We sat down with neurologist Dr. William T. Hu who studies neurodegeneration and long COVID at Rutgers Institute of Health, for a discussion on how COVID works in the brain and what patients should know about brain health and COVID in the long term.
More than one in 10 people who catch COVID don’t fully recover. Symptoms persist, and doctors call that chronic condition “long COVID.” Those symptoms may include things from vertigo to hair loss to brain fog. And when it comes to brain health in particular, some studies have found that COVID infections are associated with brain shrinkage, altered brain structure, and an increased risk of developing Alzheimer’s.
Researchers, including Rutgers neurologist Dr. William T. Hu, have been investigating the links between COVID and Alzheimer’s. Hu’s team recently ran a recent study involving patients living with long COVID and brain fog, to better understand the behavior of the immune system both during the infection and months later.
Hu focuses his research on biomarkers related to Alzheimer’s disease, frontotemporal dementia, and long COVID. He has led several pioneering studies on the prevalence of neurodegenerative diseases in Asian and Pacific American populations. Read a Q&A with Hu below or watch the full interview here.
1. How do viruses like COVID-19 enter the brain?
Dr. William T. Hu: When [COVID-19] first hit back in 2020, I jumped into service, as [did] many of my colleagues. We started seeing people who had seizures and strokes and other forms of brain diseases that we eventually [grouped] under encephalitis. Then at the time, we asked the question, “Does the SARS-CoV-2 virus enter the brain?”
If it did, it was very, very hard to detect using available technology. What we’re able to see, and what others have reported, is that the virus is seen in the blood vessels in the brain. They likely enter the brain in small amounts and hide out in the brain cells or the inflammatory cells.
But just by using conventional techniques like RT PCR, we have a hard time seeing it. RT PCR [is the] PCR test that we initially used. It’s not to say it’s not there; it’s just that our available technology cannot confirm it.
[Beyond COVID-19], each virus will use different receptors, which are kind of like the little seats that the virus is right on, to get into a cell. Viruses need to get into our cells to replicate and to survive in a way. How they get in often determines where in the body they will go.
If the brain cells have these receptors, then the viruses are getting in. If the blood vessel wall cells have these receptors, then the virus can get into those cells. Of course, sometimes, there’s what we call a “broad leakage.” You’re very sick, and you’re not getting enough oxygen, your body is trying to save yourself, and this sacred barrier between the blood and the brain opens up. Then, a lot of things can get in. Once you get better, it may be very hard for things to get out.
2. Why do people with long COVID have lingering symptoms like brain fog or exhaustion?
Hu: We don’t quite know what causes the symptoms. From a clinical and scientific perspective, it’s very hard to draw a line between what we see in the laboratory [and] what people feel. Then again, we kind of use the association type of test: [For example] if we see something [and] you feel something, [and then] we see that thing get better [and] you get better. Then whatever we saw earlier was probably causing — or at least related to — what you were feeling.
“For people who have long COVID, the
key thing is to avoid getting [COVID] again.
That’s what we tell all our patients
and research participants.”
If we’re going to use that approach, then I think a lot of what our study showed is that people were feeling these brain fog symptoms because there was a lot of inflammatory change going on in the brain that was detectable in the spinal fluid.
3. What is the role of inflammation in long COVID?
Hu: Inflammation is what we call the triple-edged sword. We used to think it was a double edge: it can help, and it can hurt. But over the past 20 years, we really have come to understand that inflammatory proteins, the little proteins that are secreted between inflammatory cells, can actually help neurons process, survive, and do other activities.
It seems that our brain, at some point in time, thousands [of years] or millennia ago, hijacked the immune system to also serve…our thinking [and] speed up our processing. Whenever there is a brain infection or a brain inflammatory event, not only are the inflammatory cells hurting your neurons — these little chemicals that are released can be altering the people’s thinking and processing, so that itself may be a side effect or bystander effect of inflammation in the brain that can cause brain fog.
4. Are there any medications or treatments that help with long COVID?
Hu: A lot of times, scientists are very good at observing a problem— we’re not very good at solving the problem. Once we found the evidence that the spinal fluid is [telling] us that there’s still a virus going on, then we started to look to see whether better prognosis or recovery over time is associated with a particular subtype.
What we’re able to find in people who subsequently recovered is that they mounted a very effective interferon response. Whereas the people didn’t recover, they’re, in a way, still struggling to get their interferons applied to fight infection. Following that, what we propose is that some sort of antiviral therapy should really be considered whether to suppress the virus by itself or enhance the body’s natural antiviral processes through interferon to clear the virus.
