Eyes May Reveal Risk of Alzheimer’s Disease with Amani Fawzi, MD

Erin Spain: This is Breakthroughs a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain executive editor of the Breakthroughs newsletter. They say the eyes are windows to the soul but with new infrared camera technology the eyes also serve as windows into the brain In a paper published in PLOS ONE Northwestern scientists detail a noninvasive approach that detects blood capillary changes in the eyes of people with mild cognitive impairment. These changes in the eye, maybe early noninvasive biomarkers of Alzheimer's disease. Dr. Amani Fawzi a professor of ophthalmology at Northwestern led this study and she's here with the details. Thanks so much for being here.

Amani Fawzi: Thank you very much Erin. It's a pleasure to be here this afternoon.

Erin Spain: So there's already a known connection between eyes and Alzheimer's disease. Tell me about that.

Amani Fawzi: In the early eighties, eye scientists started looking at the eye in terms of its connection to Alzheimer's and using donor eyes from patients who passed away and donated their eyes who had Alzheimer's, a scientist at the University of Southern California found that the eye also has damage in these patients. Since then, a lot of noninvasive studies done in living people found that the eyes are affected and people will suffer Alzheimer's. So end stage or Frank Alzheimer's dementia, the eyes are actually affected. And that's something that's been known. People have been looking for more delicate or elegant ways to detect it. Some labs have been trying to find the plaques, the amyloid plaques that are markers of brain Alzheimer's in the eye and you can see them in and donor eyes. But a lot of work is going into trying to do this with imaging of the eye in living people. So the idea is that unlike the brain that's covered with a big skull that is not penetrable, you have to use a big MRI machine with a lot of magnets and high powered technology to look into the brain to try to find these deposits. In the eye, if we dilate the pupil, we can use really delicate cameras to look into the eye with optical technology that has much higher resolution. So people have been using things like curcumin, for example, to stick to these plaques and then make them light up in the eye and take pictures of the back of the eye and see the little light bulbs that are amyloid plaques. That's sort of early stage research and it works on some labs and it doesn't work in others, but these are patients who are already affected with Alzheimer's.

Erin Spain: So this study actually takes a different approach. You were looking at the eyes of people in the earliest stages of cognitive decline, which is different. They have not been diagnosed with Alzheimer's. Tell me, why did you decide to take this approach and look at this set of people?

Amani Fawzi: The problem with diagnosing patients when they're already have cognitive decline or dementia of sorts, it's already too late. A scientist, the brain scientists, the neurologist and the psychiatrist have told us that it may be too late to treat the disease at this stage. The brain has already suffered. There's damage, there's loss. Neurons have died or begun to die. And it's sort of on a vicious cycle of death. So trying to treat patients at that stage may be too late and the cat may be already out of the bag. The new approaches are trying to find subjects who are at higher risk of progressing. And these will be people who are suffering a little bit into their activities of daily living. They're forgetting a lot more than we all forget. And these people may be at higher risk of going on to develop Alzheimer's, but forgetting alone does not really put you at risk. There's other things that can be biomarkers. So some of the things that are already being done is looking at the plaques in the brain with MRIS and PET scans where we labeled those plaques to light up in a certain way. If you have forgetfulness plus these plaques, you are at higher risk. If you have forgetfulness and your spinal fluid tap shows these plaques in the spinal fluid, you are at higher risk. People are trying to identify these subjects and these subjects then can be put into groups of observational studies or they could be targets for treatments that are coming out to delay the disease or prevent the dementia from happening. So this is a very important area of research right now.

Erin Spain: Finding these people who are in this early cognitive decline isn't always so easy, but a strength of the study was that you had that group of people and that was thanks to your collaboration with Northwestern's Muslim Center for cognitive neurology and Alzheimer's disease you were able to collaborate with this group who had already sort of found some subjects for you. Tell me about that.

