Early axonal injury in fentanyl intoxication.

The rapid rise in fatalities linked to illicit synthetic opioids has positioned fentanyl as a leading cause of sudden death worldwide. Its extreme potency and swift penetration into the central nervous system can induce abrupt respiratory collapse and profound cerebral hypoxia within minutes—often before clinical intervention is possible. Despite the scale of the fentanyl crisis, the earliest neuropathological changes in these deaths remain poorly understood, particularly when survival is too brief for the development of classical hypoxic markers such as neuronal necrosis. Understanding the immediate pathology of fentanyl-induced hypoxia is therefore essential for accurate forensic diagnosis and for advancing the neuropathological framework of opioid-related mortality. We employed β-amyloid and amyloid precursor protein (APP) immunohistochemistry to determine whether axonal pathology is an early marker of hypoxic-ischemic encephalopathy in fentanyl intoxication and other etiologies of sudden death. We examined fourteen autopsy brains from individuals aged 20–64 years: 11 fentanyl-related deaths, 2 sudden cardiac arrhythmias, and 1 carbon monoxide intoxication. Four additional cases with prolonged hypoxic survival (24 h–1 month) served as positive controls. Multiple brain regions underwent routine histopathology and immunohistochemistry for β-amyloid, APP, and phospho-tau (AT8). β-amyloid and APP immunostains consistently revealed prominent axonal swellings, spheroids, and focal fragmentation, most pronounced in frontal white matter and hippocampus, with additional involvement of temporal, parietal, occipital, cerebellar, and pontine white matter in some cases. Brains were free of traumatic pathology, edema, or neuronal necrosis on H&E staining. No significant confounding amyloid plaque or chronic traumatic encephalopathy pathology was identified. APP- and β-amyloid–positive axonopathy represent a highly sensitive and very early marker of hypoxic-ischemic brain injury, detectable even in the absence of neuronal necrosis. Systematic assessment of axonal immunoreactivity improves postmortem evaluation of sudden unexplained death, particularly where conventional indicators of hypoxia are lacking.