Traumatic Brain Injury and Neurodegenerative Disease: A Marriage Made in Sport?
The watershed moment in understanding of traumatic brain injury (TBI) occurred with Holbourne’s theory that rotational head movement and shear strains were limiting factors in producing parenchymal brain damage . He based this on physical properties of the brain, including its extreme incompressibility and lack of rigidity. Holbourne’s theory was substantiated and elaborated upon in primate experiments, in which coronal plane rotation of sufficient magnitude and pulse duration rendered subjects vulnerable to diffuse axonal injury [2, 3], while sagittal plane rotation and relatively short pulse duration predisposed to bridging vein rupture and subdural hematoma . Related concepts have been invoked to explain the contrecoup contusion phenomenon .
Although subsequent modifications were inevitable, the initial theory coupled with experimental observations provided the biomechanical underpinnings for cardinal traumatic brain lesions—namely, subdural hematoma, contusion, and diffuse axonal injury. These same concepts have since been exploited to improve neuroprotection in motor vehicle accidents, military service, and sport, and are still relevant today. Myriad biochemical cascades in TBI have been elaborated, along with advances in diagnosis and acute management of a multiplicity of lesions. It is perhaps noteworthy that the foundational knowledge was acquired in the absence of computer technology, modern molecular biology, and immunohistochemical analysis of autopsied brain tissue.
A parallel line of inquiry into the enigmatic condition known initially as “punch drunk”  and later dementia pugilistica (DP)  was somewhat different and has been a source of confusion since its description. Punch drunk was called to attention in 1928 not because of acute injury, but because neurological signs were observed in boxers over the course of their boxing career and afterwards. DP was also a stationary condition in most cases , a feature distinct from classical neurodegenerative diseases. This may in part explain why no autopsy information on boxers was reported until 1954 , despite considerable interest in the topic in the 1930s and 1940s. It is also interesting, though largely unrecognized, that the index autopsy report in boxers was in fact a case of early-onset Alzheimer’s disease, a condition of genetic etiology having nothing to do with boxing. The largest case series of DP to date emphasized a spectrum of brain lesions , some clearly traumatic in line with Holbrourne’s theory (e.g., septal fenestrations), but the focus since has been on the neurofibrillary tangle as a bridge between acquired neurotrauma and neurodegeneration.
The third line of inquiry is genuine neurodegenerative disease. Unlike neurotrauma, no acquired etiologies have been verified scientifically aside from spongiform encephalopathies, there is no stationary condition once initiated, and there is often highly selective cell type vulnerability. In all major neurodegenerative disease phenotypes, an invariably progressive and fatal neurological deterioration is associated with consistent neuropathological lesions and anatomically distinct neurodegeneration. None of these features are found consistently in the DP literature or modern case series using the term “chronic traumatic encephalopathy” (CTE). Indeed, neurodegeneration in the true sense, that is, loss of neurons, is neither a required nor supportive criterion in the current consensus iteration of CTE pathology .
A bewildering superstructure has nevertheless been assembled for TBI-neurodegeneration theory, which may highlight enthusiasm for hypothesis confirmation rather than hypothesis testing. The search for biomarkers in line with the preferred theory, including PET scanning for putative tau surrogates , serum and cerebrospinal fluid protein analyses , and examination of a broad array of neuropsychiatric endpoints , all emphasize sensitivity over specificity. Sophisticated experimental mechanisms have been invoked to explain disease progression , while progression in vivo has not been demonstrated. Constructs hypothesizing causality between TBI and neurodegeneration have been suggested , while evidence of marginal risk or no risk in large scale epidemiological surveys [17–24] essentially preclude causality. Sport-neurodegeneration theory is embedded in medical science, yet a quality evidence base is entirely lacking. The TBI-neurodegeneration hypothesis apart from sport is also broadly accepted, yet relies on a literature replete with methodological weaknesses . Remarkably, it has become customary to view sport as a surrogate for environmental TBI exposure , yet modern athlete case series are devoid of empirical manifestations of TBI (e.g., contusions, subdural collections, post-traumatic epilepsy). Clearly, more research, and perhaps more skepticism, is needed.
