Abstract Background: Neuropsychiatric symptoms are prominent and can have a substantial functional impact in many people with Long COVID (LC). The underlying pathophysiology of neuropsychiatric LC (N-LC) is unknown. Methods: 28 individuals with acute COVID-19 (AC), 50 N-LC (new or worsening neuropsychiatric symptoms >3 months after COVID-19), and 29 post-COVID-19 controls with no LC (>3 months prior) were enrolled. Participants underwent cross-sectional blood testing, and the N-LC and control groups underwent neuropsychiatric testing, including verbal learning and memory, fluency, processing speed, and mental health assessments. Fourteen soluble biomarkers of vascular health were measured in plasma. ANCOVA testing with a Benjamini-Hochberg procedure was used to compare biomarkers between groups adjusting for co-morbidities. Findings: Participants with N-LC and controls were similar demographically, while the AC group had higher rates of obesity and hypertension. Biomarkers of leukocyte adhesion to the endothelium and endothelial inflammation were elevated in N-LC compared to controls, including L-selectin, ADAMTS13, sP-selectin, and sICAM-1, whereas coagulopathy measures (D-dimer, fibrinogen) did not differ. Most biomarkers were highest in AC and lower in N-LC (AGP, CRP, haptoglobin, SAA, ADAMTS13, PF4, sP-selectin, sVCAM-1, and D-dimer). However, three biomarkers were highest in N-LC compared to AC: Fetuin (vascular calcification), L-selectin (leukocyte adhesion), and α-2 macroglobulin (endothelial adhesion). In N-LC, higher sP-selectin was strongly associated with lower fluency and verbal learning. Lower AGP was strongly associated with lower verbal memory, verbal learning, fluency, mood, and anxiety. Interpretation: Alterations in biomarkers of vascular inflammation strongly associate with the presence of N-LC. Biomarkers of endothelial adhesion and vascular calcification are only elevated in N-LC compared to both groups, suggesting a pathophysiology distinct from the resolving effects of AC. Biomarkers related to endothelial adhesion and systemic inflammation associate with specific cognitive domains, linking vascular inflammation with brain function. Identifying abnormalities in vascular endothelial function, calcification, and remodeling may lead to therapeutic targets for N-LC. LINK
