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1 From the Department of Anatomy and Cell Biology and 2 Kresge Eye Institute, Wayne State University, Detroit, Michigan; 3 Department of Ophthalmology and Visual Science, University of Wisconsin, Madison; 4 Department of Medicine/Endocrinology, Case Western Reserve University, Cleveland, Ohio; and 5 Wyeth–Ayerst Research, Princeton, New Jersey.
Abstract
PURPOSE. Determining which patients are at risk for the development of diabetic retinopathy is expected to greatly improve existing prevention and treatment options. In this study, using an animal model of diabetic retinopathy, the hypothesis was tested that magnetic resonance imaging (MRI) and a carbogen inhalation challenge provides important diagnostic information regarding the risk of developing diabetic retinopathy.
METHODS. MRI was used to measure noninvasively the change in oxygen tension along the entire inner retina (i.e., from superior ora serrata to inferior ora serrata) during a carbogen (95% O2/5% CO2) inhalation challenge (IOVS 1996;37:2089). Two animal groups were examined by this MRI method at two time points: (1) rats fed either normal rat chow (n = 20) or a 50% galactose diet (n = 20) for 3.5 months (i.e., before the appearance of extensive retinal lesions) or (2) rats fed either normal rat chow (n = 3) for 15 months or a 30% galactose diet (n = 4) for 15 to 18 months (i.e., when lesions are present). Retinal biochemical and morphometric measurements were also obtained.
RESULTS. After 3.5 months of galactosemia, before the appearance of extensive retinal morphologic lesions, a significant (P < 0.05) reduction in the panretinal oxygenation response was observed in the galactosemic group compared with its age-matched control. These galactose-fed animals also displayed a significantly (P < 0.05) larger oxygenation response in the inferior hemiretina than in the superior hemiretina. After 15 to 18 months of galactosemia, during the period when lesions are present, the panretinal oxygenation response remained significantly (P < 0.05) lower in the galactose-fed animals than in their age-matched controls. In contrast to the 3.5-month results, the oxygenation response in galactosemic animals at 15 to 18 months was significantly (P < 0.05) larger in the superior than in the inferior hemiretina. Hemiretinal oxygenation responses were not different in normal controls at either duration.
CONCLUSIONS. MRI measurement of the retinal oxygenation response to a carbogen challenge appears to be a powerful new and noninvasive approach that may be useful for assessing aspects of pathophysiology underlying the development of diabetic retinopathy in galactosemic rats. These results support our working hypothesis and suggest that further research into the diagnostic potential of this MRI approach for predicting the development of diabetic retinopathy is warranted.
Determining which patients are at risk for the development of diabetic retinopathy before retinal damage becomes clinically evident is expected to greatly improve existing prevention and treatment options.1 It is commonly thought that early changes in retinal perfusion, perfusion reserve, and autoregulation are strongly associated with the subsequent appearance of diabetic retinopathy.1 2 Consequently, rational management of diabetic retinopathy may be possible based on early detection of changes in retinal perfusion, perfusion reserve, and autoregulation.
To date, it has been difficult to accurately determine the magnitude and direction of early abnormalities in retinal perfusion, perfusion reserve, and autoregulation in diabetes.1 Current noninvasive methods for measuring these physiological parameters are either not quantitative (e.g., fluorescein angiography), have limited spatial resolution and sensitivity (e.g., laser Doppler velocimetry), or are limited by media opacities such as cataracts (e.g., video fluorescein angiography). In experimental models, these noninvasive methods cannot be applied over long periods of time because of the relatively rapid formation of cataracts. Although invasive methods (e.g., microspheres3 ) have been used, such methods are highly destructive (which may confound data interpretation), suffer from limited sensitivity (e.g., few microspheres are captured) and limited spatial resolution (e.g., flow values represent the whole retina), and cannot be applied in humans. Clearly, there is a need for an accurate and sensitive measurement of retinal perfusion, perfusion reserve, and autoregulation that can be performed in the presence of cataracts.
