Biomarkers

Background: Long COVID is an under-characterized disorder that affects a wide range of individuals after COVID-19 resolution. Long COVID individuals report persistent neurological manifestations, such as anxiety. Understanding its effects in the brain might help uncover the actual burden imposed by the pandemic sequelae and either define or discard long COVID as a risk factor for neurodegenerative diseases. Here, we aim to identify whether there is an association between brain metabolism and anxiety in an underrepresented population.

Method: Community-dwelling individuals, above 50 years old, from Porto Alegre, Brazil, were divided into long COVID (n=39) and control groups (n=10) were evaluated with a battery of neuropsychological testing, including the GAD-7 scale of anxiety. Then, they underwent a brain [¹⁸F]FDG-PET scan (images normalized by the pons). We conducted a voxel-wise linear regression testing the association between [¹⁸F]FDG metabolism and GAD-7, and corrected for education, sex, and age. The analysis was corrected for multiple comparisons using the cluster-wise random field theory method (significant t<-3.34 and t>3.34, p<0.001, df=35).

Result: We found that GAD-7 score presented a widespread negative association with [¹⁸F]FDG metabolism in multiple gray and white matter regions (Figure 1). Specifically, hippocampus (t_max =-3.34, p=0.002), amygdala (t_max=-3.82, p=0.0005), cerebellum (t_max=-4.28, p=0.0001), and lateral occipitotemporal gyrus (t_max=-5.26, p=0.0001) had the most relevant associated clusters in gray matter, while temporal lobe (t_max=-3.9, p=0.0004) and frontal lobe (t_max=-4.33, p=0.0001) presented the most relevant associated clusters in white matter.

Conclusion: Anxiety symptoms are a highly self-reported symptom in long COVID. Here we show that anxiety is widely associated with reduced brain glucose metabolism in crucial areas for the limbic system and cognition, such as the hippocampus and amygdala. The peculiar associations between anxiety and FDG metabolism in white matter may suggest inflammatory responses triggered by long COVID. These data provide new insights into the mechanisms underlying long COVID symptoms in the brain.