Predicting intracranial hypertension as a secondary insult using the pathological peptidome of brain injured patients

Intracranial hypertension (IHT) is a common secondary insult that worsens morbidity and death after acute brain injury from traumatic and hemorrhagic events. Suspicion of IHT is determined with a combination of neurological examination and imaging but is often hampered by sedation and limited by cost and radiation exposure for repeated assessment. Given the uncertainty, many at risk for IHT may not have intracranial pressure (ICP) monitors inserted when weighed against the risks of this invasive surgical procedure. Thus, the availability of blood-based biomarkers diagnostic of IHT would represent a major advance in neurointensive care. Pathological processes of brain injury, such as IHT-causing vasogenic edema, involve intra- and extra-cellular proteolytic activity, producing small-sized peptide byproducts cleared through waste streams. Thus, novel peptide content introduced to the blood with brain injury was assessed in this early-phase hypothesis generating study for its biomarker potential to prognose IHT using samples from thirteen patients that either had acute brain injury and ICP monitors inserted or had exclusively extra-cranial injuries as hospitalized control cases. Patients were then classified into high ICP (n = 6) or normotensive (n = 7) populations. Mass spectrometry was performed to build a peptide panel prognostic of high ICP (> 20 mmHg) events within 72 h of injury. Seventy-nine peptides were identified that differentiated patients with high ICP events through an increase in serum concentrations that preceded ICP elevation within the 72-hour window. Seven top-performing peptides were selected for the final model, which were derived from COL5A2, MICAL2, MRTFA, PCSK1, PRDM16, PRSS56, and SMAD6 proteins. Receiver operating characteristic curves showed that the top-ranked peptides achieved an area under the curve of 0.97. Functionally, these peptides were associated with perivascular dynamics relevant to vasogenic edema. The assay remained prognostic throughout the 72-h window, supporting its potential longitudinal use in the intensive care setting. In conclusion, peptides produced during brain injury pathobiology promise a new biomarker source with the potential to inform on secondary insults such as IHT, supporting further investigation.