Long COVID Cognitive, Depressive Symptoms Tied to Brain Inflammation Marker

An index of gliosis was linked with persistent neurocognitive symptoms after mild or moderate SARS-CoV-2 infection, a small case-control study showed.

Compared with healthy controls, PET measures of translocator protein total distribution volume (TSPO V_T), a marker of gliosis, was elevated in people with ongoing cognitive and depressive symptoms after COVID-19 (mean percentage difference 17%), reported Jeffrey Meyer, MD, PhD, of University of Toronto, and co-authors.

Increased TSPO expression was prominent in the ventral striatum (mean percentage difference 26%) and dorsal putamen (mean percentage difference 24%), Meyer and colleagues said in JAMA Psychiatry.

Motor speed on a finger-tapping test negatively correlated with dorsal putamen TSPO volume (r −0.53, 95% CI −0.79 to −0.09). People with post-COVID neurocognitive symptoms and the slowest finger-tapping speeds had higher dorsal putamen TSPO volume than healthy persons by 27%.

The study is the first to assess brain gliosis in long COVID, also known as post-acute sequelae of SARS-CoV-2 infection, Meyer and co-authors said. "We focused our sample to represent the common clinical phenomenon of depressive or cognitive symptoms after acute mild or moderate SARS-CoV-2 (COVID-DC)," they wrote.

"We found generalized differences in TSPO V_T between persons with COVID-DC and healthy control participants, most prominent in the ventral striatum and dorsal putamen, and that greater severity of motor slowing correlated with higher dorsal putamen TSPO V_T," they added. "These findings have important implications for understanding the pathology of COVID-DC and for developing clinical interventions."

How COVID may cause persistent neuropsychiatric symptoms remains a mystery, observed Alexander Gerhard, MD, of the University of Manchester in England, in an accompanying editorial.

"Since as many as 20% of individuals might experience cognitive impairment 12 or more weeks following COVID-19 diagnosis, it is paramount to understand the underlying pathophysiology in order to develop potential therapeutic avenues," Gerhard wrote. "Microglial activation as part of the neuroinflammatory response of the brain can occur as an answer to a direct insult to the brain (this includes viral infection), but can also occur following respiratory inflammation and might play an important role in the development of cognitive problems after COVID-19 infection."

This study has "important pilot character, as it elucidates a possible mechanism behind neurocognitive symptoms after COVID-19 infection," Gerhard said.

"While this is an important piece in the jigsaw puzzle of neuroinflammation in chronic neurological disease, it is important to keep in mind that we still lack understanding of the complex picture for several reasons," he pointed out.

The PET signal for this and other TSPO tracers is particularly noisy and is not restricted to microglial cells, Gerhard noted. Moreover, TSPO expression is only one part of the complex neuroinflammatory response of the brain.

"To target neuroinflammatory changes therapeutically, we will need a much more detailed understanding of microglial activation at different time points of neurological disorders," Gerhard stated. "Not surprisingly, relatively simplistic attempts to suppress microglial activation have so far not resulted in clinical meaningful results."

Meyer and co-authors evaluated 40 people with a mean age of 33; 60% were women. Half had depressive or cognitive symptoms after acute mild or moderate COVID and half were healthy controls. The study was conducted in Canada from April 2021 through June 2022.

To qualify for the study, people with COVID-DC had to have a new major depressive episode within 3 months of acute mild or moderate COVID-19 illness. Healthy controls had no history of psychiatric illness. Prominent symptoms of COVID-DC were anhedonia, motor speed slowing, energy problems, and cognitive concerns.

Mechanisms for neurocognitive symptoms after COVID-19 may be heterogenous and outcomes may differ after severe SARS-CoV-2 infection, Meyer and co-authors noted.

In addition, elevated TSPO expression is not completely specific to glial cells, the researchers acknowledged. "Although most TSPO in neuropsychiatric disease is typically expressed in microglia, and to a lesser extent in astroglia, the next most common cellular expression is in endothelial cells," they wrote. "However, endothelial cell content is unlikely to fully account for the findings."

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