Biofluid Markers of Ischemic Penumbra in Stroke: A Systematic Review and Pathway Analysis
Yuki Kawamura1, Shubham Misra1, Erum Khan2, Amr Elshahat3, Pei Yi Chook4, Ethan Wang5, Priyal Shah5, Mark Reed6, Melissa Funaro7, Nishant Mishra1
1Yale University, 2Neurology, The University of Alabama at Birmingham, 3Yale university, 4Universiti Malaya, 5Yale School of Medicine, 6California Northstate University, 7Yale
Objective:
This systematic review aims to assess biomarkers associated with the penumbra in acute ischemic stroke and their underlying molecular pathways.
Background:
Ischemic penumbra is metabolically active, functionally impaired brain tissue surrounding the infarct core in acute ischemic stroke (AIS). While imaging can identify penumbra via perfusion–diffusion mismatch, access is limited. Biofluid biomarkers may provide a scalable, cost-effective alternative.
Design/Methods:
A search of Ovid MEDLINE, Embase, PsycINFO, and Web of Science (till September 2023) identified studies involving adults or animal AIS models with imaging-confirmed penumbra, following PRISMA 2020 guidelines. Study quality was assessed using QUADAS-2. Biomarkers were analyzed using STRING (protein–protein interactions) and clusterProfiler (pathway enrichment via Reactome, KEGG, GO).
Results:
Ten studies (1,293 humans and 8 primates) met inclusion criteria, identifying 51 biomarkers. Four biomarkers demonstrated statistical association with penumbra, interleukin-10 (IL-10; SMD 1.94 [95% CI 0.85–3.03], p = 0.04), mid-regional pro-adrenomedullin (MR-proADM; SMD 0.81 [0.50–1.11], p < 0.001), F2-isoprostanes (F2-isoPs; SMD 0.18 [–0.10–0.48], p = 0.19), and circular OGDH RNA (circOGDH; SMD 0.71 [–0.66–2.07], p = 0.31). 2 of these, IL-10 and MR-proADM were statistically significant. Correlation analyses identified 34 significant genes (e.g., STK26 r = 0.58, p = 0.003; MGA r = 0.58, p = 0.004; IL1B r = –0.59, p = 0.003; NUP98 r = –0.71, p < 0.001) and NT-proBNP (r = 0.199, p < 0.001). Protein–protein network analysis showed IL-1β with highest connectivity (9 interactions), followed by IL-10 (5) and HDAC1/HCAR2 (4). Pathway enrichment revealed positive associations with angiogenesis (FDR < 0.05) and IL-12 signaling, and negative associations with leukocyte migration, chemokine signaling, and platelet activation.
Conclusions:
IL-10 and MR-proADM were significant penumbra markers, reflecting anti-inflammatory and vasodilatory mechanisms. Markers of leukocyte migration and platelet activation (IL-1β, PF4) were negatively associated. Findings support circulating biomarkers as complementary or alternative tools to imaging for identifying salvageable brain tissue in AIS.
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