Daniel I. Simon, MD (Host): Thank you for listening to another episode. Today, I am happy to be joined by our guest, Dr. Jennifer Villwock, Vice Chair of Research in the Department of Otolaryngology and Head and Neck Surgery at University Hospitals. She's a Professor of Otolaryngology and a fellowship-trained rhinologist and anterior skull base surgeon. Welcome.

Jennifer Villwock, MD: Yeah. Thank you so much for having me.

Host: Well, we're in for a real treat today, because Dr. Villwock is a smell doctor. And olfaction is, you know, one of those senses that we kind of learn in medical school, and then we don't really think much more about it. But you're very, very famous for a special test in smell called Aroma. And we're going to get to that in a moment.

But before we get started, Jennifer, maybe you could just tell us how you got into medicine, where did the interest come from, and a little bit about your journey to University Hospitals.

Jennifer Villwock, MD: Yeah, absolutely. So, medicine for me, I think, was a way to have an impact. And my brain is very scientifically oriented. And, you know, most of my research endeavors, they come from I see things that don't make sense or that we don't have a better explanation for. And I just cannot handle that. And so, it's like, "All right. Well, we need to investigate more and find better ways to do things." And so, medicine was an ideal fit for that. I went to medical school at Michigan State. And I actually did my two clinical years in Flint, Michigan, which is now famous for the Flint water crisis. And so, that really instilled in me not just a need for accessible medicine, but really to be engaged with the communities that we care for as well to get the outcomes that we want.

I subsequently did my residency training at SUNY Upstate in Syracuse, New York. And then, decided that I really loved rhinology. And so, for those who are not familiar with the field, the way that I think about rhinology is that I'm a tiny carpenter inside the nose. So, most of the procedures that I do are with cameras through the nose, really optimizing the architecture or sometimes fixing. You know, if there's leaks in the ceiling and we have cerebrospinal fluid coming down, I'm just doing some HGTV-style renovations, but inside the nose to improve the health of my patients. And that's what led me to stay on as faculty at my prior institution, and that's where all of my work in olfaction really began.

Host: That's really great. So, you know, let's start really basic here for our listeners, because even the doctors in the audience, this goes back to cranial nerves, olfaction, smell receptors going to what part of the brain? Tell us just a little bit about the basic neurocircuitry of smell, because that really factors into diseases that we're going to talk about.

Jennifer Villwock, MD: Yeah. Absolutely. For folks that, you know, you hear cranial nerves and your brain turns off, I always tell folks, "I'm like, well, then I think olfaction might be your jam because you have the olfactory receptor neurons." And then, they're hanging out on the nose side of things in the sinonasal cavity in the olfactory cleft. They go through the cribriform plate, and then they synapse in the olfactory bulb. Boom, you're done. That's your pathway. So, for those of us that like the elegance of simplicity, olfaction is a great cranial nerve to study.

And then, of course, from there, the neuroanatomy gets much more complicated in terms of where all those signals are routed centrally. And that's where we start talking about the impact of different disease states on olfaction.

Host: It's interesting. As a cardiologist, we think of the eye as a window on the brain. So, we can see changes in vessels that give us hints into atherosclerosis, diabetes, we have changes in the eye. And now, you hear about people who studied dementia looking in the eye. I hate to say it, but smell seems to be the forgotten one that's also very assessable. So, maybe that'll lead us in to our first real question about what your real passion, which is your test called Aroma. You developed this, it's affordable, rapid. You can embed it in real-world clinical workflow. So, tell me a little bit about it. What is it and how does it work?

Jennifer Villwock, MD: So, Aroma was really born out of frustration with some of the existing tests. You know, in today's health economic climate, there's always reasons to or to not do things. And a lot of times, if you want to be reimbursed and have recoupment of your costs, you need a CPT code that's billable. And that's something that is still lacking within the realm of olfactory testing. And you can't really afford to give every patient a very expensive test without thinking about those financial considerations.

Another area of frustration was when I took a step back and I looked at the way that a lot of the tests were done, they use relatively simple chemical mixtures or compounds to test olfaction. And that was problematic for me, because there have been a lot of really elegant studies that have shown that the way that your brain recognizes different scents requires all the different aspects that are present in that scent.

