From forgetfulness to difficulties concentrating, many people who have long Covid experience “brain fog”. Now researchers say the symptom could be down to the blood-brain barrier becoming leaky.

The barrier controls which substances or materials enter and exit the brain. “It’s all about regulating a balance of material in blood compared to brain,” said Prof Matthew Campbell, co-author of the research at Trinity College Dublin.

“If that is off balance then it can drive changes in neural function and if this happens in brain regions that allow for memory consolidation/storage then it can wreak havoc.”

Writing in the journal Nature Neuroscience, Campbell and colleagues report how they analysed serum and plasma samples from 76 patients who were hospitalised with Covid in March or April 2020, as well 25 people before the pandemic.

Among other findings, the team discovered that samples from the 14 Covid patients who 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 within the brain, and is not normally found in the blood, suggesting these patients had a breakdown of the blood-brain barrier.

The researchers then recruited 10 people who had recovered from Covid and 22 people with long Covid – 11 of whom reported having brain fog. None had, at that point, received a Covid vaccine, or been hospitalised for Covid.

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

The results reveal long 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 was possible people with a tighter blood-brain barrier might be better protected from brain fog should they develop long Covid, explaining why the symptom did not arise in all patients.

Further work in a subgroup of participants revealed long Covid patients with brain fog also showed signs of increased levels of proteins involved in clotting.

Campbell said the results were not a surprise as disruptions to proteins involved in clotting could go hand in hand with disruption to cells that lined blood vessels. “The whole concept that a lot of these neurological conditions, including brain fog, could be treated by simply regulating the integrity of the blood-brain barrier is really exciting,” he said.

While the study focuses on long Covid patients, Campbell said the results might have relevance to people with brain fog relating to other conditions – such as ME – although extensive work would be needed to confirm that.

Prof Paul Harrison from the University of Oxford, an author of earlier work suggesting blood clots in the brain may be one cause of brain fog in people with long Covid, said the new study was important.

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

But he added that the results came from patients who had Covid in the first wave, meaning it was plausible but unclear whether the same mechanisms occurred in others, such as those with later variants of the virus, or who were vaccinated.

Harrison said: “Likely, a range of processes explain brain fog and other features of post-Covid syndrome.”

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

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