In this study, a measure of retinal vascular perfusion, perfusion
reserve, and autoregulation was achieved by determining the change in
retinal oxygenation (
PO2; units mm
Hg) produced during a carbogen (95% O2/5%
CO2) inhalation challenge (vide
infra).4
5
6
7
Normally, carbogen breathing induces a maximum
oxygenation response from the retinal circulation.4
However, if retinal perfusion or perfusion reserve are low, retinal
autoregulation dysfunctional, or both, a smaller than normal
PO2 will be produced during the
carbogen challenge (vide infra).7
The magnitude of the
PO2 is noninvasively measured
using magnetic resonance imaging (MRI). In earlier studies, we found
good agreement between the MRI-measured
PO2 and that determined using an
oxygen electrode in normal rat retina under similar
conditions.4
The purpose of this study is to begin testing the hypothesis that the
retinal PO2, measured during a
carbogen challenge, is strongly associated with the development of
diabetic retinopathy. To this end, we measured the retinal
PO2 before the appearance of
extensive retinal lesions and during the period when retinal lesions
were present in the galactose-fed rat model. The important features of
the galactosemia model, in this context, are that it produces a
diabetes-like retinopathy in 100% of the animals after more than 15
months, but without many of the metabolic anomalies associated with
diabetes (e.g., alterations in the concentration of insulin, glucose,
fatty acids, and amino acids).8
9
Methods
The animals were treated in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the ARVO Statement on the Use of Animals in Ophthalmic and Vision Research.
Animal Model
The galactosemic rat model has been described in detail
elsewhere.10
11
Briefly, galactosemia was induced by
feeding powered rat chow (Purina 5001) diluted with either 50% or 30%
by weight with D-galactose for either 3.5 months
(n = 20) or 15 to 18 months (n = 4),
respectively. Age-matched controls (n = 20 or
n = 3, respectively) were fed normal rat chow. The
difference in galactose diets between the 3.5 and 15 to 18 month
animals is not expected to confound data interpretation because the
30% and 50% galactose diets both result in essentially the same gross
morphologic changes in the retinal vessels.9
Animals
scheduled for study were fasted overnight.
MRI Examination
On the day of the experiment, anesthesia was induced by a single
intraperitoneal injection of urethane (36% solution, 0.083 ml/20 g
animal weight, prepared fresh daily; Aldrich, Milwaukee, WI). Although
a mild hyperglycemia is associated with urethane
anesthesia,12
the hyperglycemic response after the
overnight fast did not differ (P > 0.05) among the
groups. Each rat was gently positioned on an MRI-compatible homemade
holder with its nose placed in a plastic nose cone. Animals were
allowed to breathe spontaneously during the experiment. To maintain the
core temperature of the rat, a recirculating heated water blanket was
used. Rectal temperature, pulse, and hemoglobin oxygen saturation (data
not shown) were continuously monitored while the animal was inside the
magnet, as previously described.4
MRI data were acquired on a 4.7-T system using a two-turn transmit/receive surface coil (1.5 cm diameter) placed over the eye and an adiabatic spin–echo imaging sequence (repetition time [TR] 1 second; echo time [TE] 22.7 msec; number of acquisitions [NA] 1; matrix size, 128 x 256; slice thickness, 1 mm; field of view, 30 x 30 mm; sweep width, 25,000 Hz; 2 min/image). A capillary tube (1.5-mm inner diameter) filled with distilled water was used as the external standard. Five sequential 2-minute images were acquired as follows: four control images while the animal breathed room air and one image during carbogen breathing. Carbogen exposure was started at the end of the fourth image. Animals were returned to room air for 15 minutes to allow recovery from the inhalation challenge and removal from the magnet. Blood from the descending abdominal aorta was collected immediately after a second 2-minute carbogen challenge and analyzed for PaO2, PaCO2, pH, and glucose concentration. After the blood collection, the animal was euthanatized with an intracardiac potassium chloride injection, and tissues were collected for further analysis (see below).
Attempts to measure preretinal vitreous PO2 by subtracting images obtained during room air breathing and death (or hypoxemia) were not successful (data not shown). The major problem was that ocular perfusion pressure and eye shape changed from normal during death or hypoxemia. These changes significantly confounded quantitative pixel-by-pixel interpretation of the data. Furthermore, producing death or hypoxemia in humans is clearly problematic. Thus, we chose carbogen breathing because this method induces a maximum oxygenation response from the retinal circulation, makes detection of subtle differences between groups more robust and precise, and has clinical potential.
Data Analysis
To be included in this study, the animal must have demonstrated:
minimal eye movement during the MRI examination, nongasping respiratory
pattern before the MRI examination, rectal temperatures in the range
36.5°C to 38.5°C, and PaO2 > 350 mm Hg and
PaCO2 between 45 and 65 mm Hg during the carbogen
challenge. The number of animals examined by MRI that satisfied the
inclusion criterion for the 3.5-month control, 3.5-month galactosemia,
15- to 18-month control, and 15- to 18-month galactosemia groups were,
respectively, 7, 10, 3, and 4. The MRI data from these animals were
transferred to a Macintosh IIcx computer. Image registration was
performed using software written inhouse for the program IMAGE (a
freeware program available at http://rsb.info.nih.gov/nih-image/).
