The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic

• Published in: Brain, behavior, and immunity Vol. 102; pp. 89 - 97
• Main Authors: Brusaferri, Ludovica, Alshelh, Zeynab, Martins, Daniel, Kim, Minhae, Weerasekera, Akila, Housman, Hope, Morrissey, Erin J., Knight, Paulina C., Castro-Blanco, Kelly A., Albrecht, Daniel S., Tseng, Chieh-En, Zürcher, Nicole R., Ratai, Eva-Maria, Akeju, Oluwaseun, Makary, Meena M., Catana, Ciprian, Mercaldo, Nathaniel D., Hadjikhani, Nouchine, Veronese, Mattia, Turkheimer, Federico, Rosen, Bruce R., Hooker, Jacob M., Loggia, Marco L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-05-2022
• Subjects: adult; Biomarkers - metabolism; Brain - metabolism; Communicable Disease Control; coronavirus disease 2019; COVID-19; fatigue; female; Full-length; gene expression; human; Humans; inositol; interleukin 16; lockdown; male; mental fatigue; Mental health; middle aged; molecular imaging; monocyte chemotactic protein 1; MRS; multimodal imaging; nervous system inflammation; Neuroimaging; Neuroinflammatory Diseases; Neurologi; Neurology; nuclear magnetic resonance spectroscopy; Pandemic; Pandemics; PET; physiological stress; positron emission tomography; Receptors, GABA - metabolism; retrospective study; SARS-CoV-2; SARS-CoV-2 antibody; Stress; transcriptomics; Neuroimaging; Pandemic; PET; Stress; Mental health; MRS
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2022.02.018

•Human study measuring pandemic-related neuroinflammation in individuals negative to COVID-19 antibodies.•Multimodal PET/MR brain imaging shows elevation in two independent putative markers of glial activation.•PET signal increases are associated with physical/mental fatigue indices.•Imaging transcriptomics analyses reveal a spatial overlap with the expression of genes related to neuroimmune responses.•Marginally elevated serum inflammatory markers correlate with neuroimaging markers.
While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus.
We compared fifty-seven ‘Pre-Pandemic’ and fifteen ‘Pandemic’ datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation.
Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions.
This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.