====== Chronic traumatic encephalopathy ====== //J.Sales-Llopis// //Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain// ===== General information ===== Often described in retired boxers, chronic [[traumatic encephalopathy]] (CTE) encompasses a spectrum of symptoms that range from mild to severe form AKA dementia pugilistica or punch drunk syndrome (among others). Symptoms involve motor, cognitive, and psychiatric systems. CTE is distinct from posttraumatic dementia (which may follow a single closed head injury) or from posttraumatic Alzheimer’s syndrome. Although generally accepted, not all authorities agree that repeated concussions have any long-term sequelae. There are some similarities with Alzheimer’s disease (AD), including the presence of neurofibrillary tangles having similar microscopic characteristics (the main difference is that they tend to be more superficial in CTE than in AD) and the development of [[amyloid angiopathy]] with the attendant risk of [[intracerebral hemorrhage]]. EEG changes occur in one-third to one-half of professional boxers (diffuse slowing or low-voltage records). ===== Definition ===== "Chronic traumatic [[encephalopathy]]" (CTE) is described as a slowly progressive [[neurodegenerative disease]] believed to result from multiple [[concussion]]s. The damaging neurological effects of sports-related repetitive [[head trauma]] were described by Harrison S. Martland in 1928 ((Martland HS (1928) Punch Drunk. JAMA 91: 1103–1107.)). 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 ((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. )). 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 ((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)) ((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)). There is insufficient evidence to establish causation between sports concussion and CTE. It is likely that many of the cases with neuropathological findings represent the normal aging process, the effects of opiate abuse, or a variant of frontotemporal lobar degeneration. Whether particular genetic causes may place athletes at greater risk of neurodegenerative disease is yet to be determined ((Davis GA, Castellani RJ, McCrory P. Neurodegeneration and Sport. Neurosurgery. 2015 Jun;76(6):643-656. PubMed PMID: 25988925. )). see [[Chronic traumatic encephalopathy in American football players]] ====Epidemiology==== Former [[American football player]]s are at risk for [[chronic traumatic encephalopathy]] (CTE) which may have [[parkinsonism]] as a clinical feature. ---- 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 ((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)). 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 ((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)). 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 ((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.)). ====Pathophysiology==== 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 ((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.)). 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 ((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. )). ===== Neuropathology ===== [[Chronic traumatic encephalopathy neuropathology]] ===== 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 ((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.)). Parkinsonian symptoms may occur in chronic traumatic encephalopathy, see [[dementia pugilistica]] ====Diagnosis==== 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 ((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)) ((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)). Results from new experimental diagnostic tools are promising, but these tools are not yet available. Omalu et al. present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18][[FDDNP PET]] findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients ((Omalu B, Small GW, Bailes J, Ercoli LM, Merrill DA, Wong KP, Huang SC, Satyamurthy N, Hammers JL, Lee J, Fitzsimmons RP, Barrio JR. Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. Neurosurgery. 2017 Nov 10. doi: 10.1093/neuros/nyx536. [Epub ahead of print] PubMed PMID: 29136240. )). ====Differential diagnosis==== Chronic postconcussion syndrome, and chronic neurocognitive impairment ((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.)). ====Management==== The mainstay of managing this disease is prevention and early detection of its first symptoms. see [[endocannabinoid]]. ===== Retrospective cohort studies ===== A retrospective examination of consecutive, deceased, male brain donors with repetitive head impact exposure from the Understanding Neurologic Injury and Traumatic Encephalopathy Study at Boston University from 2014 to 2021. Neuropathologists diagnosed CTE using established National Institute of Neurological Disorders and Stroke criteria. Informants were administered the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and were queried regarding 1°FHMI. Exploratory factor analysis evaluated BGLHA factor structure. Stratified by CTE status, linear regression analyses examined relationships between 1°FHMI and standardized adult BGLHA scores and factor scores. Models were adjusted for race, age at death, education, years of contact sports play, military history, substance use treatment history, psychologically traumatic event history, and BGLHA childhood score. Results: Among 845 brain donors, the mean age at death was 60.3 (SD = 19.6) years. 589 donors (69.7%) had CTE, and 383 donors (45.3%) had a 1°FHMI. 1°FHMI was significantly associated with standardized adult BGLHA scores in those with CTE, but not in those without CTE (CTE present: β = 0.16, 95% CI 0.02-0.29; CTE absent: β = 0.10, 95% CI -0.12 to 0.32). The largest effects were observed among those with CTE, aged 40-59 years (CTE present: β = 0.64, 95% CI 0.32-0.96; CTE absent: β = 0.05, 95% CI -0.44 to 0.54), particularly for BGLHA factors of emotional dysregulation/impulsiveness (CTE present: β = 1.68, 95% CI 0.78-2.58; CTE absent: β = 0.09, 95% CI -1.20 to 1.37) and antisocial behavior (CTE present: β = 1.56, 95% CI 0.64-2.47; CTE absent: β = 0.10, 95% CI -1.19 to 1.40). Discussion: Among brain donors exposed to repetitive head impacts, CTE pathology moderated the effect of 1°FHMI on BGLHA scores, with the largest effects in midlife. Predisposition to mental illness and CTE pathology may increase the risk of aggression beyond each risk factor's additive effects. Prospective studies are needed to confirm these results ((Uretsky M, Nair E, Burton R, Cronin SW, Rousseau D, Tuz-Zahra F, Durape S, Abdolmohammadi B, Baucom Z, Saltiel N, Shah A, Martin B, Palmisano J, Cherry JD, Daneshvar D, Dwyer B, Dams-O'Connor K, Crary J, Goldstein L, Huber B, Katz D, Kowall N, Cantu RC, Alvarez VE, Stern RA, Stein TD, Tripodis Y, McKee AC, Alosco ML, Mez J. Chronic Traumatic Encephalopathy, Family History of Mental Illness, and Aggression in Brain Donors With Repetitive Head Impact Exposure. Neurology. 2024 Dec 24;103(12):e210056. doi: 10.1212/WNL.0000000000210056. Epub 2024 Nov 27. PMID: 39602665.))