Truth may literally be in the eye of the beholder

How a novel biomarker could support earlier, non-invasive diagnosis and treatment for ALS

“It’s very meaningful for our entire team – from our students, technicians, and research assistants to our collaborators from various disciplines – to work together on this project and keep in mind the patients and their families first.” – Dr. Yeni Yucel

We’ve long heard that the eyes are the window to the soul. But researchers are finding a new twist on this proverb that has powerful implications for understanding neurodegenerative diseases like ALS: the eyes as the window to the brain.

With funding from the ALS Society of Canada and Brain Canada, an interdisciplinary team from Unity Health Toronto, led by Dr. Yeni Yucel and Dr. Neeru Gupta, is using widely available imaging technology to find out something completely novel: what eyes can tell us about ALS.

In doing so, they hope to find a non-invasive, highly accessible way to detect a potential new ALS biomarker – contributing to better quality of life, easier care management, and more streamlined clinical trials for ALS patients.

A PART OF THE BRAIN THAT SEES – AND CAN BE SEEN

Dr. Gupta is an ophthalmologist, while Dr. Yucel is a neuropathologist and eye pathology expert. They’ve both been interested in what eyes can tell us about the brain for many years.

“The eye is actually an extension of the brain,” says Dr. Gupta, “So we’ve always been very interested in it as a window into neurodegenerative disease.”

The benefit of working with eyes is that you can, well, see them. If a disease begins to present itself in the brain or spinal cord, it’s either impossible to see directly or takes expensive, sophisticated equipment to uncover. The tools needed to explore eyes are already available in ophthalmologist offices around the world.

But what do the eyes have to do with ALS?

THE POTENTIAL FOR AN ACCESSIBLE NEW BIOMARKER

Right now, ALS is diagnosed through a process of elimination, which can often lead to a delay between symptom onset and starting a treatment plan. During this undiagnosed time, motor neurons are degenerating – fast.

This is because there are few reliable, easily detected biomarkers for ALS.

In 2013, Dr. Gupta led the launch of the Human Eye Biobank for Research (HEBR) at St. Michael’s Hospital in Toronto. This biobank made eye tissue samples from donors with a wide-range of diseases easily accessible to researchers for the first time.

Looking at post-mortem tissue samples, Dr. Yucel began to notice something unique. Many ALS patient samples showed evidence of axonal spheroids in the eye. These spheroids, which are swellings in the axons of the retina, are similar to a pathological hallmark of axonal injury found in the brains and spinal cords of ALS patients.

He began to hypothesize that if we looked in the eyes of living patients and detected these spheroids, it might provide a simple, non-invasive, and much faster way to diagnose the disease and track its progression.

THE POTENTIAL FOR BETTER TESTING AND HIGHER QUALITY OF LIFE

With support from the Discovery Grant, Dr. Yucel and Dr. Gupta, along with a highly collaborative team, will attempt to determine whether widely available clinical eye imaging devices such as scanning laser ophthalmoscope (SLO) and optical coherence tomography (OCT) can be used to define the presence of spheroids in patients. In addition to using standard technology to ask new questions, they will also explore more enhanced imaging techniques to see how they can best characterize the profile of the eye.

If successful, this project will establish the groundwork for a non-contact, non-invasive, rapid and relatively inexpensive biomarker for ALS. In addition to assisting in an earlier, more reliable diagnosis, these biomarkers could someday be used to track progress during clinical trials or shed light on the speed at which the disease is progressing.

“I think the unique piece here is that this is something we’ve never seen or heard of anybody doing in the field before,” says Dr. David Taylor, Vice President of Research for the ALS Society of Canada. “These spheroids are definitely worth examining, because there could be something really powerful there.”

A PERSONAL MOTIVATION

Both Dr. Yucel and Dr. Gupta are motivated by more than curiosity.

“One of my very close friends from my PhD studies was suffering from ALS,” Dr. Yucel shared. “When that close of a friend is affected, you really see the impact of the disease.” Though his friend has passed away, he is still in touch with the family of this friend, who are very supportive of his work.

Both researchers also had a colleague who died from ALS, and have interacted with a number of patients through ALS Society of Canada – relationships that have contributed to their desire to find less invasive, more accessible options for patients.

Drs. Yucel and Gupta emphasize their gratitude for the patients and their families they serve – those experiencing ALS right now, and the ones who donated their tissues to the biobank after they passed.

“Our work is a way to honour these patients who have trusted us with their precious tissue,” says Dr. Gupta. “It’s a way to serve the community.”

Funding that makes an impact

Since 2014, the partnership between Brain Canada and ALS Canada has resulted in more than $24 million being invested in leading-edge ALS research that has helped further understanding of the disease. The Discovery Grant Program is designed to fuel innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve quality of life for people and families affected by this devastating disease. In 2022, nine projects awarded through the 2021 Discovery Grant Program will benefit from $1.125 million in funding.

“The benefits of partnerships like the one between Brain Canada and the ALS Society of Canada goes far beyond much-needed financial investments in ALS research,” says Dr. Catherine Ferland, Chief Research and Programs Officer at Brain Canada. “Any time we can further our understanding of a rare and debilitating brain disease like ALS, we open the door to a more hopeful future.”

The Discovery Grant Program has been made possible with the financial support of Health Canada, through the Canada Brain Research Fund, an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada, and of the generosity of provincial ALS Societies, ALS Canada donors and community-based efforts, including 40 per cent of net proceeds from the Walk to End ALS.