Long COVID and Its Effect on Cognition

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer’s disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer’s disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Today I’m joined by Dr. Jim Jackson, a research professor at Vanderbilt University. Dr. Jackson is the director of behavioral health of the ICU Recovery Center and the lead psychologist for the Critical Illness, Brain Dysfunction and Survivorship Center at Vanderbilt. His work typically focuses on chronic illness and Post-Intensive Care Syndrome (PICS), but, after seeing how COVID-19 was affecting individuals long-term, he has shifted to studying the effects of long COVID on the brain. Since then, he’s been working on numerous studies surrounding long COVID and has published a book, Clearing the Fog: From Surviving to Thriving with Long COVID. Dr. Jackson, welcome to Dementia Matters.

Dr. Jim Jackson: Dementia does matter, and it's really great to be with you today. Thank you.

Chin: And I know you're able to speak to this whole spectrum, but for our purposes today, let's speak to the older adult. So, to begin, what got you into the field of critical illness, and then what led to you studying long COVID, especially its effects on cognition?
Jackson: You know, it's such an interesting question. I have a lot of mentees, like you may, that I interact with, and they talk about career development, and they often talk about it like it's a linear path. But I think it's anything but a linear path, and I think sometimes you just find yourself in a place, and there's a lot of serendipity, and good things happen. For me, that's really my story. I came to the Vanderbilt VA Psychology Consortium from a school in California. I had a lot of interest in neuropsychology and rehabilitation, health psychology, etc. During that year, I met a man who's now become a close friend and colleague, Wes Ely. He was a few years older than I, a few years farther in his development, and he had this idea that—he's an intensive care doctor—he had this idea that intensive care patients were perhaps surviving the ICU, and medically they were perhaps fine but cognitively they perhaps were anything but fine. He wanted to study that and I just happened to be the psychologist that was kind of in the room. It was really that simple. I liked him, he liked me, and he said, "Would you like a job? We'll pay you $50,000," which, in 2001, seemed like a lot of money. And I said, "Sold!" It was that simple, and the timing was good. So much of success, I think, is about timing, and we just happened to be kind of on the tip of the spear. We were the first people, really, among a few others, asking these questions about cognitive outcomes after debilitating critical illness. There was a colleague, a close friend of mine, Dr. Mona Hopkins from Brigham Young. We were the only ones, she and I and Wes, and it was really a situation where we pulled a string and the story started to really unravel. We began to really understand—not surprisingly now—that critical illness–being on a ventilator, having issues with delirium, having enough sedatives to knock a horse out–we began to understand that that, along with inflammation, was harmful to the brain. In those days, people didn't believe it. I worked as an expert witness occasionally on cases, and the opposing psychologist would say things like, "I don't think sepsis really is harmful to the brain. I don't really think critical illness is harmful to the brain." Of course now we know it's incredibly deleterious to the brain, and so that's really my background. That's my story.

Chin: So luck and timing. I have a lot of professors and mentees come on the show, Jim, and I'll say they echo some of your sentiments. But I think an important ingredient is your willingness and ability to take on the next challenge. And so, your willingness to say yes.

Jackson: You've got to be willing to jump in the deep end of the pool, right? And I did. In the early days, we would start these studies, and Wes–Wes Ely, Dr. Ely–would say, "Jim, do you know how to do X Y Z? Do you know how to put a battery together? Do you know how to do a cognitive assessment for mild cognitive impairment?" I would say yes, and then I'd run to my office, I’d find someone on PubMed, I would call them on the phone, and they would tell me. I'm being a little self-deprecating, but it was a lot like this. I think your point is right. You have to be willing and you've got to do the work, right? You've got to do the work and it's hard work, but it's really gratifying. Our goal in research has been to impact the lives of people, even those we never meet, right? And that idea—that you can perhaps transform some aspects of medicine or generate some new knowledge that is not only going to help people in your immediate sphere but that it is going to impact people around the world that you've never met—that's animating and motivating, and that gets me out of bed every morning.

