Professional Documents
Culture Documents
a r t i c l e
i n f o
Article history:
Received 31 December 2014
Revised 25 February 2015
Accepted 2 March 2015
Available online 5 March 2015
Keywords:
Chronic traumatic encephalopathy
Traumatic brain injury
Mild traumatic brain injury
Concussion
Neurodegenerative disease
Epidemiology
a b s t r a c t
Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion.
More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large
epidemiological studies have additionally identied MTBI as a risk factor for dementia. The role of MTBI in risk of
PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to
increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE
is a unique neurodegenerative tauopathy rst described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE
have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or subconcussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting
methodological challenges and critical future directions of research in this eld. This article is part of a Special
Issue entitled SI:Traumatic Brain Injury.
Published by Elsevier Inc.
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
What is MTBI? . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.
How common is MTBI and repetitive MTBI? . . . . . . . . . . . . . . .
4.
Does TBI increase risk for neurodegeneration? . . . . . . . . . . . . . .
5.
Does MTBI increase risk for neurodegeneration? . . . . . . . . . . . . .
6.
Does repetitive MTBI increase risk for neurodegeneration? . . . . . . . .
7.
The epidemiology of chronic traumatic encephalopathy is largely unknown
8.
Risk factors for post-TBI neurodegenerative diseases and CTE . . . . . . .
9.
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
75
76
76
77
77
77
78
79
79
79
79
1. Introduction
Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; CTE, chronic
traumatic encephalopathy; MTBI, mild traumatic brain injury; PD, Parkinson's disease; TBI,
traumatic brain injury.
Corresponding author at: 4150 Clement St., Neurology #127, San Francisco, CA 94121,
United States.
E-mail address: raquel.gardner@ucsf.edu (R.C. Gardner).
http://dx.doi.org/10.1016/j.mcn.2015.03.001
1044-7431/Published by Elsevier Inc.
76
et al., 2013). Relatively fewer studies have assessed the association specifically between mild TBI (MTBI) and neurodegenerative diseases, and thus
this association is not as well established (Kristman et al., 2014; Marras
et al., 2014). Since the highly publicized report of a series of autopsy
cases of professional American football players with chronic traumatic
encephalopathy (CTE) (Omalu et al., 2005, 2006), however, there has
been a resurgence of interest in unraveling the potential link between
MTBI and neurodegenerative disease including CTE. This resurgence of interest has led to a number of recent studies that have investigated the risk
of neurodegenerative diseases following MTBI or prevalence of neurodegenerative diagnoses or suggestive symptoms among individuals with
high levels of exposure to repetitive MTBI. While this burgeoning eld is
rapidly making important new discoveries that are largely in support of
a link between MTBI particularly repetitive MTBI and neurodegeneration, many questions remain. What is the population prevalence of CTE?
What is the long-term risk of playing contact sports? What is the longterm risk of combat deployment and blast injury? How many head
traumas (concussive or otherwise) are necessary to produce CTE? What
are the biological mechanisms or risk factors?
Currently, CTE is a neuropathological diagnosis that cannot be made
during life. Thus, all modern studies of CTE have been based on autopsy
series while most large epidemiological studies of post-TBI neurodegenerative diseases have been based on clinical diagnoses of common neurodegenerative syndromes. Thus, the relationship between
CTE neuropathology and post-TBI neurodegenerative syndromes (AD,
PD, frontotemporal dementia, ALS) is unknown. It is plausible, for
example, that some cases of clinically-diagnosed post-TBI AD, PD, or
ALS actually reect CTE neuropathology (or vice versa, as a signicant
minority of cases of CTE have had additional co-occurring neuropathologies (McKee et al., 2013)). This review will summarize the current
literature regarding the epidemiology of MTBI, the epidemiology of
post-TBI dementias and Parkinson's disease, and the epidemiology of
CTE. Where appropriate, important avenues for future research will be
highlighted.
2. What is MTBI?
The terms MTBI and concussion are often used interchangeably.
