Blood/Brain Biomarkers of Inflammation After Stroke and Their Association With Outcome: From C-Reactive Protein to Damage-Associated Molecular Patterns

Abstract

Stroke represents one of the most important causes of disability and death in developed countries. However, there is a lack of prognostic tools in clinical practice to monitor the neurological condition and predict the final outcome. Blood biomarkers have been proposed and studied in this indication; however, no biomarker is currently used in clinical practice. The stroke-related neuroinflammatory processes have been associated with a poor outcome in stroke, as well as with poststroke complications. In this review, we focus on the most studied blood biomarkers of this inflammatory processes, cytokines, and C-reactive protein, evaluating its association with outcome and complications in stroke through the literature, and performing a systematic review on the association of C-reactive protein and functional outcome after stroke. Globally, we identified uncertainty with regard to the association of the evaluated biomarkers with stroke outcome, with little added value on top of clinical predictors such as age or stroke severity, which makes its implementation unlikely in clinical practice for global outcome prediction. Regarding poststroke complications, despite being more practical scenarios in which to make medical decisions following a biomarker prediction, not many studies have been performed, although there are now some candidates for prediction of poststroke infections. Finally, as potential new candidates, we reviewed the pathophysiological actions of damage-associated molecular patterns as triggers of the neuroinflammatory cascade of stroke, and their possible use as biomarkers.

C‐reactive protein in the detection of post‐stroke infections: systematic review and individual participant data analysis

“…The inflammatory response that stroke triggers conditions an elevation of systemic inflammatory markers such as CRP (Pepys and Hirschfield ), but also contributes to the immunosuppressive state that facilitates the development of post‐stroke infections (Bustamante et al . ). Therefore, it seems unlikely that a single biomarker from this cascade could be specifically associated with infections in the setting of acute cerebral ischemia.…”

<p>The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke</p>

“…They can also lead to secondary complications such as swelling and hemorrhagic transformation. 8,27 The constant influx of leukocytes leads to lymphocytopenia, contributing to significant immunodepression which increases the risk of infection after stroke. In addition, the disproportionate concentration of pro-inflammatory mediators activates the autonomic nervous system, which leads to the inhibition of pro-inflammatory pathways and stimulation of antiinflammatory mechanisms by the release of interleukins and growth factors.…”

“…In addition, the disproportionate concentration of pro-inflammatory mediators activates the autonomic nervous system, which leads to the inhibition of pro-inflammatory pathways and stimulation of antiinflammatory mechanisms by the release of interleukins and growth factors. 25,27 Furthermore, necrotic neurons release "hazard signals" that activate the immune system and secrete molecular patterns (DAMP). 19,27 DAMP induces the Toll-like receptors (TLRs) on microglia, which in turn stimulates the NF-κB to synthesize most of the pro-inflammatory cytokines.…”

Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke

“…Furthermore, various studies suggested a potential role of CRP as predictor of worse neurological outcome, but this evidence remains controversial [158,159,160,161,162,163,164,167,168,195]. In this regard, a recent systematic review from 46 studies recognized CRP as independent predictor of long-term functional outcome in only 13 studies [196]. The high variability in the study design and the lack of classification/discrimination over clinical variables further challenge the clinical use of CRP, at least as single biomarker.…”