Disorders of Aging: March 2021

The eyes could show early warnings for Alzheimer's, researchers say

Elizabeth Anne Brown

Feb. 27, 2021 (The Washington Post) — Forget the soul, it turns out the eyes may be the best window to the brain. Changes to the retina may foreshadow Alzheimer’s and Parkinson’s diseases, and researchers say a picture of your eye could assess your future risk of neurodegenerative disease.

Pinched off from the brain during embryonic development, the retina contains layers of neurons that seem to experience neurodegenerative disease along with their cousins inside the skull. The key difference is that these retinal neurons, right against the jellylike vitreous of the eyeball, live and die where scientists can see them.

Is there a link between Alzheimer’s and Parkinson’s Disease? The country’s leading Parkinson’s specialists, Dave Anders, from Wits University’s Donald Gordon Medical Centre, speaks on this.

Early detection “is sort of the holy grail,” said Ron Petersen, director of Mayo Clinic’s Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging. By the time a patient complains of memory problems or tremors, the machinery of neurodegenerative disease has been at work probably for years or decades.

Experts liken it to a cancer that only manifests symptoms at Stage 3 or 4. When patients begin to feel neurodegenerative disease’s impact on their daily life, it’s almost too late for treatment.

Catching the warning signs of neurodegenerative disease earlier could give patients more time to plan for the future – whether that’s making caregiving arrangements, spending more time with family or writing the Great American novel.

In the longer term, researchers hope the ability to notice brain changes before symptoms begin could eventually lead to early treatments more successful at slowing or stopping the progress of Parkinson’s and Alzheimer’s, since no such treatment is currently available. The hope is that “the sooner we intervene, the better we will be” at preventing cognitive impairment, Petersen said

While scientists developing blood tests for Alzheimer’s and Parkinson’s continue to receive the lion’s share of the research funding, retinal screening could be noninvasive, inexpensive and remarkably sensitive, proponents say.

Alzheimer’s and Parkinson’s cause sweeping changes to the landscape of the brain before there are any behavioral shifts – blood vessels atrophy, neurons die prematurely and snarls of misfolded proteins disrupt communication between surviving neurons. Current techniques for detecting these shifts, including PET imaging at $3,000 to $6,000, can identify Parkinson’s and Alzheimer’s pathology in the brain before symptoms begin, but they’re too invasive and costly for widespread use. But identifying parallel changes in the retina is a different story.

Maya Koronyo-Hamaoui, a neuroscientist and professor of neurosurgery, studies early Alzheimer’s intervention and treatment at Cedars-Sinai. She and her team have pioneered a technique to visualize the plaques associated with Alzheimer’s in the retinal neurons of live patients with mild cognitive impairments, at a cost of about $285 a scan. All it requires is modified ophthalmological equipment – and a lot of curry flavoring.

Patients prepping for Koronyo-Hamaoui’s retinal exam load up on protein shakes spiked with curcumin, the naturally occurring compound that gives turmeric its color and flavor and is central in curry. Curcumin has an extreme affinity for amyloid beta, the protein that makes up Alzheimer’s plaques. Surprisingly for those of us with turmeric in our spice drawers, it also glows yellow when exposed to blue light (yes, you can try this on your spice rack at home). Scientists have tied retinal amyloid beta to lower scores on cognitive tests, more plaque in the brain and reduced volume in the hippocampus, the brain’s memory hub.

If Koronyo-Hamaoui’s imaging system seems low-tech to neuroscientists accustomed to PET’s radioactive tracers and million-dollar scanners, Ruogu Fang’s technique for Parkinson’s screening is downright stone age.

Fang is a biomedical engineer who researches applications of artificial intelligence in health and medicine. She and her collaborators at the University of Florida use a fundus camera – a specialized iPhone attachment about the size of a book – to take high-resolution photos of the microscopic blood vessels in the back of the eye. Changes to the blood vessels in the brain are characteristic of both Parkinson’s and Alzheimer’s disease, as oxygen deprivation contributes to premature neuron death, and there’s strong evidence that blood vessels in the retina mirror those changes.

Initial results suggest that computer algorithms are able to use these fundus images to distinguish Parkinson’s patients from healthy controls with an accuracy upward of 70 percent.

Neither of these biomarkers are perfect candidates – amyloid beta accumulates in the healthy brain with age and many people with elevated amyloid beta remain cognitively normal, Koronyo-Hamaoui acknowledged. Fang noted that vascular changes are present in myriad other conditions including diabetic retinopathy – a vision condition caused when high blood sugar blocks blood vessels to the retina – and traumatic brain injury.

But it’s not about finding a single, silver-bullet biomarker, said Sharon Fekrat, a vitreoretinal surgeon and co-director of the Duke Neurodegenerative Disease Retinal Imaging Repository.

To try to figure out which biomarkers are most effective forecasters of Alzheimer’s, Fekrat and her collaborators are feeding extensive patient profiles – including images of the retinal vasculature and measurements of the various layers of the retina in people who have known Alzheimer’s pathology – into a neural network, a form of machine learning that identifies patterns based on a set of training data. The network then experiments with different combinations of data points to pin down how to get the most accurate diagnosis with the least patient information.

So far, according to Fekrat’s neural network, thinning of the retina’s ganglion cell layer has the most predictive power for an Alzheimer’s diagnosis – in other words, the neural network was able to use the thickness of a layer of the retina to distinguish between patients with clinically diagnosed Alzheimer’s and healthy controls of a similar age. That measurement can be achieved using optical coherence tomography, a patient eye scanning system most eye doctors already use.

Fekrat’s and the Duke team’s vision is for a cheap and accessible retinal scan that could identify warning signs for various neurodegenerative diseases at the same time. Right now, they’re training their neural network to scour images of the retina for the hallmarks of Parkinson’s, Alzheimer’s, and Lewy body dementia, which can cause hallucinations and delusions as dementia sets in.

“We could set up a machine next to a pharmacy,” Fekrat said. Patients could sit down in a booth like the ones with blood pressure cuffs already omnipresent in drugstores, have their eyes imaged, and “we’ll have our deep learning algorithm analyze it and spit out a risk score, or a diagnostic index” that can direct them to a neurologist if necessary.

Identifying any of these biomarkers in the retina doesn’t mean a patient will develop full-blown Alzheimer’s or Parkinson’s within their lifetime, Petersen said. Such information should be considered a warning sign – like high blood sugar levels – that prompts both doctor and patient to be vigilant for other changes.

It’s also an opportunity for the patient to be proactive about preventive measures that may slow the progression of neurodegenerative diseases, such as exercise and improved diet. “Exercise is the only thing I’ve seen that really helps with Alzheimer’s and Parkinson’s,” said Laura Volpicelli-Daley, an assistant professor of neurology at the University of Alabama at Birmingham. She added that she hopes biomarkers that show a patient their personal risk will make reasons to change their habits tangible and urgent.

“It’s like with 23andMe,” Fekrat points out, referring to the popular DNA test that identifies genes associated with an elevated likelihood of developing a disease or condition. “When people know their risk, they say, ‘Oh, I have the gene for macular degeneration. I’m not going to smoke.’ ”

 

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