Probing the Cellular Origins of Age-Related Macular Degeneration

May 11, 2021

New R01 Study To Examine and Compare Cellular Changes in AMD and Normal Aging in Human Subjects

Age-related macular degeneration (AMD) – both dry and wet classifications – constitute the leading cause of vision loss and blindness in older adults. While several new treatment options have emerged for the wet form of AMD in recent years, the far more common dry form of the disease has no effective therapies to slow, stop, or reverse its blinding effects on the cellular and vascular constituents and layers of the human retina. With more adults living longer, the prevalence of the disease continues to increase, along with its devastating effects on vision and overall quality of life.

Complicating the study of the disease is the biological conundrum that only primates have a macula, and among primates, only humans manifest AMD; model systems of the disease are few. The best option currently available to researchers is studying the disease processes and phenotypes directly in the living retinas of human subjects. However, this endeavor is complicated by many factors, not the least of which is the sheer difficulty in imaging the cellular components of the retina due to their size and near-transparent nature.

UPMC Department of Ophthalmology research scientist, Ethan A. Rossi, PhD, director of the Advanced Ophthalmic Imaging Laboratory, was awarded a National Institutes of Health R01 grant to better elucidate the cellular differences and changes in the normal aging retina versus the cellular changes in human retinas with varying states of age-related macular degeneration. This work aims to more fully articulate the earliest cellular changes in the retina that are indicative of AMD and to characterize how these changes progress or evolve as individuals age. This is Dr. Rossi’s first R01 grant to support his research.

Study Aims and Details

"There has been significant work done that has established characteristics and cellular changes in the very late stages of AMD, but very little has been done to this point to pry apart what the earliest indicators of AMD look like at the cellular level and how those changes vary from normal changes in the retina as a part of the aging process. Our study, in its essence, will characterize the aging process of the retina – normal aging changes and degradations versus at what points in time and in what ways this diverges in some individuals to AMD" says Dr. Rossi.

Dr. Rossi and colleagues’ study will recruit participants with no identifiable traces of AMD across a spectrum of ages from 18 years to 80 years and image their retinas in order to classify at the cellular level changes and variations to photoreceptor topography (rods and cones) and cell morphometry of the retinal pigment epithelium (RPE). The study also will recruit individuals aged 55-80 with clinically identified early AMD for imaging and comparative analyses.

Dr. Rossi’s study has two broad aims. The first is to define for the first time the in vivo cellular-level morphometry of the aging photoreceptor-RPE complex in healthy individuals at different ages in order to show what normal aging changes look like in terms of photoreceptor loss (which is known to happen with age), and to understand if RPE cells also are lost in the processes of aging, which is subject to conjecture at present. The second aim of the study will be to characterize and compare the photoreceptor and RPE cell morphometry data in the cohort of participants with early AMD against those of the healthy subjects from the first part of the study to quantitatively define the early changes of AMD at the cellular level.

“By understanding the very earliest cellular changes that push the retina toward a path of AMD, we could devise standardized testing protocols to screen for the disease in far advance of its earliest clinical manifestations. Understanding the cellular changes at the very beginning of the disease may afford us the opportunity for new therapeutic targets or interventions to potentially halt, reverse, or significantly delay the effects of the disease,” says Dr. Rossi.

Imaging The Nearly Invisible

To conduct these studies, Dr. Rossi will employ a number of imaging and clinical tests, including his laboratory's advanced adaptive optics ophthalmoscopy (AAO) technologies (see below for more information) in order to capture the cellular level images of the retina's photoreceptors and RPE.

"Using our imaging techniques coupled with adaptive optics technologies, we are able to turn the eye itself into a high-powered microscope to visualize the cellular components and layers of the retina. The technology we have at our disposal is at the very apex of our imaging abilities, yet it is still very challenging to image these structures due to their size and transparency. Rods are particularly challenging to image. They are at the very cusp of what our imaging abilities can see at present," says Dr. Rossi.

More About Dr. Rossi

Ethan A. Rossi, PhD, is the director of the Advanced Ophthalmic Imaging Laboratory in the Department of Ophthalmology at the University of Pittsburgh School of Medicine. Dr. Rossi joined the Department in 2016 as an assistant professor of ophthalmology. He also holds a secondary appointment as assistant professor in the Department of Bioengineering at the University of Pittsburgh Swanson School of Engineering. Dr. Rossi also is a member of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, and is a training faculty member at the Center for Neuroscience at the University of Pittsburgh (CNUP).

Dr. Rossi earned his doctorate in vision science at the University of California, Berkeley, followed by postdoctoral fellowships at Berkeley and at the University of Rochester in the laboratory of David R. Williams, PhD, where he studied age-related macular degeneration (AMD) and developed improved techniques to image the cells of the retinal pigment epithelium (RPE) using adaptive optics imaging systems.

Dr. Rossi’s work is devoted to understanding the cellular organization and characteristics of the human retina in both the normal eye and in the presence of disease. Among other technologies, Dr. Rossi’s research uses adaptive optics imaging platforms to study anatomical structures within the eye at the cellular level and how disease processes such as macular degeneration and glaucoma affect and change the cellular makeup of interocular structures like the retina. His work and that of his collaborators have made significant advances over the last decade in the ability to image and study the layers and structural components of the human retina. During his postdoctoral work, Dr. Rossi collaborated with the optics and imaging company Canon Inc. to design and develop new technologies for the commercial use of adaptive optics in ophthalmoscopy. To date, Dr. Rossi’s work was resulted in four patents related to methods and techniques for imaging multiple retinal structures in which he is either sole inventor or a co-inventor.

In addition to his current NIH R01 grant, Dr. Rossi also is a co-investigator in a University of Pittsburgh study called “Next Generation Optogenetics for Vision Restoration” funded by the Foundation Fighting Blindness. Prior work includes a grant from the BrightFocus Foundation for a study designed to perform in vivo imaging of retinal ganglion cells in glaucoma, and a grant from the Edward N. and Della L. Thome Memorial Foundation for a study involving high-resolution structural phenotyping of intermediated and advanced AMD.

Recent Publications From the Rossi Lab

Zhang M, Gofas-Salas E, Leonard BT, Rui Y, Snyder VC, Reecher HM, Mecê P, Rossi EA. Strip-based digital image registration for distortion minimization and robust eye motion measurement from scanned ophthalmic imaging systems. BOE. 2021; 12(4): 2353–2372. 

Song H, Rossi EA, Williams DR. Reduced foveal cone density in early idiopathic macular telangiectasia. BMJ Open Ophthalmology. 2021; 6:e000603. 

Mecê P, Gofas-Salas E, Rui Y, Sahel JA, & Rossi EA. Spatial Frequency-Based Image Reconstruction to Improve Image Contrast in Multi-Offset Adaptive Optics Ophthalmoscopy. Optics Letters. 2021; 46(5): 1085-1088.

Amarasekera S, Williams AM, Freund KB, Rossi EA, & Dansingani, KK. Multimodal Imaging of Multifocal Choroiditis With Adaptive Optics Ophthalmoscopy. Retinal Cases & Brief Reports. 2021; Accepted January 21st, 2021.

Suthaharan S, Rossi EA, Snyder V, et al. Laplacian feature detection and feature alignment for multimodal ophthalmic image registration using phase correlation and Hessian affine feature space. Signal Process. Published online 2020:107733. 

Vienola KV, Zhang M, Snyder VC, Sahel J-A, Dansingani KK, Rossi EA. Microstructure of the retinal pigment epithelium near-infrared autofluorescence in healthy young eyes and in patients with AMD. Sci Rep. 2020; 10(1): 9561.