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Abstract
Objective To examine the relationship between neonatal inflammatory cytokines and perinatal stroke using a systems biology approach analyzing serum and blood-spot cytokines from 47 patients.
Methods This was a population-based, controlled cohort study with prospective and retrospective case ascertainment. Participants were recruited through the Alberta Perinatal Stroke Project. Stroke was classified as neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or periventricular venous infarction (PVI). Biosamples were stored blood spots (retrospective) and acute serum (prospective). Controls had comparable gestational and maternal ages. Sixty-five cytokines were measured (Luminex). Hierarchical clustering analysis was performed to create heat maps. The Fisher linear discriminant analysis was used to create projection models to determine discriminatory boundaries between stroke types and controls.
Results A total of 197 participants were analyzed (27 with NAIS, 8 with APPIS, 12 with PVI, 150 controls). Cytokines were quantifiable with quality control measures satisfied (standards testing, decay analysis). Linear discriminant analysis had high accuracy in using cytokine profiles to separate groups. Profiles in participants with PVI and controls were similar. NAIS separation was accurate (sensitivity 77%, specificity 97%). APPIS mapping was also distinguishable from NAIS (sensitivity 86%, specificity 99%). Classification tree analysis generated similar diagnostic accuracy.
Conclusions Unique inflammatory biomarker signatures are associated with specific perinatal stroke diseases. Findings support an acquired pathophysiology and suggest the possibility that at-risk pregnancies might be identified to develop prevention strategies.
Classification of evidence This study provides Class III evidence that differences in acute neonatal serum cytokine profiles can discriminate between patients with specific perinatal stroke diseases and controls.
Glossary
- APPIS=
- arterial presumed perinatal ischemic stroke;
- APSP=
- Alberta Perinatal Stroke Project;
- BCA-1=
- B-cell–attracting chemokine-1;
- CI=
- confidence interval;
- CTACK=
- cutaneous T-cell–attracting chemokine;
- ENA-78=
- epithelial-neutrophil activating peptide-78;
- FGF-2=
- fibroblast growth factor 2;
- GRO=
- growth-regulated oncogene;
- HIE=
- hypoxic ischemic encephalopathy;
- ICD=
- International Classification of Diseases;
- IFN=
- interferon;
- IL=
- interleukin;
- IL-1ra=
- interleukin-1 receptor antagonist;
- IP-10=
- IFN-γ–inducible protein;
- LDA=
- linear discriminant analysis;
- LIF=
- leukemia inhibitory factor;
- MCP=
- mast cell protease;
- MDC=
- macrophage-derived chemokine;
- MIP=
- macrophage inflammatory protein;
- NAIS=
- neonatal arterial ischemic stroke;
- PDGF=
- platelet-derived growth factor;
- PVI=
- periventricular venous infarction;
- RANTES=
- regulated on activation normal T cell expressed and secreted;
- sCD40L=
- soluble cluster of differentiation 40 ligand;
- SCF=
- stem cell factor;
- SDF-1=
- stromal cell–derived factor;
- TARC=
- thymus and activation-regulated chemokine;
- TGFα=
- transforming growth factor-α;
- TNF=
- tumor necrosis factor;
- TSLP=
- thymic stromal lymphopoietin;
- VEGF=
- vascular endothelial growth factor
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Class of Evidence: NPub.org/coe
- Received August 29, 2019.
- Accepted in final form March 30, 2020.
- © 2020 American Academy of Neurology
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