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, 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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