Discovery of molecular signature of long-term psychiatric sequelae in COVID-19 through proteome profiling of dried blood spots

Neuropsychiatric sequelae represent a significant aspect of post-acute sequelae of SARS-CoV-2 (PASC, or long COVID), posing considerable public health challenges. This study identified molecular signatures associated with PASC in individuals with psychiatric morbidities via dried blood spot proteomic analysis. We evaluated 51 COVID-19 survivors ≥ 60 days post-infection, categorizing them into three groups: those with new-onset psychiatric disorders (n = 16, psychiatric PASC), those with persistent symptoms but no psychiatric disorders (n = 18, general PASC), and those symptomatically recovered (n = 17, recovered). Liquid chromatography-mass spectrometry analysis identified 1604 proteins. Differentially expressed proteins underwent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Protein panels, including isoform 1 of fibronectin, sorbitol dehydrogenase, cytosolic acyl coenzyme A thioester hydrolase, and apolipoprotein A-II, differentiated psychiatric PASC from recovered individuals with an area under the curve (AUC) of 0.865 (95% CI: 0.658-1). Filamin A and vacuolar protein sorting-associated protein VTA1 homolog distinguished psychiatric PASC from general PASC at an AUC of 0.831 (95% CI: 0.6-1). Decision tree analysis revealed that alpha-synuclein, pyruvate kinase PKM, and sorbitol dehydrogenase effectively distinguished the three groups with 82% classification accuracy. These findings suggest that alterations in immune, glucose, and lipid metabolism pathways, along with neuroinflammation and neurodegeneration, contribute to the psychiatric PASC phenotype and highlight potential biomarkers for psychiatric disorders during the long-term COVID-19 clinical course.