Therapy development for diffuse axonal injury.
Therapy development for diffuse axonal injury.
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DOI：
10.1089/neu.2012.2825
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发表时间：
2013-03
影响因子：
4.2
通讯作者：
Douglas H. Smith;R. Hicks;J. Povlishock
中科院分区：
文献类型：
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作者：
Douglas H. Smith;R. Hicks;J. Povlishock
弥漫性轴索损伤（DAI）仍然是人类创伤性脑损伤（TBI）的突出特征，并且是其随后发病率的主要参与者。这种广泛的轴突损伤的重要性已被多种方法证实，包括常规的死后神经病理学以及先进的成像技术，现在能够检测创伤诱导的轴突损伤的签名跨一系列创伤性脑损伤的人。尽管对DAI及其对脑损伤患者的整体影响的兴趣增加，但关于TBI的这一组成部分及其潜在的治疗靶向仍然存在许多问题。为了解决这些缺陷，并确定未来的方向，以填补我们对TBI的这一组成部分的理解的关键空白，国家神经疾病和中风研究所于2011年5月举办了一个研讨会。该研讨会旨在确定在动物损伤模型以及人类临床环境中DAI的发病机制。研讨会还讨论了新的工具，以帮助识别这种轴突损伤，同时还确定了与DAI相关的更合理的治疗靶点，以进行持续的临床前研究，并最终进行临床转化。本报告概括了本次研讨会的口头和书面部分，讨论了DAI病理生物学的关键特征，其起始病理学中涉及的生物力学，以及与人类TBI生物力学特征相关的实验动物建模考虑因素。DAI检测的替代形式包括但不限于先进的神经影像学，电生理学，生物标志物和神经行为评价的平行考虑，以及如何更好地使用和整合这些技术的建议，以更全面地了解DAI的病理生物学及其整体结构和功能的影响。最后，该文件以与DAI发病机制相关的靶点的全面综述结束，同时还提供了迄今为止已使用的基于靶点的治疗的详细报告，并考虑了其对未来临床前发现和随后转化为临床的总体影响。尽管所有与会者都认识到，在我们对创伤性脑损伤这一复杂组成部分的理解和治疗方面仍存在各种研究空白，但本次研讨会首次对这些问题进行了提炼，全面了解了已经做了哪些工作，以及哪些关键需求尚未得到满足。
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.