Some would argue that these terms represent fundamentally different
concepts and that concussion is a type of MTBI (McCrory et al.,
2013a). Sub-concussive injury refers to a traumatic impact to the head
that does not result in any immediately appreciable clinical symptoms.
(Spiotta et al., 2011) According to the World Health Organization Collaborating Center Task Force and the Centers for Disease Control and
Prevention (CDC):
MTBI is an acute brain injury resulting from mechanical energy to
the head from external physical forces. Operational criteria for clinical identication include: (1) one or more of the following: confusion or disorientation, loss of consciousness for 30 min or less,
post-traumatic amnesia for less than 24 h, and/or other transient
neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; and (2) Glasgow Coma Scale score
of 1315 after 30 min post-injury or later upon presentation for
healthcare. (3) These manifestations of MTBI must not be due to
drugs, alcohol, medications, caused by other injuries or treatment
for other injuries (e.g., systemic injuries, facial injuries or intubation), caused by other problems (e.g., psychological trauma, language barrier or coexisting medical conditions) or caused by
penetrating craniocerebral injury.
[(Carroll et al., 2004a)]
The CDC has proposed specic International Classication of Diseases 9 (ICD-9) codes for the classication of MTBI (National Center
for Injury Prevention, 2003). These denitions are not yet universally
used. A recent study (Kristman et al., 2014) by the International
77
Table 1
Methodological challenges of epidemiological studies of CTE.
Challenge
Consequence
78
Table 2
Denitions of pertinent epidemiological concepts.
Epidemiological
term
Denition
Selection/referral
bias
neurodegenerative causes compared to the typical population frequency, particularly for AD and ALS (Lehman et al., 2012). On the
other hand, a study of aging adults who played high school American
football in Rochester, Minnesota between 1946 and 1956 found no increased rate of later developing dementia, PD, or ALS (Savica et al.,
2012). It is unclear to what degree this study may apply to modern
day high school athletes given the changes in the sport over the past
half century.
7. The epidemiology of chronic traumatic encephalopathy is largely
unknown
CTE is a neurodegenerative tauopathy linked to exposure to repetitive MTBI. CTE has been associated with mood, behavior, cognitive,
and/or motor symptoms (including parkinsonism and/or motor neuron
disease) (Stern et al., 2013; McKee et al., 2010) that may closely resemble AD, PD, frontotemporal dementia, or even ALS. Recently reported
cases have typically developed progressive neurobehavioral symptoms
years or decades following exposure to MTBI (Stern et al., 2013),
although at least one incipient case of CTE has been reported in a highschool football player who died unexpectedly (Omalu et al., 2011).
Because CTE is a neuropathological diagnosis, the prevalence of CTE in
the general population is unknown. To date, large populationbased studies of CTE have not been possible due to the lack of consensus clinical diagnostic criteria for CTE, thus precluding diagnosis
during life. Estimates of prevalence of CTE must then rely upon autopsy series of neuropathologically conrmed cases of CTE or clinical
case series assessing prevalence of suggestive clinical syndromes in
populations exposed to repetitive MTBI such as professional contact
sport athletes or military veterans. Furthermore, among epidemiological studies reporting an association between TBI (or MTBI or repetitive MTBI) and neurodegenerative syndromes that lack autopsyconrmation, the degree to which these clinical syndromic diagnoses
reect true PD, AD, frontotemporal dementia, ALS, CTE, or any combination of the above, remains unknown. Table 1 outlines just a few of the
methodological challenges facing epidemiological studies of CTE.
Table 2 provides denitions of pertinent epidemiological terminology.
An association between repetitive MTBI and chronic or progressive
neurologic dysfunction was rst reported in the medical literature by
79
Table 3
Possible risk factors for post-TBI dementia, PD, and CTE.
Risk factor category
Dementia
PD
CTE
Demographic
Genetic
TBI factors
Other environmental
exposures
Abbreviations: APOE = apolipoprotein; TBI = traumatic brain injury. Other abbreviations per Table 1.
biomarkers of CTE are critically important. Lastly, prospective, longitudinal studies of high-risk subgroups are needed to better quantify
MTBI exposure, subsequent risk of CTE, and additional risk factors for
CTE, as are already underway among boxers (Bernick et al., 2013) and
recently returned U.S. military veterans (Mac Donald et al., 2014).