And the example that I like to use is the scent of clove. We just exited the holiday season. A lot of people were doing a lot of winter baking, making gingerbread and other things where clove is a predominant component. And so if you have a strong memory linked to, "Oh, I walk into grandma's house and she was making gingerbread, and this is the smell of clove," that is very different-- that whole scent that triggers that memory-- than just saying, "Okay, here's some eugenol. Consciously, that might smell like clove, but the way that your brain responds to that and the way that it lights up on functional MRI and other type studies is different. And we wanted to be able to capitalize on that. So, to make our test more affordable and more reflective of real-world olfaction, we actually use essential oils and dilutions of those to test olfaction in our patients.

Host: So, what smells are there in the aroma test?

Jennifer Villwock, MD: Ooh, this is like a quiz. Can I remember all 14 scents? So, we try to have a pretty diverse array of scents, right? In terms of the categories. So within the floral category, we have things like rose, lavender, eucalyptus, rosemary. We have mints as well, so things like spearmint, peppermint. There is also a citrus category. So, we have things like ginger, lemon, and orange. And then, we have some of our more aromatics. Those are the things like cinnamon and clove. And then, we also have the most pungent one, we keep this one, but when we haven't made our concentrations in like multiple layers because it's just so pungent, it's garlic. So, that one's almost like a positive control because most people can smell that even if they can't smell anything else.

Host: So, how did you discover that diseases-- Alzheimer's, dementia after traumatic brain injury-- how did you discover that those were associated with defects in smell? Did you expect it? Was it surprising? How did you get to that link?

Jennifer Villwock, MD: Yeah, I think what was surprising for me, you know, and I, in no way, discovered or established any of the decades of literature that we have on this topic. But to your point from earlier, I think what really surprised me as I started getting into the realm of olfaction was how we have so much knowledge going back, 10, 20, sometimes even 30 years, depending on what publication you're reading that does consistently link olfactory dysfunction and deficits to these other really important outcomes that we care about. And yet, it's almost as if we're like, "Well, we don't have great methods and we haven't really figured it out, so we're just going to like ignore it," which to me, that was the really surprising part. Like, I became interested in olfaction because I wanted a better way to monitor my patients that had nasal polyps. Nasal polyps are benign, inflammatory growths in the nose. But as you can imagine, if you've got basically big water balloons on the inside of your nose, olfactory stimuli is not going to get to the regions where it needs to get to.

And I had patients in Kansas who lived six, seven, eight hours away, the way that we check for nasal polyps is usually we look in the nose with a camera that takes less than one minute. And so, I felt some sort of way about them driving six hours, brief clinic visit and procedure. Just for me to say, "Looks great, come back in three to six months when I knew, well, olfaction is one of the first things to decrease when your polyps come back, what if we could monitor them at home? And that's what started me on this.

But then, I think most of us know how it goes. You type something into PubMed, and then 1 million rabbit holes appear for you to dive into. And so, as I was pursuing some of these rabbit holes, I really stumbled across all of this really strong and compelling literature about olfaction and how it's linked to cognitive outcomes. It can be used to help differentiate Parkinson's disease from some other primary movement disorders. It's something that's impacted by traumatic brain injury. You know, the most recent rabbit hole that I've gone down is how sensory function is impacted by hormones and menopause. And maybe some of the sensory changes that are occurring during menopause will help explain why women have an increased risk of dementia versus men when you look at those numbers globally. So, I think there's a lot still to explore.

Host: So for most, lay people and also doctors, we suddenly got this explosion of interest in olfaction from COVID. My wife, one day, she had COVID, and one day she says, "I lost my sense of smell and taste. And that's like everybody knows someone. Then, suddenly, there was this burst of literature. So, tell us a little bit about that story. I mean, that is obviously the COVID-19 virus directly injuring olfactory neurons. I mean, tell us about that story and its recovery and maybe some of the work that you did in COVID.

Jennifer Villwock, MD: Definitely COVID put olfaction on the map, that is for sure. Typically, we know that different viruses can impact the olfactory system in different ways. So, pre-COVID, I was still seeing patients in my clinic that had either idiopathic, meaning we don't know, but assume it was some sort of virus or were recovering from a viral upper respiratory tract infection and they had persistent olfactory loss. Some viruses are known to directly impact the olfactory receptor neurons, and some of them impact the supporting cells. So, it seems that, in the case of COVID, it is more the latter. But of course, if the support cells are not in place, you know, to help with energy supply, metabolic waste distribution, et cetera, you're going to get injury to that whole system.

