Allison Grossberg on Long-Covid and Brain Injury
Introduction
Chad Foster and Padmini Konidena interviewed Allison Grossberg in July 2022. They lightly edited the interview for clarity.
In this interview, Allison talks about her current study about long-Covid and its connection to brain injury. She discusses her personal history, the background of the study, a potential treatment option, the usefulness of biomarkers in long-Covid diagnosis and other applications, the difference between Covid and long-Covid patients, the connections between long-Covid and concussions, and general thoughts about the study’s importance.
Allison Grossberg is a Ph.D. candidate in the Cellular and Molecular Biology program at the University of Denver’s Knoebel Institute for Healthy Aging. Her research is focused on the systemic effects of traumatic brain injury, the interaction between brain injury and infection, and the relationship between traumatic brain injury and neurodegenerative disease.
For more information, read our page Long-Covid.
Interview
What is your current research investigating?
Chad Foster:
All right. So we have a couple of questions to ask you, but if you wanted to start off talking a bit about what you guys are doing [in your research study about long-Covid], that would be helpful for some background.
Allison Grossberg:
Yeah, that'd be great. We're currently running a longitudinal study on the long-term brain health effects of Covid-19 in individuals with and without traumatic brain injury.
Most of my work to date is on the systemic impacts of brain injury and how that relates to downstream neurodegeneration. Some of that work had to do with Lyme disease and brain injury and possible interactions there. And then, when the pandemic started, we were able to switch gears a bit.
I worked on an antibody study with a new serological test for Covid and we started really thinking Covid is actually really similar to Lyme disease in many ways. Maybe we can look at something similar and try to understand possible interactions between infection and brain injury.
So that's kind of the background of the study. The study itself, we hope will last five years. It's tricky to get participants to stick around for that long. So we'll see if we can manage the full five, but the idea is they come in for yearly study visits and do a series of tests with us.
We do a cognitive test called the Automated Neuropsychological Assessment Metric or the ANAM, which you might be familiar with. And then we run them through a very, very long questionnaire, which is demographics, detailed medical history, history of Covid, and Covid vaccination status. And then the history of traumatic brain injury.
Those sections are really similar, but essentially we're looking at symptoms and trying to get a sense of what symptoms patients had prior to brain injury or infection, during that acute period [early stage of illness] following injury or infection, and long-after illness/injury [chronic stage]. They also tell us about any treatments they underwent and things like that.
We also assess work-ability and functional outcomes. So how well can they actually participate in their lives? And then lots of questions on physical and mental health in there as well. And then we take blood samples and we do lots of cool stuff back in the lab with those. We look [look in the blood for] markers of brain health, markers associated with neurodegenerative disease, inflammatory cytokines, things like that.
We can also do something really cool where we isolate exosomes from the blood. And these are little vesicles [tiny, circular sacs that transport material in the body] that are shed by all cells in the body including brain cells. And so they actually pass through the blood-brain barrier and we can pull out vesicles that were excreted by a neuron or an astrocyte [both are cells in the brain]. And they're kind of like little packages. So inside are proteins or RNA species that tell us something about what's going on inside the brain. And then we're also looking at a bunch of markers of autoimmunity.
[With the study, the] only thing I left out was we have four groups: a healthy control group, folks without any history of Covid or brain injury; folks with only a history of brain injury, but no Covid; folks with only Covid and no brain injury; and individuals with a history of both.
Is there a relationship between brain injury and long-Covid?
Chad Foster:
That's super interesting. Wow. So I guess we can kind of get into one of our first questions. I think we'll start with this, does a history of brain injury increase the chances of long-Covid or are you guys seeing any relationship between the two?
Allison Grossberg:
Yeah, so that's a really good question. Unfortunately, I don't have a great answer for you. That sort of remains to be seen in our study. The literature on Covid certainly would suggest that many preexisting conditions do increase the risk for long-Covid. That’s still being actively studied, but brain injury should definitely not be ruled out in that context.
And then in our work with Lyme disease, we didn't have data to suggest if folks had brain injury prior to being infected with Lyme disease but we do see worse outcomes when individuals have both compared to one or the other. So certainly there's some interaction there that is increasing the risk for prolonged symptoms or the severity of those symptoms.
Is graduated exercise therapy recommended?
Padmini Konidena:
Okay. We're also interested in specific treatment methods. We have a couple of things that we've looked at for concussion patients. We’re specifically interested in graduated exercise therapy, which some places say they do recommend for Covid patients, some say they don’t. Have you looked into that at all?
Allison Grossberg:
We don't research much in the way of treatments, at least for now, on the Covid side of things. On the traumatic brain injury side of things, our lab primarily looks at antioxidant therapies, especially in nutraceutical compounds. These are compounds found in fruits and veggies that have really deep colors, if you think of blueberries or beets. These compounds can scavenge free radicals [highly reactive molecules that can harm the body in large amounts] in the brain. If there's a lot of inflammation [the antioxidant therapy] can really help.
