Molecular and Cellular Neuroscience 66 (2015) 73–74
Contents lists available at ScienceDirect
Molecular and Cellular Neuroscience journal homepage: www.elsevier.com/locate/ymcne
Editorial
Repetitive concussions — How dangerous are they? Keywords: Concussion Chronic traumatic encephalopathy Amyloid Tau Risk factors
A blow to the head may result in anything from a superficial skin laceration to severe brain injury. In his early writings, Hippocrates commented on the potential gravity of head injuries and a famous sentence is attributed to him: “Nullum vulnus capitis contemnendum est” or, as our current day English would have it, “No wound of the head is to be viewed as a negligible matter.” This sentence also introduces Sir Percivall Pott's book “Observations on the nature and consequences of those injuries to which the head is liable from external violence” from 1773. This is a fascinating and humbling piece of work in which Sir Pott, an English surgeon noted for his many insightful and comprehensive surgical writings, goes into great detail on how to differentiate diffuse brain injury (concussion or the archaic “commotion”), which is best treated with phlebotomy and bed rest in a dark room as an entity separate and distinct from intra-cranial bleeding in which dangerous but potentially life-saving trephination may be indicated. “Whoever seriously reflects on the nature of these two causes of evil within the cranium,” he writes, “and considers them as liable to frequent combination in the same subject, and at the same time considers, that in many instances no degree of information can be obtained from the only person capable of giving it (the patient), will immediately recognize how very difficult a part a practitioner has to play in the outcomes of many of these cases.” Sir Pott would have been delighted to have been able to be present to see the current use of modern neuroimaging techniques in emergency care units. However, he was not only interested in diagnosing acute catastrophic traumatic brain injury (TBI) but he was also very aware that concussions, also in the absence of focal injury, sometimes produced chronic and even progressive neurological symptoms that we now recognize as one of the chronic traumatic encephalopathies (“…a debility of understanding, an idiot look, a failure of memory…”). In 1928, the New Jersey pathologist Harrison Martland described symptoms such as slowed movement, tremor, confusion, and speech problems in a group of former boxers, calling it “the punch drunk syndrome” (Martland, 1928). A few years later, Millspaugh called this syndrome dementia pugilistica (Millspaugh, 1937). The syndrome has now been extended to include a complex neuropathological and clinical diagnosis known today as chronic traumatic encephalopathy (CTE). Post-traumatic Alzheimer's disease (AD) could also be considered to be an element of the CTE spectrum. At post-mortem, amyloid plaques
http://dx.doi.org/10.1016/j.mcn.2015.02.004 1044-7431/© 2015 Elsevier Inc. All rights reserved.
are present in all patients with AD but in only half of those with CTE. This has led some to emphasize the neurofibrillary tangle (NFT) or tauopathy as the signature lesion of CTE. While this is not completely wrong, it is also not completely right. Acute amyloid deposition has been identified in the brains of young subjects within hours to days following a severe TBI (DeKosky et al., 2007; Hong et al., 2014; Ikonomovic et al., 2004). There are clinicogenetic implications to this issue. Carriers of the APOE ε4 allele have poorer outcomes and are known to be less efficient in abetting glia in their cleanup of protein debris in the brain, including amyloid debris (Gandy and Dekosky, 2012). Despite the fact that amyloid may be gone by end stage, one cannot exclude the possibility that bursts of diffuse amyloid deposition occur acutely after each TBI and that the tauopathy is driven by the toxic nature of this amyloid. The significance, in turn, is that we have in hand safe effective amyloiddetecting tests and amyloid-treating drugs (Gandy et al., 2014), so if amyloid is driving the tauopathy treatment or pre-treatment during the acute phase could improve outcome. The term CTE first showed up in a chapter titled “Punch drunk syndrome: The chronic traumatic encephalopathy of boxers,” that the British neurologist MacDonald Critchley contributed to a 1949 book edited