While samplesfrom this population have been described, " wereport new relationships between drusen andaging, resolution loss, sex, and colonymatriarchal lineages.

Material and methodsThe colony was established on Cayo Santiago, asmall island off the east coast of Puerto Rico, in1938 and no new animals have been introducedsince.16 Since 1956 all monkeys have been indivi-dually identified and daily census records main-tained. The social history and matriarchallineages (matrilines) for eight to 10 generationsare known for each animal. Commercial monkeydiet and water are provided in addition to naturalforage. Only social and behavioural observations

are allowed on the island except during annualmedical examinations, when limited, non-in-vasive, biomedical research is possible. Animalsremoved to reduce the colony's size are housed,with a number of non-colony animals, in large,outdoor corrals at a second facility (Sabana Seca)on the Puerto Rican mainland. The CPRCmaintains over 2000 monkeys, the majoritybeing derived from original Cayo Santiagomatriarchs.We conducted 315 eye examinations on 246

monkeys from the Cayo Santiago matrilines.Sixty-one ofthese were repeat examinations afterone to three years, and eight were accidentalduplicates (after one to two days). Examinationswere conducted at Sabana Seca and on CayoSantiago. Only data from animals with traceableCayo Santiago lineages are included in thisreport.

All monkeys were anaesthetised by initialintramuscular injection of ketamine hydro-chloride (12 mg/kg, Vetalar), with supplementa-tion (6-12 mg/kg) as necessary to maintain aneffective level of anaesthesia. Pupils were dilatedwith phenylephrine (10%, Neo-Synephrine)and tropicamide (1%, Mydriacil). Corneas werekept moist with artificial tears (Tears Naturale)and anaesthetised with propacaine (0-5%,Alcaine).Eye examinations consisted of notation of

abnormalities of the externae and anterior seg-ments, intraocular pressure measurement, in-direct and direct ophthalmoscopy, and, for someaffected monkeys, fundus photography and,rarely, fluorescein angiography. The animalswere not refracted but extreme refractive errorswere noted when detected under direct oph-thalmoscopy.

In the retinal examinations gross abnormalitieswere noted, cup/disc ratios estimated, and detect-able macular drusen were counted, under directophthalmoscopy, up to 15. The drusen countswere recorded either directly or in quantitativeincrements of five, as 0,

Hope, Dawson, Engel, Ulshafer, Kessler, Sherwood

W/2,142 df). Comparisons based on drusencategories yielded kappas"7 between 0 40 and0 50 for pairs of examiners. These levels ofagreement are significantly (p

A primate modelfor age related maculardrusen

ResultsFigure 1 presents right and left eyes of monkeyno. 909, an 11 YO (at examination) female frommatriline 091. Both eyes of this animal fell intodrusen category 4 (>15 drusen). The lesionsseen here are typical of those seen in the eyes ofCPRC monkeys. Note that drusen in OS appearto be larger, confluent and more foveal than inOD.Age distributions (Fig 2) show that our sample

was selective for older animals, while the colonydistribution was heavily skewed by large numbersof very young monkeys.'9 The majority of oursample were over 10 years of age. Ordy andBrizzee'0 have estimated that one monkey year isequal to about 3-3.5 human years. By thisestimate our sample ranges up to the humanequivalent of about 85-100 years of age.A total of490 fundi from the 246 animals from

the Cayo Santiago matrilines were examined(cataracts obscured two fundi). Drusen werefound in 142 of246 animals (57-7%) and in 232 ofthe 490 retinas (47 3%). Ages of animals whoseretinas contained drusen ranged from 3 to 29years, or 9-10 to 85-100 human years.20 Per-centages of affected animals and eyes increasedlinearly with increasing age (Fig 3). The correla-tions, r=0-858 and r=0-861, are significant(p

Hope, Dawson, Engel, Ulshafer, Kessler, Sherwood

0 0 05 0 0 0 -0.0 0

.

P

oo 0 , o*,-.

o ,-

oOo 0

o 0 0 0

0 -M MALESo -- FEMALES

5 10 15 20 25 30

AGE (Years)

Figure 5 Relationships between age and prevalenceformales andfemales. Abscissa is age inyears, ordinate indicatesprevalence in percent. Relationshipsfrom linear regression areprovided in the lower right corner ofthe graph.

Table I Comparisons ofdrusen in retinas ofmale andfemale monkeys

Males Females Total

MonkeysNumber 114 132 246% Total sample 46-3 53 7 100Mean age (yrs) 10-98 11-4 11-2Number with drusen** 53 89 142% of same sex** 46 5 67-4% of all with drusen*** 37-3 62-7 100% total sample* 21-5 36-2 57.7EyesNumber 226 264 490% total sample 46-1 53 9 100Number with drusen*** 81 151 232%ofsamesex** 35 8 57-1% of all with drusen*** 34-9 65-1 100% total sample* 16-5 30-8 47-3Mean drusen category*** 0-52 1-02 0-79

***p

A primate modelfor age related macular drusen

*-* Small Scattered Drusenz

< _ o~~~~-- - -o

/ --0- Large Foveal Drusen

2

Table 2 Effects ofdrusen on electrophysiological indices ofvisualfunction

Total root mean square signal size

Field t testsize >lO drusen

Hope, Dawson, Engel, Ulshafer, Kessler, Shervood

mostly free ranging and are geophagous.30 Theythus may differ from monkeys in US facilities incontent of, and/or access to, soil. Severalelements have been found to occur in abnormalconcentrations in the blood and, notably, drusenof AMD patients.3'-34 CPRC animals are alsosubjected to lifelong exposure to more directCaribbean sunlight. A solar irradiation contribu-tion to human AMD, while generally suspected,has been unsupported or supported only in-directly."37 However, recently presentedepidemiological evidence implicates exposure tothe blue portion of the visible spectrum late inlife as a possible risk factor in AMD.35 Influences*due to differences in ingested minerals andelements and differential solar irradiation offerinteresting, though speculative possibilities forexploration.

Finally, since no animals have been added tothe colony since 1938,16 all current inhabitants ofthe island are the progeny of the breedingfemales surviving the original introduction.While males tend to migrate among social groups,females tend to remain in the group into whichthey are born.39 Early introduction of a geneticpropensity to develop drusen could, in thesucceeding eight to 10 generations, have beentransmitted through the closed colony by malesyet be more heavily represented in a few primarilyaffected matrilines. Relationships betweenmaternal lineage and drusen developmentdemonstrated here and the familial - especiallymaternal - associations observed in AMD inhumans22 implicate this as a potentially impor-tant factor in explaining the dramatic differencebetween drusen prevalence in CPRC monkeysand their US counterparts.The evidence indicates that all features

associated with age related macular drusen inhumans can be found in the CPRC rhesuspopulation. Comparisons of these monkeys withthose from other populations suggest that thiscolony is uniquely predisposed to develop drusen.While environmental factors may have a role, theassociations between drusen development andmatriline shown above suggest that a majordifference between this closed colony and otherssurveyed is probably genetic, hence theiruniqueness. It appears therefore that CPRCmatriline monkeys offer the best human substi-tute reported so far for the study of spontaneousdevelopment of age related drusen, the principalprecursor to age related macular degeneration.

This work was supported by NIH Grant1 P40 RR3640 to theCarribbean Primate ResearchCenter; NEI Grant2R01 EY04460to W W Dawson; and an unrestricted grant from Research toPrevent Blindness to the Department of Ophthalmology, Univer-sity of Florida.

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