Detection of Apoptosing Retinal Cells in Glaucoma Diagnosis

Study Proposal

Investigating a possible correlation between DARC (Detection of Apoptosing Retinal Cells) and Psychophysical methods (e.g. Contrast Sensitivity, Colour Vision, LogMAR Visual Acuity in different contrast levels) in Glaucoma diagnosis and assessing treatment efficacy.

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Glaucoma is a neurodegenerative eye disease and one of the major causes offor blindness in developed countries. It is a chronic degenerative disease of the optic nerve, which has been characterised by a progressive loss of retinal ganglion cells (RGCs) and their axons (Sommer, 1989). Glaucoma is a collective term for a complex group of conditions that cause progressive optic neuropathy, which may result in irreversible loss of visual function.[E1] Therefore, assessment of visual function is essential in diagnosis and treatment of Glaucoma.

Although several diagnostic tools have been developed to detect and monitor this disease, none is sensitive enough to identify it at a preclinical stage or to distinguish small changes in retinal health in a relatively short periods (Normando et al., 2013)

In Glaucoma, irreversible visual changes may occur before neuronal damages are discovered. The detection of glaucomatous structural damage might happen before, during and after glaucomatous visual field defects findings (Kass et al., 2002). Clinical assessment of visual function in parafoveal regions is mostly dependent on the examination of visual fields by using standard perimetry (Rauscher et al., 2013). Perimetry plots often do not represent full extent of visual loss as conventional field assessments only examine a single feature at the location tested, which usually is the differential light threshold. Although, outcome for absolute thresholds of flashed stimuli is useful but frequently these findings are the final component of visual function that are affected in disease. It should be taken into consideration that visual field defects cannot be detected until 20-40% of retinal ganglion cells (RGCs) which are the key cells associated with the development of irreversible blindness in glaucoma, have already been lost (Guo and Cordeiro, 2008). In many of the eye disease, sensitivity for detection of fine spatial detail and colour signals can be damaged prior to visual field loss (Barbur and Konstantakopoulou, 2012).

In studies such as (Rauscher et al., 2013) colour thresholds revealed the highest sensitivity to early glaucomatous changes and Red/Green losses tended to happen before perimetric loss of binocular visual field sensitivity. It should be noted that simple measures of perimetriy are not sensitive enough to detect selective loss of specific visual attributes and therefore fail to show a strong correlation with Quality Of Life (QOL) measures.

Moreover, the ability to differentiate contrast plays an important role in patients’ everyday vision and quality of life. Contrast sensitivity testing can identify many ocular diseases and provides additional useful clinical information to standard visual acuity assessments (Richman et al., 2013).

Additionally, a new noninvasive real-time imaging technology, has recently been developed which is named DARC (Detection of Apoptosing Retinal Cells). Apoptosis is a form of programmed cell death that is involved in both pathological and physiological processes throughout the body. Although, Apoptosis plays a vital role in normal development and ageing but deregulation of this process is responsible for many disease including neurodegenerative disorders. Therefore, in vivo imaging of apoptosis may prove a useful tool for both laboratory research and clinical diagnostics (Galvao et al., 2013)

DARC visualizes single RGC, which undergo apoptosis, as the earliest sign of glaucoma. Use of fluorescent annexin A5 is one of the most widely accepted in vitro assay for apoptotic cells (Normando et al., 2013). DARC is a non-radioactive approach that can evaluate the efficiency of the treatments by monitoring RGC apoptosis in the same living eye over time by using fluorescently labeled annexin 5 and confocal laser scanning ophthalmoscopy. DARC uses unique optical properties of the eye for direct microscopic observation of cellular processes in the retina. DARC has been used to assess different neuroprotective therapies in glaucoma-related animal models and demonstrated to be a useful tool in screening neuroprotective strategies. As DARC directly evaluates the RGC death process, it will potentially provide a meaningful clinical end point. DARC can be used in tracking disease, assessing treatment efficacy and may lead to the early identification of patients with glaucoma (Cordeiro et al., 2010; Cordeiro et al., 2011; Guo and Cordeiro, 2008; Normando et al., 2013).

