Some small imaging studies have shown brain damage after hospitalized people had recovered from severe COVID-19. Can milder bouts injure the brain, too? Yes, say scientists led by Gwenaëlle Douaud and Stephen Smith at the University of Oxford, U.K. In Nature on March 7, they reported that four months after a mild COVID infection, adults ages 51 to 81 had slightly thinner gray matter and more signs of tissue damage in their olfactory areas than they did before infection, even after accounting for age-related brain changes that showed up in uninfected controls. This is the first longitudinal study on the brain effects of COVID that compares MRI scans before and after infection.
- With U.K. Biobank data, scientists compared brains pre- and post-COVID.
- After mild infection, abnormalities appeared in limbic system structures connected to sense of smell.
- Whole brain size shrank slightly, and cognitive decline accelerated.
- A separate study from Wuhan found worsening decline one year after severe COVID.
Executive function also declined more rapidly after illness. How these brain structure and cognition changes could influence dementia risk remains an important question.
“Having two time points to tease out subtle brain changes is the beauty of this study,” Markus Glatzel, University Medical Center Hamburg-Eppendorf, Germany, noted. Jonas Hosp, University Hospital Freiburg, Germany, agreed. “This impressive, high-quality study analyzed a unique imaging cohort in an unbiased way to show that systemic infectious diseases, such as COVID, may indeed alter brain structure,” he said.
Studies on brain health after recovery from COVID-19 infection have uncovered transient cerebrovascular damage, brain hypometabolism, worsening of pre-existing neurological problems, and impaired cognition (Jan 2021 news; Apr 2021 conference news; Hosp et al., 2021). However, most of this data is from MRI or PET studies of small cohorts, and none had pre-COVID data from which to draw.
To address this shortcoming, first author Douaud turned to the U.K. Biobank, a massive effort to collect comprehensive health and genetic information on half a million people aged 40 to 69. The biobank includes an imaging substudy of 100,000 participants (Oct 2016 news). Since 2016, it has scanned the brains of almost 43,000 volunteers older than 45.
Douaud identified biobank participants aged 51 to 81 who had had COVID-19 between two imaging sessions. They tested positive an average of 4.5 months before their second scan. The scientists matched each person to an uninfected control by age, sex, ethnicity, and time between pre- and post-COVID scans, which averaged three years. The scientists compared rates of change among infected people with rates of change in matched controls to account for age-related alterations in the brain. They collected structural, diffusion-weighted, and resting-state functional MRI scans on 384 controls and 401 COVID cases. Of the latter, only 15 had been in the hospital; the rest recovered at home from a mild to moderate course.
The scientists used an algorithm to identify changes in more than 2,000 image-based phenotypes (IDPs). These could be shapes, sizes, or metabolic activities of regions of interest, for example, the volume of the putamen or the diffusion index of the anterior cingulate cortex. In calculating rates of change due to the infection, the researchers gauged the effects of 6,300 non-imaging variables at baseline. Variables included lifestyle factors, family health history, and COVID-19 risk factors, such as obesity, blood pressure, smoking status, and diabetes. None significantly influenced longitudinal brain changes, indicating that COVID was indeed to blame.
Then how did COVID alter the brain? Sixty-five of these 2000+ IDPs changed after illness. Of the five with the most robust correlation, whole brain volume shrank slightly more in COVID cases compared to controls, cerebrospinal fluid volume increased, and the lateral ventricles widened. The other two phenotypes were more localized. Tissue microstructure was compromised in the fronto-occipital fasciculus, which connects with areas of white matter altered after COVID. The orbitofrontal cortex, anterior cingulate cortex, hippocampus, parahippocampal gyrus, and amygdala, saw a rise in their diffusion indices, a proxy for tissue damage. These structures comprise the piriform network that functionally connects to the piriform cortex, which interprets smell.
Blunted or complete loss of smell is a telltale sign of early COVID infection. To see what other brain change might explain this, the scientists focused on 297 image-derived phenotypes related to smell. They found that infection had altered 68, most notably the orbitofrontal cortex had thinned, and diffusion indices rose in five regions of the piriform and olfactory tubercle functional networks. The researchers were unable to measure changes directly in the piriform cortex or olfactory bulb because those tiny areas near the sinuses tend to be distorted in MRI images.
To analyze brain differences another way, the scientists tracked changes in whole-brain cortical surface thickness and mean water diffusivity before and after COVID, then compared the changes to those in controls. Again, many of the same areas identified by IDP analysis were altered by infection (see image below). Overall, the most consistent abnormalities were within the orbitofrontal cortex and the parahippocampal gyrus.
“This well-done study by first-class authors points to a distinct anatomy within the brain that is selectively vulnerable to COVID,” remarked Marcus Raichle, Washington University, St. Louis. The imaging abnormalities held even after excluding the 15 hospitalized participants, who had more severe atrophy and tissue damage than people with milder infections.
Covid Change. Compared to controls, gray matter thinned after COVID in areas related to sensory processing (orbitofrontal cortex and insula), memory (parahippocampal gyrus and temporal pole), executive function (anterior cingulate cortex), and language processing (supramarginal gyrus, left). Mean diffusivity, a measure of tissue damage, rose in the orbitofrontal cortex, insula, anterior cingulate cortex, and amygdala (right). In general, atrophy and tissue damage were worse in the left hemisphere. [Courtesy of Douaud et al., Nature, 2022.]
