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.

Some Diets Better Than Others for Heart Protection

A new analysis of randomized trials suggests that the Mediterranean diet and low-fat diets probably reduce the risk of death and nonfatal myocardial infarction (MI) in adults at increased risk for cardiovascular disease (CVD), while the Mediterranean diet also likely reduces the risk of stroke.

Five other popular diets appeared to have little or no benefit with regard to these outcomes.

"These findings with data presentations are extremely important for patients who are skeptical about the desirability of diet change," write the authors, led by Giorgio Karam, with University of Manitoba, Winnipeg, Canada.

The results were published online March 29 in The BMJ.

Dietary guidelines recommend various diets along with physical activity or other cointerventions for adults at increased CVD risk, but they are often based on low-certainty evidence from nonrandomized studies and on surrogate outcomes.

Several meta-analyses of randomized controlled trials with mortality and major CV outcomes have reported benefits of some dietary programs, but those studies did not use network meta-analysis to give absolute estimates and certainty of estimates for adults at intermediate and high risk, the authors note.

For this study, Karam and colleagues conducted a comprehensive systematic review and network meta-analysis in which they compared the effects of seven popular structured diets on mortality and CVD events for adults with CVD or CVD risk factors.

The seven diet plans were the Mediterranean, low fat, very low fat, modified fat, combined low fat and low sodium, Ornish, and Pritikin diets. Data for the analysis came from 40 randomized controlled trials that involved 35,548 participants who were followed for an average of 3 years.

There was evidence of "moderate" certainty that the Mediterranean diet was superior to minimal intervention for all-cause mortality (odds ratio [OR], 0.72), CV mortality (OR, 0.55), stroke (OR, 0.65), and nonfatal MI (OR, 0.48).

On an absolute basis (per 1000 over 5 years), the Mediterranean diet let to 17 fewer deaths from any cause, 13 fewer CV deaths, seven fewer strokes, and 17 fewer nonfatal MIs.

There was evidence of moderate certainty that a low-fat diet was superior to minimal intervention for prevention of all-cause mortality (OR, 0.84; nine fewer deaths per 1000) and nonfatal MI (OR, 0.77; seven fewer deaths per 1000). The low-fat diet had little to no benefit with regard to stroke reduction.

The Mediterranean diet was not "convincingly" superior to a low-fat diet for mortality or nonfatal MI, the authors note.

The absolute effects for the Mediterranean and low-fat diets were more pronounced in adults at high CVD risk. With the Mediterranean diet, there were 36 fewer all-cause deaths and 39 fewer CV deaths per 1000 over 5 years.

The five other dietary programs generally had "little or no benefit" compared with minimal intervention. The evidence was of low to moderate certainty.

The studies did not provide enough data to gauge the impact of the diets on angina, heart failure, peripheral vascular events, and atrial fibrillation.

The researchers say that strengths of their analysis include a comprehensive review and thorough literature search and a rigorous assessment of study bias. In addition, the researchers adhered to recognized GRADE methods for assessing the certainty of estimates.

Limitations of their work include not being able to measure adherence to dietary programs and the possibility that some of the benefits may have been due to other factors, such as drug treatment and support for quitting smoking.

The study had no specific funding. The authors have disclosed no relevant financial relationships. 

BMJ. Published online March 29, 2023. Full text