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Can Basic Science Provide the Link Between Structural and Functional Deterioration?
occurring in bursts distributed in time and retinal location. High dendritic tree of individual RGCs.
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Although some of these techniques
variability in apoptotic rate between individuals will require a greater are not likely to be useful in humans, the principle of detecting sick
number of images to determine the average rate of deterioration. It is cells may be as useful as detecting those committed to die, and is
also conceivable that other tests, such as visual field and nerve fibre worthy of further exploration.
layer analysis, could be used to target areas of the retina deemed ‘at
risk’ of progression for apoptosis imaging. Such questions can only be Summary
answered fully in human glaucoma and thus the results of human Basic science approaches are the key to understanding the links
trials are awaited with great interest, assuming the technique is found between RGC injury in glaucoma and the resultant structural and
to be safe and effective. functional deterioration that occurs as the disease progresses.
Understanding the basic mechanisms of RGC degeneration can not
One limitation of apoptosis imaging is the relatively small number only facilitate the identification of new therapeutic targets, but
of cells likely to be undergoing apoptosis at any given time when also suggest new ways in which progression can be detected and
glaucoma progression is slow. An alternative approach would be to quantified. Moreover, basic science is essential for the ultimate goal
identify sick RGCs that are not yet committed to die. The rationale of rapidly identifying progressing patients for their inclusion in
for this approach is that there may be a larger population of sick shorter, more affordable clinical trials of novel potential
cells evident for much longer than the end stage of apoptosis. The neuroprotective therapies. n
challenge here is to identify detectable markers of sick RGCs. To
this end, there are several possible approaches that are showing
Keith R Martin is lead clinician for glaucoma at
promise. As discussed earlier, axonal transport dysfunction is a
Addenbrooke’s Hospital and heads the Glaucoma
major early event in glaucoma. Techniques now exist to visualise Research Laboratory at the Centre for Brain Repair at
axonal transport in living axons, for example by imaging the
the University of Cambridge. Clinically, he specialises
in the medical and surgical management of adult and
movement of mitochondria in transgenic animals where these
paediatric glaucoma patients, with a particular
organelles are fluorescently labelled.
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The combination of such interest in advanced, complex and uveitic disease.
techniques with high-resolution
His research work is focused on the mechanisms of
in vivo imaging of the eye could
visual loss in glaucoma and the development of new
theoretically allow axonal transport to be assessed as a marker
treatment approaches. Dr Martin is Treasurer of the World Glaucoma Association
of RGC health. and Basic Science Section Editor of the Journal of Glaucoma. He qualified from
Oxford University and trained in general medicine and neurology in London and
Oxford before higher specialist training in ophthalmology in Cambridge. He
Other possible approaches include searching for characteristic optical
completed three years of post-doctoral research on the pathogenesis of glaucoma
‘signatures’ of sick RGCs using techniques such as ocular coherence at the Wilmer Eye Institute at Johns Hopkins University in Baltimore and at the
tomography (James Morgan, unpublished data). In transgenic animal
Institute of Ophthalmology in London. Dr Martin was awarded a research doctorate
by Oxford University in 2004 and a GlaxoSmithKline (GSK) Clinician Scientist
models that possess small numbers of fluorescent retinal neurons, it
Fellowship in 2005.
is also possible to track the effect of injuries such as glaucoma on the
1. Kass MA, Heuer DK, Higginbotham EJ, et al., The Ocular and other compartmentalised processes?, Prog Retin Eye recommendations for measuring rates of visual field
Hypertension Treatment Study: a randomized trial Res, 2005;24(6):639–62. change in glaucoma, Br J Ophthalmol, 2008;92(4):569–73.
determines that topical ocular hypotensive medication 9. Quigley HA, Nickells RW, Kerrigan LA, et al., Retinal 18. Viswanathan AC, Crabb DP, McNaught AI, et al.,
delays or prevents the onset of primary open-angle ganglion cell death in experimental glaucoma and after Interobserver agreement on visual field progression in
glaucoma, Arch Ophthalmol, 2002;120(6):701–13, discussion axotomy occurs by apoptosis, Invest Ophthalmol Vis Sci, glaucoma: a comparison of methods, Br J Ophthalmol,
829–30. 1995;36(5):774–86. 2003;87(6):726–30.
