Perfusion imaging predicts therapeutic cooling response and tracks cis-p-tau pathology in porcine brain injuries.

Traumatic brain injury (TBI) and ischemic stroke cause substantial morbidity and mortality, yet effective neuroprotective therapies remain elusive. Although therapeutic hypothermia shows strong neuroprotection in lissencephalic rodent models, adult clinical trials have repeatedly failed, largely due to poor preclinical translatability and uniform cooling protocols that overlook patient heterogeneity. Using a large cohort of gyrencephalic porcine models (n = 89) of TBI and stroke, subjects were allocated to sham, injury, or therapeutic cooling groups administered via a custom-designed, non-invasive intranasal selective brain cooling device for pre-hospital and hospital settings. We combined clinical CT perfusion and neuropathology to identify biomarkers that predict cooling efficacy. Brain cooling significantly reduced mortality in TBI and stroke compared to untreated controls. We showed that concurrent hyperemia (elevated cerebral blood flow) and blood-brain barrier (BBB) leakage during cooling predicted intracranial hypertension, which may facilitate identification of high-risk subjects that require intervention. Sustained hyperemia was pathological. Neuropathological assessment revealed that cis-phosphorylated-tau (cis-p-tau), a major early driver of both TBI and stroke, is correlated with injury severity, treatment response, and BBB permeability. In TBI, mild selective brain cooling (∼1.3 °C reduction) was associated with reduced secondary brain damage, whereas deeper cooling (≥3 °C) offered no added benefit in this cohort. These findings suggest that integrating perfusion imaging and the early molecular driver cis P-tau can guide personalized hypothermia, advancing the field toward precision medicine in acute brain injury neuroprotection.