MRI Assessment of Post-Ischemic Neuroinflammation in Stroke: Experimental and Clinical Studies

Abstract

Stroke is a major healthcare issue in both industrialized and developing countries (Yach et al., 2004): it is the third leading cause of death, after myocardial infarction and cancer, the second leading cause of dementia, and the leading cause of permanent disability in Western countries (Pendlebury et al., 2009; Rothwell et al., 2011). Ischemic stroke accounts for up to 85% of total stroke events (Feigin et al., 2003). Cerebral ischemia is caused by blood-clot obstruction of a cerebral artery. Occlusion of a brain vessel leads to a critical reduction in cerebral perfusion and, within minutes, to ischemic infarction. The resulting lesion comprises a central infarct core of irreversibly damaged brain tissue and a surrounding area of hypoperfused but still viable brain tissue (the ischemic penumbra), which can potentially be salvaged by rapid restoration of the blood flow. Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of symptom onset can improve the clinical outcome (NINDS, 1995; Hacke et al., 2008). Endovascular strategies (e.g. thrombectomy) can enhance reperfusion rates in large artery occlusions, but remain to be validated in randomized clinical trials. Although approved by North American and European authorities, only a small proportion of patients receive acute revascularization therapies, mainly because of late diagnosis and limited access to specialized stroke units. Neuroprotective drugs aim at salvaging the ischemic brain by targeting multiple pathophysiological processes: prolonging the time window for reperfusion therapies, limiting reperfusion injury and the risk of hemorrhage, minimizing the deleterious effects of inflammation. Compounds regulating the inflammatory response are being evaluated by the pharmaceutical industry (Barone & Parsons, 2000). Indeed, stroke triggers a marked inflammatory reaction, involving several types of immune cells, including those of the mononuclear phagocyte system. There has been a longstanding controversy about the respective role of these cells, whether they are infiltrating blood-borne macrophages or resident microglia. On one hand, there is evidence that inflammation can contribute to secondary ischemic injury and worsening of neurological status (Iadecola & Alexander, 2001). On the other hand, inflammation under certain circumstances could promote functional recovery, by supporting neurogenesis and plasticity (Ekdahl et al., 2009). Therefore, targeted intervention to control specific aspects of post-ischemic neuro-