Most people who acquired olfactory dysfunction because of COVID-19 have at this point recovered. However, most is not all. And so, there are still quite a few folks, when we look at the overall prevalence of longstanding olfactory dysfunction, it's still in the 2-5% of people, which is a lot when you look at the overall global burden of COVID-19. And it makes me think about populations where perhaps they are just not articulating that they experience this symptom. You know, I think about kids. There are some folks who believe that some children that have picky eating, you know, and other new aversions might be because their sense of smell and taste are off. We just have not really developed an effective way to, at a population health level, screen for olfactory dysfunction. There are a number of things that we've learned in terms of supportive treatments, but we still don't have any clear slam dunks.

Host: So just for a sense of understanding the aroma test and dementia risk, are there abnormalities in smell before cognitive decline or are the abnormalities in smell in parallel with cognitive decline? In other words, can you use it to predict adverse course, future course, maybe even to administer drugs that clear amyloid, that kind of thing?

Jennifer Villwock, MD: Yeah. So, the answer to your question is, yes, it is a preclinical sign of cognitive decline that's been shown in a number of studies. My ongoing work right now is to better answer the question that you just asked. Right now, what we're doing is we are studying folks all across the cognitive spectrum. So, some of them are cognitively unimpaired, some have mild cognitive impairment, and some have been diagnosed with Alzheimer's disease. And we want to know are there specific scents or concentrations of specific scents that are correlated with these clinical outcomes? And we also want to know, are there patterns within those phenotypes of olfactory performance that also help us predict other things that are typically pretty resource-intense to figure out otherwise? So, that's like plasma biomarker status for Alzheimer's disease or other markers of brain and cognitive health, like hippocampal volume on MRI.

The other thing that we're interested in too is understanding how does olfactory performance predict how you're going to be doing in a couple of years, right? Because that's the real value. But if we can find some of these links and we have pilot data to support what we believe we're going to find in this study, the potential public health outcome is huge, right? Because if we can identify people early, especially now that we're in the era of amyloid-clearing medications, et cetera, you know, I always tell folks I'm about breakthroughs not bummers.

And so, we don't just want to have a way to diagnose a bummer earlier. But now, if we can say, "Hey, your profile predicts this, you probably want to get more evaluation and assessment so that you can be eligible for these earlier stage clinical trials, et cetera, that has real potential to move the whole needle when we think of Alzheimer's disease and related dementias."

Host: This might sound kind of funny, but is there something like smell therapy? Is there a way to get somebody who has a defect in olfaction to be able to sense smells. Can you train? What can you do for someone who has deficits in smell?

Jennifer Villwock, MD: There are a couple of options. The first is exactly what you mentioned in terms of training. The way that I think about it is if you recall, you know, people that are real into things like coffee or wine, et cetera, they train their sense of smell because there's such an intimate relationship between smell and taste. So, we know just from those occupational use cases that, yes, we can train our sense of smell to be better.

In individuals who have olfactory dysfunction, what we call that technique is olfactory training or olfactory retraining. It's very much the same process. It's typically a panel of odorants where you smell it, and you're consciously in your mind thinking, "Okay, this one says it's lemon." Even if you don't smell anything at all in your brain, you're like, "All right, brain, here it comes. This is lemon. This is lemon." And you're consciously reinforcing that component of your perception, and it always sounds like a little bit funny when I describe it to patients, but an analogy that seems to work well, particularly for those who have a viral cause of their olfactory loss. As I tell them, "Your system literally got a virus," we know that the hardware does continue to regenerate itself in terms of the olfactory system. Those nerves are unique that they can recover and they will. So, we just have to have faith that the hardware's going to be there. So, some people will do different oral supplements, et cetera, so that all those building blocks are present as the system is regenerating. So while the hardware is regenerating itself, we're also trying to upgrade the software, right? You need a system update, because something went wrong. And that's the role of olfactory training.

Now, that also is not a slam dunk, but it's very non-invasive. It's not a procedure, it's something that you just do at home. So for a lot of folks, there's not really anything to lose by trying this. And this is one of the things that we have the best data to support for its use.

Host: Well, Jennifer, this has been incredibly interesting. I think that we have a hole in our training. We don't get a lot of smell training in medical school or even as residents and fellows. It's so great to be able to hear that not only can we use the eye as a window on neurologic disease, but we should use smell as well.

So, thank you so much for taking the time to speak to us today. To learn more about research at University Hospitals, please visit uhhospitals.org/uhresearch. Thank you, Dr. Villwock.