After registration, the room air images were averaged to improve the
signal–to–noise ratio. All pixel signal intensities in the average
room air image and the 2-minute carbogen image were then normalized to
the external standard intensity. On a pixel-by-pixel basis, signal
intensity changes during carbogen breathing were calculated, converted
to PO2 values, and displayed as a
pseudocolor parameter map as previously described.7
Data
along a 1-pixel-thick line (200 µm) drawn in the preretinal vitreous
space were extracted and displayed as a preretinal vitreous
PO2 band. Each band represents ora
serrata–to–ora serrata PO2
values over a 1-mm-thick section of retina (the MRI slice thickness).
The width of the bands is arbitrary. The longer white tick mark in the
center of each band represents the posterior pole near the optic nerve;
the shorter tick marks represent 0.5-mm increments along the retinal
surface.
Statistical Analysis
The physiological (i.e., blood gas values, rectal temperatures,
and blood glucose data) and biochemical data were normally distributed
and are presented as mean ± SEM. Comparisons were performed using
an unpaired t-test, with P < 0.05
considered significant. The MRI and morphometric data were not normally
distributed and are presented as the median. The nonparametric
statistical tests used were as follows: a paired Wilcoxon signed ranked
test using the individual oxygenation responses from each pixel in the
region of interest to investigate superior–inferior hemiretinal
differences within a group and a Kruskal–Wallis test. In all cases,
P < 0.05 was considered significant. The individual
oxygenation response bands for each animal in a group were combined on
a pixel-by-pixel basis and displayed as a median band.
Biochemical Analysis
In the 3.5-month groups, retinal and blood samples were analyzed
to determine the concentrations of glucose, galactose, galactitol,
sorbitol, fructose, and myoinositol using methods previously
described.13
Retinal hexose and polyol concentrations were
normalized to tissue protein levels. Red blood cell hexose and polyol
concentrations were normalized to hemoglobin levels. The percent
glycohemoglobin was measured using GlycoTestII affinity columns
(Pierce, Rockford, IL). Note that the affinity columns do not
differentiate between glucosylated and galactosylated hemoglobin.
Samples were stored at -80°C for less than 3 weeks before the
biochemical analyses.
Trypsin Digest
One half retina of one eye per animal was fixed in 10% buffered
formalin. Trypsin digests of retinas from all groups were performed as
previously described.10
The digests were analyzed for
acellular capillaries and pericyte ghosts in multiple fields across the
entire sample and were expressed as the median frequencies of acellular
capillaries per squared millimeter of retinal area and pericyte ghosts
per 1000 capillary cells, respectively. Pericyte ghosts were defined as
an "out pouching" of basement membrane on capillaries possessing at
least one endothelia or pericyte nucleus. Because only four 15- to
18-month galactose-fed rats were available for this study, statistical
statements concerning the retinal lesions in this group were not
possible.
Results
Systemic Physiology
A summary of the blood parameters measured during a 2-minute
carbogen challenge is present in Table 1
. Although there were some differences between the galactose-fed and
age-matched control groups, all the values fell within the expected
range for carbogen breathing. The magnitude of the hyperglycemia
associated with urethane12
did not differ between the
experimental groups.
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MRI
In control eyes (Fig. 1
, left), MRI provides a clear image of ocular anatomy including the
retina/choroid complex (seen as a white line in the posterior region of
the eye) and the nucleus and cortex of the lens. In the galactose-fed
animals, the retina/choroid complex is also easily observed, even in
the presence of a nearly complete cataract. The cataractous lens
appears hyperintense in the 3.5-month galactose-fed rat (Fig. 1
, right)
and had a similar appearance in the 15- to 18-month galactosemic rats
(not shown).
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The results of the present study highlight the use of MRI and a
carbogen inhalation challenge as a powerful quantitative and
noninvasive approach that may be useful for assessing the risk of
developing retinopathy. The measurement of retinal
PO2 using MRI has several
advantages: it is noninvasive; it is applicable to a wide range of age
groups and species, possibly including humans; it can survey the entire
two dimensional retinal surface; and it is not affected by media
opacities, such as cataracts. Because early cataract formation occurs
in many experimental diabetic animals, researchers using light-based
methods must limit their measurement of retinal physiology to extremely
early times (as short as 1 week in some studies) relative to the
appearance of retinal lesions (over 1.5 years later). However, the
relevance of such early information to the eventual appearance of
retinal vascular lesions remains unclear. It is possible that such
early changes may reflect only the short-term adaptations of the
retinal circulation to the diabetic or galactosemic provocation and not
the more likely relevant long-term changes induced by elevated blood
sugar concentrations. These considerations underscore the application
of MRI and a carbogen inhalation challenge as a new and potentially
important diagnostic approach for assessing the risk for the
development of diabetic retinopathy.
