Had COVID? Part of the Virus May Stick Around in Your Brain

If you or someone you know is experiencing "brain fog" after COVID-19, scientists now have a possible explanation — and it might not bring much comfort.

Researchers in Germany found that part of the virus, the spike protein, remains in the brain long after the virus clears out.

 

These investigators discovered the spike protein from the virus in brain tissue of animals and people after death. The finding suggests these virus fragments build up, stick around, and trigger inflammation that causes long COVID symptoms.

About 15% of COVID patients continue to have long-term effects of the infection despite their recovery, said senior study author Ali Ertürk, PhD, director of the Institute for Tissue Engineering and Regenerative Medicine at the Helmholtz Center Munich in Germany.

 

Reported neurological problems include brain fog, brain tissue loss, a decline in thinking abilities, and problems with memory, he said.

"These symptoms clearly suggest damages and long-term changes caused by SARS-CoV-2 in the brain, the exact molecular mechanisms of which are still poorly understood," Ertürk said.

 

The researchers also propose a way the spike protein can get into the brain in their preprint report published online before peer review April 5 on bioRxiv.

Delivered by circulating blood, the spike protein can stay inside small openings in the bone marrow of the skull called niches. It can also reside in the meninges, thin layers of cells that act as a buffer between the skull and the brain. From there, one theory goes, the spike protein uses channels to enter the brain itself.

The hope is researchers can develop treatments that block one or more steps in this process and help people avoid long COVID brain issues.

 

'Very Concerning'

"This is a very concerning report that literally demonstrates the SARS-CoV-2 spike protein in the skull-meninges-brain axis in postmortem individuals," said Eric Topol, MD, director of the Scripps Research Translational Institute in La Jolla, CA, and editor-in-chief of Medscape, WebMD's sister site for medical professionals.

Having the spike protein accumulate in structures right outside the brain and causing ongoing inflammation makes sense to Topol. The clustering of spike proteins would trigger an immune response from this niche reservoir of immune cells that cause the inflammation associated with long COVID and the symptoms such as brain fog, he said.

 

Problems with thinking and memory after COVID infection are relatively common. One research team found 22% of people with long COVID specifically reported this issue, on average, across 43 published studies. Even people who had mild COVID illness can develop brain fog later, Ertürk and colleagues note.

 

So why are researchers blaming the spike protein and not the whole COVID virus? As part of the study, they found SARS-CoV-2 virus RNA in some people after death and not in others, suggesting the virus does not need to be there to trigger brain fog. They also injected the spike protein directly into the brains of mice and showed it can cause cells to die.

Researchers also found no SARS-CoV-2 virus in the brain parenchyma, the functional tissue in the brain containing nerve cells and non-nerve (called glial) cells, but they did detect the spike protein there.

Surprising Findings

Investigators were surprised to find spike protein in the skull niches of people who survived COVID and died later from another cause. Ertürk, lead author and PhD student Zhouyi Rong, and their colleagues found spike protein in 10 of 34 skulls from people who died from non-COVID causes in 2021 and 2022.

 

They also found COVID can change how proteins act in and around the brain. Some of these proteins are linked to Parkinson's disease and Alzheimer's disease, but have never before been linked to the virus

Another unexpected finding was how close the findings were in mice and humans. There was a "remarkable similarity of distribution of the viral spike protein and dysregulated proteins identified in the mouse and human samples," Ertürk said.

Future Treatments?

Tests for protein changes in the skull or meninges would be invasive but possible compared to sampling the parenchyma inside the brain. Even less invasive would be testing blood samples for altered proteins that could identify people most at risk of developing brain complications after COVID illness.

It will take more brain science to get there. "Designing treatment strategies for these neurological symptoms requires an in-depth knowledge of molecules dysregulated by the virus in the brain tissues," Ertürk said.

The New Obesity Breakthrough Drugs

There are many holy grails in medicine, with failure after failure, like finding a way to prevent Alzheimer's disease or a non-invasive means for accurately measuring ambulatory blood pressure. But one of the biggest and most daunting has been finding drugs that can tackle obesity — achieving a substantial amount of weight loss without serious side effects. Many attempts to get there now fill a graveyard of failed drugs, such as fen-phen in the 1990s when a single small study of this drug combination in 121 people unleashed millions of prescriptions, some leading to serious heart valve lesions that resulted in withdrawal of the drug in 1995. The drug rimonabant, an endocannabinoid receptor blocker (think of blocking the munchies after marijuana) looked encouraging in randomized trials. However, subsequently, in a trial that I led of nearly 19,000 participants in 42 countries around the world, there was a significant excess of depression, neuropsychiatric side-effects and suicidal ideation which spelled the end of that drug's life.

