Quantitative Analysis of the Relationship between Intra- Axonal Neurofilament Compaction and Impaired Axonal Transport following Diffuse Traumatic Brain Injury

Marmarou, Christina R.; Walker, Susan; Davis, Cora; Povlishock, John T.

doi:10.1089/neu.2005.22.1066

Cited by 95 publications

(82 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There was no staining contralateral to the injury site or in uninjured tissue. These findings are consistent with previous descriptions of axonal injury as defined by neurofilament light chain immunostaining (Christman et al, 1994;Grady et al, 1993;Marmarou and Povlishock, 2006;Marmarou et al, 2005;Yaghmai and Povlishock, 1992).…”

Section: Resultssupporting

confidence: 93%

“…Although robust in its ability to determine the density of APP stained axonal varicosities in an unbiased fashion, there is a possibility that over-counting of injured axons may occur as a single injured axon may have multiple APP stained varicosities. In addition, under-counting may occur as some injured axons may not stain with APP (Marmarou et al, 2005;Stone et al, 2001). Thus, the quantitative estimates of axonal injury should be regarded as approximate.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that the histological characterization of axonal injury by neurofilament and APP immunostaining serve as complementary markers of axonal injury (Marmarou et al, 2005;Stone et al, 2001). APP, which normally traverses the length of the axon (Koo et al, 1990), accumulates at axonal retraction bulbs and varicosities in response to injury (Gentleman et al, 1993;Lewen et al, 1995;Sherriff et al, 1994;Smith et al, 1999;Stone et al, 2000;Stone et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Donald

Dikranian

Song

et al. 2007

Experimental Neurology

275

209

View full text Add to dashboard Cite

Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 hours and 24 hours post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters -axial diffusivity and relative anisotropy -were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectible on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP tained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure.Corresponding Author: David Brody, MD PhD, Department of Neurology, Washington University, 660 S. Euclid, Campus Box 8111, St. Louis, MO 63110, Phone: 314-747-0286, Fax: 314-362-2244 Email: brodyd@neuro.wustl.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose. NIH Public Access

show abstract

Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Donald

Dikranian

Song

et al. 2007

Experimental Neurology

275

209

View full text Add to dashboard Cite

show abstract

“…2). [50][51][52][53] In contrast to these two morphological manifestations of injury, axons with significantly less severe mechanical injury may have a much slower progression of swelling in one or multiple regions along the cylinder. For these axons, it is thought that some may actually recover with the restoration of ionic homeostasis and axonal transport-a finding confirmed by recent electrophysiological studies, while others continue to slowly swell and disconnect (Fig.…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

Self Cite

173

146

View full text Add to dashboard Cite

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.

show abstract

“…Three serial APPimmunolabeled coronal sections (100 µm apart) adjacent to those used for capspase-3 counting were selected at 30 min, 5, 16 and 24 hrs post-trauma (6 animals per group). Individual injured APP immunolabeled axonal profiles were identified in the outlined regions at 60x oil objective and counted as described previously (Marmarou et al, 2005;Mac Donald et al, 2007b). The total number APP-immunopositive profiles within the cingulum/external capsule region was expressed as the density of axons per mm 3 .…”

Section: Morphometric and Statistical Analysismentioning

confidence: 99%

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Dikranian

Cohen

Donald

et al. 2008

Experimental Neurology

View full text Add to dashboard Cite

The immature brain in the first several years of childhood is very vulnerable to trauma. Traumatic brain injury (TBI) during this critical period often leads to neuropathological and cognitive impairment. Previous experimental studies in rodent models of infant TBI were mostly concentrated on neuronal degeneration, while axonal injury and its relationship to cell death have attracted much less attention. To address this, we developed a closed controlled head injury model in infant (P7) mice and characterized the temporospatial pattern of axonal degeneration and neuronal cell death in the brain following mild injury. Using amyloid precursor protein (APP) as marker of axonal injury we found that mild head trauma causes robust axonal degeneration in the cingulum/external capsule as early as 30 min post-impact. These levels of axonal injury persisted throughout a 24 hr period, but significantly declined by 48 hrs. During the first 24 hrs injured axons underwent significant and rapid pathomorphological changes. Initial small axonal swellings evolved into larger spheroids and clublike swellings indicating the early disconnection of axons. Ultrastructural analysis revealed compaction of organelles, axolemmal and cytoskeletal defects. Axonal degeneration was followed by profound apoptotic cell death in the posterior cingulate and retrosplenial cortex and anterior thalamus which peaked between 16 and 24 hrs post-injury. At early stages post-injury no evidence of excitotoxic neuronal death at the impact site was found. At 48 hrs apoptotic cell death was reduced and paralleled with the reduction in the number of APP-labeled axonal profiles. Our data suggest that early degenerative response to injury in axons of the cingulum and external capsule may cause disconnection between cortical and thalamic neurons, and lead to their delayed apoptotic death.

show abstract

Quantitative Analysis of the Relationship between Intra- Axonal Neurofilament Compaction and Impaired Axonal Transport following Diffuse Traumatic Brain Injury

Cited by 95 publications

References 63 publications

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Therapy Development for Diffuse Axonal Injury

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Contact Info

Product

Resources

About