Pathobiology of traumatically induced axonal injury in animals and man

“…within an elastic extracellular surround (Javid et al., 2014) and deleterious mechanical stress experienced at the onset of TBI-induced damage produces immediate plasmalemmal instability and cytoskeletal disassembly (Povlishock, 1993; Pettus and Povlishock, 1996; Singleton and Povlishock, 2004).”

“…be twofold: one, the axons may simply seal off at the proximal end of the transection, and continued axoplasmic flow re-sults in its dilation; alternatively, as demonstrated by Povlishock (1993), this change may represent a dysfunction of the axon without disruption in its anatomical continuity.”

“around blood vessels or at the gray-white matter interface) (16, 26, 80).”

“the grey/ white interface), decussate, or are of large calibre, they may be more susceptible to injury [26–29].”

“Therefore, the sustained Ca(21) increase found in stretchinjured axons may play an important role in the observed damage of the cytoskeleton and disruption of axonal transport after dynamic stretch injury of axons (Povlishock, 1993; Maxwell et al., 1997).”

“Rather, trauma evokes a cascade of changes to the axon that may ultimately result in secondary disconnection [108, 109].”

“Patients with DAI are more likely to develop persistent oma and are less likely to return to previous level of functionng (Maxwell et al., 1997; Povlishock, 1993).”

“TBI has been shown to damage axons 61 and result in white matter damage.”

“A constant feature of TBI is diffuse damage to axons, which first manifests as focal disruption of neurofilaments, followed by impairment of axonal transport, with consequent swelling and disconnection (Povlishock, 1993).”

“Remarkably, this process has been observed to occur over the course of hours to even months after injury (Povlishock and Becker, 1985; Povlishock, 1993; Sherriff et al., 1994; Pierce et al., 1998).”

“However, other than diffuse axonal injury [ 46 ], the temporal evolution and underlying mechanisms associated with these pathological findings are poorly understood.”

“DAI is a microscopic shearing injury of axons and small blood vessels that occurs throughout the brain but disproportionately involves the deep frontal white matter (Povlishock, 1993).”

“A difference between ischemic brain injury where all components of the brain tissue are damaged, and blunt traumatic injury, where the most important type of damage is an axonal disruption (15), which might lead to abnormal β PP and/or amyloid β (1-42) processing.”

“…and different studies have demonstrated an increased susceptibility of the hippocampus to injury, the brain region most critical for cognitive performance, specifically learning and memory (Hicks et al., 1993; McIntosh et al., 1989; Miller et al., 1990; Miyazaki et al., 1992; Povlishock, 1993).”

“Introduction Diffuse axonal injury (DAI) has long been known to be one of the main reasons for degenerative changes in white matter structures in traumatic brain injury (TBI; Bigler, 1990; Povlishock, 1993; Gean, 1994).”

“Importantly, the observation of immunopositive NF68 BDPs in the cortical impact model complicates the interpretation ofimmunohistochemical data and could provide an alternate explanation for localized increases in NF68 immunoreactivity postinjury (Povlishock, 1993; Yaghmai and Povlishock, 1992).”

“…and rotation of the head, exerting both the shearing and tensile forces that cause the primary pathological changes associated with TBI (Povlishock, 1993; Ray et al., 0955-8810 c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32833d8bc9 Copyright ©…”

“The first type of injury occurs for example in the brainstem and the corpus callosum and is described by Povlishock (1993), who observed that axonal injury was present at locations where the axons have to deviate from a straight path because of an obstruction (e.g., a blood vessel or a cell body).”

“For example, in rats subjected to fluid percussion injury, axonal pathology is discernable within 4 h, whereas cats exhibit these changes somewhat later, and in pigs and humans, alterations first become obvious over 1-2 days (Yaghami and Povlishock, 1992; Povlishock, 1993).”

“Therefore these observations provide strong evidence of traumatic axonal injury in our model, supporting the hypothesis that traumatic axonal injury is the primary pathology associated with adverse outcomes following mTBI (44).”

