SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury

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• 作者：Victoria E. Johnson ; William Stewart ; Maura T. Weber…
• 关键词：Traumatic brain injury ; TBI ; Concussion ; Mild TBI ; Diffuse axonal injury ; Spectrin breakdown ; SNTF ; Axonal pathology ; Amyloid precursor protein ; Neurofilaments
• 刊名：Acta Neuropathologica
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：131
• 期：1
• 页码：115-135
• 全文大小：3,859 KB
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• 作者单位：Victoria E. Johnson (1)
  William Stewart (1) (2) (3)
  Maura T. Weber (1)
  D. Kacy Cullen (1)
  Robert Siman (1)
  Douglas H. Smith (1)
  
  1. Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA, 19104, USA
  2. Department of Neuropathology, Queen Elizabeth Glasgow University Hospital, Glasgow, G51 4TF, UK
  3. University of Glasgow, Glasgow, G12 8QQ, UK
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pathology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0533

文摘

Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or “concussion”. The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, “SNTF”, was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI. Keywords Traumatic brain injury TBI Concussion Mild TBI Diffuse axonal injury Spectrin breakdown SNTF Axonal pathology Amyloid precursor protein Neurofilaments