Glial activation among individuals with neurological post-acute sequelae of coronavirus disease 2019: A positron emission tomography study of brain fog using [18F]-FEPPA

Abstract

Background: This study examined the regional distribution of glial activation in essential workers with neurological post-acute sequelae of coronavirus disease 2019 (COVID-19) infections (N-PASC).

Methods: We injected ≤185 MBq of [¹⁸F]-FEPPA as an intravenous bolus and positron-emission tomography over 2 h. To measure distribution volume (V_T) we recruited 24 essential workers (14 N-PASC, 10 Never-COVID-19 Controls, of whom 22 successfully placed arterial lines). Individuals with low binding affinity were excluded from this study, and V_T was adjusted for translocator protein genotype. Analyses that passed the false discovery rate are reported.

Results: Participants at midlife survived mild to moderate COVID-19 without hospitalization but reported onset of post-acute sequelae of COVID-19 (PASC) for, on average, 22 months before undergoing neuroimaging. Hippocampal V_T was higher (V_T = 1.70, 95% C.I. = [1.30-2.21], p = 0.001) in participants with persistent brain fog after COVID-19, reflecting an increase of 10.58 mL/cm³ in V_T (area under the receiver-operating curve, AUC = 0.95 [0.85-1.00]). At a cutoff of 10.6, sensitivity/specificity/accuracy were 0.88/0.93/0.91.

Conclusion: The results from this study imply that neuroimmune response is a distinct and identifiable characteristic of brain fog after COVID-19. Results suggest that [¹⁸F]-FEPPA could be used to support N-PASC diagnosis.

Keywords: Brain Fog; COVID-19; Essential Workers; FEPPA; Glial activation; Positron emission tomography; Post-acute sequelae of COVID-19; Respiratory infection; Translocator protein.

Graphical abstract

Fig. 1

Violin Plot showing cortical [¹⁸F]-FEPPA distribution volume (Vt) in 22 essential workers, comparing N-PASC versus Pre-Pandemic controls and stratified by cerebral region: A: Anterior Cingulate; B: Receiver Operating Curves for N-PASC when examining [¹⁸F]-FEPPA binding in the strongest four cerebral regions; C: Medial Prefrontal Cortex; D: Orbital Prefrontal Cortex; E: Hippocampus; F: Ventral Striatum; G: Cerebellum. H: Gray Matter, H: All p-values shown are statistically significant after adjusting for the false discovery rate (FDR = 0.05).

Fig. 2

Fused [¹⁸F]-FEPPA and Structural Image showing differences by standardized uptake values (SUV) in participants with persistent Brain Fog following COVID-19 infection as compared to pre-pandemic controls. Panel A shows TSPO SUV in N-PASC + participants, mapped to the cerebral surface. Panel B shows [¹⁸F]-FEPPA SUV values mapped to the cerebral parenchyma. Panel C shows [¹⁸F]-FEPPA SUV values for pre-pandemic controls mapped onto the cerebral surface. Panel D shows similar values for [¹⁸F]-FEPPA SUV values among pre-pandemic controls throughout the cerebral parenchyma.

Fig. 3

Associations between regional [¹⁸F]-FEPPA V_T and cognitive function and depressive symptoms in participants with and without Neurological Post-Acute Sequelae of COVID-19: A) scatter and overlaid linear plots examining association between Gray Matter [¹⁸F]-FEPPA V_T and Verbal Fluency, stratified into N-PASC + participants (black dots, solid line) and pre-pandemic controls (empty dots, dashed line); B) scatter and overlaid linear plots examining association between Hippocampal [¹⁸F]-FEPPA V_T and Global Cognition, stratified into N-PASC + participants (black dots, solid line) and pre-pandemic controls (empty dots, dashed line); C) full correlation results reporting Spearman's rho describing associations between regional [¹⁸F]-FEPPA Binding (Vt) with all measures of cognitive function and depressive symptoms among participants with Neurological Post-Acute Sequelae of COVID-19. Results for all reasons shown, results with moderate correlations (||rho||>0.30) are shown in black typeface. Statistically significant (p < 0.05) correlations are shown using bold italics.