Varying Levels of Inflammatory Activity in Brain and Body of Patients with Persistent Fatigue and Difficulty Concentrating After COVID-19: A TSPO PET Study.

Abstract

A significant number of patients report persistent fatigue and difficulty concentrating after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a condition known as post-coronavirus disease 2019 (post-COVID) syndrome. The underlying mechanisms for these complaints remain poorly understood. Dysregulated immune and neurologic systems may play a role in the pathophysiology of post-COVID syndrome. A target providing direct information on immune activation is the 18-kDa translocator protein (TSPO), which is upregulated in activated microglia. The PET tracer N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide ([¹⁸F]DPA-714) binds with high affinity to TSPO and serves as a biomarker for neuroinflammation. We aimed to assess whole-body inflammatory activity with TSPO PET in individuals with and without persistent severe fatigue and difficulty concentrating 2 y after infection with SARS-CoV-2 as well as its association with complaint severity. Methods: In this cross-sectional cohort study, we evaluated 47 post-COVID individuals, 33 of whom had severe fatigue and difficulty concentrating (age, 50 ± 8 y; 27 ± 9 mo after initial infection) and 14 who did not have these complaints (age, 47 ± 9 y; 25 ± 10 mo after initial infection). All individuals were high-affinity binders according to their TSPO genotype and completed whole-body 60-min dynamic [¹⁸F]DPA-714 PET with arterial sampling, MRI, genotyping, and questionnaires. Tracer binding was quantified using binding potential for cerebral regions and inhibitory constant or total distribution volume for extracerebral regions. Parameters were compared between 33 individuals with persistent complaints (severe fatigue and difficulty concentrating) and 14 without, and associations between parameters were assessed. Results: We found globally increased cerebral [¹⁸F]DPA-714 binding in some individuals reporting persistent complaints when compared with individuals without these complaints. No group-level differences were found in extracerebral binding. Large variability in cerebral and extracerebral binding was observed among individuals. Cerebral and extracerebral binding levels were not correlated with each other or with complaint severity. Conclusion: Increased specific [¹⁸F]DPA-714 binding was found in some individuals with post-COVID syndrome, indicating the presence of an inflammatory subtype and further supporting the role of neuroinflammation in subtypes of post-COVID syndrome.