The interested reader should keep in mind that this handbook does not simply explore the deleterious effects of genuine TBI, which are substantial, but rather the relationship between TBI and neurodegeneration. It was inevitable that some articles would touch upon the hypothetical CTE construct given the controversy and media exposure, although the interest in critical review on the part of multiple authors of diverse background was noteworthy. Casson and Viano, for example, bring to bear decades of experience and expertise in contact sport, and review in copious detail the stark differences between boxing and American football, not only clinically, but radiographically, and pathologically . They appropriately highlight that neurological sequelae from boxing has traditionally been defined by clinical examination, whereas the putative condition described in football is purely pathological, or more precisely immunohistochemical, with no discernible clinical substrate. The totality of their review casts doubt, in a definitive sense, on the common rhetorical claim that “repetitive head impacts” from whatever sport is DP by another name.
Brett et al.  critically examine neuropathological and clinical criteria for CTE, and identify a noticeable lack of probabilistic assessments, which are otherwise customary when attempting to characterize ill-defined and hypothetical entities. They also expose the problematic emphasis on sensitivity over specificity. Zuckerman et al.  describe a number of limitations in CTE research, including ascertainment bias, recall bias, lack of generalizability of samples of convenience, lack of accounting for substance abuse, lack of adequate controls, and a CTE definition that has no lower limit. Schwab and Hazrati  further point out pervasive flaws in the CTE studies, including a decided lack of an evidence base as noted, insufficient samples, pathological inconsistencies, unreliable clinical data, and flawed study design. They raise the legitimate possibility of unintended consequences on broader society from promoting a fatalistic view of an uncharacterized process. The problem of amending public policy prematurely is also raised, and may warrant more attention than that afforded by a medical science community immersed in patient care and research.
Iverson et al.  provide a thorough evaluation of clinicopathological correlation in the CTE construct, and suggest that CTE neuropathology might be disambiguated from hypothesized clinical features in order to better understand each component in future research. The collective works from Castellani and Perry [32, 33], Castellani et al. , and Tripathy et al.  suggest a number of additional unresolved questions, such as the kinetics of progression in DP, the existence of a TBI-neurodegenerative proteinopathy construct in general, the role of tau as a driver of disease, the reliability of postmortem diagnostic interpretation in an emotionally charged environment, and the existence, if any, of CTE in military service members.
Overall, the articles consist of a roughly equal proportion of reviews and primary data papers. The majority discuss human disease, either in review form or as original research, with a few articles exploring TBI in animal models [36–39]. The human studies span a spectrum of endpoints, including PET imaging of putative tau surrogates , perfusion neuroimaging , potential biomarkers such as MCP-1  and BDNF polymorphism , and postmortem proteinopathy as noted above.
The overarching theme of this Handbook is thus the marriage between neurodegenerative disease and neurotrauma by virtue of sport or military service, and the legitimacy of that marriage. Overall, it may be gleaned from these pages that, controversy notwithstanding, there is much to be learned about the biological effects of TBI, the presence and extent of genuine TBI in athletes and military service members, pathogenic mechanisms and substrates for long-term sequelae, the relationship between TBI and diverse neuropsychiatric disorders, and targets for therapy. If there is any broad message to the neuroscience community from the collective contributions, it is that the null hypothesis—that there is no relationship between TBI and neurodegenerative proteinopathy—is still very much in play.
Rudy J. Castellani MD
Professor of Pathology and Neuroscience
West Virginia University and
Rockefeller Neuroscience Institute
The author’s disclosure is available online (https://www.j-alz.com/manuscript-disclosures/19-1269).
 Holbourn AHS (1943) Mechanics of head injuries. Lancet 242, 438-441.
 Ommaya AK, Corrao PG, Letcher FS (1973) Head injury in the chimpanzee. Part 1: Biodynamics of traumatic unconsciousness. J Neurosurg 39, 152-166.
 Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982) Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12, 564-574.
 Gennarelli TA, Thibault LE (1982) Biomechanics of acute subdural hematoma. J Trauma 22, 680-686.
