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Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers

Abstract

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE)—which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression—has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE.

Key Points

  • Traumatic brain injury (TBI) can lead to delayed-onset neurodegenerative syndromes that include Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE)

  • CTE has gained attention owing to increasing media coverage of neuropsychiatric dysfunction in players of high-impact sport, such as boxing and American football

  • Brain pathology after single-incident severe TBI is similar to early amyloid pathology in AD, whereas repetitive TBI can produce tauopathy with or without amyloidosis that resembles pathology of boxers' dementia

  • Estimation of the risk and prevalence of CTE remains challenging, and accurate prediction of TBI outcome and CTE risk for soldiers and players of high-impact sports is not yet possible

  • Several genetic risk factors for CTE have been proposed but remain to be established

  • Cerebrospinal fluid and neuroimaging biomarkers of TBI and CTE are emerging and hold promise for antemortem diagnosis of CTE, prediction of CTE risk, and monitoring of neuropathology progression

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Figure 1: Spectrum of pathological features and outcomes of mild and severe TBI.
Figure 2: Histopathology of the temporal cortex in TBI and AD.
Figure 3: Histopathological features of chronic traumatic encephalopathy in a former professional football player.
Figure 4: 18F-THK523 as a tauopathy marker.
Figure 5: CSF neurofilament light polypeptide in Olympic boxers after a bout.

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Acknowledgements

The authors gratefully acknowledge the support of NIH grants P01NS30318, P01AG14449 and P50AG05133 (S. T. DeKosky and M. D. Ikonomovic), and VA MERIT review grants 1I01BX000348 (S. Gandy) and 1I01RX000511 (M. D. Ikonomovic). S. Gandy also acknowledges the support of the Cure Alzheimer's Fund and of US NIH P50 AG05138. The authors thank P. Davies (North Shore-Hofstra) for helpful discussions.

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DeKosky, S., Blennow, K., Ikonomovic, M. et al. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol 9, 192–200 (2013). https://doi.org/10.1038/nrneurol.2013.36

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