In the present study, we began to test our working hypothesis that a
decrease in the retinal oxygenation response to a carbogen challenge is
strongly associated with the development of diabetic retinopathy.
Indeed, we found a significantly reduced panretinal oxygenation
response in the galactose-fed rats both well before the appearance of
extensive retinal lesions (at 3.5 months on the diet) and when lesions
were evident (at 15–18 months on the diet). It is possible that the
loss in retinal vasculature may contribute to the observed subnormal
PO2 in the 15- to 18-month
galactose-fed animals. However, this mechanism is not likely to play a
role in the observed oxygenation response changes at 3.5 months (Table 2 , vide infra). These data strongly support our working hypothesis and
warrant further research into the diagnostic potential of our MRI
approach in diabetic retinopathy.
Unexpectedly, we found an asymmetry in the hemiretinal oxygenation
response before and after the appearance of retinal lesions in the
galactosemic groups. The superior hemiretinal
PO2 in the 3.5-month galactosemic
rats was significantly (P < 0.05) greater than the
inferior PO2. This pattern
was reversed in the 15- to 18-month galactosemic animals. The
significance of these hemiretinal asymmetries is not clear and deserves
further study.14
The control group did not demonstrate a
superior–inferior asymmetry at either time point. We are unaware of
any reports describing a superior–inferior regional morphometric or
physiological differences in experimental diabetic rat models.
The exact mechanisms underlying the reduction in panretinal oxygenation
response in the galactosemic animals are not known. The following
suggests that the subnormal PO2 is
due to perturbations of retinal vascular physiology and not retinal
oxygen consumption. The PO2 of the
posterior vitreous during room air breathing is a measure of the amount
of oxygen supplied to the retina minus the amount consumed. During the
carbogen challenge the amount of oxygen supplied to the retina
increases approximately 400% (the arterial oxygen levels change from
100 to 
500 mm Hg during the challenge). Because this increase is
likely much greater than the change in retinal oxygen consumption,
PO2 is expected to reflect
primarily the change in retinal oxygen supply and to be sensitive to a
variety of vascular physiological processes governing retinal oxygen
supply during the carbogen challenge, such as retinal perfusion,
perfusion reserve, and autoregulation.
Galactose-related biochemical alterations probably underlie the observed pathophysiology.15 The subset of biochemical changes reported in this study is consistent with those in the literature.13 However, establishing an association between these biochemical changes and the observed changes in retinal vascular physiology was beyond the scope of the present work. Nonetheless, MRI studies of the galactose model, and probably diabetic models, appear to be an appropriate system for future experiments designed to investigate the association between abnormal metabolism and pathophysiology.
The pathogenesis of diabetic retinopathy is unclear, although hypoxia may be responsible at least for its later-developing lesions, specifically neovascularization. Results of several studies in human and animal retinas indicate that vascular endothelial growth factor, a mitogen whose expression is known to be stimulated by hypoxia, appears in increased amounts in retinas of diabetic humans and animals that demonstrate few, or no, vascular lesions.16 17 Direct experimental evidence supporting the hypoxia hypothesis has remained somewhat elusive.18 Recent data from Linsenmeier et al. demonstrated an abnormally low preretinal vitreous PO2 during room air breathing in long-term diabetic cats in the absence of gross retinal vascular morphology changes.18 The low oxygenation response observed in the present study is also consistent with the presence of hypoxia, but it cannot yet be unambiguously interpreted as a measure of hypoxia. Experiments in this laboratory are ongoing to further study this relationship.
Acknowledgements
The oversight of the galactose rat model, and initial trypsin digests, by Alexander Kennedy is gratefully appreciated. We also thank Mark Larson and Linda Vandevelde for their technical assistance.
Footnotes
Reprint requests: Bruce A. Berkowitz, Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201.
Supported by National Institutes of Health Grants RO1 EY10221 (BAB) and RO1 EY00300 (TSK), the Juvenile Diabetes Foundation International (RNF), and the American Diabetes Association (RAK).
Submitted for publication January 21, 1999; revised March 30, 1999; accepted April 29, 1999.
Proprietary interest category: N.
References
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