Axonal pathology in traumatic brain injury

Abstract

Over the past 70years, diffuse axonal injury (DAI) has emerged as one of the most common and important pathological features of traumatic brain injury (TBI). Axons in the white matter appear to be especially vulnerable to injury due to the mechanical loading of the brain during TBI. As such, DAI has been found in all severities of TBI and may represent a key pathologic substrate of mild TBI (concussion). Pathologically, DAI encompasses a spectrum of abnormalities from primary mechanical breaking of the axonal cytoskeleton, to transport interruption, swelling and proteolysis, through secondary physiological changes. Depending on the severity and extent of injury, these changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and/or cognitive dysfunction. In addition, recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as insidiously progressive axonal pathology. Indeed, axonal degeneration has been found to continue even years after injury in humans, and appears to play a role in the development of Alzheimer's disease-like pathological changes. Here we review the current understanding of DAI as a uniquely mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI.

Keywords: Axon; Axonal pathology; DAI; Diffuse axonal Injury; Head injury; Microtubule; Neurodegeneration; Rotational acceleration; TBI; Traumatic brain injury.

Figure 1. Representative Images of Axonal Pathology Following TBI in Humans Identified Using APP Immunohistochemistry

(a) Extensive axonal pathology with classic varicosities and axonal bulb formation in a region of the corpus callosum of an young male who died 10 hours following blunt force trauma to the head. Scale bar: 100μm (b) High magnification of a single axon immunoreactive for APP displaying the classic morphology of an axonal bulb. Scale Bar 15 μm. (c-d) High magnification of a single axon accumulating APP. Axons are morphologically varicose, exhibiting multiple points of transport interruption to give the appearance of beads on a string. Scale bars: 30μm.

Figure 2. Accumulation of Aβ and Associated Proteins in Axonal Bulbs Following TBI in Humans

(a-c) Double immunofluorescent labeling showing co-accumulation of APP with Aβ in multiple axonal bulbs following TBI. Further immunohistochemical analyses showing co-accumulation of BACE and PS-1 with APP (d–g) and Aβ (h–k) in axonal bulbs. Scale bar: 50 μm.