Update: Chronic traumatic encephalopathy

Chronic traumatic encephalopathy

Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain
“Chronic traumatic encephalopathy” (CTE) is described as a slowly progressive neurodegenerative diseasebelieved to result from multiple concussions.
The damaging neurological effects of sports-related repetitive head trauma were described by Harrison S. Martland in 1928 1). His clinical description of ‘punch drunk syndrome’ in a group of former boxers has been extended to include a complex neuropathological and clinical diagnosis known today as Chronic Traumatic Encephalopathy (CTE).
The more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma 2).
This has prompted renewed interest and controversy regarding the potential for long-term neurodegenerative changes to occur after concussive and even sub-concussive repetitive or blast wave associated head trauma 3) 4).
In recent years, there has been tremendous media attention regarding CTE, primarily because of the deaths of high profile American football players who were found to have CTE upon neuropathological examination. However, the study of CTE remains in its infancy 5).


Thus far CTE research has been limited to selective case reports. There are no published systematic studies incorporating both sport and non-sport related head trauma populations. Based on this lack of data, it is currently impossible to determine the incidence of new cases occurring within contact sport. Additionally, overall prevalence of CTE amongst all cases of head trauma cannot be determined at this time. Finally, due to the fragmented data collected in case reports, no conclusions can be drawn about potential risk factors for developing CTE in contact sports 6).
To date, all pathologically confirmed CTE cases have had a history of head trauma; however, the reported degree of severity, frequency of blows to the head, and documentation of prior concussion is highly variable 7).
Of 153 pathologically confirmed cases of CTE represents the most current and most complete number of confirmed CTE cases in the medical literature. The final number of CTE cases was determined after accounting for 113 duplicate reported cases. Duplicate cases accounted for 43% of all cases of CTE identified in the medical literature by this review. Although Maroon et al. acknowledge the occasional need for re-evaluating former CTE cases in order to further understand CTE findings presented to date, the high rate of re-reporting cases often without explicit notation of previous documentation has led to an erroneous, inflated impression of the number of CTE cases reported. The 153 CTE cases described in the review also include four unique cases of CTE found in media reports which were substantiated by cross confirmation from multiple sources including quotes from CTE investigators.
Of the 153 unique pathologically confirmed cases of CTE, six major mTBI subgroups were identified: former boxers, former football players, former hockey players, former military veterans, former professional wrestlers, and other miscellaneous causes of head trauma. Former boxers and football players made up the majority of all cases (86.2%). This observation is consistent with the long standing history of CTE research in the sport of boxing and the recent focus on former football players 8).


Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau protein, similar to that seen in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).
There is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment 9).
Chronic traumatic encephalopathy is characterized by a unique pattern of accumulation of hyperphosphorylated tau in neurons and astrocytes. The tau abnormalities begin focally and perivascularly at the depths of the cerebral sulci, spread to the superficial layers of the adjacent cortex, and eventually become widespread throughout the medial temporal lobes, diencephalon, and brainstem. Abnormalities in 43 kDa TAR DNA-binding protein are also found in most cases of CTE. To date, CTE can only be diagnosed by postmortem neuropathological examination, although there are many ongoing research studies examining imaging techniques and biomarkers that might prove to have diagnostic utility. Currently, the incidence and prevalence of CTE are unknown, although great strides are being made to better understand the clinical symptoms and signs of CTE. Further research is critically needed to better identify the genetic and environmental risk factors for CTE as well as potential rehabilitation and therapeutic strategies 10).


Although it shares certain histopathological findings with Alzheimer disease, chronic traumatic encephalopathy has a more specific presentation (hyperphosphorylated tau protein deposited as neurofibrillary tangles, associated with neuropil threads and sometimes with beta-amyloid plaques).
The neuropathological findings in a animal model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation 11).

Clinical features

Its clinical presentation is insidious; patients show mild cognitive and emotional symptoms before progressing to parkinsonian motor signs and finally dementia.
The clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition, frequently resulting in debilitating dementia 12).


Several recent reviews have focused on the various neuropathological findings and the clinical criteria used for the diagnosis of CTE and have drawn attention to the confusion and inconsistency of the diagnosis of CTE 13) 14).
Results from new experimental diagnostic tools are promising, but these tools are not yet available.

Differential diagnosis

Chronic postconcussion syndrome, and chronic neurocognitive impairment 15).


