Authors (including presenting author) :
Zhang XD(1), Cai YE(1), Zhang YL(1), Li QY(1), Fan WN(2), Ip C(1), Jiao YQ(1), Lau GKK(3), Xu AM(4), Rainer TH(1)
Affiliation :
(1) Department of Emergency Medicine, The University of Hong Kong, Hong Kong SAR, China. (2) The Department of Neurology, Ningbo No.2 Hospital, Ningbo, China. (3) Division of Neurology, Department of Medicine, The University of Hong Kong, Hong Kong SAR, China. (4) Departments of Medicine and Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China.
Keyword 1: :
early ischaemic stroke
Keyword 3: :
circulating proteins
Keyword 4: :
mass spectrometry
Keyword 5: :
Olink platform
Introduction :
Rapid identification of ischaemic stroke (IS) is challenging in emergency medical services (EMS). Blood proteins hold potential for the diagnosis of Early onset IS (EIS), as they reflect IS-related pathophysiological changes and exhibit stability in the bloodstream.
Objectives :
To investigate potential plasma proteins associated with EIS, to explore their utility as diagnostic markers, and to build diagnostic models for EIS.
Methodology :
We conducted a retrospective multi-center study between June 2022 and June 2025, recruiting EIS patients (symptom onset time ≤4.5 h), late IS (LIS, symptom onset 4.5-24 h) and matched risk controls (Con). We used mass spectrometry-based (MS), non-targeted, proteomic analysis in a discovery cohort of 16 EIS, 14 LIS, and 14 Con. We further applied Olink-based targeted assay in a validation cohort of 18 EIS, 22 LIS, and 24 Con. Potential diagnostic biomarkers were identified and validated via bioinformatic analysis and confounder adjustment. Temporal changes in protein levels were analyzed within 24 hours after stroke onset. We used the Bradford Hill Criteria to assess the causal relationship between biomarker and EIS. We further use stepwise logistic regression to establish an optimal diagnostic model for EIS.
Result & Outcome :
We identified a biologically plausible, tyrosine receptor protein (TRP) responsible for brain barrier repair and neuroprotection, that has a strong positive association with EIS both in the MS discovery cohort (adjusted OR of 6.14, P = 0.014) and Olink validation cohort (adjusted OR of 2.69, P = 0.028). The plasma level of TRP increased in patients with EIS compared with Con and then shown a decreasing trend after stroke onset in both cohorts. TRP demonstrated potential causal relationship with EIS, fulfilling 8 of 9 Bradford Hill Criteria. It showed AUCs of 0.804 (95%CI 0.615-0.992), and 0.745 (95%CI 0.584 - 0.906) for differentiating EIS from Con in the discovery cohort, and validation cohort respectively. When combined with age, diabetes, hypertension, and hyperlipidemia the AUC increased to 0.911 (0.795 - 1.000) for diagnosing EIS from Con in the discovery cohort. In the validation cohort, the model had an AUC of 0.850 (0.722 - 0.977) for differentiating EIS from controls, overperforming the first brain CT (AUC 0.722 (0.604 - 0.840)) with a ΔAUC of 0.127. In conclusion, : We identified TRP, a protein pathophysiologically linked to EIS. it’s a model lcuding TRP and clinical features may facilitate clinical identification of EIS patients within the reperfusion treatment window at EMS.