8. Risk factors for post-TBI neurodegenerative diseases and CTE
The absence of CTE neuropathology in some multiply-concussed
professional American football players (Hazrati et al., 2013) as well as
the absence of neurodegenerative disease in the majority of adults
with a history of prior MTBI or concussion, suggests that there must
be multiple additional risk and protective factors that determine
whether an individual person develops a post-TBI neurodegenerative disease.
Apolipoprotein E (APOE) 4 allele, the strongest susceptibility gene
for AD, is associated with modied risk for many neurodegenerative diseases following TBI (McKee et al., 2010; Guo et al., 2000; Jordan, 2000;
Schmidt et al., 2010; Jordan et al., 1997). This association between
APOE allele and CTE, however, remains unclear given competing results
of recent studies (Constantinidis and Tissot, 1967; Bernick et al., 2013;
Guo et al., 2000). Specic mutations in genes encoding -synuclein
have been associated with increased risk of PD after TBI (Goldman
et al., 2012; Lee et al., 2014) and this risk is augmented in a more than
additive manner with exposure to paraquat-containing pesticides (Lee
et al., 2012) (Table 3).
It is unknown whether recreational drug or steroid use, alcohol
abuse, chronic psychiatric disease, or cardiovascular risk factors modify
risk of CTE, though these conditions may have been over-represented in
modern autopsy series of CTE comprised largely of professional athletes.
There is some evidence that TBI in children or adolescents may be
particularly morbid (Field et al., 2003; Pullela et al., 2006). On the
other hand, we have found that older adults are at higher risk of dementia after MTBI compared to middle-aged adults (Gardner et al., 2014).
These results suggest that there may be critical periods during
which TBI may be more likely to produce chronic neurologic sequelae
or neurodegeneration. Gender effects are also understudied. The vast
majority of cases of CTE have been in males, presumably due to referral
bias.
9. Summary
MTBI is extremely common affecting roughly 42 million people annually worldwide. Denitions of MTBI across studies are inconsistent,
highlighting the need for ongoing efforts to develop and rene TBI common data elements. Moderate or severe TBI is an established risk factor
for neurodegenerative diseases such as dementia, PD, and ALS. Recently,
large epidemiological studies have reported that MTBI and repetitive
MTBI are also signicant risk factors for neurodegenerative diseases,
but these associations are not yet as well established and require further
replication. CTE is a neuropathological diagnosis that has been associated with repetitive MTBI exposure. Prevalence of CTE is unknown due to
referral bias limiting autopsy studies and lack of consensus clinical
criteria limiting unbiased population-based studies. Among athletes exposed to extremely high levels of repetitive MTBI or repetitive subconcussive head traumas, such as former American football players,
CTE has been reported in 50% to 97% of players that have gone to autopsy. Consensus clinical diagnostic criteria for CTE are needed. Clinical
overlap between symptoms associated with CTE and other more common neurodegenerative diseases such as AD and PD suggest that CTE
clinical criteria will likely require a combination of TBI history, clinical
symptoms, and biomarkers. Improved quantication of MTBI exposure
as well as prospective longitudinal studies of outcomes and risk factors
will be critical to elucidate the actual burden of neurodegenerative diseases including CTE among athletes, military personnel, and civilians
exposed to single or repetitive MTBI.
Acknowledgments
RCG is supported by the Department of Veterans Affairs Ofce of Academic Afliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the San
Francisco Veterans Affairs Medical Center, and the Department of Veterans Affairs Sierra-Pacic Mental Illness Research, Education, and Clinical Center (MIRECC). KY has received research support from the
National Institutes of Health (NIH) via K24 AG031155, the Department
of Defense via W81XWH-12-1-0581, the Department of Veterans Affairs, the California Department of Public Health, the Bright Focus Foundation, and the Alzheimer's Association.
References
Bernick, C., Banks, S., Phillips, M., et al., 2013. Professional ghters brain health study:
rationale and methods. Am. J. Epidemiol. 178 (2), 280286 (Jul 15).
