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Published Online: 5 March 2013

Therapy Development for Diffuse Axonal Injury

Publication: Journal of Neurotrauma
Volume 30, Issue Number 5

Abstract

Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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cover image Journal of Neurotrauma
Journal of Neurotrauma
Volume 30Issue Number 5March 1, 2013
Pages: 307 - 323
PubMed: 23252624

History

Published online: 5 March 2013
Published in print: March 1, 2013
Published ahead of print: 14 February 2013
Published ahead of production: 20 December 2012

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Douglas H. Smith
Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Ramona Hicks
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
John T. Povlishock
Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.

Notes

Address correspondence to:John T. Povlishock, PhDDepartment of Anatomy and NeurobiologyVirginia Commonwealth University Medical CenterPO Box 980709Richmond, VA 23298E-mail: [email protected]

Author Disclosure Statement

The views expressed are those of the authors and do not necessarily reflect those of the agencies or institutions with which they are affiliated, including the United States Department of Health and Human Services. This work is not an official document, guidance, or policy of the United States government, nor should any official endorsement be inferred.
No competing or conflicting financial interests exist.

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