Common cell death mechanism seen in glaucoma, Alzheimer’s
Imaging of amyloid plaques may allow early detection of disease, says researcher.
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SARASOTA, Fla. – The discovery of a common mechanism of cell death in both glaucoma and Alzheimer’s disease might pave the way for earlier detection and mapping of disease progression, according to a surgeon who spoke at the annual meeting of the American Glaucoma Society.
The link lies in amyloid plaques that accumulate in the eyes and brains, respectively, of glaucoma and Alzheimer’s patients, said Stuart J. McKinnon, MD, PhD. In glaucomatous eyes, amyloid buildup begins prior to visual field loss, he said, suggesting that tracking amyloid might have diagnostic value.
Dr. McKinnon and colleagues studied the feasibility of imaging glaucomatous eyes with K-114 dye. The soluble dye has been shown in previous studies to bind to amyloid, allowing fluorescent detection on diagnostic imaging devices.
Dr. McKinnon presented data on rat and enucleated human eyes that had been imaged with K-114.
Methodology
The study included rats with moderate to severe chronic ocular hypertension (COH) in the right eye; left eyes served as normotensive controls. After IV injection of K-114, rat retinas, optic nerves and brains were cryosectioned and imaged by fluorescent microscopy.
Enucleated human eyes with and without glaucoma were also stained.
In both human and rat glaucoma eyes, Dr. McKinnon found significant amyloid buildup in the optic nerve. COH rats with more moderate IOPs revealed amyloid buildup confined to the lamina cribosa. Severe cases showed amyloid labeling in both the lamina and retrolaminar optic nerve. Brain labeling of amyloid was also detected in the COH rats. Control eyes showed no plaque labeling.
“The next step is to use radiolabeled versions of these dyes to perform in vivo imaging of our chronic ocular hypertensive rats in a small animal imager,” Dr. McKinnon told Ocular Surgery News, “and actually be able to, in live animals, … quantify the amyloid buildup as a function of pressure exposure.”
Diagnostic implications
Mapping of amyloid accumulation on human optic nerves could allow glaucoma specialists to chart disease progression prior to visual field loss, Dr. McKinnon noted.
“In glaucoma, there’s a diagnostic problem in that standard white-on-white visual field testing typically doesn’t detect any visual field loss until 30% to 50% of retinal ganglion cells are lost,” he said. “We see amyloid in the retinal ganglion cells in our rat glaucoma model at pressure exposures before ganglion cell death occurs.”
The exact role of amyloid in COH is still unclear. What investigators do know is that caspase-3, a protease involved in cell death, is known to cleave amyloid precursor protein and upregulate amyloid beta production, Dr. McKinnon noted.
“Amyloid production appears to be a byproduct of early events of apoptosis,” he said. “It appears to me that this is a process that is occurring before cell death.”
The buildup of amyloid-containing proteins is believed to be neurotoxic, Dr. McKinnon said at the meeting. Glaucoma patients might be experiencing a toxicity in the optic nerve and visual centers of the brain, he noted. In Alzheimer’s patients, amyloid buildup is also correlated with a higher incidence of hemorrhagic stroke, he said. He further postulated this as a mechanism for optic nerve head splinter hemorrhages that are sometimes seen in glaucoma patients.
All images courtesy of Stuart J. McKinnon, MD, PhD. |
Links to Alzheimer’s
The link between glaucoma and Alzheimer’s disease has been studied since the 1970s, when pathologists noticed that a significant number of Alzheimer’s patients also had glaucoma, according to Dr. McKinnon.
“And then in the 1980s, a group led by Dr. Alfredo Sadun started looking at the optic nerve and the retinal nerve fiber layer … and reported loss of nerve fiber layer and optic nerve changes in Alzheimer’s patients,” he said.
More recent studies have found both a greater prevalence of glaucoma in Alzheimer’s patients, as well as a faster rate of visual field loss. In a recent age-matched study of 112 patients, Dr. Andreas Bayer found that glaucoma was prevalent in 26% of Alzheimer’s patients compared to just 8% of the control patients, he said.
“It goes to a common mechanism of cell death,” Dr. McKinnon said, adding that while the diseases seem to have a similar pathology, the exact pathogenesis of the two diseases is still unknown. “It’s been a subject of some debate for a number of years,” he said.
Dr. McKinnon receives grant support from the American Health Assistance Foundation, which supports both glaucoma and Alzheimer’s research, Research to Prevent Blindness, the San Antonio Area Foundation, and the William and Ella Owens Medical Research Foundation.
For Your Information:
- Stuart J. McKinnon, MD, PhD, can be reached at the University of Texas Health and Science Center of San Antonio, Ophthalmology, 7703 Floyd Curl Dr., MC6230, San Antonio, TX 78229-3900; 210-567-8463; fax: 210-567-8413; e-mail: mckinnon@uthscsa.edu.