Chin: Well I think that relates to COVID, so let's talk about long COVID. Before you tell us about your work and the things you're seeing, can you give a brief description of what exactly is long COVID?

Jackson: It's a great question. It's difficult to define; there are different definitions that people use, but you know it when you see it. In general, it is this idea that someone has had an acute illness, and that acute illness, of course, is COVID, and on the heels of that, they develop brand new problems they didn't have before. Those problems are persisting—that's why we call it long COVID. Typically, when we think of long COVID, those problems are persisting for two months or three months, four months—something like that. They haven't gone away. They may not be getting worse, but they haven't gone away. And that, in effect, is long COVID. It's a little bit hard to talk about long COVID because often we talk about it as if it is a thing—as if it is a single thing. The problem, I think, is it's a multi-faceted, complex thing. It's a lot of things. For instance, we see some people with long COVID–in quotes “long COVID”–they have cognitive problems only. Some people have fatigue only. Some people have mental health challenges only, balance problems only. Some people have the whole shebang and everything in between. We have some limitations, I think, to the language, to the term long COVID. It's not very scientific. I think an equal challenge exists with the term brain fog, which people kick around a lot, right? I think if you went to a medical center, whether it is the excellent University of Wisconsin Medical Center or Vanderbilt or wherever it would be, and find 10 neurologists, ask them how to define brain fog, you're going to get about eight and a half different answers. Whether it's long COVID or brain fog, we need a little more precision.

Chin: Well, given the work you do in post-acute illness, does long COVID present itself similarly to these other diseases and, if so, how? Or how is it different?

Jackson: I think it's quite similar, and you know, this is hotly debated: is it completely new? Is it some version of things that we've seen before in terms of how it presents? It’s hotly debated. I think what's unappreciated a lot is the idea that there are a lot of acute illnesses. There are a lot of post-viral syndromes that do have cognitive consequences. They present with cognitive challenges. If we take the flu, for instance–if we look at the flu, we've studied people who have been hospitalized with the flu, and in some cases, in the ICU with the flu. Not surprisingly to me, maybe surprisingly to some of your guests—or some of your listeners, rather—but not surprisingly to me, people after the flu often have persistent cognitive problems. Now they're usually fairly mild, often they go away, but that happens after the flu. That happens after being hospitalized without the flu in some cases, right? It happens to so many people. Sometimes it's a function of actual neurologic phenomena at work; sometimes it's a function of the impact of anxiety and depression on cognition, right, which can masquerade as a brain injury, let's say, and sometimes it's due to the effects of things like inflammation. I'm not sure long COVID is as different in the cognitive arena as people think. I think it's pretty similar to other things.

Chin: And those other things—in your book, you talk about potentially a similarity with chronic fatigue syndrome, which I think many people know, and, of course in our neck of the woods, Lyme disease or having these persistent symptoms after Lyme. Do you feel like there is a shared underlying mechanism or process, and is that inflammation?

Jackson: Yeah, I think that's right. I think it likely is inflammation, and the clinical presentation is certainly the same. It's interesting. I get a lot of emails—well, I got a lot of emails before writing the book, but since writing the book, I mean, they just come. You know, they just come. I got one not long ago from someone who said they really loved the book, and I was encouraged and all of that, and they said, "You know, I never had COVID. I had Lyme disease." And so, I think a lot of the people that have been impacted by the book are people with chronic illness that may not have been COVID necessarily, may not have been long COVID—long Lyme, chronic fatigue—but the presentations are so similar. They're really similar in some ways to brain injuries in that, as you know, dementia percolates slowly, right? It kind of develops slowly over time. Usually, if we think of Alzheimer's disease it's a problem of memory before it is anything else. When you look at the cognitive issues and the patterns of long COVID, it's not a slow burn. It is quite abrupt. Often there is some improvement that doesn't tend to involve memory as much as it involves attention, processing speed and some executive functioning. I think the Alzheimer's analogy exists in some older, frail, vulnerable patients that we see who likely already had a candle that was lit, if you will. That problem is accelerated greatly but brain injuries are a great model for what happens to long COVID patients cognitively.