And we do see after brain injury, which I suspect is also happening after Covid as well, chronic, I mean, literally, 20 years later, patients still have antioxidant depletion. So their endogenous [internal] antioxidant systems are not working properly and they have very high, chronic levels of inflammation. Those are the treatments that I'm most familiar with. The clinics that I work at do use those exercise therapies certainly, I've seen that.
There's been some suggestion of using immune modulatory meds, things that tamp down inflammatory processes. The tricky thing there is that inflammation is a really good thing acutely [in small amounts]. And with both injury and viral infection, the time course looks different for everyone. So variability really is the rule, not the exception. It's really hard to know when you would give someone a drug that would decrease inflammation.
So those are the things I'm most familiar with. We are hoping that through biomarker development, we might be able to kind of guess what a good treatment strategy would be, but I don't have any specific ones related to this study.
Can biomarkers help with diagnosis?
Chad Foster:
Thank you. Going off biomarkers, I'm glad you said that, are you able to use biomarkers to diagnose long-Covid or the extent of long-Covid? Because that was another one of our questions– how are we able to diagnose long-Covid when so many of these long-Covid symptoms can be explained by other illnesses? How do you know it's long-Covid and not something else?
Allison Grossberg:
Definitely. I think that's really tricky. his is such an active area of exploration, there isn't one good answer, but I think you have to break it down a little bit. The symptoms that patients experience following long-Covid might be related to peripheral nerve damage. Some might be related to nervous system involvement, like CNS [central nervous system, which includes the brain] involvement. Some could be completely outside of the realm of the nervous system.
So we look at biomarkers that we know are involved in brain injury. The idea is to compare and contrast and see if there's overlap. And then, of course, to better understand what's going on inflammation-wise. There are tons of cytokines and chemokines, and then [we want] to understand autoimmunity. Those are a panel that gives us a sense of blood-brain barrier disruption. So, are we getting the production of antibodies targeted against proteins from the brain?
The answer to your question is that there are no current biomarkers for long-Covid. When we try to actually look for those, the hope is that you can match a biomarker to a specific patient profile or a specific set of symptoms. Maybe the loss of smell or taste are specifically related to a marker of axonal degeneration or something like that. That's the hope.
There are a few FDA-approved biomarkers for traumatic brain injury, but they're primarily used not to diagnose a patient, but to tell them whether or not they should undergo further testing. And those are GFAP, UCH-L1, and NfL. Those are things we'll look at in relation to Covid to see if we're seeing any changes in those markers.
Chad Foster:
Interesting. Awesome.
Why is analyzing biomarkers important?
Padmini Konidena:
Would you mind explaining some more about why we need to use biomarkers, specifically cytokines, and chemokines, and why we need to read the information from exosomes in the brain?
Allison Grossberg:
Sure. You are probably familiar with cytokines [proteins that help regulate the immune system], maybe IL-6 [interleukin-6, a cytokine that controls inflammation] in the context of severe Covid infection. In patients who are hospitalized, they have this really strong inflammatory response to viral infection, and those cytokines do a lot of damage. And so you end up with basically your immune system kind of going haywire, and it's not really able to shut off. And then your own immune system is damaging your tissue.
What's not talked about as commonly, is that we see something really similar, just not as acute or as large of a response after brain injury and mild Covid. Essentially, what we think is happening is that brain injury kicks your immune system into a hyperactive state. We get the production of lots of pro-inflammatory cytokines that drive [increase] inflammation and then downregulation of anti-inflammatory cytokines that would bring the system back into balance.
And this, as I mentioned, we've seen this last in patients 20 plus years. So it's like a slow burn of inflammation over time. That's one of the primary hypotheses for why repeated concussions are increasing the risk for neurodegenerative disease.
With Covid, there are a couple of hypotheses, so you can think about Covid, mild Covid cases, kind of doing the same thing. The profile of inflammation looks really similar to what it looks like in brain injury. And that can be, you can imagine if someone primarily had respiratory symptoms, it could be systemic inflammation driving that, and then you've got this brain-body interaction. It could be actual brain inflammation, and there are many, many hypotheses there as well.
But in terms of the interaction between the two, if you have a brain injury, and then you end up with an infection that's impacting the brain, whether directly or because of systemic interaction, it's really similar to a multi-hit model. So it's almost like you've got a second brain injury because the molecular pathways getting turned on and the things going on in the brain are so similar to what happens after brain injury. So you can think of it kind of like that. Like if you get one brain injury and then a month later, another one, your immune system is already in this really active state. And then all of a sudden you're trying to repair and shut it down and you get hit again. If that happens, we don't know the exact mechanism, but it seems like then the immune system just can't really shut off and inflammation continues for years. [Inflammation is an adaptive response to this kind of secondary insult. The problem arises when normal processes that bring the body back into homeostasis are not functioning as they should and the body remains in that inflammatory state long-term.] And so Covid would be the same thing in that scenario. That would be like that second hit.