Many people have heard about the Paxlovid trial, and in long COVID, it does not seem to have helped. That is probably not going to be the solution. In China, some scientists are using HIV medications again, along with the antiviral therapy approach, and we’re waiting to hear the findings.
There are many forms of interferon, interferon-alpha, interferon-gamma, and interferon-lambda, that are already being tested in multiple groups of diseases other than COVID-19. Interferon lambda itself has been found to be effective in acute COVID-19. I believe a clinical trial using these interferons is the next logical step.
5. Are there any myths about long COVID that you want to dispel?
Hu: There are so many myths that it’s hard to pick one. I think I may have to settle on two. One is something that many of us use: “It’s just depression or anxiety.” We know it’s not both from a molecular perspective but also from a statistical perspective when we study the symptoms each person has.
The other [myth] is very similar to what many people with myalgic encephalitis have experienced, which is that rehabilitation or therapies will get you out of long COVID. Very often, it actually makes symptoms worse. We don’t tell people with chronic HIV or chronic hepatitis to go to rehab to get rid of the viruses. So, why do we tell people long COVID to do that? I think those are important questions the medical community and the medical establishment will have to answer.
6. What is your advice for living with long COVID?
Hu: The only thing that we found effective is pacing. Again, this is something that we borrow from the folks living with chronic fatigue syndrome, which is that you have to reduce the amount of what you expect to do on a daily basis. [This is] so that you give your body a chance to recover in the long run.
“We don’t tell people with chronic HIV
or chronic hepatitis to go to rehab to get
rid of the viruses. So, why do we tell
people long COVID to do that? I think
those are important questions the
medical community and the medical
establishment will have to answer.”
Often it is a struggle because some people feel better one day, and they feel they can do more, but then they end up very often paying a price the day after or even three days after. If people living with long COVID [are] able to reduce their amount of activity — we aim for something in the 60- to 80-percent range. You know what you can do, but you know what your body can handle — lower that a little bit, and then see how today goes.
[Chronic fatigue and brain fog] both come hand in hand. The other symptoms that we haven’t talked about include headaches and lightheadedness, which are not always, at least clinically, associated with POTS and are difficult to explain, but they tend to go hand in hand. When they get better, they all get better. When they don’t get better, none of them really improves.
7. What have we learned about COVID-19 in the past four years in terms of whether it contributes to Alzheimer’s risk?
Hu: There are three ways to answer that question. Number one is: does acute [COVID-19] lead to acute Alzheimer’s-type changes? There were some early studies in the blood that seemed to suggest that, which led us to really ask the question: can we go deeper? Can we use more accurate markers to see if long COVID can be explained in some way by the Alzheimer’s marker changes? The answer is no. I think it was a fairly convincing “No” that we no longer believe that [COVID-19], either in an acute form or long COVID form, will lead to sudden Alzheimer’s type of changes— even if the symptoms of long COVID and Alzheimer’s disease can be similar to outsiders.
Number two is: In the long term, does having [COVID-19] or long COVID increase your future risk for Alzheimer’s disease? That we don’t know yet. That is something that we continue to follow some people over time who’ve experienced long COVID — some of whom have gotten better, others have not — to see whether there’s a difference in future risk for Alzheimer’s disease. The answer to that question probably won’t be apparent for another five to 10 years.
“Then there’s a final group of people who
are very interesting to us:
They’re the people who already have
some brain changes of Alzheimer’s
disease that, without [COVID], likely
wouldn’t have been symptomatic yet.”
Then there’s a final group of people who are very interesting to us: They’re the people who already have some brain changes of Alzheimer’s disease that, without [COVID], likely wouldn’t have been symptomatic yet. They will be what’s called the asymptomatic or pre-symptomatic Alzheimer’s disease stage. Then, because of [COVID-19], or even sometimes because of other infections and hospitalizations, their brain disease starts to manifest outwardly. We think that studying this group of people may help us address some of the answers in the meantime as to whether long COVID or [COVID-19] causes a future increase in Alzheimer’s disease risks.
8. What is the impact of multiple infections and strains of COVID-19 on long COVID?
Hu: These are questions we ask ourselves every day. It’s been very challenging to understand the impact of multiple infections because of the lack of testing and the lack of specificity regarding the strain. Most of what we can do is guess the strain according to when somebody got sick. We don’t have confirmation of exactly what strain it was, and so there’s a little bit of a leap of faith there to better understand it.
At some point in time, people thought that if clearing infection is key, maybe when you have another dose of SARS-CoV-2, your body can jump into action and clear the virus. That has not turned out to be the case.
If your immune system is not able to do the first time, it doesn’t seem able to do the second time. For people who have long COVID, the key thing is to avoid getting [COVID] again. That’s what we tell all our patients and research participants.