The mainstay of managing this disease is prevention and early detection of its first symptoms.
The inhibition of monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, significantly reduced CTE-like neuropathologic changes in a mouse model of repetitive mild closed head injury (rmCHI). Inhibition of 2-AG metabolism promoted neurologic recovery following rmCHI and reduced proinflammatory cytokines, astroglial reactivity, expression of amyloid precursor protein and the enzymes that make Aβ, as well as formation of Aβ. Importantly, neurodegeneration, TDP-43 protein aggregation, and tau phosphorylation, which are the neuropathologic hallmarks of CTE, were significantly suppressed by MAGL inactivation. Furthermore, alterations in expression of glutamate receptor subunits and impairments in basal synaptic transmission, long-term synaptic plasticity, and spatial learning and memory were recovered by inhibition of 2-AG metabolism in animals exposed to rmCHI. The results suggest that MAGL inhibition, which boosts 2-AG and reduces 2-AG metabolites prostaglandins in the brain, may lead to a new therapy for CTE 16).
1) Martland HS (1928) Punch Drunk. JAMA 91: 1103–1107.
2) Montenigro PH, Baugh CM, Daneshvar DH, Mez J, Budson AE, Au R, Katz DI, Cantu RC, Stern RA. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimers Res Ther. 2014 Sep 24;6(5):68. doi: 10.1186/s13195-014-0068-z. eCollection 2014. Review. PubMed PMID: 25580160; PubMed Central PMCID: PMC4288217.
3) McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, et al. (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136: 43–64 doi: 10.1093/brain/aws30723208308
4) Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, et al. (2011) Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69: 173–183 doi: 10.1227/NEU.0b013e318212bc7b21358359
5) Riley DO, Robbins CA, Cantu RC, Stern RA. Chronic traumatic encephalopathy: Contributions from the Boston University Center for the Study of Traumatic Encephalopathy. Brain Inj. 2015;29(2):154-63. doi: 10.3109/02699052.2014.965215. PubMed PMID: 25587744.
6) McCrory P (2013) Consensus Statement on Concussion in Sport: The 4th International Conference on Concussion in Sport Held in Zurich (November 2012). Br J Sports Med 47: 250–258 doi: 10.1136/bjsports-2013-09231323479479
7) McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, et al. (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68: 709–735 doi: 10.1097/NEN.0b013e3181a9d50319535999
8) Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PLoS One. 2015 Feb 11;10(2):e0117338. doi: 10.1371/journal.pone.0117338. eCollection 2015. PubMed PMID: 25671598; PubMed Central PMCID: PMC4324991.
9) Tartaglia MC, Hazrati LN, Davis KD, Green RE, Wennberg R, Mikulis D, Ezerins LJ, Keightley M, Tator C. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies. Front Hum Neurosci. 2014 Jan 31;8:30. doi: 10.3389/fnhum.2014.00030. eCollection 2014. PubMed PMID: 24550810; PubMed Central PMCID: PMC3907709.
10) Kiernan PT, Montenigro PH, Solomon TM, McKee AC. Chronic Traumatic Encephalopathy: A Neurodegenerative Consequence of Repetitive Traumatic Brain Injury. Semin Neurol. 2015 Feb;35(1):20-28. Epub 2015 Feb 25. PubMed PMID: 25714864.
11) Petraglia AL, Plog BA, Dayawansa S, Dashnaw ML, Czerniecka K, Walker CT, Chen M, Hyrien O, Iliff JJ, Deane R, Huang JH, Nedergaard M. The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surg Neurol Int. 2014 Dec 23;5:184. doi: 10.4103/2152-7806.147566. eCollection 2014. PubMed PMID: 25593768; PubMed Central PMCID: PMC4287910.
12) Montenigro PH, Corp DT, Stein TD, Cantu RC, Stern RA. Chronic Traumatic Encephalopathy: Historical Origins and Current Perspective. Annu Rev Clin Psychol. 2015 Jan 12. [Epub ahead of print] PubMed PMID: 25581233.
13) Smith DH, Johnson VE, Stewart W (2013) Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol 9:211–221 doi: 10.1038/nrneurol.2013.2923458973
14) Gardner A, Iverson GL, McCrory P (2013) Chronic traumatic encephalopathy in sport: a systematic review. Br J Sports Med 48: 84–90 doi:10.1136/bjsports-2013-09264623803602
15) Jordan BD. Chronic traumatic encephalopathy and other long-term sequelae. Continuum (Minneap Minn). 2014 Dec;20(6 Sports Neurology):1588-604. doi: 10.1212/01.CON.0000458972.94013.e1. PubMed PMID: 25470162.
16) Zhang J, Teng Z, Song Y, Hu M, Chen C. Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury. J Cereb Blood Flow Metab. 2014 Dec 10. doi: 10.1038/jcbfm.2014.216. [Epub ahead of print] PubMed PMID: 25492114.

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