Chin: Jim, that was my next question. This idea of what are the common symptoms when it comes to cognition that go with long COVID. You just mentioned some of the cognitive domains, and if there are others, please share with us, especially for the older adult. What do people tend to present with or notice when it comes to their thinking ability?
Jackson: If you remember, and I'm dating myself here, but when the war in Iraq unfolded—of course, I work at the VA a bit, so I'm familiar with all of this—eople started talking about TBI, mTBI, being the signature injury of the war in Iraq, and indeed it probably was. I think one of the signature injuries, if we want to use that language, of long COVID is deficits, in particular, in processing speed and attention. Those are the areas where, when we do cognitive testing, when we really drill down, people are most reliably affected and impaired. What’s confusing often is, when patients come to see you—and of course this isn't unique to long COVID—they complain of memory problems, right? It can throw you off a little bit, especially if you're an internist or in primary care because you may not be quite as savvy in this neurologic space. While people are being sincere, they’re conflating memory with what I would call processing speed or what I would call attention. When we drill down, we don't see a lot of amnestic deficits in people per se; we see some working memory deficits, and when people get cognitive rehab—as so many of our patients do for deficits in attention and processing speed—they usually do so much better, and that's been one really encouraging finding during this hard season.

Chin: When you mention inflammation, and even a similarity with traumatic brain injury, do we know the underlying mechanism or how exactly long COVID is damaging the brain, or if it's permanently damaging the brain or not?

Jackson: I'm not sure we know exactly what the underlying mechanism is. In our ICU survivors who had COVID, it's a little more straightforward to understand. That is, in the first wave if you recall there were people so critically ill, so many—a lot of them dying, a lot of them surviving but in the hospital for sixty days, eighty days. One of our patients, her husband was in the ICU for literally like two hundred days. When that happened, early in 2020, maybe 2021, the mechanisms are obvious there. They often had sepsis. They often were on a ventilator for a long period of time. They had hypoxic injuries that were pretty straightforward. For the patients with COVID who were never really sick, right, who developed long COVID, I'm certainly not understanding with much precision what those mechanisms are. I think it's a little bit mysterious still, and we need to obviously figure that out.
Chin: Have you noticed a difference in how long COVID affects women versus men, or different racial groups, or just different backgrounds when it comes to older adults?

Jackson: Yeah, certainly. We have found that our older patients are much more vulnerable to cognitive insults than our younger ones are. I think that fits just generally with what we know about cognitive reserve and the idea that our patients in the sixth or seventh or maybe especially the eighth decade of life, they've got much diminished reserve, right? They're a lot more vulnerable. We definitely see some unique challenges in them. We do see far more women than men who are attending our support groups, attending our clinics, reporting cognitive challenges. I don't know if that's because there are any deficits fundamentally or whether it's simply because, as a general rule, many of the women that we see are somewhat more open to reporting symptoms than a lot of the men that we see.

Chin: And have you seen any differences in racial backgrounds across the U.S.?
Jackson: We haven't seen a lot of differences in terms of symptom presentation per se. I think in terms of treatment and in terms of access, we certainly have seen some differences. You know, certainly in some minority communities where they might not be as resource-rich as we would hope they would be, access is a challenge. Certainly in rural America, access is a big challenge. I was on a podcast not long ago in Michigan. It was about rural healthcare, and we talked about the unique, particular and really widespread difficulties people in rural America have finding a long COVID clinic. There are a hundred-and-some-odd long COVID clinics in the United States, so that's fantastic, but there are some predominantly rural states that don't have one at all and there are some large states where there may be one and it's two hundred miles away. This is a really big problem. Along with a related problem, which is even pretty sophisticated healthcare consumers who have COVID, they don't know what a neuropsychologist is, right? They don't understand the difference between a neuropsychologist and a neurologist. They have no idea what a speech-language pathologist is. So when we're making some of these recommendations to them, gosh, they have no idea where to turn. If we're not making them, unfortunately, nobody else very often is. You know, help’s available, but people don't know how to pursue it, and that's a sad reality.

