Similarities seen in ocular protein deposits in glaucoma, dementia

Reviewed by Neeru Gupta MD, PhD, MBA

Toronto-It may be no accident that so many patients with dementia also have vision loss, or that older patients with glaucoma may also show signs of dementia.

A growing body of evidence is finding a growing number of similarities between glaucoma and dementia at the molecular level as well as at the population level, said Neeru Gupta MD, PhD, MBA.

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“Little is known about the disease and no curative treatments are available,” said Dr. Gupta, professor and Dorothy Pitts Chair of Ophthalmology, St. Michael’s Hospital, and chief of glaucoma, at the University of Toronto.

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“You might think that is a description of glaucoma, but these are quotes from Alzheimer’s papers,” she added. “Both are age-related, progressive diseases that give rise to characteristic protein aggregates.”

The two conditions do not give rise to identical proteinaceous ocular deposits, Dr. Gupta said.

Explaining the similarities

Explaining similarities

But similarities between the pseudoexfoliation seen in some glaucoma patients and the protein aggregates found in the eyes of some dementia patients suggest shared pathophysiological pathways and the potential for using readily detectable changes in the eye as biomarkers of neurodegenerative disorders.

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Dr. Gupta’s research is based on the recognition that most, possibly all, neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, glaucoma, and others, feature the same physiologic dysfunction, a misfolding of proteins.

“Think of a protein misfolding disorder as an origami gone wrong-a beautiful, mathematical, three-dimensional structure that goes wrong,” she said. “Because the protein is not folded properly, all of the molecular cues are wrong, and these proteins don’t know where to go or what to do.”

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Dr. Gupta and other researchers have long noted mechanistic similarities between glaucoma and dementia. Common features include increasing incidence with age, retinal ganglion cell degeneration, and deposition of abnormal protein aggregates.

In glaucoma, these aggregates take the familiar form of pseudoexfoliation, protein deposits seen in the anterior chamber.

Beta amyloid plaques

Different forms of dementia are marked by typical protein deposits including the presence of beta amyloid plaques. A postmortem finding of beta amyloid plaques in cerebral tissue is still the key diagnostic marker of Alzheimer’s disease 110 years after their initial description by German psychiatrist and pathologist by Alois Alzheimer in 1906.

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The deposition of protein aggregates through pseudoexfoliation is an important marker of pseudoexfoliation glaucoma, Dr. Gupta said. It was not known if Alzheimer’s or other forms of dementia gave rise to their own characteristic extracellular protein deposits that could also be detected in the eye.

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The research team in Toronto examined a large number of post-mortem eyes from patients with a history of glaucoma and dementia,  obtained from the Human Eye Biobank for Research at St. Michael’s Hospital (www.humaneyebank.com).

Eyes were examined by two independent examiners who were blinded to the case diagnosis,  and compared with cases without glaucoma, dementia or other diagnosed neurodegenerative disorder, she added.

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Routine histology, fluorescent and immunocytochemical approaches to evaluate the proteins found in the eyes, included known markers for dementia and pseudoexfoliation glaucoma. Classic pseudoexfoliation material was seen in glaucoma eyes with the typical pattern characteristic of these deposits.

Some dementia cases

In some dementia cases, abundant aggregates were also seen lining anterior segment structures, with morphological patterns that were different from pseudoexfoliation cases.

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“These deposits were polymorphic in morphology compared to the pseudoexfoliation deposits, but very similar histochemically to the pseudoexfoliation glaucoma deposits,” she said.

These findings suggest there may be different pathologies underlying these diseases, but that there are some shared pathways in glaucoma and dementia, she noted.

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“We need more research to characterize these deposits,” Dr. Gupta said, “but this is very compelling evidence to look more closely at the eye for biomarkers of neurodegenerative disorders.”

Neeru Gupta MD, PhD, MBA

E: guptan@smh.ca

This article was adapted from Dr. Gupta’s presentation at the 2016 meeting of the American Glaucoma Society. Dr. Gupta did not indicate any financial interest in the subject matter.