by the French neurosurgeon Clovis Vincent. CTE is now the preferred term, since it has become increasingly clear that the syndrome is not restricted to boxers. In 1973, a group led by Nick Corsellis described the typical neuropathological findings of CTE after postmortem examinations of the brains of 15 former boxers (Corsellis et al., 1973). Their key findings included neurofibrillary tangles in cortical areas, cerebellar atrophy and gliosis, hypopigmentation of the substantia nigra, and cavum septum pellucidum (a cerebrospinal fluid-filled space between the leaflets of the septum pellucidum, the membrane separating the anterior horns of the left and right lateral ventricles). The Corsellis paper prompted the intense and continuing debate on the medical consequences and ethics of boxing as a sport and contributed to statements by the World Medical Association that boxing should be banned (http://www.wma.net/en/30publications/ 10policies/b6/index.html). This began the drive to make boxing more “underground” and less “marquee” in character and venue but it is not clear that the sport is any less popular. The world's highest moneymaking athlete in 2014 was a boxer. More recently, case reports demonstrate pathologically confirmed CTE in former combat military personnel and contact sport athletes other than boxers (Goldstein et al., 2012; Omalu et al., 2005, 2006). This has resulted in renewed interest and controversy regarding the potential for long-term neurodegenerative changes to occur after concussive and sub-concussive repetitive and blast wave-associated head trauma (McKee et al., 2013). But more precisely, how dangerous is concussion and how strong is the link between repetitive concussions and CTE? Is there individual susceptibility that could be identified? The short answer is that we do
74
Editorial
not know. There are clearly highly exposed boxers who are apparently intact. So far, most clinical CTE research has been based on autopsies of athletes' brains that were donated from families concerned about the players' cognitive and behavioral symptoms before dying. But such non-random case series can bias findings because the samples may not be representative of the entire population having suffered repetitive concussions. Nevertheless, the results obtained so far are in our view alarming enough to warrant prospective studies of contact sports athletes and other risk groups with ambitious phenotyping and follow-up to give stronger data on the association of concussion with chronic or progressive neurologic sequelae, to identify risk factors and disease mechanisms and to give clues on how CTE can be best prevented and treated. This themed issue of Molecular and Cellular Neuroscience is dedicated to research into TBI with a special focus on the potential links between repetitive concussions and CTE. The papers review the epidemiology of concussion and CTE, the pathophysiology and pathology of TBI and fluid and neuroimaging biomarkers for central nervous system changes following TBI. Two articles are focused on sports-related TBI and TBI due to military exposures, since these constitute two entities that have attracted considerable media attention and both legal and public debate during recent years. Altogether, it is our hope that this journal issue will give the reader an updated view on the current state of knowledge regarding potential neurological consequences of repetitive brain injuries, not only from severe head trauma but also from concussive or sub-concussive head blows that are not uncommon in the everyday life of quite a number of individuals. Acknowledgments Work in the authors' laboratories are supported by the Wolfson Foundation (HZ), the Knut and Alice Wallenberg Foundation (HZ), the Swedish Research Council (HZ), the Alzheimer Foundation (HZ), the Alzheimer's Drug Discovery Foundation (SG), and the US Department of Veterans Affairs MERIT Review Program in RRD (SG). References Corsellis, J.A., Bruton, C.J., Freeman-Browne, D., 1973. The aftermath of boxing. Psychol. Med. 3, 270–303. DeKosky, S.T., Abrahamson, E.E., Ciallella, J.R., Paljug, W.R., Wisniewski, S.R., Clark, R.S., Ikonomovic, M.D., 2007. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch. Neurol. 64, 541–544. Gandy, S., Dekosky, S.T., 2012. APOE epsilon4 status and traumatic brain injury on the gridiron or the battlefield. Sci. Transl. Med. 4, 134ed134.