 

In the United States, where there had not been an anti-obesity drug approved by the FDA since 2014, Wegovy (semaglutide), a once-weekly injection was approved in June 2021. The same drug, at a lower dose, is known as Ozempic (as in O-O-O, Ozempic, the ubiquitous commercial that you undoubtedly hear and see on TV) and had already been approved in January 2020 for improving glucose regulation in diabetes. The next drug on fast track at FDA to be imminently approved is tirzepatide (Mounjaro) following its approval for diabetes in May 2022. It is noteworthy that the discovery of these drugs for weight loss was serendipitous: they were being developed for improving glucose regulation and unexpectedly were found to achieve significant weight reduction.

Both semaglutide and tirzepatide underwent randomized, placebo-controlled trials for obesity, with marked reduction of weight as shown below. Tirzepatide at dose of 10 to 15 mg per week achieved >20% body weight reduction. Semaglutide at a dose of 2.4 mg achieved ~17% reduction. These per cent changes in body weight are 7-9 fold more than seen with placebo (2-3% reduction). Note: these levels of per cent body weight reduction resemble what is typically achieved with the different types of bariatric surgery, such as gastric bypass.

 

Another way to present the data for the 2 trials is shown here, with an edge for tirzepatide at high (10-15 mg) doses, extending to >25% body weight reduction.

 

 

The results with semaglutide were extended to teens in a randomized trial (as shown below), and a similar trial with tirzepatide is in progress.

 

How Do These Drugs Work?

 

These are peptides in the class of incretins, mimicking gut hormones that are secreted after food intake which stimulate insulin secretion.

 

These 2 drugs have in common long half-lives (~ 5 days), which affords once-weekly dosing, but have different mechanisms of action. Semaglutide activates (an agonist) the GLP-1 receptor, while tirzepatide is in a new class of dual agonists: it activates (mimics) both the GLP-1 receptor and GIP receptors (Gastric inhibit polypeptide is also known as glucose-dependent insulinotropic polypeptide.) The potency of activation for tirzepatide is 5-fold more for GIPR than GLP1. As seen below, there are body wide effects that include the brain, liver, pancreas, stomach, intestine, skeletal muscle and fat tissue. While their mode of action is somewhat different, their clinical effects are overlapping, which include enhancing satiety, delaying gastric emptying, increasing insulin and its sensitivity, decreasing glucagon, and, of course, reducing high glucose levels. The overlap extends to side effects of nausea, vomiting, abdominal pain, constipation and diarrhea. Yet only 4 to 6% of participants discontinued the drug in these trials, mostly owing to these GI side effects (and 1-2% in the placebo group discontinued the study drug for the same reasons).

In randomized trials among people with Type 2 diabetes, the drugs achieved HbA1c reduction of at least an absolute 2 percentage points which led to their FDA approvals (For semaglutide in January 2020, and for tirzepatide in May 2022). The edge that tirzepatide has exhibited for weight loss reduction may be related to its dual agonist role, but the enhancement via GIP receptor activation is not fully resolved (as seen below with GIP? designation). The Amgen drug in development (AMG-133) has a marked weight loss effect but inhibits GIP rather than mimics it, clouding our precise understanding of the mechanism.

 

The gut-brain regulation of food intake with the many gut hormones (including leptin, gherlin, PYY, amylin) and targets in the body and brain regions. From Muller et al, Nature Reviews Drug Discovery March 2022. 

Nevertheless, when the two drugs were directly compared in a randomized trial for improving glucose regulation, tirzepatide was superior to semaglutide, as shown below. Of note, both drugs achieved very favorable effects on lipids, reducing triglycerides, LDL and raising HDL cholesterol, along with reduction of blood pressure, an outgrowth of the indirect effect of weight reduction and direct metabolic effects of the drugs.

 

While there has been a concern about other side effects besides the GI ones noted above, review of all the trials to date in these classes of medication do not reinforce a risk of acute pancreatitis. Other rare side effects that have been noted with these drugs include allergic reactions, gallstones (which can occur with a large amount of weight loss), and potential of medullary thyroid cancer (so far only documented in rats, not people), which is why they are contraindicated in people with Type 2 multiple endocrine neoplasia syndrome.

