Axonal degeneration in hemorrhagic stroke: A systematic review

Hemorrhagic stroke occurs due to a rupture of a blood vessel in the brain. This leads to initial mechanical damage at the site of injury and secondary injuries including axonal degeneration (AxD). Since axons are critical for all brain functions, we systematically reviewed studies that focused on axonal degeneration in two major types of hemorrhagic stroke, intracerebral hemorrhage and subarachnoid hemorrhage, to understand how and to what extent AxD develops and to interrogate underlying mechanisms and potential therapeutic targets. After screening 817 publications published until September 18, 2024, we identified 68 records to be included. AxD was detected in patients as early as 24 hours and in animal models as early as 6 hours. Several outcomes were reported including the release of neurofilaments into the CSF and blood, increased serum or cerebral levels of tau protein, the accumulation of beta-amyloid precursor protein at the sites of axonal damage, degenerative changes in axonal density and shape observed with light and electron microscopy, or white matter disruption in diffusion magnetic resonance imaging. AxD is correlated with hematoma volume and worsening of clinical outcomes. It occurs in various locations, especially in the perihemorrhagic zone, and its extent increases over time. Targeting neuroinflammation, improving energy metabolism, inhibiting microtubule breakdown, and stimulating axonal growth and regeneration were assessed as therapeutic options. Further investigations are needed to understand whether any of these options could be developed into novel interventions for hemorrhagic stroke. • Axonal degeneration (AxD) occurs as early as 6 hours after hemorrhagic stroke • AxD biomarkers include neurofilaments, tau, and beta-amyloid precursor protein • Diffusion MRI reveals white matter damage associated with AxD • AxD is linked to poor outcomes in hemorrhagic stroke patients • Neuroinflammation, energy metabolism, and axonal repair are therapeutic targets