Gliosis may explain depressive or cognitive symptoms after COVID

Patients with persistent depressive or cognitive symptoms after an acute SARS-CoV-2 infection have elevated gliosis – a secondary event to brain injury – and inflammation as shown in a case-control study.

The level of translocator protein total distribution volume (TSPO V_T) – a marker of gliosis – was higher in 20 patients who had COVID-19 (9.23 mL/cm³₎ than in 20 healthy controls (7.72 mL/cm³) who were treated at a tertiary care psychiatric hospital in Canada. [JAMA Psychiatry 2023; e231321]

The mean differences between COVID-patients and controls were particularly remarkable in the ventral striatum and dorsal putamen [1.97 mL/cm³and 1.70 mL/cm³, respectively) structures of the brain.

“These findings suggest that gliosis, especially in the ventral striatum and dorsal putamen, may reflect injury, ongoing inflammation, or both, and provide directions for further therapeutic development,” said study author Dr Jeffrey Meyer from the University of Toronto.

Persistent depressive and cognitive symptoms commonly occur after COVID-19. Gliosis is often suspected but had not been studied until this study, added Meyer.

Looking into brain TSPO

The researchers sought to determine whether TSPO V_T levels that are quantifiable with positron emission tomography (PET) are elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of these patients compared with those who had no COVID. Meyer said injury in these regions, which can cause gliosis, also induces COVID-related depression and cognitive symptoms.

The study ran from April 1, 2021 to June 30, 2022. The mean age of COVID patients was 32.7 years. Sixty percent were women. The 20 controls were selected for their matching rs6971 genotype, which affects radiotracer binding to TSPO.

TSPO V_T was measured with fluorine F18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET whereas depression and cognitive symptoms with neuropsychological and psychological tests. COVID-19 symptoms include anhedonia, slow motor speed, and low motivation or energy.

“In COVID-19 patients, greater dorsal putamen TSPO V_T was associated with slower motor speed, measured with mean T-scores on the finger-tapping test (p=0.02). The 10 patients who had the slowest motor speed had higher mean dorsal putamen TSPO V_T than the healthy controls by 2.3 mL/cm³,” reported Meyer.

Any possible association between the ventral striatum TSPO V_T and anhedonia was not ascertained. No significant correlations were found between depression and TSPO V_T in the prefrontal cortex or anterior cingulate cortex nor between cognitive failure score and hippocampal TSPO V_T.

As the study was cross-sectional, the duration of persistently elevated TSPO V_T is not known. “Although correlations with finger-tapping test performance reflect associations between brain changes and symptoms, they do not prove cause and effect,” explained Meyer.

Clinical implications

While the results are important for better understanding of neuroinflammation in chronic neurological disease, more studies are warranted to determine if treatments that influence inflammation are helpful in these patients, he added.

“Increased microglial activation in the ventral striatal and dorsal putamen reflects a possible mechanism to explain the persistent depressive and cognitive symptoms after COVID, but we still lack understanding of the complex picture for several reasons,” commented Dr Alexander Gerhard from the University of Manchester in Manchester, UK, in an accompanying editorial. [JAMA Psychiatry 2023;doi:10.1001/jamapsychiatry.2023.0664]

One caveat, he said, is that the PET technique used in the study is particularly noisy and not specific to microglial cells. “It does not allow us to distinguish between different states of microglial activation either,” Gerhard added. “A detailed understanding of microglial activation at different time points is likewise needed before neuroinflammatory changes can be targeted therapeutically.”