The Use of Antibodies Targeted Against the Neurofilament Subunits for the Detection of Diffuse Axonal Injury in Humans

Grady, M. Sean; McLaughlin, Mark R.; Christman, Carole W.; Valadka, Alex B.; Fligner, Corinne L.; Povlishock, John T.

doi:10.1097/00005072-199303000-00007

Cited by 184 publications

(106 citation statements)

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“…Specifically, swellings in the form of discrete axonal bulbs and axonal varicosities were observed in the roots of the gyri, at the interface of the grey and white matter, and within the deep white matter. These profiles were observed in a wide range of shapes and sizes, identical to the character of traumatic axonal pathology found in humans with TBI (Adams et al, 1989;Chen et al, 2009;Grady et al, 1993;Povlishock et al, 1983;Uryu et al, 2007). (A and B), parietal (C and D), and medulla (E and F) regions of the brain.…”

Section: Axonal Pathologysupporting

confidence: 62%

“…Unique to traumatic axonal injury, this immediate transport interruption may reflect mechanical disruption of the axonal cytoskeleton, such as breaking of microtubules due the dynamic aspect of the deformation (Smith et al, 1999b;Tang-Schomer et al, 2010). Ultimately, these axons may disconnect at distal points of swellings, which triggers degeneration within days after injury, as characterized by Povlishock and colleagues (Povlishock and Becker, 1985;Grady et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

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Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Browne

Chen²,

Meaney³

et al. 2011

Journal of Neurotrauma

217

172

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Until recently, mild traumatic brain injury (mTBI) or ''concussion'' was generally ignored as a major health issue. However, emerging evidence suggests that this injury is by no means mild, considering it induces persisting neurocognitive dysfunction in many individuals. Although little is known about the pathophysiological aspects of mTBI, there is growing opinion that diffuse axonal injury (DAI) may play a key role. To explore this possibility, we adapted a model of head rotational acceleration in swine to produce mTBI by scaling the mechanical loading conditions based on available biomechanical data on concussion thresholds in humans. Using these input parameters, head rotational acceleration was induced in either the axial plane (transverse to the brainstem; n = 3), causing a 10-to 35-min loss of consciousness, or coronal plane (circumferential to the brainstem; n = 2), which did not produce a sustained loss of consciousness. Seven days following injury, immunohistochemical analyses of the brains revealed that both planes of head rotation induced extensive axonal pathology throughout the white matter, characterized as swollen axonal bulbs or varicosities that were immunoreactive for accumulating neurofilament protein. However, the distribution of the axonal pathology was different between planes of head rotation. In particular, more swollen axonal profiles were observed in the brainstems of animals injured in the axial plane, suggesting an anatomic substrate for prolonged loss of consciousness in mTBI. Overall, these data support DAI as an important pathological feature of mTBI, and demonstrate that surprisingly overt axonal pathology may be present, even in cases without a sustained loss of consciousness.

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Section: Axonal Pathologysupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Browne

Chen²,

Meaney³

et al. 2011

Journal of Neurotrauma

217

172

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“…3,6,11 More modern approaches using antibodies to transported proteins, Research, NICHD, NIH such as amyloid precursor protein (APP), however, have become the gold standard in evaluating the occurrence of DAI in both the routine neuropathologic and forensic settings as well as animal investigations. 10,[12][13][14][15][16][17][18] Specifically, as APP moves down the axonal cylinder via anterograde axonal transport, any focal disruption/ perturbation of the axon and its transport kinetics can lead to local swelling that then can be easily identified by the pooling of APP. 19,20 Through the use of these antibodies in both neuropathologic and forensic settings, the overall occurrence and distribution of traumatically induced axonal change has become even more apparent and has extended many of those observations initially made via the use of more traditional histological approaches (Fig.…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

“…3,11,24,31 Typically in humans, reactive axonal swellings can be recognized within the first hours post-injury as large focal axonal swellings 10-20 lm in diameter that expand in size over 24-48 h reaching up to approximately 50 lm. 1,3,8,15,18,25,32 During this time, both axonal bulbs and varicosities are often observed together in various ratios, presumably reflecting the different rates of swelling and progression toward disconnection in individual injured axons. It is thought that axons sustaining more severe injury manifest local calcium dysregulation that causes progressive focal dissolution of the subaxolemmal spectrin and ankyrin network.…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

Self Cite

174

146

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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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“…Injured axons are thus a diagnostic marker for cognitive and behavioral deficits [3,21], both in animals and humans [22][23][24][25]. In extreme cases, axons are sheared or disconnected, leading to cell death.…”

Section: Introductionmentioning

confidence: 99%

Cognitive and behavioral deficits arising from neurodegeneration and traumatic brain injury: a model for the underlying role of focal axonal swellings in neuronal networks with plasticity

Rudy¹,

Maia²,

Kutz³

2016

J Integr Syst Neurosci

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Neurodegenerative diseases and traumatic brain injury, whose hallmark features are the presence of focal axonal swellings (FAS), are leading causes of cognitive dysfunction. By leveraging biophysical observations of FAS statistics, we develop a theoretical model of functional neural network activity driven by adaptive changes from plasticity. Based upon the FORCE model of Sussillo and Abbott [1], our innovations highlight the role of plasticity in overcoming injuries and degeneration of neurons in a network architecture. We provide a quantitative measure, on a network level, of cognitive deficits arising from injury. We demonstrate that plasticity is capable of overcoming mild injuries while failing to compensate for more severe injuries. Such injuries are characterized by their underlying effect on spike trains propagating through the neurons in a network architecture. Specifically, spike trains can be filtered in firing rate, or blocked under more severe FAS. The level of injury dictates the FORCE model's ability to produce a desired output functionality (and associated behavior) and allows for quantitative metrics for accessing cognitive and behavioral deficits. Thus a direct link between FAS in neural networks and compromised functional response can be established. The theoretical framework developed is a promising computational framework for providing a deeper understanding of the cognitive deficits arising in, for instance, Alzheimer's, Parkinson's, Multiple-Sclerosis, and TBI.

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The Use of Antibodies Targeted Against the Neurofilament Subunits for the Detection of Diffuse Axonal Injury in Humans

Cited by 184 publications

References 0 publications

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Therapy Development for Diffuse Axonal Injury

Cognitive and behavioral deficits arising from neurodegeneration and traumatic brain injury: a model for the underlying role of focal axonal swellings in neuronal networks with plasticity

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