Increased cell-free DNA in CSF and serum of hip fracture patients with delirium

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Abstract Delirium is a neuropsychiatric syndrome commonly presenting during acute illness. The pathophysiology of delirium is unknown, but neuroinflammation is suggested to play a role. In this cross-sectional study, we aimed to investigate whether cell-free DNA and markers of neutrophil extracellular traps in serum and CSF were associated with delirium and neuronal damage, assessed by neurofilament light chain. Hip fracture patients (n= 491) with a median (25, 75 percentiles) age of 83 (74, 88) years and 69% females were enrolled at Oslo University Hospital, Diakonhjemmet Hospital, Akershus University Hospital, and Bærum Hospital. Delirium was assessed daily, pre- and postoperatively. Cognitively healthy adults (n= 32) with a median (25, 75 percentiles) age of 75 (70, 77) years and 53% females were included as controls. Cell-free DNA was measured by using the fluorescent nucleic acid stain Quant-iT PicoGreen® in serum and CSF. Myeloperoxidase-DNA and citrullinated histone H3 were analysed by ELISA in serum. Hip fracture patients have significantly higher levels of cell-free DNA and neutrophil extracellular traps in blood than cognitively healthy controls. In hip fracture patients without dementia, cell-free DNA in CSF and serum was significantly higher in patients with (n= 68) vs without (n= 221) delirium after adjusting for age and sex (70 (59, 84) vs 62 (53, 77) ng/ml, p= 0.037) and 601 (504, 684) vs 508 (458, 572) ng/ml, p= 0.007, respectively). In the total hip fracture cohort, CSF levels of cell-free DNA and neurofilament light chain were significantly correlated after adjusting for age and sex (r= 0.441, p< 0.001). The correlation was stronger in those with delirium (r= 0.468, p< 0.001) and strongest in delirious patients without dementia (r= 0.765, p= 0.045). In delirious patients without dementia, significantly higher levels of cell-free DNA in CSF and serum were shown. The association between cell-free DNA and neurofilament light chain suggest simultaneous release of cell-free DNA and neuronal damage during delirium.