ARVO 2009 Poster

1. MRI In Vivo Assessment of Optic Nerve
Degeneration in Experimental Glaucoma
Miller J. Ogidigben1, Alex Coimbra2, Lynn O’Neill-Davis1, M. Holahan2, Cathy Thut1, J. Cook2, D. Williams2
1
Ophthalmics Research, and 2Imaging Department, Merck Research Laboratories, West Point, PA, United States
Purpose Methods (continued) Results
Glaucoma is a multifactorial neurodegenerative disease of the optic nerve • Reconstructed images and parametric maps reoriented to standard position. In normotensive eyes, IOP was 15.0±1.7 mmHg (mean±S.D.) and ON area was Figure 4. Correlation between diffusivity and IOP. Scatter
(ON) with pathophysiological consequences of unilateral or bilateral • The chiasms were identified and cross-sectional areas (CAs) were estimated on the 6.4±0.8 mm2. In contrast, IOP in hypertensive eyes was 34.1±6.6 mmHg and plots showing relationship between intraocular
blindness. The clinical management is currently limited to intraocular chiasm central coronal planes. ON area was 4.5±4.7 mm2 (single-sided t-test, P=0.027). ON CAs correlated with pressure and diffusivity parameters, axial and
pressure (IOP) reduction strategy. Current methods for examining ON IOPs (Figure 2, Pearson’s r=0.66, P=0.008). DTI diffusivity parameters in ON radial diffusivity, and ADC (top panel) and
• CAs of left and right ONs were computed 4 mm anterior to the chiasm plane
degeneration in glaucoma are ex vivo preclinical studies and in vivo imaging of normotensive eyes were 1.16±0.2 and 0.71±0.23 s/mm2 for axial and radial fractional anisotropy (bottom panel) of the
(Figure 1).
of nerve fiber layer in the periphery of the ON head. The present study diffusivity, respectively. In the ON of hypertensive eyes, those parameters were optic nerve. All diffusivity parameters of the ON
assessed the ability of MRI to quantify degeneration of the ON in the retro- • Four DTI parameters were analyzed: axial and radial diffusivity; fractional 0.95±0.19 and 0.47±0.12 s/mm2, respectively (P=0.034 for axial and P=0.013 for
anisotropy (FA); and apparent diffusion coefficient (ADC).
increased as a linear function of IOP. Fractional
orbital space of laser-induced glaucoma monkeys, and shows that MRI radial diffusivity). Fractional anisotropy was also lower in the ON of the hypertensive
anisotropy decreased with increasing IOP.
renders quantitative indices that correlate with atrophy and IOP and may • Intraocular pressure (IOP) was measured in all 16 eyes. eye (0.35±0.09) when compared with the normotensive eye (0.45±0.07, single-
be used to study IOP-induced ON degeneration (radial with respect to the sided t-test, P=0.0167). Finally, the overall ADC in the ON of the hypertensive eye
• However, data from one eye was dropped because of failure to obtain a reliable 1.6
nerve’s main axis). was larger (0.86±0.23 s/mm2) than in the normotensive eye (0.63±0.14 s/mm2,
IOP measurement.
P=0.017). Pearson correlation coefficients between IOP and axial and radial 1.4
• Comparative statistical analysis was performed between ON MRI parameters of
Introduction normotensive and hypertensive eyes. Correlation between ON parameters and
diffusivity, FA, and ADC were 0.58 (P=0.02), 0.71 (P=0.003), -0.59 (P=0.02), and
0.67 (P=0.006), respectively (Figure 3).
Diffusivity (s/mm2)
1.2
IOPs was also assessed.