In terms of exosomes, they are a novel technology. [Exosomes are tiny, sealed vesicles (or sacs) in the body that carry around proteins, RNA, DNA, and more. They are helpful in looking at cell-to-cell communication and biological responses such as inflammation because they carry markers of these processes. The exosomes that were produced by brain cells can be purified by using protein markers on the surface that are specific to certain cell types.] The very cool thing is being able to compare a biomarker in peripheral circulation [within the body, except the brain] to that same biomarker inside of an exosome produced in the brain. So that kind of gives us a sense of what's actually going on peripherally [outside of the brain] or what molecules might be entering the bloodstream from the blood-brain barrier versus what molecules are actually involved in cell-to-cell communication in the brain.
The exosome technology has been called a liquid biopsy of the brain. And so it basically allows us to zoom in and see what's actually being communicated between neurons and astrocytes, or astrocytes and microglia [neurons, astrocytes, and microglia are all different cells in the brain]. And it's not just limited to proteins, like I said, we can look at RNA species and DNA as well.
Some papers have also reported the presence of viral particles in exosomes. So there are tons of biomarkers we can look at, that you can't really easily look at just with a blood sample.
How do Covid and long-Covid differ?
Chad Foster:
Right. That is super interesting. Okay. So we've talked a lot about how concussions or traumatic brain injury and long-Covid are looking similar. How do acute Covid, the initial phase of Covid, and long-Covid differ, neurologically? Are we seeing the same things in an acute infection of Covid that we see in these long-Covid patients?
Allison Grossberg:
I think that's a really good question. And it really varies depending on the severity of the infection. You see really different profiles depending on preexisting conditions in patients. So again, I don't know that there's a perfect answer to that question. Just in this study, I can tell you we've seen lots of different sorts of patient profiles. So you've got folks who, let's say they got Covid, they had a horrible headache for three days, and then it resolved and they were like, "Okay, guess that's it." And then over the next six months, they develop brain fog and chronic fatigue, and some of these other symptoms.
Or you might have people who have loss of taste or smell, and that's one of the first symptoms they notice. And then it just doesn't go away for months. You've got other people who have preexisting depression, let's say, they get Covid and then those symptoms just become really severe, not manageable at all. Or you could flip that. You've also got people who never had depression in their life. And then all of a sudden they have developed severe clinical depression after a bout of Covid.
So I think there are tons of different patient profiles in terms of where things sort of transition between acute and post-acute. And I think they're not always the same symptoms either. So people don't report always having headaches in the acute phase and then headache in the post-acute phase. Sometimes they kind of switch.
Chad Foster:
That's super interesting. Basically, you just can't generalize because every patient is unique and it's sort of similar to traumatic brain injury where every patient is unique.
Allison Grossberg:
Yeah, I do think there are... So in really severe cases, when you see things like stroke or hemorrhage or some of these more severe neurological manifestations those, I think, are most often reported in that acute phase. And that's most often in a really severe Covid case. And all of these things hold true for brain injury symptoms as well.
How is long-Covid more related to concussions rather than Covid?
Padmini Konidena:
Yeah. And kind of going off of that, how are concussions fitting into that? How did you all figure out that long-Covid is more similar to concussions rather than Covid and what are kind of the similarities that you're seeing?
Allison Grossberg:
Respiratory symptoms, like those seen in Covid (difficulty breathing, shortness of breath, cough, etc.) are not commonly reported following brain injury. But I think on the severe side of things, you can get similar brain effects in both brain injury and severe Covid. You can get things like stroke and seizure and hemorrhage and all of these things.
With brain injury, that's usually caused by the actual impact itself. Whereas in Covid it's some other systemic manifestation or inflammation. It's a little bit different. So I think the answer to your question is that long-Covid, especially in patients who have a mild infection, there's not typically a very specific physical pathology you can point to that says, "That's what's causing this specific symptom." And that's the case in brain injury as well.
The symptoms of long-Covid and protracted post-concussion syndrome symptoms are very similar, but they're often very vague symptoms that are common to many illnesses. What's striking is when you go to actually look at the molecular mechanisms at play, they are very, very similar. So you've got a lot of the same damage to neurons going on, the same kind of disruption to immune cells and inflammation, and so there is a lot of overlap between Covid and brain injury. (There is also going to be some overlap between brain injury and cases of severe Covid (in terms of neurological manifestations like brain bleeds, seizures, stroke, loss of consciousness, etc.). These typically occur acutely following infection/injury. The major overlap between Covid and brain injury is the protracted symptoms that a subpopulation of patients go on to develop after the acute stage of illness/injury. In the case of Covid, we have termed this condition "long-Covid" and in the case of brain injury many of these symptoms fall under "post-concussion syndrome" while others are just classified as "persistent post-concussive symptoms". These symptoms are generally non-specific (common to many diseases/illnesses/disorders), highly variable between patients, and can range from things like "brain fog" to muscle pain/weakness, to headache, to gastrointestinal symptoms, to depression and anxiety.)