Amani Fawzi: Alzheimer's research has been sort of a focus of mine since a long time. So as soon as I got to Northwestern and I looked for people who work in that area and I was really lucky to meet with Dr. Weintraub and her team and she was very collaborative and opening to doing research with us. So we started collaborating maybe from 2013. We've been going at this methodically and trying to find the best study in the eye that can help us target those patients. So far this is turning out to be the best approach before we started looking at thickness of the retina. Just seeing if the retina starts to lose some of its structure in these early subjects. That didn't really pan out, but when we started looking at blood flow. We asked Dr. Weintraub and her team to identify those subjects that are really on the spectrum of this forgetfulness that she thinks are high risk. Her population also includes volunteers, people who are completely normal but are participating in research to help the community. So we get a group of people who were tested completely normal for that age and those are the control group. With Dr. Weintraub we go at it at a very, very rigorous way. So we match every subject by age, by gender, by race. Because we know all these things affect your cognitive function, but also the eye. And when we had this pure population of the two groups, that's when we found that difference. In those subjects, when we compare them their same age, same gender, everything, the only difference between them and this is their cognitive scores and their cognitive function and they would be able to function mostly normal in life, but their retinas look very different. Their blood vessels, the capillaries in the back of the eye are very, very different - are statistically different.

Erin Spain: This was a very strong association you found.

Amani Fawzi: Yeah, it's really fascinating. Because we were sort of hoping to find something, but this is really amazing because I think it really speaks to the strength of the study design and the purity of the population that we had and how rigorous we are and excluding other things, especially eye things that can affect the blood vessels. Any eye condition, any disease in the eye can affect the blood vessels, especially in an aging population. A lot of things can affect those blood vessels so we had to really be careful to look at the patients very carefully and exclude anybody who had anything in the eye that could confound us and that's when where we found this.

Erin Spain: And again, tell me the results. What did you find?

Amani Fawzi: We take pictures of the back of the eye with this camera and we can see the individual capillaries around the center of the eye. That's where the fine vision happens. And then we can take the camera and focus it on the optic nerve. That is basically the direct connection to the brain and image it there. If we look at the small capillaries, we found that the subjects that have this mild cognitive impairment have lost a lot of their capillaries and the blood flow had decreased around their central vision. This wouldn't be something that they notice in every day as vision loss because it's very subtle. These are microscopic changes. So they won't be suffering with vision loss. They're all 20, 20, and healthy eyes otherwise, but very subtle changes in the back of the eye.

Erin Spain: And you would never have been able to discover this without this technology, this special camera that you're talking about that offers these views. Tell me a little bit about that technology.

Amani Fawzi: It's based on the technology that was developed in the 90s at MIT and it basically uses a infrared light to scan the back of the eye. It's almost like ultrasound of the back of the eye, but with light. So it gives us a lot higher resolution. We could see the retina, which is, you know, less than a millimeter thick. We can see all it's layers in high resolution, almost five micron resolution. We've had this for awhile now, so we could see structure, we can do ultrasound in the back of the eye with this light. But the new things about, about this technology is a really clever software approach where they take two pictures separated by three milliseconds of the back of the eye they subtract out everything that didn't move between those three milliseconds and only show us everything that's moving and anything that's moving. In this situation if the patient didn't move, everything else that's moving is blood flow. So subtract out all the non moving things in the back of the eye and only show blood vessels and it's just striking how amazing and quick that happens.

Erin Spain: As you mentioned, this technology has only been used in clinical studies since about 2014. It's pretty new. There hasn't been that many studies using it.

Amani Fawzi: It's really exciting. We've been lucky to have this technology since 2015, so maybe a year after other people started working with this. We saw the potential for it to see these microscopic changes. So we've been really pushing the boundaries of this technology. We've used it in all our diabetic patients. We've been able to get funding for that and, and learned a lot about diabetes and how intricately complicated the retina is. But in Alzheimer's, it really gave us a new perspective on those changes.

Erin Spain: For people who want to know - tell me the name of the technology that we're talking about.

Amani Fawzi: The basic hardware is called optical coherence tomography and the update, which is the flow difference is called angiography. So it's optical coherence tomography angiography or OCT-A.

Erin Spain: And other groups around the world are using the same technology for Alzheimer's. But as you said, this study is just a little different than anything else that's been out there and it actually could help scientists one day show which people could be available for, for experimental therapies.