How They Are Given and Practical Considerations

 

For semaglutide, which has FDA approval, the indication is a BMI of 30 kg/m2 or greater than 27 kg/m2 and a weight related medical condition (such as hypertension. hypercholesterolemia or diabetes). To reduce the GI side effects, which mainly occur in the early dose escalation period, semaglutide is given in increasing doses by a prefilled pen by self-injection under the skin (abdomen, thigh or arm) starting at 0.25 mg for a month and gradual increases each month reaching the maximum dose of 2.4 mg at month 5. The FDA label for dosing of tirzepatide has not been provided yet but in the weight loss trial there was a similar dose escalation from 2.5 mg up to 15 mg by month 5. The escalation is essential to reduce the frequent GI side effects, such as seen below in the tirzepatide trial.

 

Semaglutide is very expensive, ~$1500 per month, and not covered by Medicare. There are manufacturer starter coupons from Novo Nordisk, but that is just for the first month. These drugs have to be taken for a year to 18 months to have their full effect and without changes in lifestyle that are durable, it is likely that weight will be regained after stopping them.

What Does This Mean?

 

More than 650 million adults are obese and 13% of the 8 billion world's population (including over 340 million ages 5-18) is obese — that sums us to over 1 billion people. The global obesity epidemic has been relentless, worsening each year, and a driver of "diabesity," the combined dual epidemic. We now have a breakthrough class of drugs that can achieve profound weight loss equivalent to bariatric surgery, along with the side benefits of reducing cardiovascular risk factors (hypertension and hyperlipidemia), improving glucose regulation, reversing fatty liver, and the many detrimental long-term effects of obesity such as osteoarthritis and various cancers. That, in itself, is remarkable. Revolutionary.

 

But the downsides are also obvious. Self-injections, even though they are once a week, are not palatable for many. We have seen far more of these injectables in recent years such as the PCSK-9 inhibitors for hypercholesterolemia or the TNF blockers for autoimmune conditions. That still will not make them a popular item for such an enormous population of potential users.

That brings me to Rybelsus, the oral form of semaglutide, which is approved for glucose regulation improvement but not obesity. It effects for weight loss have been modest compared to Wegovy (5 to 8 pounds for the 7 and 14 mg dose, respectively). But the potential for the very high efficacy of an injectable to be achievable via a pill represents an important path going forward—it could help markedly reduce the cost and uptake.

The problem of discontinuation of the drugs is big, since there are limited data and the likelihood is that the weight will be regained unless there are substantial changes in lifestyle. We know how hard it is to durably achieve such changes, along with the undesirability (and uncertainty with respect to unknown side-effects) of having to take injectable drugs for many years, no less the cost of doing that.

The cost of these drugs will clearly and profoundly exacerbate inequities, since they are eminently affordable by the rich, but the need is extreme among the indigent. We've already seen celebrities take Wegovy for weight loss who are not obese, a window into how these drugs can and will be used without supportive data. As one physician recently observed, "Other than Viagra and Botox, I've seen no other medication so quickly become part of modern culture's social vernacular." Already there are concerns that such use is preventing access to the drugs for those who qualify and need them.

 

There are multiple agents in the class under development which should help increase competition and reduce cost, but they will remain expensive. There is private insurance reimbursement, often with a significant copay, for people who tightly fit the inclusion criteria. Eventual coverage by Medicare will markedly expand their use, and we can expect cost-effectiveness studies to be published showing how much saving there is for the drugs compared with bariatric surgery or not achieving the weight loss. But that doesn't change the cost at the societal level. Even as we've seen with generics, which will ultimately be available, the alleviation of the cost problem isn't what we'd hoped.

 

This is not unlike the recent triumphs of gene therapy, as in $3.5 million for a cure of hemophilia that just got FDA approval, but instead of a rare disease we are talking about the most common medical condition in the world. We finally get across the long sought after (what many would qualify as miraculous) goal line, but the economics collide with the uptake and real benefit.

 

These concerns can't be put aside in the health inequity-laden world we live in, that will unquestionably be exacerbated. However, we cannot miss that this represents one of the most important, biggest medical breakthroughs in history. This may signify the end or marked reduction in the need for bariatric surgery. These drugs will likely become some of the most prescribed of all medications in the upcoming years. While there are many drawbacks, we shouldn't miss such an extraordinary advance in medicine—the first real, potent and safe treatment of obesity.