XiangRun Huang, Ph.D.
Optical Properties of Ocular Tissues; Damage Mechanisms of Glaucoma
Physiological Optics, Glaucoma, Retinal Disease
Glaucoma, the second leading cause of blindness, is characterized by retinal ganglion cell death and optic nerve degeneration. Delays in detecting glaucoma can lead to inadequate treatment and irreversible visual loss. The retina nerve fiber layer (RNFL) in human eyes consists of the axons of retinal ganglion cells. Recognizable loss of the RNFL precedes measurable loss of vision and thus measurement of RNFL may provide early diagnosis of glaucoma. Several quantitative methods for optically assessing the RNFL promise enhanced sensitivity and objectivity over previous methods, such as visual field testing. All these techniques measure some aspect of the optical properties of the RNFL. These properties, however, and their damage mechanisms under the development of glaucoma are not fully understood. The goals of Dr. Huang’s research are to provide a comprehensive quantitative description of the optical properties of the RNFL and their changes in the context of glaucoma, to study the anatomic origins underlying the RNFL optical properties, and to translate basic knowledge into improvements in clinical diagnosis of glaucoma.
Optical Properties of RNFL in Glaucomatous Retinas
RNFL reflectance arises from light scattering by cylinders. In normal retinas, RNFL reflectance is wavelength dependent with high reflectance at short wavelengths and low reflectance at long wavelengths. Because RNFL reflectance directly depends on the cytostructure of RNFL, to the extent that glaucoma damages axonal ultrastructure RNFL reflectance is expected to change. By using an animal model of glaucoma, Dr. Huang’s group discovered that RNFL reflectance spectrum changes with glaucomatous damage and decrease of RNFL reflectance is detected early at short wavelengths (Fig. 1). Current optical methods often use near infrared to detect RNFL reflectance. These findings will impact the improvement of early detection of glaucoma by measuring RNFL reflectance at short wavelengths.
The RNFL exhibits form birefringence due to preferentially oriented ultrastructure. By studying the distributions of RNFL birefringence in normal retinas and retinas with different degrees of glaucomatous damage, Dr. Huang’s group found that RNFL birefringence decreases in glaucomatous retinas and the change occurs first near the Optic Nerve Head (ONH). The finding suggests that RNFL birefringence measured near the ONH provides earlier indication of glaucomatous damage, a practical guidance for clinical assessment of RNFL change.
Relationship between RNFL Optical Properties and Axonal Ultrastructure
Both RNFL reflectance and birefringence are found to decrease prior to thinning of the RNFL and be accompanied with distortion of axonal cytoskeleton. The results suggest that the optical properties of RNFL can provide early detection of glaucomatous damage before apparent loss of axons. It also suggests that measuring RNFL reflectance and birefringence is more sensitive to detect glaucomatous damage than by measuring RNFL thickness, which is commonly used in current clinical practice.
Further studies by Dr. Huang’s group will determine the quantitative relationship between RNFL optical properties and cytoskeletal density in normal and glaucomatous retinas. The obtained relationship is expected to provide a direct estimate of change of axonal cytoskeleton in retinas with glaucomatous damage. The study is expected to significantly impact clinical diagnosis and monitoring of glaucoma because it may provide estimates of axonal cytoskeletal change from clinically measurable RNFL optical properties.
RNFL Reflectance Speckle and Axonal Dynamic Activity
Speckle arises from interference of coherent light scattering from different parts of an object. Movement of scattering particles causes fluctuations in interference and thus changes speckle pattern. In turn, change of speckle pattern in time suggests temporal change of scattering structures and, hence, change of speckle has been used to measure blood flow. Axons are dynamic structures with organelles continuously moving by axonal transport. To the extent that the movement of the organelles affects the reflecting structures, this dynamic activity should induce change in RNFL reflectance speckle (Fig. 2). Recently Dr. Huang’s group demonstrated that temporal change of RNFL speckle is related to axonal physiologic activity. One objective of Dr. Huang’s current research is to seek a new approach to assess axonal dynamic activity by measuring temporal change of RNFL speckle. Because physiologic change of axons occurs prior to cytostructural alteration, the method explored by the study may provide a new sensitive approach to detect axonal degeneration in glaucoma and other ocular neuropathic diseases.
Damage Mechanisms of Axonal Cytoskeleton in Glaucoma
Studies of damage mechanisms of axonal cytoskeleton in the context of glaucoma reveal changes of cytoskeletal components, including F-actin, MTs and neurofilaments (NFs). Elevation of intraocular pressure (IOP) in experimental animals causes non-uniform alternation of cytoskeletal distribution across the retina. The damage usually occurs first in the dorsal retina and changes start near the ONH and propagate toward the ganglion cell bodies. The degree of damage varies from distortion of cytoskeleton staining to the total disappearance of the structure. Features of cytoskeletal changes also include 1) different distortion patterns for different cytoskeletal components; 2) for each cytoskeletal component the pattern of alteration varies through the depth of the RNFL and also depends on the stage of tissue damage; and 3) F-actin may be the most sensitive and vulnerable structure responding to elevated IOP. The results suggest that different mechanisms may be involved in damage of different components. Change of F-actin may be an early sign of glaucomatous damage.