Gandy, S., Ikonomovic, M.D., Mitsis, E., Elder, G., Ahlers, S.T., Barth, J., Stone, J.R., DeKosky, S.T., 2014. Chronic traumatic encephalopathy: clinical-biomarker correlations and current concepts in pathogenesis. Mol. Neurodegener. 9, 37. Goldstein, L.E., Fisher, A.M., Tagge, C.A., Zhang, X.L., Velisek, L., Sullivan, J.A., Upreti, C., Kracht, J.M., Ericsson, M., Wojnarowicz, M.W., et al., 2012. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci. Transl. Med. 4, 134ra160. Hong, Y.T., Veenith, T., Dewar, D., Outtrim, J.G., Mani, V., Williams, C., Pimlott, S., Hutchinson, P.J., Tavares, A., Canales, R., et al., 2014. Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol. 71, 23–31. Ikonomovic, M.D., Uryu, K., Abrahamson, E.E., Ciallella, J.R., Trojanowski, J.Q., Lee, V.M., Clark, R.S., Marion, D.W., Wisniewski, S.R., DeKosky, S.T., 2004. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp. Neurol. 190, 192–203. Martland, H., 1928. Punch drunk. JAMA 91, 1103–1107. McKee, A.C., Stern, R.A., Nowinski, C.J., Stein, T.D., Alvarez, V.E., Daneshvar, D.H., Lee, H.S., Wojtowicz, S.M., Hall, G., Baugh, C.M., et al., 2013. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64. Millspaugh, J., 1937. Dementia pugilistica. U. S. Nav. Med. Bull. 35, 297–302. 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, 128–134 (discussion 128–134). Omalu, B.I., DeKosky, S.T., Hamilton, R.L., Minster, R.L., Kamboh, M.I., Shakir, A.M., Wecht, C.H., 2006. Chronic traumatic encephalopathy in a National Football League player: part II. Neurosurgery 59, 1086–1092 (discussion 1092–1083).
Henrik Zetterberg Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK Corresponding author at: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden. E-mail address: [email protected]. Sam Gandy Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA The Mount Sinai Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA James J Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA 25 January 2015
Contents lists available at ScienceDirect
Molecular and Cellular Neuroscience journal homepage: www.elsevier.com/locate/ymcne
Editorial
Repetitive concussions — How dangerous are they? Keywords: Concussion Chronic traumatic encephalopathy Amyloid Tau Risk factors
A blow to the head may result in anything from a superficial skin laceration to severe brain injury. In his early writings, Hippocrates commented on the potential gravity of head injuries and a famous sentence is attributed to him: “Nullum vulnus capitis contemnendum est” or, as our current day English would have it, “No wound of the head is to be viewed as a negligible matter.” This sentence also introduces Sir Percivall Pott's book “Observations on the nature and consequences of those injuries to which the head is liable from external violence” from 1773. This is a fascinating and humbling piece of work in which Sir Pott, an English surgeon noted for his many insightful and comprehensive surgical writings, goes into great detail on how to differentiate diffuse brain injury (concussion or the archaic “commotion”), which is best treated with phlebotomy and bed rest in a dark room as an entity separate and distinct from intra-cranial bleeding in which dangerous but potentially life-saving trephination may be indicated. “Whoever seriously reflects on the nature of these two causes of evil within the cranium,” he writes, “and considers them as liable to frequent combination in the same subject, and at the same time considers, that in many instances no degree of information can be obtained from the only person capable of giving it (the patient), will immediately recognize how very difficult a part a practitioner has to play in the outcomes of many of these cases.” Sir Pott would have been delighted to have been able to be present to see the current use of modern neuroimaging techniques in emergency care units. However, he was not only interested in diagnosing acute catastrophic traumatic brain injury (TBI) but he was also very aware that concussions, also in the absence of focal injury, sometimes produced chronic and even progressive neurological symptoms that we now recognize as one of the chronic traumatic encephalopathies (“…a debility of understanding, an idiot look, a failure of memory…”). In 1928, the New Jersey pathologist Harrison Martland described symptoms such as slowed movement, tremor, confusion, and speech problems in a group of former boxers, calling it “the punch drunk syndrome” (Martland, 1928). A few years later, Millspaugh called this syndrome dementia pugilistica (Millspaugh, 1937). The syndrome has now been extended to include a complex neuropathological and clinical diagnosis known today as chronic traumatic encephalopathy (CTE). Post-traumatic Alzheimer's disease (AD) could also be considered to be an element of the CTE spectrum. At post-mortem, amyloid plaques
http://dx.doi.org/10.1016/j.mcn.2015.02.004 1044-7431/© 2015 Elsevier Inc. All rights reserved.