DARC uses a novel automated algorithm, which enables accurate quantification of apoptosing RGCs and is highly comparable to manual counting. This appears to minimise operator-bias and at the same time being both fast and reproducible. Quantification of apoptosing retinal cells may prove to be a valuable method, particularly in relation to translation in the clinic now that a Phase I clinical trial of DARC in glaucoma patients is due to start shortly (Bizrah et al., 2014).

3 year plan
1st Year
Ethics approval
Pre-Screening patients with glaucoma for suitability using LogMAR visual acuity in low contrast level and any available visual field findings
2nd Year
Recruiting candidates
Study both psychophysical methods (Contrast sensitivity and colour vision) and DARC
3RD Year
Data analyzing
Writing up
Expecting outcome
Better evaluation of sensation in patients with glaucoma
Better evaluation of Quality Of Life (QOL)
Better evaluation of the most suitable method for early diagnostic and follow-up treatments in glaucoma
Possible diagnostic and follow-up applications of the selected methods for other neurodegenerative disease such as Alzheimer and Parkinson

Barbur JL, Konstantakopoulou E (2012) Changes in color vision with decreasing light level: separating the effects of normal aging from disease. J Opt Soc Am A Opt Image Sci Vis 29:A27–A35

Bizrah, M., S. C. Dakin, L. Guo, F. Rahman, M. Parnell, E. Normando, S. Nizari, B. Davis, A. Younis, and M. F. Cordeiro, 2014, A semi-automated technique for labeling and counting of apoptosing retinal cells: BMC Bioinformatics, v. 15, p. 169.

Cordeiro, M. F., L. Guo, K. M. Coxon, J. Duggan, S. Nizari, E. M. Normando, S. L. Sensi, A. M. Sillito, F. W. Fitzke, T. E. Salt, and S. E. Moss, 2010, Imaging multiple phases of neurodegeneration: a novel approach to assessing cell death in vivo: Cell Death Dis, v. 1, p. e3.

Cordeiro, M. F., C. Migdal, P. Bloom, F. W. Fitzke, and S. E. Moss, 2011, Imaging apoptosis in the eye: Eye (Lond), v. 25, p. 545-53.

Galvao, J., B. M. Davis, and M. F. Cordeiro, 2013, In vivo imaging of retinal ganglion cell apoptosis: Curr Opin Pharmacol, v. 13, p. 123-7.

Guo, L., and M. F. Cordeiro, 2008, Assessment of neuroprotection in the retina with DARC: Prog Brain Res, v. 173, p. 437-50.

Kass, M. A., D. K. Heuer, E. J. Higginbotham, C. A. Johnson, J. L. Keltner, J. P. Miller, R. K. Parrish, M. R. Wilson, and M. O. Gordon, 2002, The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma: Arch Ophthalmol, v. 120, p. 701-13; discussion 829-30.

Lek, J. J., A. J. Vingrys, and A. M. McKendrick, 2014, Rapid contrast adaptation in glaucoma and in aging: Invest Ophthalmol Vis Sci, v. 55, p. 3171-8.

Normando, E. M., L. A. Turner, and M. F. Cordeiro, 2013, The potential of annexin-labelling for the diagnosis and follow-up of glaucoma: Cell Tissue Res, v. 353, p. 279-85.

Rauscher, F. G., C. M. Chisholm, D. F. Edgar, and J. L. Barbur, 2013, Assessment of novel binocular colour, motion and contrast tests in glaucoma: Cell Tissue Res, v. 353, p. 297-310.

Richman, J., G. L. Spaeth, and B. Wirostko, 2013, Contrast sensitivity basics and a critique of currently available tests: J Cataract Refract Surg, v. 39, p. 1100-6.

Sommer, A., 1989, Intraocular pressure and glaucoma: Am J Ophthalmol, v. 107, p. 186-8.

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