Bower, J.H., Maraganore, D.M., Peterson, B.J., McDonnell, S.K., Ahlskog, J.E., Rocca,
W.A., 2003. Head trauma preceding PD: a casecontrol study. Neurology 60
(10), 16101615 (May 27).
Carroll, L.J., Cassidy, J.D., Holm, L., Kraus, J., Coronado, V.G., 2004a. Injury WHOCCTFoMTB.
Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
J. Rehabil. Med. (43 Suppl.), 113125 (Feb).
Carroll, L.J., Cassidy, J.D., Peloso, P.M., et al., 2004b. Prognosis for mild traumatic brain
injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain
Injury. J. Rehabil. Med. (43 Suppl.), 84105 (Feb).
Cassidy, J.D., Carroll, L.J., Peloso, P.M., et al., 2004. Incidence, risk factors and prevention of
mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on
Mild Traumatic Brain Injury. J. Rehabil. Med. (43 Suppl.), 2860 (Feb).
Chen, H., Richard, M., Sandler, D.P., Umbach, D.M., Kamel, F., 2007. Head injury and amyotrophic lateral sclerosis. Am. J. Epidemiol. 166 (7), 810816 (Oct 1).
Clausen, H., McCrory, P., Anderson, V., 2005. The risk of chronic traumatic brain injury in
professional boxing: change in exposure variables over the past century. Br. J. Sports
Med. 39 (9), 661664 (Sep, discussion 4).
Constantinidis, J., Tissot, R., 1967. Generalized Alzheimer's neurobrillary lesions without
senile plaques. (Presentation of one anatomo-clinical case). Schweiz. Arch. Neurol.
Neurochir. Psychiatr. 100 (1), 117130.
80
Corsellis, J.A., Bruton, C.J., Freeman-Browne, D., 1973. The aftermath of boxing. Psychol.
Med. 3 (3), 270303 (Aug).
Crisco, J.J., Fiore, R., Beckwith, J.G., et al., 2010. Frequency and location of head impact exposures
in individual collegiate football players. J. Athl. Train. 45 (6), 549559 (NovDec).
Dams-O'Connor, K., Gibbons, L.E., Bowen, J.D., McCurry, S.M., Larson, E.B., Crane, P.K.,
2013. Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: a population-based study. J. Neurol. Neurosurg. Psychiatry 84
(2), 177182 (Feb).
Field, M., Collins, M.W., Lovell, M.R., Maroon, J., 2003. Does age play a role in recovery
from sports-related concussion? A comparison of high school and collegiate athletes.
J. Pediatr. 142 (5), 546553 (May).
Fischer, B.L., Parsons, M., Durgerian, S., et al., 2014. Neural activation during response
inhibition differentiates blast from mechanical causes of mild to moderate traumatic
brain injury. J. Neurotrauma 31 (2), 169179 (Jan 15).
Fleminger, S., Oliver, D.L., Lovestone, S., Rabe-Hesketh, S., Giora, A., 2003. Head injury as a
risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication.
J. Neurol. Neurosurg. Psychiatry 74 (7), 857862 (Jul).
Gardner, A., Iverson, G.L., McCrory, P., 2013. Chronic traumatic encephalopathy in sport: a
systematic review. Br. J. Sports Med. 26 (Jun).
Gardner, R.C., Burke, J.F., Nettiksimmons, J., Kaup, A., Barnes, D.E., Yaffe, K., 2014. Dementia
risk after traumatic brain injury vs nonbrain trauma: the role of age and severity.
JAMA Neurol. 71 (12), 14901497 (Dec).
Gardner, R.C., Burke, J.F., Nettiksimmons, J., Goldman, S., Tanner, C.M., Yaffe, K., 2015. Traumatic
brain injury in later life increases risk for Parkinson's disease. Ann Neurol. (Feb 27).
Gavett, B.E., Stern, R.A., McKee, A.C., 2011. Chronic traumatic encephalopathy: a potential
late effect of sport-related concussive and subconcussive head trauma. Clin. Sports
Med. 30 (1), 179188 (Jan, xi).