“The most typical damage is often produced within the frontal poles and the anterior areas of the temporal lobes in addition to diffuse axonal injury [14, 15].”

“…neurons and synthesized in neuronal mitochondria, and occurrence of direct neuronal transection is considered unlikely for those with mild injury (Povlishock, 1993), these results may indicate either longer-term axonal degeneration leading to neuroima-ging-invisible diffuse white-matter damage,…”

“Traumatic axonal injury (TAI) is an additional source of accumulating APP (127, 128).”

“Following TBI in humans, nerve fibers/axons are damaged ultimately resulting in neuronal cytoskeletal disin-tegration (Kampfl et al., 1997; Maxwell et al., 1997; Povlishock, 1993).”

“This is significant in light of data indicating that even mild brain injuries can cause structural or functional brain disturbances, often not evident on CT imaging (MacKenzie et al., 2002; Povlishock, 1993; Umile et al., 2002).”

“…of the brain during TBI (Li and Feng, 2009; Maxwell et al., 1997) have the greatest effect at the interface of two regions with different physical characteristics (Chan et al., 2003; Meythaler et al., 2001; Povlishock, 1993), such as the white and gray matter interface present in the SN.”

“The so called primary axotomy, resulting from mechanical tearing of neurites by the trauma is rather an ephemeral and marginal event (Maxwell et al., 1993; Povlishock, 1993).”

“The morbidity and mortality associated with TBI result principally from secondary injury mechanisms that develop over the days, weeks, and months following the traumatic episode (Hayes et al., 1992; Povlishock, 1993; Povlishock and Jenkins, 1995).”

“…axonal pathology seen in this model is similar to what is observed in human axonal injury (Strich, 1956; Adams et al., 1982; Blumbergs et al., 1989; Povlishock, 1993); that is, parts of the nerve exhibit different types of axonal injury (swellings versus retraction bulbs) and a majority of axons…”

“Later work described microscopic DAI pathology throughout the neuraxis at the gray/white matter cortical interface and in subcortical white matter and nuclei in the absence of macroscopic lesions (Povlishock, 1993).”

“Povlishock (1993) provided similar evidence for early (i.e., 1 h) axonal damage after focal brain injury in rats.”

“As mentioned previously, DAI is found to be related to discrete focal impairment of axons (Povlishock 1993).”

“Some of the medium- and large-diameter axons in the TTXtreated tissue had abnormal concentrations of organelles reminiscent of terminal clubs (Kao et al., 1977) or restrictions within axoplasm that impede axonal transport of organelles (Povlishock, 1993).”

“…defects in the axonal membrane may lead to a disruption of ionic and osmotic homeostatic mechanisms, and extracellular Ca2+, which is usually rigorously controlled in the intra-axonal environment, may accumulate in damaged axons (Povlishock et al, 1993; Pettus et al, 1994; Povlishock et al, 1997).”

“However, while areas of diffuse axonal injury of sufficient size can be detected in MRI (Su and Bell, 2016), the full extent of diffuse axonal injury can only be detected histopathologically (Adams et al., 1991; Povlishock, 1993; Johnson et al., 2013).”

“However, in that Blumbergs et al., 1989; Povlishock, 1993; Povlishock et study, we did not examine the role of identifiable lesions al., 1992; Christman et al., 1994).”

“Multiple reports, both in vivo and in vitro , provide evidence of Ca 2 (cid:1) -mediated damage to white matter, emphasizing the role that Ca 2 (cid:1) influx plays in axonal injury (He et al., 1999; Maxwell et al., 1995; Povlishock, 1993; Povlishock and Pettus, 1996; Wolf et al., 2001).”

“During head trauma, inertial forces from rapid accelerationdeceleration and rotation of the brain lead to diffuse TBI, where there is diffuse axonal injury (DAI); tearing injuries to axons, causing axonal swelling and disconnection (Povlishock, 1993; Gaetz, 2004; Werner and Engelhard, 2007).”

