In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study

Abstract

Traumatic brain injury causes diffuse axonal injury and loss of cortical neurons. These features are well recognized histologically, but their in vivo monitoring remains challenging. In vivo cortical microdialysis samples the extracellular fluid adjacent to neurons and axons. Here, we describe a novel neuronal proteolytic pathway and demonstrate the exclusive neuro-axonal expression of Pavlov’s enterokinase. Enterokinase is membrane bound and cleaves the neurofilament heavy chain at positions 476 and 986. Using a 100 kDa microdialysis cut-off membrane the two proteolytic breakdown products, extracellular fluid neurofilament heavy chains NfH476−986 and NfH476−1026, can be quantified with a relative recovery of 20%. In a prospective clinical in vivo study, we included 10 patients with traumatic brain injury with a median Glasgow Coma Score of 9, providing 640 cortical extracellular fluid samples for longitudinal data analysis. Following high-velocity impact traumatic brain injury, microdialysate extracellular fluid neurofilament heavy chain levels were significantly higher (6.18 ± 2.94 ng/ml) and detectable for longer (>4 days) compared with traumatic brain injury secondary to falls (0.84 ± 1.77 ng/ml, <2 days). During the initial 16 h following traumatic brain injury, strong correlations were found between extracellular fluid neurofilament heavy chain levels and physiological parameters (systemic blood pressure, anaerobic cerebral metabolism, excessive brain tissue oxygenation, elevated brain temperature). Finally, extracellular fluid neurofilament heavy chain levels were of prognostic value, predicting mortality with an odds ratio of 7.68 (confidence interval 2.15–27.46, P = 0.001). In conclusion, this study describes the discovery of Pavlov’s enterokinase in the human brain, a novel neuronal proteolytic pathway that gives rise to specific protein biomarkers (NfH476−986 and NfH476−1026) applicable to in vivo monitoring of diffuse axonal injury and neuronal loss in traumatic brain injury.

Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina

“…Increased apoptosis in MBP and NF damage the white matter of CNS (Petzold et al, 2011;Pun et al, 2011). In consistence, we find that the impairment in postnatal oligodendrocytes and axons further increased cellular apoptosis in the brain and O.N.…”

“…extension (Chow et al, 2009). An enhanced apoptosis reduces the white matter content in CNS (Petzold et al, 2011).…”

Hyperacute Detection of Neurofilament Heavy Chain in Serum Following Stroke: A Transient Sign

“…Indeed, biomarkers released by cortical pathology are likely to be found quicker and at higher concentration in the bloodstream due to diffusion through the cortical arachnoid villi [22]. Potential factors influencing NfH release include systemic blood pressure, haemodilution and brain temperature [26]. Glucose metabolism and glutamate toxicity are additional factors which could influence NfH release in the setting of cerebral ischemia.…”

The Role of Invasive Monitoring in Traumatic Brain Injury

“…Lactate: pyruvate ratios reflect anaerobic glycolysis secondary to ischemia and mitochondrial failure with ratios >20-25 being associated with poor outcome in TBI [36][37][38]. Glycerol levels of >100 μmol/L, glucose levels <1.5-2 mmol/L, and glutamate levels >15-20 mol/L are also associated with poor outcome and reflect metabolic crisis in TBI [39]. This technique has allowed the exploration of other biomarkers such as neurofilament heavy chain which, in one study, had an OR 7.68 for predicting mortality in TBI which was superior to ICP, GCS, and CPP [40•] and Tau levels which, in another preliminary study, were found to correlate with MRI DTI and may be a possible marker for traumatic axonal injury [41•].…”