Godbolt, A.K., Cancelliere, C., Hincapie, C.A., et al., 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 (3S), S245S256 (Mar).
Goldman, S.M., Tanner, C.M., Oakes, D., Bhudhikanok, G.S., Gupta, A., Langston, J.W., 2006.
Head injury and Parkinson's disease risk in twins. Ann. Neurol. 60 (1), 6572 (Jul).
Goldman, S.M., Kamel, F., Ross, G.W., et al., 2012. Head injury, alpha-synuclein Rep1, and
Parkinson's disease. Ann. Neurol. 71 (1), 4048 (Jan).
Graves, A.B., White, E., Koepsell, T.D., et al., 1990. The association between head trauma
and Alzheimer's disease. Am. J. Epidemiol. 131 (3), 491501 (Mar).
Greenwald, R.M., Gwin, J.T., Chu, J.J., Crisco, J.J., 2008. Head impact severity measures for
evaluating mild traumatic brain injury risk exposure. Neurosurgery 62 (4),
789798 (Apr, discussion 98).
Guo, Z., Cupples, L.A., Kurz, A., et al., 2000. Head injury and the risk of AD in the MIRAGE
study. Neurology 54 (6), 13161323 (Mar 28).
Hagel, B., Meeuwisse, W., 2004. Risk compensation: a side effect of sport injury prevention? Clin. J. Sport Med. 14 (4), 193196 (Jul).
Hazrati, L.N., Tartaglia, M.C., Diamandis, P., et al., 2013. Absence of chronic traumatic
encephalopathy in retired football players with multiple concussions and neurological symptomatology. Front. Hum. Neurosci. 7, 222.
Helmes, E., Ostbye, T., Steenhuis, R.E., 2011. Incremental contribution of reported previous
head injury to the prediction of diagnosis and cognitive functioning in older adults.
Brain Inj. 25 (4), 338347.
Jafari, S., Etminan, M., Aminzadeh, F., Samii, A., 2013. Head injury and risk of Parkinson disease: a systematic review and meta-analysis. Mov. Disord. 28 (9), 12221229 (Aug).
Jordan, B.D., 2000. Chronic traumatic brain injury associated with boxing. Semin. Neurol.
20 (2), 179185.
Jordan, B.D., 2013. The clinical spectrum of sport-related traumatic brain injury. Nat. Rev.
Neurol. 9 (4), 222230 (Apr).
Jordan, B.D., 2014. Chronic traumatic encephalopathy and other long-term sequelae. Continuum 20 (6 Sports Neurology), 15881604 (Dec).
Jordan, B.D., Relkin, N.R., Ravdin, L.D., Jacobs, A.R., Bennett, A., Gandy, S., 1997. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278
(2), 136140 (Jul 9).
Kalkonde, Y.V., Jawaid, A., Qureshi, S.U., et al., 2012. Medical and environmental risk
factors associated with frontotemporal dementia: a casecontrol study in a veteran
population. Alzheimers Dement. 8 (3), 204210 (May).
Kristman, V.L., Borg, J., Godbolt, A.K., et al., 2014. Methodological issues and research recommendations for prognosis after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch. Phys. Med.
Rehabil. 95 (3 Suppl.), S265S277 (Mar).
Kuopio, A.M., Marttila, R.J., Helenius, H., Rinne, U.K., 1999. Environmental risk factors in
Parkinson's disease. Mov. Disord. 14 (6), 928939 (Nov).
Lee, P.C., Bordelon, Y., Bronstein, J., Ritz, B., 2012. Traumatic brain injury, paraquat exposure,
and their relationship to Parkinson disease. Neurology 79 (20), 20612066 (Nov 13).
Lee, Y.K., Hou, S.W., Lee, C.C., Hsu, C.Y., Huang, Y.S., Su, Y.C., 2013. Increased risk of dementia in patients with mild traumatic brain injury: a nationwide cohort study. PLoS One
8 (5), e62422.
