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Background: After acute COVID-19, 5% of people experience persistent depressive symptoms and reduced cognitive function (COVID-DC). Theoretical models propose that astrogliosis is important in long COVID, but measures primarily indicative of astrogliosis have not been studied in the brain of long COVID or COVID-DC. The objective of the current study was to measure [ 11 C]SL25.1188 total distribution volume ([ 11 C]SL25.1188 V T ), an index of monoamine oxidase B density and a marker of astrogliosis, with positron emission tomography in participants with COVID-DC and compare with healthy control participants., Methods: In 21 COVID-DC cases and 21 healthy control participants, [ 11 C]SL25.1188 V T was measured in the prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum. Depressive symptoms were measured with the Beck Depression Inventory-II, and cognitive symptoms were measured with neuropsychological tests., Results: [ 11 C]SL25.1188 V T was higher in participants with COVID-DC in the prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum than in healthy control participants. Depressive symptom severity negatively correlated with [ 11 C]SL25.1188 V T across prioritized brain regions. More recent acute COVID-19 positively correlated with [ 11 C]SL25.1188 V T , reflecting higher values since predominance of the Omicron variant. Exploratory analyses found greater [ 11 C]SL25.1188 V T in the hippocampus, dorsal putamen, and ventral striatum of COVID-DC participants than control participants with a major depressive episode with no history of COVID-19, and there was no relationship to cognitive testing in prioritized regions., Conclusions: Results strongly support the presence of monoamine oxidase B-labeled astrogliosis in COVID-DC throughout the regions assessed, although the association of greater astrogliosis with fewer symptoms raises the possibility of a protective role. The magnitude of astrogliosis in COVID-DC is greater since the emergence of the Omicron variant., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)