To examine markers of immune dysfunction and neural injury in Post-Acute Sequelae of SARS-CoV-2 (PASC) and their relationship with cognitive functioning in individuals who were not hospitalized due to COVID-19 infection.

Neurological issues, particularly cognitive difficulties, stand out as some of the most prevalent, widespread, and profoundly disabling PASC symptoms. However, the pathophysiological mechanisms underlying these remain poorly understood, hindering the development of predictive models for PASC prognosis and targeted treatments.

This study included 55 PASC participants who were infected an average of 470 days before enrollment (μ_age: 46) and 37 controls without PASC (μ_age: 43). PASC symptoms and their severity were assessed using a self-report questionnaire. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) word list and the Trail Making Test Part B (TMT-B). We measured markers of inflammation, including CX3CL1/Fractalkine, Macrophage inflammatory protein-1 alpha (CCL3/MIP-1α), TNF-α, Granzyme B (GzmB), Interleukin-4 (IL-4), and IFN-β, and of neural injury (Ubiquitin C-terminal hydrolase L1 [UCH-L1]) in plasma. All analyses controlled for age.

Participants with PASC reported an average of 12 PASC symptoms. Neurological symptoms were among the most pervasive, with headaches, insomnia, and brain fog being rated as some of the most severe. The PASC group demonstrated significantly higher levels of CX3CL1 (p<0.001), CCL3 (p=0.002), GzmB (p=0.018), IL-4 (p=0.041), and TNF-α (p=0.002), but not IFN-β. UCH-L1 levels were higher in the PASC group but did not reach significance when adjusting for age (p=0.09). Higher UCH-L1 levels were predictive of worse TMT-B scores (p=0.024).

We found evidence of heightened inflammation potentially from endothelial cells, cytotoxic immune, and T helper 2 cells in individuals with PASC, along with moderately elevated markers of neural injury. Findings suggest that an abnormal immune response may underly PASC symptoms, representing a potential target for intervention.