Cell-type specific signatures of regional brain vulnerability in COVID-19

Emerging evidence reveals widespread brain abnormalities in individuals with coronavirus disease 2019 (COVID-19); however, the longitudinal trajectory and regional selectivity alterations remain poorly understood. In this study, we investigated brain alterations in 67 UK Biobank participants (49 severe acute respiratory syndrome coronavirus 2-positive individuals and 18 age-matched healthy controls) and integrated these with gene expression data from the publicly available Allen Human Brain Atlas, which provides comprehensive microarray profiles across multiple brain regions from six neurologically healthy adult donors. We established a gray matter morphological similarity network and extracted white matter volume from T1-Weighted Images (T1WI) to assess regional vulnerability. We hypothesized that spatial variations in cell type-specific gene expression may underlie the observed patterns of regional abnormalities. We found that COVID-19 generally induced cortical changes in a network of regions that were functionally connected to the primary olfactory cortex, mainly including the entorhinal cortex, anterior cingulate cortex, orbitofrontal cortex and middle temporal cortex. Notably, regional cortical alterations were positively associated with the expression of Primary Somatosensory Cortex Pyramidal Neurons (S1 pyramidal) neuron-specific and interneuron-related genes and negatively associated with markers of microglia, astrocytes, ependymal cells, and oligodendrocytes. Furthermore, the expression of S1 pyramidal neuron-related genes accounted for 23.2% of the variance in regional white matter alterations. These findings suggest that modulation of neuronal activity—particularly enhancement of S1 pyramidal neuron function—may represent a potential therapeutic strategy for brain abnormalities in individuals recovering from COVID-19.