Chronic Traumatic Encephalopathy

4 December 2018

Recently, Zuckerman et al. [1] presented an interesting history of chronic traumatic encephalopathy (CTE), previously referred to as dementia pugilistica [2], beginning from Hippocrates up to recent publications, with emphasis on contact sports and American football. With regard to CTE in boxers, except for the first report of "punch drunk" [3] and a few others [4], they unfortunately did not refer to a number of other important contributions about brain damage in boxers, many of them having been mentioned previously [5]. The term "dementia pugilistica" was introduced by Millspaugh in 1937 [2], referring to the observations in professional pugilists [6-8], later discussed by Critchley [9] and Roberts [4], most of them unaccompanied by autopsy records. In 1954, Brandenburg & Hallervorden [10] described the autopsy findings in a male aged 51 years who had boxed from age 18 to 29 and, at age 39, developed dementia. The most remarkable findings at autopsy were extensive Alzheimer-related pathology suggesting the presence of early-onset AD. Unfortunately, no family history nor genetic findings were available in this case. Another male aged 46, who had boxed between the ages 15 and 25 and developed progressive neurological decline at age 36, died from cerebral venous thrombosis and showed neurofibrillary changes in the brainstem and medial temporal lobe [11], while other cases of dementia pugilistica, at autopsy, showed cerebrovascular lesions [12] or nonspecific brain pathologies [13, 14]. The landmark study of CTE was published by Courville et al. [15] who emphasized neurofibrillary degeneration particularly in substantia nigra and medial temporal lobe but rather limited plaque pathology, thus separating CTE from typical AD. Although their sample showed heterotopic neuropathologies and numerous co-morbidities, they focussed on the importance of neurodegenerative pathology and, in particular, neurofibrillary degeneration in CTE in relation to boxing, the basis of which had been paved by Brandenburg & Hallervorden [10]. Whereas in 2016, a consensus on thew preliminary neuropathologic diagnostic criteria for CTE, with pathognomonic lesions of hyperphosphorylated tau in both neurons and astrocytes at the basis of cortical sulci was reached [16], despite extensive research, neither the etiopathogenesis of CTE nor that of AD are fully understood yet [17, 18].

Kurt A. Jellinger
Institute of Clinical Neurobiology, Vienna, Austria

REFERENCES
[1] Zuckerman SL, Brett BL, Jeckell A, Yengo-Kahn AM, Solomon GS (2018) Chronic traumatic encephalopathy and neurodegeneration in contact sports and American football. J Alzheimers Dis 66, 37-55.
[2] Millspaugh JA (1937) Dementia pugilistica. U S Nav Med Bull 35, 297-303.
[3] Martland HS (1927) Punch drunk. J Am Med Assoc 91, 1103-1107.
[4] Roberts AH (1969) Brain damage in boxers: Study of the prevalence of traumatic encephalopathy among ex-professional boxers. Pitman Medical & Scientific Publishing Co., Turnbridge Wells, Kent, England.
[5] Castellani RJ, Perry G (2017) Dementia pugilistica revisited. J Alzheimers Dis 60, 1209-1221.
[6] Parker HL (1934) Traumatic encephalopathy ('punch drunk') of professional pugilists. J Neurol Psychopathol 15, 20-28.
[7] Jokl E, Guttman E (1933) Neurologisch-psychiatrische Untersuchungen an Boxern. Munch Med Wochenschr 80, 560-562.
[8] Carroll E (1936) Punch drunk. Am J Med Sci 191, 706–712.
[9] Critchley M (1949) Punch-drunk syndromes: The chronic traumatic encephalopathy of boxers. Maloine, Paris.
[10] Brandenburg W, Hallervorden J (1954) [Dementia pugilistica with anatomical findings]. Virchows Arch Pathol Anat Physiol Klin Med 325, 680-709.
[11] Grahmann H, Ule G (1957) [Diagnosis of chronic cerebral symptoms in boxers (dementia pugilistica & traumatic encephalopathy of boxers)]. Psychiatr Neurol (Basel) 134, 261-283.
[12] Spillane JD (1962) Five boxers. Br Med J 2, 1205-1210.
[13] Payne EE (1968) Brains of boxers. Neurochirurgia (Stuttg) 11, 173-188.
[14] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3, 270-303.
[15] Courville CB (1962) Punch drunk. Its pathogenesis and pathology on the basis of a verified case. Bull Los Angel Neuro Soc 27, 160-168.
[16] McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O'Connor K, Alvarez VE, Gordon WA (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131, 75-86.
[17] Morris GP, Clark IA, Vissel B (2018) Questions concerning the role of amyloid-beta in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathol 136, 663-689.
[18] Goldfinger MH, Ling H, Tilley BS, Liu AKL, Davey K, Holton JL, Revesz T, Gentleman SM (2018) The aftermath of boxing revisited: identifying chronic traumatic encephalopathy pathology in the original Corsellis boxer series. Acta Neuropathol 136, 973-974.

