Long Covid ‘brain fog’ could be due to leaky blood-brain barrier, study shows

From forgetfulness to concentration problems, many people with long-term Covid-19 experience ‘brain fog’. Now researchers say the symptom may be due to a breach of the blood-brain barrier.

The barrier determines which substances or materials enter and leave the brain. “It’s all about regulating the balance between material in the blood and that in the brain,” says Prof. Matthew Campbell, co-author of the study from Trinity College Dublin.

“If that’s out of balance, it can trigger changes in neural function, and if this happens in areas of the brain that allow for memory consolidation/storage, it can wreak havoc.”

Writing in the journal Nature NeuroscienceCampbell and colleagues report how they analyzed serum and plasma samples from 76 patients hospitalized with Covid in March or April 2020, as well as from 25 people before the pandemic.

Among other things, the team found that samples from the 14 Covid patients who had self-reported brain fog contained higher levels of a protein called S100β than those from Covid patients without this symptom, or people who had not had Covid.

This protein is produced by cells in the brain and is not normally found in the blood, indicating that the blood-brain barrier has been broken down in these patients.

The researchers then recruited 10 people who had recovered from Covid and 22 people with long Covid-19 – 11 of whom reported having brain fog. No one had received a Covid vaccine or been hospitalized for Covid at the time.

These participants underwent an MRI scan during which a dye was administered intravenously.

The results show that long-term Covid patients with brain fog did indeed show signs of a leaky blood-brain barrier, but not those without this symptom, or who had recovered.

Campbell added that it is possible that people with a tighter blood-brain barrier are better protected against brain fog if they develop a long Covid-19 bout, explaining why the symptom does not occur in all patients.

Further research in a subset of participants found that long-term Covid patients with brain fog also showed signs of increased levels of proteins involved in clotting.

Campbell added that the results are not a surprise, because disruptions to proteins involved in clotting can go hand in hand with disruption to cells that line blood vessels. “The whole concept that many of these neurological disorders, including brain fog, can be treated by simply regulating the integrity of the blood-brain barrier is really exciting,” he said.

Although the study focuses on long Covid patients, Campbell said the results could be relevant to people with brain fog linked to other conditions – such as ME – although extensive work would be needed to confirm that.

Prof. Paul Harrison of the University of Oxford, an author of previous work, suggests blood clots in the brain may be a cause of brain fog in people with long Covid, said the new study is important.

“It shows that abnormalities in the lining of the blood vessels in the brain occur in people with brain fog after Covid-19, and adds to the evidence that abnormal blood clotting also contributes,” he said.

But he added that the results come from patients who had Covid during the first wave, meaning it is plausible but unclear whether the same mechanisms occur in others, such as those with later variants of the virus, or those who have been vaccinated.

Harrison said: “A range of processes likely explain brain fog and other features of post-Covid syndrome.”

Prof Claire Steves from King’s College London added that the small number of participants involved means it is possible that the differences between groups are due to chance, while brain fog was not clearly defined and was self-reported by participants.

“It is therefore difficult to be sure how applicable these results are to the millions of people who have experienced this phenomenon,” she said.