 Dawson SL, Hirsch CS, Lucas FV, Sebek BA (1980) The contrecoup phenomenon. Reappraisal of a classic problem. Hum Pathol 11, 155-166.
 Martland HS (1928) Punch drunk. J Am Med Assoc 91, 1103-1107.
 Millspaugh JA (1937) Dementia Pugilistica. U S Nav Med Bull 35, 297-303.
 Roberts A (1969) Brain damage in boxers: A study of prevalance of traumatic encephalopathy among exprofessional boxers, Pitman Medical Scientific Publishing Co., London.
 Brandenburg W, Hallervorden J (1954) Dementia pugilistica mit anatomischem Befund. Virchows Arch 325, S680-709.
 Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3, 270-303.
 McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee H-S, 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.
 Stern RA, Adler CH, Chen K, Navitsky M, Luo J, Dodick DW, Alosco ML, Tripodis Y, Goradia DD, Martin B, Mastroeni D, Fritts NG, Jarnagin J, Devous MD, Mintun MA, Pontecorvo MJ, Shenton ME, Reiman EM (2019) Tau positron-emission tomography in former national football league players. N Engl J Med 380, 1716-1725.
 Agoston DV, Shutes-David A, Peskind ER (2017) Biofluid biomarkers of traumatic brain injury. Brain Inj 31, 1195-1203.
 Montenigro PH, Baugh CM, Daneshvar DH, Mez J, Budson AE, Au R, Katz DI, Cantu RC, Stern RA (2014) Clinical subtypes of chronic traumatic encephalopathy: Literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome.Alzheimers Res Ther6, 68.
 Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, Miller TM, Diamond MI (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92, 796-812.
 Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE (2018) Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141, 422-458.
 Fann JR, Ribe AR, Schou Pedersen H, Fenger-GrÃÿn M, Christensen J, Benros ME, Vestergaard M (2018) Long-term risk of dementia among people with traumatic brain injury in Denmark: A population-based observational cohort study, Lancet Pscyhiatry 5, 424-431.
 Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer KA, Burke JR, Guralnik JM, Breitner JCS (2000) Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55, 1158-1166.
 Gardner RC, Byers AL, Barnes DE, Li Y, Boscardin J, Yaffe K (2018) Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study. Neurology 90, e1771-e1779.
 Seals RM, Hansen J, Gredal O, Weisskopf MG (2016) Physical trauma and amyotrophic lateral sclerosis: A population-based study using Danish National Registries. Am J Epidemiol 183, 294-301.
 Godbolt AK, Cancelliere C, HincapiÂťe CA, Marras C, Boyle E, Kristman VL, Coronado VG, Cassidy JD (2014) Systematic review of the risk of dementia and chronic cognitive impairment after mild traumatic brain injury: Results of the international collaboration on mild traumatic brain injury prognosis. Arch Phys Med Rehabil 95(3 Suppl), 245-256.
 Hamidou B, Couratier P, BesancÂÿon C, Nicol M, Preux PM, Marin B (2014) Epidemiological evidence that physical activity is not a risk factor for ALS. Eur J Epidemiol 29, 459-475.
 Manley GT, Gardner AJ, Schneider KJ, Guskiewicz KM, Bailes J, Cantu RC, Castellani RJ, Turner M, Jordan BD, Randolph C, Dvořák J, Hayden KA, Tator CH, McCrory P, Iverson GL (2017) A systematic review of potential long-term effects of sport-related concussion. Br J Sports Med 51, 969-977.
 Mackay DF, Russell ER, Stewart K, MacLean JA, Pell JP, Stewart W (2019) Neurodegenerative disease mortality among former professional soccer players. N Engl J Med 381, 1801-1808.
 Hicks AJ, James AC, Spits G, Ponsford J (2019) Traumatic brain injury as a risk factor for dementia and Alzheimer disease: Critical review of study methodologies. J Neurotrauma 36, 3191-3219.
 Alosco ML, Mez J, Tripodis Y, Kiernan PT, Abdolmohammadi B, Murphy L, Kowall NW, Stein TD, Huber BR, Goldstein LE, Cantu RC, Katz DI, Chaisson CE, Martin B, Solomon TM, McClean MD, Daneshvar DH, Nowinski CJ, Stern RA, McKee AC (2018) Age of first exposure to tackle football and chronic traumatic encephalopathy. Ann Neurol 83, 886-901.
