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

Petzold, A; Tisdall, MM; Girbes, AR; Martinian, L; Thom, M; Kitchen, N; Smith, M; (2011) In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study. BRAIN , 134 (2) 464 - 483. 10.1093/brain/awq360. Green open access

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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 NfH(476-986) and NfH(476-1026), 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 (NfH(476-986) and Nf(H476-1026)) applicable to in vivo monitoring of diffuse axonal injury and neuronal loss in traumatic brain injury.

Type: Article
Title: In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awq360
Publisher version: http://dx.doi.org/10.1093/brain/awq360
Language: English
Additional information: © The Author(s) 2011. Published by Oxford University Press on behalf of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: extracellular fluid, interstitial fluid, neurocritical care, neurodegeneration, neurofilaments, DIFFUSE AXONAL INJURY, POSITRON-EMISSION-TOMOGRAPHY, NEUROFILAMENT HEAVY-CHAIN, CENTRAL-NERVOUS-SYSTEM, CEREBRAL-BLOOD-FLOW, PC12 CELLS, THERAPEUTIC HYPOTHERMIA, NORMOBARIC HYPEROXIA, OXYGEN-TOXICITY, PHOSPHORYLATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
URI: https://discovery.ucl.ac.uk/id/eprint/1056459
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