Chin: One of the things you bring up in your book, and you mentioned it earlier in our conversation, is this idea of rehab or cognitive rehabilitation. What exactly is that? Can you explain that for our listeners, and then what's the difference between the various forms that might be available?

Jackson: Sure. It bothers me to no end, actually, that very often the only people that get cognitive rehab are people who may have had a stroke, people who may have had an obvious traumatic brain injury, when there are so many medical conditions that involve cognitive challenges, which I think could get better with rehab—lupus, multiple sclerosis. I could go down the list. Typically, when I think of cognitive rehab, I think of a Barbara Wilson-driven, compensatory, strategic-based approach, where someone is going to teach you some tools. They are going to give you a way of thinking about taking on challenges you didn't have before. That could involve reminders; it could involve the integration of strategies; it could involve mindfulness and a lot of things. It's not cognitive rehab positing that your brain is going to improve fundamentally—not this approach—but your function hopefully will improve because you're engaging problems in a different way. The method I’m a big fan of is called goal management training, validated for the treatment of attention and executive dysfunction. That's not the only approach. That contrasts–compensatory, strategic-based approaches contrasts–with more neuroplasticity-based approaches, and those, as you know, are pretty controversial. You've got true believers on both sides. Some people who think brain games–that term is used very derisively–some people who think brain games are a sham and a waste of time. Some people, of course, who think that they're the best thing since sliced bread. The truth is probably in the middle. When we engage people on computerized video games, things of that sort, some of them—not all of them—anecdotally at least report that those games help tremendously. So they're in our armamentarium. Do they work all the time? They don’t. Do they help some people? They seem to.

Chin: Thank you for actually breaking that down and splitting the two, because whenever you hear cognitive rehab in general, in my experience working with neuropsychologists, there's always a little bit of a bristle. I'm never sure what the response is going to be. Seeing the two different types and how one might be more controversial than the other is helpful. Certainly being able to help people’s strategies improve their function seems very worthwhile. In your book, you talk about the CONTACT trial. Is that speaking to this idea of neuroplasticity, or what exactly happened in this study?

Jackson: We're in the process of analyzing the results, and I actually can't talk about those before we've publicly discussed them. The CONTACT trial is explicitly based on a neuroplasticity-friendly approach. There's a company called Akili, and  they have designed a video game, essentially. It's FDA-approved for kids and teens with ADD and ADHD, and seems to improve attention in that cohort. There's some evidence to support that, and so we're interested in the proposition that it could impact cognition in adults. If you imagine that the symptoms in long COVID are not that unlike ADD or ADHD, I think it follows that treatments for ADD and ADHD could be effective. I think that's why pharmacologically—and again, I’m not recommending this, I’m just reporting—pharmacologically, there are neurologists and psychiatrists you'll find around the country who do prescribe Adderall, who prescribe Ritalin, and in particular, the one that is probably talked about the most widely is guanfacine. There's a really nice case series that was published by some folks at Yale, probably six or eight months ago, looking at the effects of guanfacine on cognition in long COVID patients. Again, not a randomized trial, a lot of limitations, but for many it seemed to be effective. I think the narrative here, Nate, is just that in the cognitive realm, at least, there are some things that seem to help. There's an overarching long COVID narrative, which is, "We don't have any treatments, nothing we can do," and that's a lot less hopeful than I want to be. In the cognitive arena, there are some things that seem very helpful for some people, and that's good news in my mind.
Chin: Well, I appreciate you. I understand you can't share any of your data, but at least it's helpful for our listeners and for me to know. I mean, this is the point of clinical trials and the point of research—to explore these things that might help people. It takes time, and unfortunately, I know people want things to happen right now, but it will take time. We look forward to hearing the results of your study.