 Casson IR, Viano DC (2019) Long-term neurological consequences related to boxing and American football: A review of the literature. J Alzheimers Dis 69, 935-952.
 Brett BL, Wilmoth K, Cummings P, Solomon GS, McCrea MA, Zuckerman SL (2019) The neuropathological and clinical diagnostic criteria of chronic traumatic encephalopathy: A critical examination in relation to other neurodegenerative diseases. J Alzheimers Dis 68, 591-608.
 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.
 Schwab N, Hazrati L-N (2018) Assessing the limitations and biases in the current understanding of chronic traumatic encephalopathy. J Alzheimers Dis 64, 1067-1076.
 Iverson GL, Keene CD, Perry G, Castellani RJ (2018) The need to separate chronic traumatic encephalopathy neuropathology from clinical features. J Alzheimers Dis 61, 17-28.
 Castellani RJ, Perry G (2017) Dementia pugilistica revisited. J Alzheimers Dis 60, 1209-1221.
 Castellani RJ, Perry G (2019) Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges. J Alzheimers Dis 67, 447-467.
 Castellani RJ, Smith M, Bailey K, Perry G, deJong JL (2019) Neuropathology in consecutive forensic consultation cases with a history of remote traumatic brain injury. J Alzheimers Dis 72, 683-691.
 Tripathy A, Shade A, Erskine B, Bailey K, Grande A, deJong JL, Perry G, Castellani RJ (2019) No evidence of increased chronic traumatic encephalopathy pathology or neurodegenerative proteinopathy in former military service members: A preliminary study. J Alzheimers Dis 67, 1277-1289.
 Chen M, Song H, Cui J, Johnson CE, Hubler GK, DePalma RG, Gu Z, Xia W (2018) Proteomic profiling of mouse brains exposed to blast-induced mild traumatic brain injury reveals changes in axonal proteins and phosphorylated tau. J Alzheimers Dis 66, 751-773.
 Cross DJ, Meabon JS, Cline MM, Richards TL, Stump AH, Cross CG, Minoshima S, Banks WA, Cook DG (2019) Paclitaxel reduces brain injury from repeated head trauma in mice. J Alzheimers Dis 67, 859-874.
 Zysk M, Clausen F, Aguilar X, Sehlin D, Syvanen S, Erlandsson A (2019) Long-term effects of traumatic brain injury in a mouse model of Alzheimer’s disease. J Alzheimers Dis 72, 161-180.
 Ju S, Xu C, Wang G, Zhang L (2019) VEGF-C induces alternative activation of microglia to promote recovery from traumatic brain injury. J Alzheimers Dis 68, 1687-1697.
 Chen ST, Siddarth P, Merrill DA, Martinez J, Emerson ND, Liu J, Wong KP, Satyamurthy N, Giza CC, Huang SC, Fitzsimmons RP, Bailes J, Omalu B, Barrio JR, Small GW (2018) FDDNP-PET tau brain protein binding patterns in military personnel with suspected chronic traumatic encephalopathy. J Alzheimers Dis 65, 79-88.
 Amen DG, Willeumier K, Omalu B, Newberg A, Raghavendra C, Raji CA (2016) Perfusion neuroimaging abnormalities alone distinguish National Football League Players from a healthy population. J Alzheimers Dis 53, 237-241.
 Ho L, Zhao W, Dams-O’Connor K, Tang CY, Gordon W, Peskind ER, Yemul S, Haroutunian V, Pasinetti GM (2012) Elevated MCP-1 concentration following traumatic brain injury as a potential “predisposition” factor associated with an increased risk for subsequent development of Alzheimer’s disease. J Alzheimers Dis 31, 301-313.
 Finan JD, Udani SV, Patel V, Bailes JE (2018) The influence of the Val66Met polymorphism of brain-derived neurotrophic factor on neurological function after traumatic brain injury. J Alzheimers Dis 65, 1055-1064.