Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI) is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key risk factor for neurodegeneration and dementias at long-term following TBI, the secondary injury processes may require prolonged monitoring. The aim of the present review is to summarize the clinical short- and long-term monitoring possibilities of axonal injury in TBI. Increased knowledge of the underlying pathophysiology achieved by advanced clinical monitoring raises hope for the development of novel treatment strategies for axonal injury in TBI.

Brain-originated peptides as possible biochemical markers of traumatic brain injury in cerebrospinal fluid post-mortem examination

“…Increased GFAP, NFL, and MBP CSF level in head injury patients corresponded with frontal lobe disseminated astrocyte clasmatodendrosis, neurofilament rupture, and diminished MBP expression, respectively. Astrocyte clasmatodendrosis and neurofilament rupture may be related to primary and secondary axotomy -due to oedema, raised intracranial pressure, cerebral blood flow dysfunction (ischemia and hypoxia), and as well changes at the cellular level, such as glutamate excitotoxicity, ionic imbalance, dysfunction of mitochondria, oxidative stress, inflammatory factors release, necrosis and apoptosis [13,29]. We find the diminished MBP expression which could be a result of secondary processes including intracellular calcium overload from glutamate toxicity or mitochondrial dysfunction and oxidative stress [2,26].…”

The Contribution of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Reducing Neurodegeneration and Promoting Neural Network Reorganization after Traumatic Brain Injury

“…Axon pathology induced by TBI has been well recognized in the field of TBI research. Diffuse axonal injury is a direct consequence of mechanical injury and induces neurodegeneration and functional deficits [61,62]. In our present long-term TBI study, the axonal injury marker, APP, is not detectable in the brain 24 weeks after TBI, suggesting that the fast axonal transport accumulation of APP may occur only in the acute phase, but not in the late subacute phase of TBI.…”

The Contribution of Stem Cell Factor and Granulocyte-Colony Stimulating Factor in Reducing Neurodegeneration and Promoting Neural Network Reorganization after Traumatic Brain Injury

“…Axon pathology induced by TBI has been well recognized in the field of TBI research. Diffuse axonal injury is a direct consequence of mechanical injury and induces neurodegeneration and functional deficits [57,58]. However, few, if any, research reported the overgrowth of axons after TBI.…”