Comments

Submitted by Scott Zuckerman on

 We appreciate the thought-provoking letter by Dr. Jellinger in response to our original article, Chronic Traumatic Encephalopathy and Neurodegeneration in Contact Sports and American Football. It is only through constructive conversation that the study of CTE in sports can progress. Our manuscript focused primarily on American football, and we certainly omitted several key articles regarding CTE in boxers. As Dr. Jellinger states, many of the early studies of CTE, or “dementia pugilistica”, were conducted in boxers. In fact, these early boxing studies were far ahead of their time, as they foreshadow the same controversies with which we struggle a century later.

Perhaps the most scientifically prescient question raised in the autopsy studies of 20th century boxers is the occurrence of concomitant neurodegenerative pathology. Dr. Jellinger astutely states that early-onset Alzheimer pathology, neurofibrillary degeneration, and numerous comorbidities were all seen in postmortem boxing studies. Fast-forward to the 21st century, many notable studies of CTE in athletes report the same concomitant neuropathology [1-4]. Mixed neurodegenerative pathology was seen in 17 of 50 football players in a 2013 convenience sample [2], 20 of 21 athletes in a study of the Mayo Clinic Jacksonville Brain Bank, and 32 of 111 athletes in a larger convenience sample. The high prevalence of concomitant neuropathology leaves us with many unanswered questions, the answers to which may drastically alter the narrative of CTE in sports:

1)    Is the single phosphorylated-tau (p-tau) lesion at the depths of cortical sulci required to diagnose CTE independent of or related to other neurodegenerative disease processes? Similarly, is CTE truly its own disease, or part of a cascade of pathologic changes from other neurodegenerative disorders?
2)    Is there truly a clinicopathological correlation between neurobehavioral antemortem clinical presentations and postmortem pathological findings?
3)    Which disease comes first, CTE or the concomitant neurodegenerative finding(s)?
4)    Is it in fact established by an international neuropathology consensus that the presence of CTE pathology diagnostically supersedes the presence of other neuropathology?
5)    Is there international neuropathology consensus that relative amounts of neuropathology are required to arrive at a primary neuropathological diagnosis?

We wholeheartedly agree with Dr. Jellinger’s assertion, that, “…despite extensive research, neither the etiopathogenesis of CTE nor that of AD are fully understood yet.” If the answers to some of these questions are clarified in coming years, the lens with which we view head impacts in sport may be dramatically changed. At the same time, when such crucial information remains to be elucidated, one is left wondering how the public and select research experts can view a hypothesis with so many remaining questions and unclear answers as resolved with complete certainty.

Scott L. Zuckerman, MD, MPH
Benjamin L. Brett, PhD
Aaron Jeckell, MD
Aaron M. Yengo-Kahn, MD
Gary S. Solomon, PhD

REFERENCES
[1]    Hazrati LN, Tartaglia MC, Diamandis P, Davis KD, Green RE, Wennberg R, Wong JC, Ezerins L, Tator CH (2013) Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Front Hum Neurosci 7, 222.
[2]    McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee HS, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43-64.
[3]    Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE, DeSaro P, Boylan KB, Graff-Radford NR, Wszolek ZK, Rademakers R, Boeve BF, McKee AC, Dickson DW (2015) Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol 130, 877-889.
[4]    Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM, Nowinski CJ, McHale L, Cormier KA, Kubilus CA, Martin BM, Murphy L, Baugh CM, Montenigro PH, Chaisson CE, Tripodis Y, Kowall NW, Weuve J, McClean MD, Cantu RC, Goldstein LE, Katz DI, Stern RA, Stein TD, McKee AC (2017) Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318, 360-370.