The animal model of glaucoma that is close to the human disease and
most frequently used in glaucoma drug discovery studies is the monkey Atrophy Diffusivity 1.0
laser photocoagulation model. This model, unlike human glaucoma, is an Figure 3. Typical diffusivity parametric maps and respective
Figure 1. Typical horizontal (top) and coronal (bottom) views of 0.8
artificial model that induces intraocular pressure (IOP) elevation in two anatomical images.
the chiasm and ON delineated by yellow contours.
to three months. However, like human glaucoma, the monkey model of 0.6
elevated IOP induced by repeated circumferential laser photocoagulation
of the trabecular meshwork is considered by many to be the best choice of axial diff
chiasm 0.4
animal models to study human glaucoma. The anatomy of the iridocorneal eyes radial diff
angle and physiology in the monkey eye are similar to the human eye. The
Anatomy 0.2
ADC
sustained elevated IOP in the monkey glaucoma model is associated with
a reduction of outflow facility, nerve fiber layer defects, and progressive 0.0
enlargement of the cup-to-disc ratio, similar to human chronic open-angle Fractional 5 15 25 35 45
glaucoma. The IOP of the monkey glaucoma model responds to single and IOP (mmHg)
multiple dosing of antiglaucoma drugs in a manner similar to humans.The
Anisotropy
effects of laser treatment on uveoscleral outflow and aqueous flow, two
parameters that are important in the control of IOP, showed that aqueous 0.6
Fractional Anisotropy (FA)
humor dynamics could be understood in this model. The model, therefore, Trace = 3x
DTI Data
0.6
provides for a better prediction of the human response to a drug. The optic Mean Diff
nerves of laser-induced glaucoma monkeys show similar characteristics of 0.5 FA
cupping as humans, and visual field changes have been demonstrated in
clinical studies. However, it has been assumed that degenerating ganglion 0.5
cell axons could result in atrophic or degenerative optic nerve. Since ocular Axial 0.4
imaging technology is primarily restricted to use in viewing inside the eye, Diffusivity
we employed magnetic resonance imaging technology to explore regions 0.4
of the optic nerve beyond the globe in a monkey model of elevated IOP.
The objective of this study was to assess diffusion tensor imaging (DTI) 0.3
parameters as a biomarker for optic nerve degeneration in monkeys with
Radial
0.3
chronically elevated IOP. Diffusivity
0.2
Methods right left right left
5 15 25
IOP (mmHg)
35 45
Figure 2. ON atrophy and IOP. Scatter plot showing relationship
Animal: between intraocular pressure and cross-sectional area
Female cynomolgus monkeys (Macaca fascicularis) (3-5 kg) were maintained of the optic nerve of corresponding eye in monkeys with
on a 12-hour light/dark cycle during these experiments. Animal care and experimental glaucoma. Cross-sectional area of the ON
treatment in this investigation complied with the ARVO resolution in the
is reduced as a linear function of IOP.
use of animals for research, and all procedures had prior approval by the
Institutional Animal Care and Use Committee (IACUC) of Merck & Co., Inc.
• Experiments were conducted in 8 cynomolgus monkeys (10-11 yrs)
scanned ~2 years after photocoagulation of the right eye trabecular
8.0 Conclusion
ON Cross-sectional Area
meshwork to induce increase of intraocular pressure.
7.0
This study shows that MRI may be used to study ON degeneration induced by increased IOP in vivo. Longitudinal studies will be
Imaging: 6.0
required to determine the onset and rate of optic nerve degeneration to confirm the suitability of this MRI methodology to delineate
• Siemens Trio 3T magnet.
5.0 surrogate markers for disease progression and address potential benefit of novel therapies to glaucoma patients.
(mm2)
• T1 weighted MPRAGE pulse sequence (TR/TE/TI/FA=1.47/4.38/870/12)
was used to obtain high-resolution images (0.5x0.5x0.8 mm3) of the 4.0
animals’ whole heads. y = -0.1122x + 8.2041
3.0
• Diffusion tensor imaging (DTI) scans to assess integrity of the ON R2 = 0.4321
(TR/TE/TI=11.4 s/118ms/2.2 s; beta=0, 1000 s/mm2, 30 diffusion- 2.0
sensitizing gradient directions, image resolution 1.5x1.5x1.5 mm3). 1.0
Analysis:
0.0
• Parametric maps of diffusivity and diffusion anisotropy extracted from the
0.0 10.0 20.0 30.0 40.0 50.0
Reference
DTI data (DTI Studio).
1. Radius and Pederson. Arch Ophthalmol. 1984.
IOP (mmHg)
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