are present in all patients with AD but in only half of those with CTE. This has led some to emphasize the neurofibrillary tangle (NFT) or tauopathy as the signature lesion of CTE. While this is not completely wrong, it is also not completely right. Acute amyloid deposition has been identified in the brains of young subjects within hours to days following a severe TBI (DeKosky et al., 2007; Hong et al., 2014; Ikonomovic et al., 2004). There are clinicogenetic implications to this issue. Carriers of the APOE ε4 allele have poorer outcomes and are known to be less efficient in abetting glia in their cleanup of protein debris in the brain, including amyloid debris (Gandy and Dekosky, 2012). Despite the fact that amyloid may be gone by end stage, one cannot exclude the possibility that bursts of diffuse amyloid deposition occur acutely after each TBI and that the tauopathy is driven by the toxic nature of this amyloid. The significance, in turn, is that we have in hand safe effective amyloiddetecting tests and amyloid-treating drugs (Gandy et al., 2014), so if amyloid is driving the tauopathy treatment or pre-treatment during the acute phase could improve outcome. The term CTE first showed up in a chapter titled “Punch drunk syndrome: The chronic traumatic encephalopathy of boxers,” that the British neurologist MacDonald Critchley contributed to a 1949 book edited by the French neurosurgeon Clovis Vincent. CTE is now the preferred term, since it has become increasingly clear that the syndrome is not restricted to boxers. In 1973, a group led by Nick Corsellis described the typical neuropathological findings of CTE after postmortem examinations of the brains of 15 former boxers (Corsellis et al., 1973). Their key findings included neurofibrillary tangles in cortical areas, cerebellar atrophy and gliosis, hypopigmentation of the substantia nigra, and cavum septum pellucidum (a cerebrospinal fluid-filled space between the leaflets of the septum pellucidum, the membrane separating the anterior horns of the left and right lateral ventricles). The Corsellis paper prompted the intense and continuing debate on the medical consequences and ethics of boxing as a sport and contributed to statements by the World Medical Association that boxing should be banned (http://www.wma.net/en/30publications/ 10policies/b6/index.html). This began the drive to make boxing more “underground” and less “marquee” in character and venue but it is not clear that the sport is any less popular. The world's highest moneymaking athlete in 2014 was a boxer. More recently, case reports demonstrate pathologically confirmed CTE in former combat military personnel and contact sport athletes other than boxers (Goldstein et al., 2012; Omalu et al., 2005, 2006). This has resulted in renewed interest and controversy regarding the potential for long-term neurodegenerative changes to occur after concussive and sub-concussive repetitive and blast wave-associated head trauma (McKee et al., 2013). But more precisely, how dangerous is concussion and how strong is the link between repetitive concussions and CTE? Is there individual susceptibility that could be identified? The short answer is that we do
74
Editorial
not know. There are clearly highly exposed boxers who are apparently intact. So far, most clinical CTE research has been based on autopsies of athletes' brains that were donated from families concerned about the players' cognitive and behavioral symptoms before dying. But such non-random case series can bias findings because the samples may not be representative of the entire population having suffered repetitive concussions. Nevertheless, the results obtained so far are in our view alarming enough to warrant prospective studies of contact sports athletes and other risk groups with ambitious phenotyping and follow-up to give stronger data on the association of concussion