Lee, P.C., Bordelon, Y., Bronstein, J., Sinsheimer, J.S., Farrer, M., Ritz, B., 2014. Head injury,
alpha-synuclein genetic variability and Parkinson's disease. Eur. J. Neurol. 5 (Nov).
Lehman, E.J., Hein, M.J., Baron, S.L., Gersic, C.M., 2012. Neurodegenerative causes of death
among retired National Football League players. Neurology 79 (19), 19701974 (Nov 6).
Lolekha, P., Phanthumchinda, K., Bhidayasiri, R., 2010. Prevalence and risk factors of Parkinson's
disease in retired Thai traditional boxers. Mov. Disord. 25 (12), 18951901 (Sep 15).
Mac Donald, C.L., Johnson, A.M., Wierzechowski, L., et al., 2014. Prospectively assessed
clinical outcomes in concussive blast vs nonblast traumatic brain injury among evacuated US military personnel. JAMA Neurol. 71 (8), 9941002 (Aug 1).
Marras, C., Hincapie, C.A., Kristman, V.L., et al., 2014. Systematic review of the risk of
Parkinson's disease after mild traumatic brain injury: results of the International
Collaboration on Mild Traumatic Brain Injury Prognosis. Arch. Phys. Med. Rehabil.
95 (3 Suppl.), S238S244 (Mar).
Martland, H.S., 1928. Punch drunk. J. Am. Med. Assoc. 91 (15), 11031107.
McCrory, P., Meeuwisse, W.H., Aubry, M., et al., 2013a. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport, Zurich,
November 2012. J. Athl. Train. 48 (4), 554575 (Jul-Aug).
McCrory, P., Meeuwisse, W.H., Kutcher, J.S., Jordan, B.D., Gardner, A., 2013b. What is the
evidence for chronic concussion-related changes in retired athletes: behavioural,
pathological and clinical outcomes? Br. J. Sports Med. 47 (5), 327330 (Apr).
McKee, A.C., Cantu, R.C., Nowinski, C.J., et al., 2009. Chronic traumatic encephalopathy in
athletes: progressive tauopathy after repetitive head injury. J. Neuropathol. Exp.
Neurol. 68 (7), 709735 (Jul).
McKee, A.C., Gavett, B.E., Stern, R.A., et al., 2010. TDP-43 proteinopathy and motor neuron
disease in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69 (9),
918929 (Sep).
McKee, A.C., Stern, R.A., Nowinski, C.J., et al., 2013. The spectrum of disease in chronic
traumatic encephalopathy. Brain 136 (Pt 1), 4364 (Jan).
Mehta, K.M., Ott, A., Kalmijn, S., et al., 1999. Head trauma and risk of dementia and
Alzheimer's disease: the Rotterdam study. Neurology 53 (9), 19591962 (Dec 10).
Millspaugh, J., 1937. Dementia pugilistica. U. S. Nav. Med. Bull. 35, 297303.
Mortimer, J.A., van Duijn, C.M., Chandra, V., et al., 1991. Head trauma as a risk factor for
Alzheimer's disease: a collaborative re-analysis of casecontrol studies. EURODEM
Risk Factors Research Group. Int. J. Epidemiol. 20 (Suppl. 2), S28S35.
National Center for Injury Prevention, 2003. Report to Congress. Mild Traumatic Brain
Injury in the United States: Steps to Prevent a Serious Public Health Problem. Centers
for Disease Control and Prevention, Atlanta.
Neselius, S., Brisby, H., Theodorsson, A., Blennow, K., Zetterberg, H., Marcusson, J., 2012.
CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma.
PLoS One 7 (4), e33606.
NINDS Common Data Elements, 2012. Traumatic Brain Injury. National Institutes of Neurological Diseases and Stroke; [cited 2014 October 15]. Available from: http://www.
commondataelements.ninds.nih.gov/TBI.aspx-tab=Data_Standards.
Nordstrom, P., Michaelsson, K., Gustafson, Y., Nordstrom, A., 2014. Traumatic brain injury and
young onset dementia: a nationwide cohort study. Ann. Neurol. 75 (3), 374381 (Mar).
