This application is a formal request for a career development award (K23) for an academic glaucoma specialist with a serious interest in the role of imaging in glaucoma using optical coherence tomography (OCT). This will allow the candidate to establish a clinical research program with the main goal of improving detection of glaucoma progression through macular imaging with spectral-domain OCT. By the time the proposed research is accomplished, the candidate will have preliminary data for continuing his research as an independent investigator and will have collected longitudinal structural and functional data in a group of advanced glaucoma patients that will serve as a platform for further improving detection of glaucoma progression with macular OCT imaging. The data will help the candidate provide preliminary results for a subsequent R01 that would potentially allow the PI to continue follow-up of the patients enrolled in the K23 award period. I have a Master's of Science degree in Clinical Investigation under my belt and intend to deepen my skills in the field of imaging and biostatistics (to be used for enhancing and handling OCT images and for analyzing longitudinal data) by completing the proposed didactic program. By the end of the award period, I expect that I will have gained additional experience, knowledge, and mentorship required to prosper as an independent clinician-scientist in the field of glaucoma. My long-term goal is to carry out longitudinal studies of glaucoma patients where current and upcoming imaging and functional tests can be applied and their utility for detection of glaucoma progression can be investigated. I am confident that the combined skills and experience of my mentors will lead to a successful outcome for the proposed K award. I also envisage myself mentoring candidates like myself in future so that our collective knowledge and wisdom can be passed along to the next generation of aspiring clinician-scientists. My objectives during the award period are as follows: 1) To develop an individual research program in glaucoma diagnostic imaging;2) to successfully complete credited coursework in biomathematics, advanced biostatistics, computer vision (image processing), epidemiology, and ethical issues in research. The main goal of the research component of this proposal is to better delineate the role of macular SD- OCT imaging for detection of glaucoma progression in advanced glaucoma.
The specific aims through which this goal will be accomplished are as follows: (1) To compare the performance of various global and regional macular measures to detect glaucoma. The potential factors influencing the performance of various macular outcome measures will be explored. Such covariates include age, race, axial length, disc size, central corneal thickness, OCT signal strength, and outer retinal thickness among others. I hypothesize that the thickness of the outer retina (outer nuclear layer to retinal pigment epithelium-Bruch's membrane complex) may be the most important factor explaining the measurement variability of the inner retinal layer thickness (GCC or ganglion cell/inner plexiform layers). (2) To determine and compare the utility of the candidate macular measures, detected through the first aim, for detection of glaucoma progression in moderately advanced to severe glaucoma. Moderately advanced to severe glaucoma will be defined as eyes with visual field mean deviation worse than -6 dB or eyes with involvement of the central 10 degrees on the 24-2 visual field. It is widely accepted that measurement of the optic nerve head or RNFL parameters in advanced glaucoma does not provide clinicians with much useful information. In contrast, the central macular ganglion cells are the last to die in glaucoma. Macular imaging in advanced glaucoma is directed towards this area where detection of change may still be possible. I hypothesize that macular OCT parameters are valid structural outcome measures (biomarkers) that can be used to follow the course of the disease in advanced glaucoma and that such measures are significantly correlated with changes in the central visual field. Changes in the macular measures over time will be first correlated with the corresponding visual field change (functional progression) over time in eyes with moderately advanced to severe glaucoma. The utility of the best candidate macular measures for predicting subsequent glaucoma progression will also be explored and compared. I hypothesize that there may be a lag period between progressive loss of macular ganglion cells and subsequent visual field progression in advanced glaucoma, and therefore, detection of worsening in one or more macular outcome measures can be used as a proxy for subsequent visual field progression. Collectively, these studies will provide a solid foundation for better understanding and integration of macular OCT imaging in the care of glaucoma patients. Timely detection of glaucoma progression in the later stages can significantly reduce visual disability and blindness through earlier aggressive treatment and will potentially reduce glaucoma's financial burden to society.

Public Health Relevance

Detection of glaucoma progression remains a challenging task in eyes demonstrating significant damage. Even small amounts of progression in advanced glaucoma can have important consequences with regard to patient's visual function and quality of life. The results of the proposed study will potentially lead to more effective and earlier detection of glaucoma progression and will allow ophthalmologists to step up treatment in a timely manner. This will in turn result in less visual morbidity and reduced blindness from glaucoma, which is projected to cause more than 10 million cases of legal blindness around the world in 2020.

National Institute of Health (NIH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZEY1)
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Agarwal, Neeraj
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Amini, Navid; Nowroozizadeh, Sara; Cirineo, Nila et al. (2014) Influence of the disc-fovea angle on limits of RNFL variability and glaucoma discrimination. Invest Ophthalmol Vis Sci 55:7332-42
Nouri-Mahdavi, Kouros; Nowroozizadeh, Sara; Nassiri, Nariman et al. (2013) Macular ganglion cell/inner plexiform layer measurements by spectral domain optical coherence tomography for detection of early glaucoma and comparison to retinal nerve fiber layer measurements. Am J Ophthalmol 156:1297-1307.e2