Therapy Development for Diffuse Axonal Injury

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.

Repeated mild traumatic brain injury: potential mechanisms of damage

“…197 Secondary messenger cascades activate protein kinases, phospholipases, and proteases, which within 6 h leads to either neurofilament instability via phosphorylation or neurofilament collapse via calpain-mediated proteolysis of side-arms. 198 Ca 2þ -mediated microtubule disassembly ensues, 199 and cytoskeletal disorganization often persists, 200 with silver staining used to visualize the punctate structures and argyrophilic fibers that are observed.…”

The current state of biomarkers of mild traumatic brain injury

“…Multiple regions of the brain can suffer axonal injury after concussion due to sheering forces that place tension on axon fibers (44). While immediate axonal disconnection typically does not occur following mTBI, the aforementioned disturbance of the cellular environment caused by excess neurotransmitter release can result in secondary axotomy (45).…”

Diffuse Axonal Injury: A Devastating Pathology

“…In the event that a patient regains consciousness and makes a near-full recovery through the management of brain swelling, hemorrhage, and neurological network status, there are a multitude of therapeutic modalities that can be pursued to maximize the chance of a near-full recovery. This plan entails a variety of medical professional care for the patient each in a specific regard [55]. Upon discharge from trauma and emergency centers, patients enter a long and intensive program for multiple forms of therapeutic care consisting of the following modalities: speech therapy, physical therapy, occupational therapy, recreational therapy, adaptive equipment training, and counseling [56].…”