MRI biomarkers in acute ischemic stroke: a conceptual framework and historical analysis.

O ver the past 2 decades, advanced multimodal imaging has offered much promise for stroke investigators and clini-cians, particularly those interested in using imaging to optimize and extend the time window for acute ischemic stroke therapies. Multimodal imaging has many potential applications in the acute stroke setting, such as the following: (1) to confirm the diagnosis of acute cerebral ischemia and exclude contrain-dications to treatment (eg, acute blood because of hemorrhagic transformation [HT]; (2) to select patients likely to benefit or not benefit from therapies (eg, by characterizing the extent of core irreversibly injured tissue, salvageable penumbra, or markers of high risk for HT); and (3) to serve as a surrogate or auxiliary outcome measure to test putative treatments. However, the promise of advanced multimodal imaging as a selection modality to optimize efficacy and safety of new treatments for stroke and also as a surrogate end point to test interventions has yet to be fully realized. Both of these applications use neuroimaging as a biomarker. A critical analysis of both the successes and missteps of studies performed to date, including translation of animal models to human studies, can provide valuable lessons that can be applied to the design of future studies. Applying current definitions and criteria for biomarkers to stroke neuroimaging research helps provide a conceptual framework for this analysis. The National Institutes of Health Biomarkers Definitions Working Group defines a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. 1 Biomarkers (Table 1 shows types, definitions, and examples) can be used as a diagnostic tool, a prognostic tool, a predictive tool (for predicting response to an intervention), or a substitute for a clinical outcome to measure the response to an intervention (surrogate end point). Biomarkers must be biologically plausible and show statistically appropriate performance characteristics. Prognostic biomarkers must correlate with clinical outcomes irrespective of treatment. Predictive biomarkers must be able to predict response to therapy. Finally, surrogate end points must additionally show responsiveness to therapeutic interventions. Thus, surrogate end points are a subset of bio-markers intended to substitute for a clinical end point, which are reasonably likely, based on epidemiological, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit (or harm or lack of either). 1 A valid surrogate end point must demonstrate both accuracy (correlation with clinical end point) and precision …