"Brain scans before and after
infection showed more loss of gray matter and tissue damage, mostly in areas
related to smell, in people who had Covid than in those who did not.
Covid-19 may cause greater loss of
gray matter and tissue damage in the brain than naturally occurs in people who
have not been infected with the virus, a large new study finds.
The study, published Monday in the
journal Nature, is believed to be the first involving people who underwent
brain scans both before they contracted Covid and months after. Neurological
experts who were not involved in the research said it was valuable and unique,
but they cautioned that the implications of the changes were unclear and did
not necessarily suggest that people might have lasting damage or that the
changes might profoundly affect thinking, memory or other functions.
The study, involving people aged 51
to 81, found shrinkage and tissue damage primarily in brain areas related to
sense of smell; some of those areas are also involved in other brain functions,
the researchers said.
“To me, this is pretty convincing
evidence that something changes in brains of this overall group of people with
Covid,” said Dr. Serena Spudich, chief of neurological infections and global
neurology at the Yale School of Medicine, who was not involved in the study.
But, she cautioned: “To make a
conclusion that this has some long-term clinical implications for the patients
I think is a stretch. We don’t want to scare the public and have them think,
‘Oh, this is proof that everyone’s going to have brain damage and not be able
to function.’”
The study involved 785 participants
in UK Biobank, a repository of medical and other data from about half a million
people in Britain. The participants each underwent two brain scans roughly
three years apart, plus some basic cognitive testing. In between their two
scans, 401 participants tested positive for the coronavirus, all infected
between March 2020 and April 2021.
The other 384 participants formed a
control group because they had not been infected with the coronavirus and had
similar characteristics to the infected patients in areas like age, sex,
medical history and socioeconomic status.
With normal aging, people lose a tiny fraction of gray
matter each year. For example, in regions related to memory, the typical annual
loss is between 0.2 percent and 0.3 percent, the researchers said.
But Covid patients in the study — who underwent their second
brain scan an average of four and a half months after their infection — lost
more than noninfected participants, experiencing between 0.2 percent and 2
percent additional gray matter loss in different brain regions over the three
years between scans. They also lost more overall brain volume and showed more
tissue damage in certain areas.
“I find it surprising in the sense
of how much more was lost and how generalized it is,” said Dr. Spudich, who has
studied the neurological effects of Covid. She added, “I wouldn’t have expected
to see quite so much percentage change.”
The effects may be particularly notable because the study
involved mostly people who — like the majority of Covid patients in the general
population — were mildly affected by their initial Covid infection, not
becoming sick enough to need hospitalization.
The study’s lead author, Gwenaëlle
Douaud, a professor in the department of clinical neurosciences at the
University of Oxford, said that although the number of hospitalized patients in
the study, 15, was too small to yield conclusive data, results suggested that
their brain atrophy was worse than the mildly afflicted patients.
People who had Covid also showed greater decline than uninfected
people on a cognitive test related to attention and efficiency in performing a
complex task.
But outside experts and Dr. Douaud
noted that the cognitive testing was rudimentary, so the study is very limited
in what it can say about whether the gray matter loss and tissue damage the
Covid patients experienced affected their cognitive skills.
“None of them got thorough enough
cognitive testing to know if they had significant deficits in these many
regions where they found these changes in volume,” said Dr. Benedict Michael,
an associate professor of neurological infections at the University of
Liverpool, who is researching the neuropsychiatric effects of Covid and was not
involved in the study. “We don’t know that it actually means anything for the
patient’s quality of life or function.”
For example, although some of the
largest gray matter loss was in areas related to smell, including the
orbitofrontal cortex and parahippocampal gyrus, those areas are also involved
in memory and other functions. But the Covid patients did not perform worse
than noninfected participants on memory tests, Dr. Douaud said, although she
added that the memory tests they took were brief and basic.
The main cognitive assessment where Covid patients showed a
deficit was the trail-making test,
a connect-the-dots type of exercise involving alternating letters and numbers.
Covid patients took longer to complete the task, which might suggest weaknesses
in focus, processing speed and other skills.
Dr. Douaud said this diminished
ability correlated with loss of gray matter in a specific region of the brain’s
cerebellum. But the study doesn’t prove cause and effect, said Dr. Spudich, who
also said that the cerebellum, primarily associated with balance, coordination
and movement, “is not the first brain structure you think of” to explain
changes in ability on the trail-making test.
One significant limitation to the
study, Dr. Douaud said, is that researchers did not have information about
people’s symptoms, including whether they lost their sense of smell. The
researchers also could not identify whether any patients had long Covid, so
it’s unclear if the findings relate to that long-term condition.
Differences between infected and
uninfected people increased with age. On the trail-making test, for example,
performance was similar in both groups for people in their 50s and early 60s,
but the gap widened significantly after that. “I don’t know if that’s because
younger people recover faster or they were not as affected to start with,” Dr.
Douaud said. “Could be either or it could be both.”
Dr. Michael cautioned that the
findings could not be extrapolated to the many younger people experiencing
post-Covid brain fog and other cognitive issues. And since gray matter and
tissue damage were measured at only one time-point after infection, “we don’t know
if it’s just a transient change that gets better with recovery,” he said.
Outside experts and the study’s
authors said the range of brain areas where Covid patients experience more gray
matter loss raised intriguing questions.
“There’s no one part of the brain
that does one thing,” Dr. Douaud said. “There are parts of the brain in the
infected participants with additional gray matter loss that have nothing to do
with the smell, and the ones that are related to smell also are involved in
other brain functions.”
The cause of the brain changes is
unclear. The authors mentioned theories including inflammation, evidence of which has been
found in other studies, and “sensory deprivation” from disrupted
sense of smell.
Dr. Avindra Nath, chief of the section on infections of the
nervous system at the National Institute of Neurological Disorders and Stroke,
who was not involved in the study, said another “critical question” was whether
the brain changes could make Covid patients more prone to dementia or other
deficits in the future.
And while the researchers did not
find the same brain changes in patients with non-Covid pneumonia, Dr. Nath
recommended studying patients with other coronaviruses or the flu “to see if
these findings are distinct for Covid-19 or more generalizable.”
Dr. Spudich said the study’s
greatest value may be its indication that “there’s been something that’s
happened in the brain in these people,” adding that “I think people have felt
that it’s so vague, so hard to measure.”
Other scientists can now build on
these findings, she and others said.
“It’s an important study, they’ve
done good work,” Dr. Michael said, adding, “now we need to do the studies to
look at cognition and psychiatric symptoms and behavioral stuff and
neurological stuff and find out what does this mean for patients.”"