Jackson: Yeah, thank you. Yeah, I think what it underscores—I mean, people are really desperate. They are so desperate, and it's really sad in that context that there are some really bad actors who’ve taken advantage of that. I was quoted in an article, I don't know, a month or so ago, about a gentleman who claimed to have some drug that would create kind of a COVID force field. You know, you take it, and you couldn't get COVID, couldn't possibly get COVID. Sensible people, at the end of the day, fall prey to some of this because they're so desperate, and I think that's why it's important to say you don't need to resort to that. There are some actual methodologies—we've just described them—that for some people in the cognitive arena really seem to help. I think it's important to note physical symptoms are a problem, loss of taste and smell—those are a problem, fatigue’s a problem. But many people would rank-order cognitive functioning as the very highest, right? That domain where impairment really is hard to deal with, that’s a domain where improvement is realistic.
Chin: Speaking about the other ailments that people might experience—do you find that older adults with long COVID tend to deal with other medical issues that could be linked to thinking change, mild cognitive impairment? Of course, I'm thinking about mental health and thinking about those declines in attention or just the overall fatigue. Do you see older adults responding differently?

Jackson: Yeah, I would say one thing that is true of older adults that works in their favor, I think, is many of them are somewhat more resilient by virtue of the hard life experiences that they've had. I think what is especially hard in the case of long COVID is we see people, often 25, 30, 40, 45, in the prime of life, no comorbidities, no medical challenges, nothing. For them, it's really like they've just been hit by a freight train, right? They have no context for anything. Many of our older patients—they've already battled cancer and survived it; they've been in the ICU; perhaps they've had a heart attack or two; maybe they've lost their spouse. It isn't that that isn't sad, but it is that, in some strange way, those losses have prepared them for the idea that, hey, life is really hard. I think for some of our previously healthy people, COVID catches them off guard a lot more than these folks who already have some skins on the wall with regard to medical problems.

Chin: Well, I guess to end today, Jim, what’s the next steps in the field in understanding long COVID and cognitive change?
Jackson: Yeah, I think there are so many next steps. From a systemic standpoint, I think one next step is we need to do a much better job integrating neuropsychology into the care of medically ill patients. I think neuropsychologists, in some ways, are uniquely qualified to operate at the intersection here of cognitive and medical health, and I wish there were more of us to be involved here. There needs to be more integration, so system-wide that’s true for neuropsychology. It’s true for speech and language pathology for sure. I think understanding the mechanisms, as we alluded, is really important. I think the better we understand the mechanisms, obviously, the better we're going to be able to develop treatments. I think figuring out how to scale cognitive rehab so that it is available to large numbers of people—I think that's really important. I think trying to better understand what the link is between mental health and cognition in our patients is also important. We certainly have seen some cases where people had pretty profound cognitive impairment after long COVID; they also had depression and anxiety. As that depression and anxiety got treated, if you will, then the cognition improved. So there's a lot to do, right? I love to smoke meat here in Tennessee, and there's a saying: there's a lot of meat on the bone. And there is a lot of meat on the bone when it comes to the work that we need to do. If any of your listeners are interested in kind of joining arms with me and with us here at Vanderbilt, I'd be delighted if they reached out to me. If they want to buy a copy of my book and engage with me around it, nothing would make me more happy. I'm really here to serve, so I hope I hear from some of your folks.
Chin: Well, thank you, Jim. I appreciate having you on the Dementia Matters podcast. You certainly—these next steps are a lot, but they are needed, and I certainly hope we are moving in that direction. But thank you again, and we hope to have you on in the future.

Jackson: Yeah, keep up the good work. Thank you.

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