Non-coding RNAs versus protein biomarkers to diagnose and differentiate acute stroke: Systematic review and meta-analysis

J Stroke Cerebrovasc Dis. 2023 Nov;32(11):107388. doi: 10.1016/j.jstrokecerebrovasdis.2023.107388. Epub 2023 Sep 29.


Background: Stroke diagnosis is dependent on lengthy clinical and neuroimaging assessments, while rapid treatment initiation improves clinical outcome. Currently, more sensitive biomarker assays of both non-coding RNA- and protein biomarkers have improved their detectability, which could accelerate stroke diagnosis. This systematic review and meta-analysis compares non-coding RNA- with protein biomarkers for their potential to diagnose and differentiate acute stroke (subtypes) in (pre-)hospital settings.

Methods: We performed a systematic review and meta-analysis of studies evaluating diagnostic performance of non-coding RNA- and protein biomarkers to differentiate acute ischemic and hemorrhagic stroke, stroke mimics, and (healthy) controls. Quality appraisal of individual studies was assessed using the QUADAS-2 tool while the meta-analysis was performed with the sROC approach and by assessing pooled sensitivity and specificity, diagnostic odds ratios, positive- and negative likelihood ratios, and the Youden Index.

Summary of review: 112 studies were included in the systematic review and 42 studies in the meta-analysis containing 11627 patients with ischemic strokes, 2110 patients with hemorrhagic strokes, 1393 patients with a stroke mimic, and 5548 healthy controls. Proteins (IL-6 and S100 calcium-binding protein B (S100B)) and microRNAs (miR-30a) have similar performance in ischemic stroke diagnosis. To differentiate between ischemic- or hemorrhagic strokes, glial fibrillary acidic protein (GFAP) levels and autoantibodies to the NR2 peptide (NR2aAb, a cleavage product of NMDA neuroreceptors) were best performing whereas no investigated protein or non-coding RNA biomarkers differentiated stroke from stroke mimics with high diagnostic potential.

Conclusions: Despite sampling time differences, circulating microRNAs (< 24 h) and proteins (< 4,5 h) perform equally well in ischemic stroke diagnosis. GFAP differentiates stroke subtypes, while a biomarker panel of GFAP and UCH-L1 improved the sensitivity and specificity of UCH-L1 alone to differentiate stroke.

Keywords: Biomarkers; Meta-analysis; Non-coding RNAs; Stroke.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Biomarkers
  • Glial Fibrillary Acidic Protein
  • Hemorrhagic Stroke*
  • Humans
  • Ischemic Stroke* / diagnosis
  • Ischemic Stroke* / therapy
  • MicroRNAs*
  • RNA, Untranslated
  • Stroke* / diagnosis


  • Biomarkers
  • Glial Fibrillary Acidic Protein
  • MicroRNAs
  • RNA, Untranslated