Fifty Years of Deciphering Stroke Pathophysiology

In the 2025 David G. Sherman Lecture, Jean-Claude Baron emphasizes the major role positron emission tomography played in the breakthroughs in ischemic stroke pathophysiology that took place in the last half-century and allowed major therapeutic advances. Based on his work using PET in both animal models and people with stroke spanning 4 decades, he details his main contributions to key milestones, including (1) the demonstration of the hemodynamic consequences of chronic carotid artery occlusion and the hemodynamic mechanism underlying some transient ischemic attacks; (2) the documentation of the existence of the ischemic penumbra in man and the formal validation, using stringent prespecified operational criteria, of the core/penumbra model; (3) the persistence of substantial penumbral volumes up to 17 hours after stroke onset in a substantial fraction of patients; (4) the demonstration that from early timepoints poststroke, a good fraction of patients do not show the extensive penumbral pattern but instead exhibit large cores or spontaneously reperfusion, indicating the importance of individual patient selection for trials and therapy based on physiological imaging instead of time since stroke onset; (5) the documentation that the salvaged penumbra may not be intact but is often affected by selective neuronal loss, which may impact functional outcome and represent a novel target for neuroprotection; and (6) the demonstration of remote metabolic effects of disconnection resulting in loss of excitatory input, such as crossed cerebellar diaschisis and thalamocortical diaschisis, which may represent additional targets for therapies aiming at adaptive plasticity.