ReviewAxonal pathology in traumatic brain injury
Introduction
Although historically ignored as a major health issue, traumatic brain injury (TBI) is a leading cause of morbidity and mortality internationally, with significant socio-economic implications. In the US alone, over 1.7 M individuals suffer a TBI each year (Faul et al., 2010) at an estimated annual healthcare cost of over $60 billion (Finkelstein et al., 2006). Moreover, there is considerable evidence indicating just a single TBI may be associated with the later onset of neurodegenerative disorders, including Alzheimer's disease (AD) (Fleminger et al., 2003, Graves et al., 1990, Guo et al., 2000, Johnson et al., in press, Mortimer et al., 1985, Mortimer et al., 1991, O'Meara et al., 1997, Plassman et al., 2000, Salib and Hillier, 1997, Schofield et al., 1997).
While the neuropathological consequences of TBI are heterogeneous, one of the most common across all severities of closed head injury is diffuse axonal injury (DAI) (Adams et al., 1982, Adams et al., 1989, Graham et al., 1988, Povlishock, 1992, Povlishock and Becker, 1985, Povlishock and Katz, 2005, Povlishock et al., 1983, Smith and Meaney, 2000), which may reflect the selective vulnerability of white matter axons to damage from mechanical loading of the brain during rapid head accelerations. After TBI, axonal degeneration arising from DAI is conventionally recognized as a progression from disruption in axonal transport leading to axonal swelling followed by secondary disconnection and, finally, Wallerian degeneration. Traditionally this process was thought to be limited to the acute and sub-acute periods following trauma. However, recent evidence has identified axonal degeneration in human brain material years following injury, suggesting TBI may precipitate a progressive, long-term neurodegenerative process, in part reflected in axonal degeneration (Chen et al., 2009). Of particular note, axonal pathology may have a role in the development of Alzheimer-like pathologies both in the acute phase following injury as well as with longer term survival (Chen et al., 2004, Chen et al., 2009, Johnson et al., 2010, Johnson et al., in press, Marklund et al., 2009, Smith et al., 1999a, Smith et al., 2003a, Smith et al., 2003b, Smith et al., 2003c, Stone et al., 2002, Tran et al., 2011). Here we explore the current understanding of the short- and long-term pathological sequelae of axonal degeneration following TBI.
Section snippets
Historical perspective of DAI
Classical descriptions of diffuse axonal injury are of a clinicopathological syndrome manifest as a patient unconscious from the time of injury where, on subsequent autopsy examination of the brain, there is widespread axonal injury in the cerebral hemispheres, cerebellum and brainstem. Approaching the middle of last century, the pathological appearances of trauma related axonal injury were first described in human tissue where, in addition to the previously well-known macroscopic focal
DAI: pathological features and identification
A primary outcome of dynamic deformation of white matter tracts during trauma is the interruption of axonal transport, resulting in accumulation of transported materials as axonal swellings within just hours of trauma (Christman et al., 1994, Povlishock and Becker, 1985, Smith et al., 1999a, Smith et al., 1999b). Commonly, these swellings appear in a periodic arrangement along the length of an axon at the site of injury, classically referred to as “axonal varicosities” (Figs. 1a,c–d). A more
DAI genesis and the link with coma and transient loss of consciousness
Animal models have been instrumental in confirming that the principal mechanical force responsible for DAI is rotational acceleration of the brain, resulting from unrestricted head movement inducing dynamic shear, tensile, and compressive strains within the tissue (Gennarelli et al., 1982, Meaney et al., 1996, Ommaya and Hirsch, 1971, Smith et al., 1997, Thibault et al., 1990). As such, the size of the human brain plays an important role in the development of DAI, as the substantial mass
Potential primary mechanical damage due to axonal trauma
With evidence that mechanical damage to axons can account directly for clinical symptoms, the biomechanical nature of TBI was increasingly recognized as an important and unique feature. Specifically, the viscoelastic properties of the brain emerged as a potential liability during the rapid mechanical loading conditions of TBI. White matter axons appear especially vulnerable to injury under such circumstances, potentially as a result of their highly anisotropic arrangement and/or their inherent
Secondary chemical cascades following TBI
During TBI, all axons within a white matter tract are thought to suffer relatively similar dynamic deformations. Yet, even in severe TBI, only a small percentage of axons within a given tract undergo transport interruption as classically identified by accumulation of transported cargoes in swellings. However, the remaining axons that do not display appreciable interruption to transport following dynamic deformation, nonetheless may suffer important pathophysiological changes capable of
Evidence for persistent axonal degeneration following TBI
Although both overt and subtle pathological changes to axons may play a role in the immediate loss of consciousness and/or cognitive dysfunction that characterizes TBI, the relative contributions of differing forms of axonal pathologies over time have yet to be determined. Using APP as a marker of DAI, axonal pathology is observed to increase to a peak in the initial 24 h following injury, thereafter leveling off (Gultekin and Smith, 1994). Although this represents the peak of pathology, damaged
TBI and the link with neurodegenerative diseases
The association between TBI and chronic progressive neurodegeneration emerged from observation of boxers at the turn of the last century, when the term “punch drunk syndrome” was first used to describe a progressive dementing disorder in participants of the sport (Martland, 1928). Subsequently termed 'dementia pugilistica' and more recently referred to as chronic traumatic encephalopathy (CTE), the disorder is believed to arise as a consequence of repetitive mild TBI and is neuropathologically
Injured axons as a source of Aβ
Although it is possible that multiple sources contribute to Aβ-plaque formation after TBI, the rapid accumulation of the precursor of Aβ, APP, in damaged axons, represents an intriguing potential source of Aβ for further investigation. Indeed, upon close examination of axonal bulbs in DAI, APP is seen to co-accumulate with the enzymes necessary for its cleavage to Aβ peptides, including presenelin-1 and beta-site APP-cleaving enzyme. Observed in both the pig model of DAI (Chen et al., 2004)
Conclusions
Recently, there has been mounting evidence of the substantial pathological consequences of DAI due to TBI. Occurring as a direct consequence of mechanical injury, DAI has been identified as responsible for immediate and persistent coma following injury and is independently a significant cause of morbidity and mortality. However, more recently it has emerged that DAI may induce a multitude of functionally detrimental effects over a far greater range of severity than previously considered.
Acknowledgments
This work is supported by the National Institute of Health grants: NS056202, NS038104 (all DHS).
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