“Since axonal injury is a pathological hallmark associated with much of the morbidity following TBI [10, 11, 14 – 18], the extent of DAI was qualitatively assessed in various regions of the micro pig brain 6 h following sham or cFPI.”

“However, recent studies have led to the understanding that DAI is in fact a progressive insult that leads to and prolongs neurological damage [15, 23, 24].”

“…result in gross loss of brain tissue (Chen, Fong, Lee, & Chiu, 2011; Farkas & Povlishock, 2007; Kelley, Farkas, Lifshitz, & Povlishock, 2006; Kelley, Lifshitz, & Povlishock, 2007; Maxwell, Povlishock, & Graham, 1997; Povlishock, 1993; Povlishock & Christman, 1995; Takeuchi & Nawashiro, 2011).”

“…after spinal cord trauma, i.e., damage not directly caused by the physical trauma, are considered to be induced by a cascade of events in which neurochemical changes, for instance glutamate release, produce additional cell injury and edema (Anderson and Hall, 1993; Faden, 1993; Povlishock, 1993).”

“Experimental models of spinal cord trauma have, to a great extent, increased our understanding of the pathophysiology associated with this type of lesion [ 29 , 34].”

“However, axonal transection sites collapse after injury (2), which was indicated by the decrease in ARA release.”

“Thus, in addition to previously documented changes in axons (Yaghmai and Povlishock, 1992; Povlishock, 1993), TBI is associated with significant injury to dendritic processes, which may extend beyond sites of focal contusion.”

“In particular, multifocal traumatic axonal injury (TAI) is a concept referring to the process of mechanical tearing of neurites by traumatic events (especially concussion) [28], causing mechanical damage of the axolemma and then loss of ionic homeostasis, such as disturbances in calcium homeostasis [29].”

“Electron micrographs show clumping, loss of microtubules and neurofilaments, loss of axon transport and accumulations of axoplasmic material identified as the retraction ball [61, 63, 75, 76, 100–102] analogous to diffuse axonal injury (DAI) in the brain [125, 127].”

“Delayed axotomy secondary to evolving pathological processes set off by the initial injury has also been well-demonstrated experimentally [6].”

“Additionally, the third and fourth ventricles increased by tion, and excitotoxicity (Endo et al., 1991; Hicks et al., 1993; Lighthall et al., 1990; Povlishock, 1992; Reich et al., 1993; Ross et al., 1993; Schmidt and Grady, 1993; Sutton et al., 1993).”

“At the time of impact, alignment of the neurofilament is disrupted and there is development of focal swelling along the axonal tract (Grady et al. 1993; Povlishock 1993).”

“A hallmark of diffuse brain injury is diffuse axonal injury (DAI), in which the caliber of axons and the organization of neurofilaments are affected [41].”

“Much of the knowledge related to TAI comes from the extensive work of Povlishock (Povlishock and Becker, 1985; Povlishock, 1986,1992,1993), Gennarelli (Gennarelli et al., 1981,1998), and several other researchers (Marmarou and Povlishock 2006; Marmarou et al., 2006; Maxwell and Graham, 1997;…”

“Extensive accumulations of organelles including elongated membranous organelles, previously described as abnormal tubular structures (Fig. 2 A), tubulovesicular structures (Fig. 2 B), swollen and deformed mitochondria (Fig. 2 C) were occasionally found in DN around a neurofilamentous core and were morphologically anal…”

“Although these assumptions were made based on gross pathology, histology, or conventional MRI (Jane et al., 1985; Povlishock, 1993), recent evidence suggests that cerebral microbleeds, or small brain hemorrhages, may lead to prolonged disability in mild TBI or DAI (Park et al., 2009; Liu et al., 2014; van der Horn et…”

“More specifically, the frontal lobes and the circuits supporting executive functions are a frequent site of damage due to their proximity to the sharp bony protuberances within the skull and the shearing damage that occurs with the force of injury [8, 9].”

“Diffuse axonal injury is considered to be the associated structural change following mTBI or concussion both in animal models of mTBI and human autopsy series where the patients with concussion died of unrelated causes [54–58].”