What do you hope to find with this study?
Chad Foster:
So what are you guys hoping to find or predict to find throughout your research? Especially with helping develop effective treatment methods for these long-Covid clinics or physical therapy clinics?
Allison Grossberg:
My hope is that the data comparing Covid and brain injury will yield some really interesting results where maybe there is a biomarker where there's some overlap. That would mean it sort of fast tracks us a little bit because there are years of data on those biomarkers in brain injury. So I think that would be very interesting. And just by developing or sort of uncovering a biomarker like that, it tells you something about the mechanism at play, what's actually going on in the brain to cause changes or upregulation in that marker.
And so I think that would be really cool and I would expect things like GFAP [one of the FDA-approved biomarkers of brain injury] to be a biomarker like that. So something that we can basically say, in both of these conditions, there's sustained astrogliosis going on in the brain. [Astrogliosis is a brain defense mechanism involving a change in the number of astrocytes (cells in the brain) and in astrocytes’ structure and function to clean the brain of unwanted cells. This is important because when astrocytes switch to their reactive state (and don't switch back) they lose some of their normal function which is very important for clearing debris, repairing tissue, supporting neurogenesis, and regulating inflammation, the immune system, and the blood-brain barrier. Astrogliosis has also been noted in Covid-19 infection and CTE, among other neurodegenerative disorders. It may be harmful to the brain if prolonged, as seen with Alzheimer’s disease.] And we see that upregulated in these patients for five years and then my guess would be that that level is even higher in patients with both Covid and brain injury.
So I think the major hypothesis is biomarkers of inflammation and axonal degeneration and astrogliosis will be much worse in patients with both Covid and brain injury. And changes in those biomarker levels will relate to, hopefully, a specific set of symptoms, or just in general, worse outcomes.
Does Lyme disease fit into the study?
Padmini Konidena:
You mentioned that you did a study on Lyme disease, so how does that fit in with concussion and Covid? Are there any similarities between these?
Allison Grossberg:
So the Lyme disease study we did was something really, really similar to the one I just described to you with Covid except instead of Covid it was Lyme disease. Lyme disease is similar in some ways to Covid, so lots of inflammation in the body and the brain.
So patients with both Lyme disease and brain injury have worse outcomes, they report more psychological distress. They report a lot of cognitive symptoms that are much worse. We've got high levels of inflammatory cytokines. We've got disruption in endocrine systems [regulates biological processes through hormones]. So compared to individuals with Lyme disease and no brain injury and healthy controls, , these patients with a combined history of Lyme disease and brain injury have a worse outlook in terms of biomarkers and symptomology.
Chad Foster:
Wow. That's super interesting. And I guess in the future you could do Lyme disease and long-Covid as well. I'm sure those have some correlations.
Allison Grossberg:
Absolutely, yeah. Definitely.
Why is this study important?
Chad Foster:
And then I think just kind of to end it off, why is this study important to you and how do you see it helping the scientific community?
Allison Grossberg:
Gosh, well, I absolutely love the work I do. So for me, I think getting to really drive a study from the very beginning is just really neat. Because of how new Covid is, we've really gotten to do that here. So that's been just super cool to get to explore this as new information's coming out. And it feels very hopeful and relevant because it is new.
I love the combination of applied science and bench science. So working with real people and then being able to take that back to the lab and do some work on the molecular side. I think that combination, for me, is just really, really cool. I have degrees in both biology and psychology, so for me, bringing in things like cognitive testing and pairing that data with biomarker data is just really impactful.
And then overall, I think, I don't know that the results of this study will be groundbreaking. They won't be super mechanistic, but I do think it'll be one of the first studies of its kind. So if you go right now and look for studies on Covid and concussion there's null. Nothing.
So I think it's a really cool place to start. We can kind of bring up these big ideas. Is it autoimmunity? Is it inflammation? Which symptoms are similar? What is going on with different patient profiles? And so my hope is that this study actually just really brings up more questions than it does answers and helps other researchers to start really diving into the mechanisms at play here. Then they can go off and develop really cool treatments.
So it would be awesome to say, "We've developed this biomarker panel." But I think realistically this will probably be more like, "Well, here's some differences we found, maybe these biomarkers are worth looking into further." And then I just hope that sort of opens the flood gates for research in this area.
Chad Foster:
Totally. All right. I'm going to stop unless you have anything else, Padmini?
Padmini Konidena:
No. Thank you so much.