How severe was the damage? In COVID cases, volumes fell and diffusivities rose an average of 0.2 to 2 percent more than they did in controls. The authors deemed this moderate. The hippocampus, for example, shrinks about 0.2-0.3 percent per year in older adults (Fraser et al., 2021).
Did this affect cognition? Before and after infection, the participants took these six tests: Trail Making to assess executive function; Symbol Digit, Pairs Matching, and total number of digits recalled correctly to measure memory; the fluid intelligence test to estimate reasoning; and speed of matching cards to measure reaction time. Only the time needed to complete the Trail Making tasks A and B differed after COVID. Participants took 8 and 12 percent longer to complete task A, which is numeric, and task B, which is alphanumeric, respectively (see image below).
Douaud thinks this tardiness might reflect poor executive function and reaction time rather than memory, since there was no difference in the three memory tasks. Intriguingly, the scientists linked slower completion of trails B to greater atrophy of the crus II of the cerebellum. Though this major hindbrain structure primarily controls balance and motor function, scientists now believe the crus II helps with executive function.
Sluggish Cognition. Compared to controls (blue), people who recovered from COVID (orange) took up to 35 percent longer (y axis) to connect numbers and letters in the Trail Making A (left) and B (right) tasks. The case/control difference grew larger with age. [Courtesy of Douaud et al., Nature, 2022.]
And ... Dementia?
The dreaded question, whether these COVID-related changes increase the risk for dementia or Alzheimer’s disease, is still open. That said, “It is a remarkably important finding that, even in mild COVID patients, the brain changed in regions we know are related to cognition and brain disorders, such as AD,” Ole Isacson, Harvard Medical School, Boston, told Alzforum. Raichle agreed. “The minute you involve the hippocampus and cortex, you bring in the default mode network that is implicated in AD,” he said.
Douaud and colleagues did not address links to dementia, but other researchers have looked cross-sectionally at changes six to 12 months after recovering from severe COVID and found hypometabolism in some of the same regions Douaud identified (Kas et al., 2021; Blazhenets et al., 2021).
New hints regarding dementia come from a longitudinal study published March 8 in JAMA Neurology (Liu et al., 2022). Scientists tracked 1,438 adults more than 60 years old who were hospitalized with COVID during the initial wave in Wuhan, China. Of those, 260 had been deemed to have severe COVID, while the others had moderate disease. The survivors and 438 uninfected spouses took the Informant Questionnaire on Cognitive Decline in the Elderly, and the Telephone Interview of Cognitive Status-40, six and 12 months after they had left the hospital. After one year, 12 percent of survivors developed dementia or mild cognitive impairment compared to 6 percent of controls. People who survived severe illness were 19 times likelier to experience progressive cognitive decline over the year than were controls. Those who had moderate COVID were 1.7 times more likely to decline during the first six months of recovery, but then their cognitive function stabilized.
While the data seem troubling, Glatzel sees no reason for panic. “Overall, COVID has pretty mild effects on the brain—no massive encephalitis, no dramatic influx of dementia cases after COVID infection. In the few cases I've seen, neuropathology returns to baseline a few months after infection, at least as judged using standard techniques,” he said. Indeed, previous studies have detected elevated plasma markers of brain injury, such as neurofilament light and glial fibrillary acidic protein, as well as lower Aβ and higher total tau and phosphotau-181, after severe COVID. All normalized within six months of hospital discharge (Sep 2021 conference news).
Intriguingly, a recent preprint reported diffuse Aβ deposits in the cortices of 10 people under age 60 who died from severe COVID-19 (Rhodes et al., 2022). Unlike amyloid plaques of AD, these did not bind thioflavin-S, and the scientists found similar deposits in five people younger than 66 who had died of acute respiratory distress, unrelated to COVID. Costantino Iadecola at Weill Cornell thinks these deposits are not the amyloid plaques seen in AD. “These Aβ deposits may turn into true fibrillar plaques, or they could be a transient response to hypoxia and cardiac arrest that go along with dying,” he told Alzforum. Colin Masters, University of Melbourne, Australia, agreed. “Very metabolically active brain areas, where APP processing is highest, are particularly susceptible to hypoxic damage and dementia,” Masters noted.
Many questions remain about brain health after COVID. “The U.K. Biobank study sets the stage for continued understanding of the vulnerability of select brain tissues and the permanence of these suspected neurodegenerative changes,” Mony de Leon and Anna Nordvig of Weill Cornell Medical College, New York, wrote (full comment below). Will the greater atrophy reverse, stop, or persist long-term? Douaud hopes to find out by analyzing biobank participant scans again in one to two years.—Chelsea Weidman Burke
- How Does COVID-19 Affect the Brain?
- COVID-19 Worsens Neurological Problems, Delirium
- 5,000 Down, 95,000 to Go: U.K. Biobank Releases First Brain-Imaging Data
- Aβ, Tau, and Other AD Markers Altered in COVID
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