Top Priorities for Cerebroprotective Studies-A Paradigm Shift: Report From STAIR XI

Abstract

Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although "time is still brain," tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.

Keywords: blood-brain barrier; brain; ischemic stroke; neuroprotection; reperfusion.

Figure 1.. Differential Vulnerability.

The several elements of the neurovascular unit each exhibit different susceptibility to oxygen-glucose deprivation. Monocellular cultures underwent varying durations of OGD, and viability was measured 24 hours later. Neurons showed greatest vulnerability, astrocytes least vulnerability, and pericytes/endothelial cells were intermediate. The term ‘brain cerebroprotection’ includes protection of each element of the neurovascular unit: neuronoprotection, vasculoprotection, and glioprotection. Upper panel reprinted by permission of SAGE Publications, Ltd. Journal of Cerebral Blood Flow & Metabolism, 39(9):1693–1709. Copyright 2019 (International Society for Cerebral Blood Flow and Metabolism). Lower panel © Patrick Lyden MD.

Figure 2.. Opportunity Windows.

Scheme for understanding the historical evolution of successful treatment for acute ischemic stroke. Green indicates beneficial outcome, red indicates death or disability, and pink indicates a transition epoch where outcome may not be best, but not worst. These graphs are provided for illustration only, are not data-derived, and are not intended to suggest specific recommendations. A. Time Window. Initially thrombolysis and thrombectomy (together known as recanalization therapy) could only be targeted using clock time, defined as the time since the patient was last known well and free of new stroke deficits. B. Tissue Window. The development of perfusion imaging allowed for the estimation of perfusion mismatch and insight into the volume of salvageable tissue. Magnetic resonance-based techniques allowed even more direct imaging of tissue injury. Both perfusion and tissue injury methods allow recanalization therapy to target salvageable tissue, rather than depending on clock time. NB: despite the appearance of the figure, the relationship between time and mismatch is likely nonlinear. C. Target Window. In the future, both recanalization and brain cerebroprotection therapy might target different elements of the neurovascular unit at different times, knowing the differential progression of pathology in differentially vulnerable regions, or different brain regions using focal, targeted delivery (not illustrated). © Patrick Lyden, MD