Chronic Traumatic Encephalopathy (CTE) due to traumatic brain injury (TBI) has become a hot topic in sports culture and media in recent years. TBI is generally divided into acute and chronic (Blennow et al., 2012). Acute consequences due to TBI may include concussion, subconcussion, hemorrhage, or other structural brain damages. The chronic consequence of TBI is CTE. CTE is a neurodegenerative condition characterized by pathologically by abnormal tau protein and neurofibrillary tangles. In this post I will be describing the pathophysiology of sports-related TBI and how to distinguish CTE.
Sports-related TBI is caused by rapid acceleration and deceleration forces on the brain. These forces typically result in an acute TBI consequence such as a concussion of subconcussion. Rotational acceleration, such as blows to the head in a boxing match, are more likely to cause concussion than linear acceleration injuries, such as those caused by head contact in American football (Ohhashi et al., 2002). These forces cause the brain and its components to stretch, which may result in a neurometabolic cascade and subsequent axonal swelling and axonal disconnection at the location of the injury (Barkhoudaria et al., 2011).
While the mechanism of acute TBI is quite well understood, neuropathological findings in the literature are rare. Previous isolated case reports have described the presence of microglial clusters appearing in less than 24 h after TBI (Oppenheimer, 1968). In cases with longer survival time, astrocytic tangles and neurofibrillary tangles (NFT) may be seen, which are both considered to be characteristic of CTE. However, the mechanism by which acute TBI leads to development of NFTs in CTE is not well understood.
Macroscoptic neuropathological features of CTE include diffuse brain atrophy, ventricular dilation cavum septum pellucidum with or without fenestrations, cerebellar scarring and depigmentation and degeneration of the substantia nigra (Ling et al., 2015). Histological hallmarks of NFTs are mixed 3-repeat (3R) and 4-repear (4R) tau isoforms. These are most commonly found in the frontal and temporal cortices, with predilection for perivascular regions (Geddes et al.,). While Alzheimer's disease (AD) is also a 3R and 4R tauopathie, CTE is distinctive by the lack of, or relatively lesser AB deposition (Table 1) (Ling et al., 2015). This is especially true in younger individuals and in early stage CTE. Meanwhile, new research is also showing that CTE and AD may be able to co-exist (Turner, RC. et al., 2016)
Table 1.
More recently, McKee et al., developed a new neuropathological criteria for the diagnosis of CTE. They defined the lesion as, "as accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of the cortical sulci and in an irregular pattern" (McKee et al,. 2015). They also defined supportive non-specific p-tau-immunoreactive features such as, "pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grainlike and dot-like structures" (McKee et al,. 2015). While these criteria haven't been proven as definitive for CTE, they provide steps toward the development of validated neuropathological criteria for CTE.
While strides are being made in the diagnosis of CTE neuropathologically, many unknowns remain. Clinical diagnostic criteria need to be worked out, whether that be via biomarkers or other means. Also, the pathophysiological cascade of events from acute TBI to CTE needs to be determined, which could allow for future therapeutic strategies to slow or stop progression of CTE.
Sources
Barkhoudarian, G., Hovda, D.A., Giza, C.C., 2011. The molecular pathophysiology of concussive brain injury. Clin. Sports Med. 30, 33–48 (vii–iii).
Blennow, K., Hardy, J., Zetterberg, H., 2012. The neuropathology and neurobiology of traumatic brain injury. Neuron 76, 886–899.
Ohhashi, G., Tani, S., Murakami, S., Kamio, M., Abe, T., Ohtuki, J., 2002. Problems in health management of professional boxers in Japan. Br. J. Sports Med. 36, 346–352 (discussion 353).
Oppenheimer, D.R., 1968. Microscopic lesions in the brain following head injury. J. Neurol. Neurosurg. Psychiatry 31, 299–306.
Ling, H., Hardy, J., Zetterberg, G., 2015. Neurological consequences of traumatic brain injuries in sports. Mol and Cell Neuroscience. 66, 114-122.
McKee et al,. 2015
McKee A., Cairns, N., Dickson, D., et al., 2015. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 131, 75-86.
Turner RC., Lucke-Wold BP., Robson MJ., et al., 2016. Alzheimer's disease and chronic traumatic encephalopathy: Distinct but possibly overlapping disease entities. Brain Inj
30 (11), 1279-1292.
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