2. Howell GR, Libby RT, Jakobs TC, et al., Axons of retinal 10. Libby RT, Li Y, Savinova OV, et al., Susceptibility to 19. Medeiros FA, Zangwill LM, Bowd C, Weinreb RN,
ganglion cells are insulted in the optic nerve early in neurodegeneration in a glaucoma is modified by Bax gene Comparison of the GDx VCC scanning laser polarimeter,
DBA/2J glaucoma, J Cell Biol, 2007;179(7):1523–37. dosage, PLoS Genet, 2005;1(1):17–26. HRT II confocal scanning laser ophthalmoscope, and
3. Tezel G, Wax MB, Increased production of tumor necrosis 11. Perry VH, Brown MC, Lunn ER, Very Slow Retrograde and stratus OCT optical coherence tomograph for the
factor-alpha by glial cells exposed to simulated ischemia Wallerian Degeneration in the CNS of C57BL/Ola Mice, detection of glaucoma, Arch Ophthalmol, 2004;122(6):
or elevated hydrostatic pressure induces apoptosis in Eur J Neurosci, 1991;3(1):102–5. 827–37.
cocultured retinal ganglion cells, J Neurosci, 2000;20(23): 12. Beirowski B, Babetto E, Coleman MP, Martin KR, The WldS 20. Leung CK, Lindsey JD, Crowston JG, et al., Longitudinal
8693–8700. gene delays axonal but not somatic degeneration in a rat profile of retinal ganglion cell damage after optic nerve
4. Ju WK, Kim KY, Lindsey JD, et al., Intraocular pressure glaucoma model, Eur J Neurosci, 2008;28(6):1166–79. crush with blue-light confocal scanning laser
elevation induces mitochondrial fission and triggers OPA1 13. Martin KR, Quigley HA, Valenta D, et al., Optic nerve dynein ophthalmoscopy, Invest Ophthalmol Vis Sci, 2008; 49(11):
release in glaucomatous optic nerve, Invest Ophthalmol Vis motor protein distribution changes with intraocular 4898–4902.
Sci, 2008;49(11):4903–11. pressure elevation in a rat model of glaucoma, Exp Eye Res, 21. Murata H, Aihara M, Chen YN, et al., Imaging mouse
5. Kong GY, Van Bergen NJ, Trounce IA, Crowston JG, 2006;83(2):255–62. retinal ganglion cells and their loss in vivo by a fundus
Mitochondrial dysfunction and glaucoma, J Glaucoma, 14. Pease ME, McKinnon SJ, Quigley HA, et al., Obstructed camera in the normal and ischemia-reperfusion model,
2009;18(2):93–100. axonal transport of BDNF and its receptor TrkB in Invest Ophthalmol Vis Sci, 2008;49(12):5546–52.
6. Martin KR, Levkovitch-Verbin H, Valenta D, et al., Retinal experimental glaucoma, Invest Ophthalmol Vis Sci, 22. Walsh MK, Quigley HA, In vivo time-lapse fluorescence
glutamate transporter changes in experimental glaucoma 2000;41(3):764–74. imaging of individual retinal ganglion cells in mice,
and after optic nerve transection in the rat, Invest 15. Martin KR, Quigley HA, Zack DJ, et al., Gene therapy with J Neurosci Methods, 2008;169(1):214–21.
Ophthalmol Vis Sci, 2002;43(7):2236–43. brain-derived neurotrophic factor as a protection: retinal 23. Cordeiro MF, Guo L, Luong V, et al., Real-time imaging of
7. Levkovitch-Verbin H, Quigley HA, Martin KR, et al., A ganglion cells in a rat glaucoma model, Invest Ophthalmol Vis single nerve cell apoptosis in retinal neurodegeneration,
model to study differences between primary and Sci, 2003;44(10):4357–65. Proc Natl Acad Sci U S A, 2004;101(36):13352–6.
secondary degeneration of retinal ganglion cells in rats by 16. Kerrigan-Baumrind LA, Quigley HA, Pease ME, et al., 24. Guo L, Cordeiro MF, Assessment of neuroprotection in the
partial optic nerve transection, Invest Ophthalmol Vis Sci, Number of ganglion cells in glaucoma eyes compared retina with DARC, Prog Brain Res, 2008;173:437–50.
2003;44(8):3388–93. with threshold visual field tests in the same persons, 25. Misgeld T, Kerschensteiner M, Bareyre FM, et al., Imaging
8. Whitmore AV, Libby RT, John SW, Glaucoma: thinking in Invest Ophthalmol Vis Sci, 2000;41(3):741–8. axonal transport of mitochondria in vivo, Nat Methods,
new ways – a role for autonomous axonal self-destruction 17. Chauhan BC, Garway-Heath DF, Goni FJ, et al., Practical 2007;4(7):559–61.
EUROPEAN OPHTHALMIC REVIEW 29
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