Biomarkers for ischaemic stroke

Abstract

Background: Current diagnostic, prognostic and risk stratification tools are inadequate for effective ischaemic stroke management. Hypothesising that –omics approaches can be used to detect novel candidate biomarkers for ischaemic stroke, this thesis aimed to evaluate the current status of biomarkers for ischaemic stroke and develop strategies for biomarker discovery.

Methods: Systematic literature review and individual patient data meta-analyses were performed to assess current candidate biomarkers associated with ischaemic stroke. Proteomic SELDI-TOF MS profiling was undertaken to identify novel blood-based protein biomarkers for the diagnosis of acute ischaemic stroke, consisting of a pilot study and a subsequent well-powered discovery study of 104 patients. In an integrative genomics study, transcriptomics data from carotid endarterectomy samples was combined with a genome-wide association study meta-analysis and subjected to functional enrichment analysis to detect differential gene expression or alternative splicing profiles that may be under the control of a genetic variant.

Results: Systematic review and meta-analysis concluded that no current candidate biomarkers could be recommended for routine clinical practice, supporting the pursuit of novel biomarkers for ischaemic stroke and informing the design of subsequent experimental studies. SELDI-TOF MS detected two plasma protein ions, m/z 3699 and m/z 6640, which could differentiate between acute cerebral ischaemia and stroke mimics. Protein ion m/z 6640, identified as ApoC 1, highlighted the role of lipid dysregulation and was postulated to be a novel candidate biomarker for acute cerebral ischaemia. Integrative genomics provided evidence for the genetic regulation of cytoskeletal organisation and extracellular matrix remodelling processes in carotid disease. The LTBP4 gene was found to be a candidate risk biomarker for ischaemic stroke by predicting plaque instability and rupture.

Conclusions: This work provides workflows for successful biomarker discovery using innovative –omics approaches, highlights key pathogenic pathways and identifies novel candidate biomarkers for ischaemic stroke diagnosis and risk stratification.