Omalu, B.I., DeKosky, S.T., Minster, R.L., Kamboh, M.I., Hamilton, R.L., Wecht, C.H., 2005.
Chronic traumatic encephalopathy in a national football league player. Neurosurgery
57 (1), 128134 (Jul, discussion 34).
Omalu, B.I., DeKosky, S.T., Hamilton, R.L., et al., 2006. Chronic traumatic encephalopathy in
a national football league player: part II. Neurosurgery 59 (5), 10861092 (Nov, discussion 923).
Omalu, B., Bailes, J., Hamilton, R.L., et al., 2011. Emerging histomorphologic phenotypes of
chronic traumatic encephalopathy in American athletes. Neurosurgery 69 (1),
173183 (Jul, discussion 83).
Parker, H.L., 1934. Traumatic encephalopathy (punch drunk) of professional pugilists.
J. Neurol. Psychopathol. 15 (57), 2028 (Jul).
Pullela, R., Raber, J., Pfankuch, T., et al., 2006. Traumatic injury to the immature brain
results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Dev. Neurosci. 28 (45), 396409.
Roberts, A.H., 1969. Brain Damage in Boxers: A Study of the Prevalence of Traumatic
Encephalopathy Among Ex-Professional Boxers. Pitman Medical & Scientic Publishing Co., Ltd.
Rosso, S.M., Landweer, E.J., Houterman, M., Donker Kaat, L., van Duijn, C.M., van Swieten,
J.C., 2003. Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective casecontrol study. J. Neurol. Neurosurg. Psychiatry 74 (11),
15741576 (Nov).
Rugbjerg, K., Ritz, B., Korbo, L., Martinussen, N., Olsen, J.H., 2008. Risk of Parkinson's
disease after hospital contact for head injury: population based casecontrol study.
BMJ 337, a2494.
Savica, R., Parisi, J.E., Wold, L.E., Josephs, K.A., Ahlskog, J.E., 2012. High school football and
risk of neurodegeneration: a community-based study. Mayo Clin. Proc. 87 (4),
335340 (Apr).
Schmidt, S., Kwee, L.C., Allen, K.D., Oddone, E.Z., 2010. Association of ALS with head injury,
cigarette smoking and APOE genotypes. J. Neurol. Sci. 291 (12), 2229 (Apr 15).
Schoeld, P.W., Tang, M., Marder, K., et al., 1997. Alzheimer's disease after remote head
injury: an incidence study. J. Neurol. Neurosurg. Psychiatry 62 (2), 119124 (Feb).
Seidler, A., Hellenbrand, W., Robra, B.P., et al., 1996. Possible environmental, occupational,
and other etiologic factors for Parkinson's disease: a casecontrol study in Germany.
Neurology 46 (5), 12751284 (May).
Setnik, L., Bazarian, J.J., 2007. The characteristics of patients who do not seek medical
treatment for traumatic brain injury. Brain Inj. 21 (1), 19 (Jan).
Spiotta, A.M., Shin, J.H., Bartsch, A.J., Benzel, E.C., 2011. Subconcussive impact in sports: a
new era of awareness. World Neurosurg. 75 (2), 175178 (Feb).
Stern, R.A., Daneshvar, D.H., Baugh, C.M., et al., 2013. Clinical presentation of chronic traumatic encephalopathy. Neurology 81 (13), 11221129 (Sep 24).
Taylor, R.B., 1953. Traumatic encephalopathy from boxing. Br. Med. J. 1 (4803), 200201
(Jan 24).
Villemagne, V.L., Fodero-Tavoletti, M.T., Masters, C.L., Rowe, C.C., 2015. Tau imaging: early
progress and future directions. Lancet Neurol. 14 (1), 114124 (Jan).
Wilk, J.E., Herrell, R.K., Wynn, G.H., Riviere, L.A., Hoge, C.W., 2012. Mild traumatic brain injury (concussion), posttraumatic stress disorder, and depression in U.S. soldiers involved in combat deployments: association with postdeployment symptoms.
Psychosom. Med. 74 (3), 249257 (Apr).