Amani Fawzi: The beauty of the study is the purity of the population, the great collaboration we have with Dr. Weintraub's group so that we were able to be able to get this pure population and compare amongst groups and find this difference. Hopefully in the future other people can replicate our work and we'll have maybe a threshold above which we could say this subject has really high risk, especially if we can follow these patients over time and if their risk changes and the eye changes along with it, then that will be a lot more evidence and stronger evidence that this technology works. The other thing we were hoping to to do is also correlate these vascular changes in the eye with the already known biomarkers, the spinal fluid, the PET scans, the amyloid plaque load and all these other things that already are known to predict the risk.

Erin Spain: As you said, there are other biomarkers that we know of right now, but in diagnosing early Alzheimer's there really isn't anything for the very early cases of someone that may develop Alzheimer's.

Amani Fawzi: I'm not an Alzheimer's expert, but I think there's an algorithm for categorizing risk based on the cumulative evidence in a certain patient. So that cognitive performance is one and then the presence of these biomarkers is another one. And hopefully one day the eye can become part of that algorithm. So if you have two of these biomarkers, for example, maybe if we can build an algorithm that incorporates the eye. Maybe the algorithm would be more powerful at predicting who is at risk. That's our hope at least.

Erin Spain: What's been the reaction from the Alzheimer's research community as well as the eye research community.

Amani Fawzi: I know that from other researchers around the country who've done similar work, even when they found an association with Alzheimer's, the community was very excited because unlike PET scans or getting spinal fluid from a subject, this is a very noninvasive test can be done even without dilating the pupil, it'd be nice if we could dilate the pupil. So that's the most, we do - an eyedrop before taking the picture and an eye exam just to make sure they don't have any other eye diseases. It's pretty straight forward other than that.

Erin Spain: And it doesn't take very long?

Amani Fawzi: And it doesn't hurt.

Erin Spain: It doesn't hurt. Right. You mentioned that you hope that other scientists will be able to replicate what you all have done here at Northwestern. What is next for this study? Do you have plans here to continue following these people?

Amani Fawzi: I just had a talk with Dr. Weintraub and we really want to take this to the next level and we're thinking about ways to do that. So one of the things as you mentioned is to follow these patients over time. The subjects who are not sick at this point. Just to follow them over time and see how their cognitive performance changes and how they're eye changes and if they develop the disease does their eye progress more rapidly. So that's one of the things we'd like to do. We also have been collaborating with Dr. Weintraub looking at other potential biomarkers in the eye. One of our studies that is still ongoing right now is looking at gliosis, which is reactive changes in the surface of the eye. So in the brain, if you have any disease or any injury, there are cells that grow to repair that injury. That's called gliosis. So in the eye we are very fortunate that we can see that process in real time with different cameras, but really high technology, high resolution technology. We can see gliosis in Vivo, in living people. We have been looking at similar groups of subjects to try to see if we can visualize gliosis and if that could be another biomarker for Alzheimer's. We are really tackling this from many aspects and we're hoping to advanced the field in this area.

Erin Spain: What is it about Alzheimer's disease that made you seek out a collaborator when you came to Northwestern? What is it?

Amani Fawzi: Oh, that's a very good question. So personally I have family members with it and I'm scared to death that I would one day succumb to it and I see the potential for the eye to provide this extra layer of being able to diagnose something so complex and so daunting with a simple test. If the eye becomes part of it, I'm hoping that will really enhance the ability to detect these high risk subjects and allow them to be treated earlier. I mean, all the clinical trials in Alzheimer's now have either failed or, you know, caused worsening of the disease because they were started so late. When you've already developed dementia. So, the hope is by taking the treatment to earlier and earlier stages the disease will be cured one day and that is what we are hoping.

Erin Spain: Well, this is a good start I think to that quest and thank you so much for joining me today and we will have more on our website for anyone who wants to read this study and find out more about what you're doing in your lab.

Amani Fawzi: Thank you so much, Erin. It's been a pleasure to be here.

Erin Spain: A note for physicians who listen to this podcast, you can now claim continuing medical education credit just by listening. Go to our website, feinberg.northwestern.edu for more information. Also, if you enjoy this podcast, please go to iTunes and rate us.