with chronic or progressive neurologic sequelae, to identify risk factors and disease mechanisms and to give clues on how CTE can be best prevented and treated. This themed issue of Molecular and Cellular Neuroscience is dedicated to research into TBI with a special focus on the potential links between repetitive concussions and CTE. The papers review the epidemiology of concussion and CTE, the pathophysiology and pathology of TBI and fluid and neuroimaging biomarkers for central nervous system changes following TBI. Two articles are focused on sports-related TBI and TBI due to military exposures, since these constitute two entities that have attracted considerable media attention and both legal and public debate during recent years. Altogether, it is our hope that this journal issue will give the reader an updated view on the current state of knowledge regarding potential neurological consequences of repetitive brain injuries, not only from severe head trauma but also from concussive or sub-concussive head blows that are not uncommon in the everyday life of quite a number of individuals. Acknowledgments Work in the authors' laboratories are supported by the Wolfson Foundation (HZ), the Knut and Alice Wallenberg Foundation (HZ), the Swedish Research Council (HZ), the Alzheimer Foundation (HZ), the Alzheimer's Drug Discovery Foundation (SG), and the US Department of Veterans Affairs MERIT Review Program in RRD (SG). References Corsellis, J.A., Bruton, C.J., Freeman-Browne, D., 1973. The aftermath of boxing. Psychol. Med. 3, 270–303. DeKosky, S.T., Abrahamson, E.E., Ciallella, J.R., Paljug, W.R., Wisniewski, S.R., Clark, R.S., Ikonomovic, M.D., 2007. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch. Neurol. 64, 541–544. Gandy, S., Dekosky, S.T., 2012. APOE epsilon4 status and traumatic brain injury on the gridiron or the battlefield. Sci. Transl. Med. 4, 134ed134.
Gandy, S., Ikonomovic, M.D., Mitsis, E., Elder, G., Ahlers, S.T., Barth, J., Stone, J.R., DeKosky, S.T., 2014. Chronic traumatic encephalopathy: clinical-biomarker correlations and current concepts in pathogenesis. Mol. Neurodegener. 9, 37. Goldstein, L.E., Fisher, A.M., Tagge, C.A., Zhang, X.L., Velisek, L., Sullivan, J.A., Upreti, C., Kracht, J.M., Ericsson, M., Wojnarowicz, M.W., et al., 2012. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci. Transl. Med. 4, 134ra160. Hong, Y.T., Veenith, T., Dewar, D., Outtrim, J.G., Mani, V., Williams, C., Pimlott, S., Hutchinson, P.J., Tavares, A., Canales, R., et al., 2014. Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol. 71, 23–31. Ikonomovic, M.D., Uryu, K., Abrahamson, E.E., Ciallella, J.R., Trojanowski, J.Q., Lee, V.M., Clark, R.S., Marion, D.W., Wisniewski, S.R., DeKosky, S.T., 2004. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp. Neurol. 190, 192–203. Martland, H., 1928. Punch drunk. JAMA 91, 1103–1107. McKee, A.C., Stern, R.A., Nowinski, C.J., Stein, T.D., Alvarez, V.E., Daneshvar, D.H., Lee, H.S., Wojtowicz, S.M., Hall, G., Baugh, C.M., et al., 2013. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64. Millspaugh, J., 1937. Dementia pugilistica. U. S. Nav. Med. Bull. 35, 297–302. 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, 128–134 (discussion 128–134). Omalu, B.I., DeKosky, S.T., Hamilton, R.L., Minster, R.L., Kamboh, M.I., Shakir, A.M., Wecht, C.H., 2006. Chronic traumatic encephalopathy in a National Football League player: part II. Neurosurgery 59, 1086–1092 (discussion 1092–1083).
Henrik Zetterberg Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK Corresponding author at: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden. E-mail address: [email protected]. Sam Gandy Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA The Mount Sinai Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA James J Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA 25 January 2015
