Cerebrospinal Fluid Immune Cell Alterations in Women With Neuropsychiatric Long COVID

Abstract

Background Women are disproportionately affected by neuropsychiatric symptoms following recovery from acute COVID-19. However, whether there are central nervous system-specific changes in gene expression in women with neuropsychiatric Long COVID (NP-Long COVID) remains unknown.Methods Twenty-two women with and 10 women without NP-Long COVID were enrolled from New Haven, Connecticut, and the surrounding region and consented to a blood draw and large volume lumbar puncture. Total RNA was extracted from cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMC). Polyadenylated RNA was sequenced, and differential expression analyses were performed.Results Both CSF and PBMC samples showed differential gene expression associated with Long COVID status. There were CSF-specific differentially expressed genes in people with Long COVID, including in genes related to oxidative stress, reactive oxygen species, and P53 response, indicating compartment-specific immune responses. Some pathways were dysregulated in both the CSF and PBMC of Long COVID compared with controls, including those related to androgen response, MTORC1 signaling, and lipid metabolism.Conclusions Women with NP-long COVID show compartment-specific, transcriptional profiles in the CSF with evidence of enrichment in cellular stress pathways. These results underscore the importance of examining CSF-specific molecular profiles to better understand post-viral neurological syndromes. Women with neuropsychiatric Long COVID exhibit unique cerebrospinal fluid transcriptional profiles, revealing central nervous system-specific immune, metabolic, and stress pathway alterations not observed in peripheral blood, highlighting compartmentalized molecular mechanisms underlying persistent post-infectious neurological symptoms.