Urokinase plasminogen activator (uPA) as a novel biomarker for cerebral amyloid angiopathy

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Abstract Background Current diagnostic criteria for cerebral amyloid angiopathy (CAA) are predominantly based on radiological identification of evidence of CAA (micro‐ or macrobleeds). These criteria present only end‐stage manifestations of the disease, however. The development of transgenic rat models for CAA, carrying the E693Q/D694N mutations in APP (rTg‐DI rats), has the potential of discovery of novel biomarkers for CAA. Shotgun proteomics analysis of rTg‐DI tissue, compared to wild‐type rats has yielded elevated levels of urokinase plasminogen activator (uPA) in CAA. uPA is a serine protease active in the conversion of plasminogen to plasmin, a fibrinolytic factor. We investigated the potential of uPA in a pilot biomarker discovery study for the diagnosis of CAA by analyzing uPA concentrations in cerebrospinal fluid (CSF) of patients with CAA compared to control patients. Method CSF was obtained from patients with possible or probable CAA (according to the current diagnostic imaging tool, the Boston Criteria) (n=28), and control subjects (n=42). uPA levels in CSF were determined using a uPA Quantikine ELISA (R&D Systems, Minneapolis, USA). Total protein levels were assayed using a Pierce® BCA Protein Assay (Thermo Fisher, Waltham, USA). Associations of uPA with known concentrations of other neurological markers, including aβ peptides and tau proteins were also analysed. Result The concentration of uPA was significantly increased in the CSF of CAA patients compared to controls (303 ± 23.2 vs. 227 ± 12.5 pg/mL; p=0.001). CSF uPA levels (very) weakly correlated with age at lumbar puncture (rSP=0.33, p=0.005) and total protein content (rSP=0.24, p=0.042). uPA levels in controls were correlated in a weak‐to‐moderate extent with Aβ‐38, 40, 42, and total‐ and phosphorylated tau protein (rSP=0.46, 0.63, 0.47, 0.53 and 0.41 respectively, p<0.02), whereas this correlation was practically absent in the CAA group. Conclusion Comparison of CSF levels of uPA shows a significant elevation in CAA patients compared against controls. CAA patients show lower levels of correlation of uPA with circulating aβ peptides and tau protein variants as compared to controls. This reinforces the potential of uPA as an effective biomarker in the diagnosis of CAA patients and incentivizes further research into this biomarker.

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