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Gavett et al. Alzheimer’s Research & Therapy 2010, 2:18 CO M M E N TA R Y Mild traumatic brain injury: a risk factor for neurodegeneration Brandon E Gavett1,2, Robert A Stern1,2, Robert C Cantu2,3,4, Christopher J Nowinski2,3 and Ann C McKee1,2,5,6* there is a genetic susceptibility to the development of CTE and whether a single severe traumatic head injury may also be causative. Abstract Recently, it has become clear that head trauma can lead to a progressive
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  A complex interaction between genetic and environ-mental risk factors has often been a suspected trigger forthe development of neurodegenerative disease. Yet of allthe possible environmental risk factors put forth, traumato the central nervous system is one of the most consis-tent candidates for initiating the molecular cascades thatresult in Alzheimer’s disease (AD), Parkinson’s disease(PD), and amyotrophic lateral sclerosis [1-3]. Recentevidence also suggests that mild traumatic brain injury (TBI), including repetitive concussive and subconcussivetrauma, can provoke another distinctive neurodegenera-tion: chronic traumatic encephalopathy (CTE) [4].CTE has to date only been described neuropatho-logically in individuals with a history of repetitive closedhead injury, most often occurring in the context of contact sports. It remains to be determined whetherthere is a genetic susceptibility to the development of CTE and whether a single severe traumatic head injury may also be causative. Chronic traumatic encephalopathy CTE is a progressive tauopathy with a distinct clinicaland neuropathological profile that becomes symptomaticmany years after an individual experiences repeated con-cussive or subconcussive blows to the head.  e charac-teristic features of CTE include: extensive tau immuno-reactive neurofibrillary tangles and astrocytic tanglesthroughout the frontal and temporal cortices in a patchy,superficial distribution, with focal epicenters at thedepths of sulci and around small vessels; extensive tauneurofibrillary tangles in the limbic and paralimbicregions, diencephalon, basal ganglia and brainstem; and arelative paucity of  β -amyloid (A β ) deposits, althoughdi ff  use plaques are present in roughly one-half of thecases. In advanced disease, there are also macroscopicabnormalities: generalized cerebral atrophy and enlarged ventricles; atrophy of the medial temporal lobe structuresand mammillary bodies; cavum septi pellucidi, often withfenestrations; and pallor of the substantia nigra.CTE typically becomes symptomatic in mid-life asdisordered cognition, most pronounced in the areas of memory and executive functioning; disturbances in moodand comportment (for example, apathy, irritability); andParkinsonian signs [4]. CTE was in the past referred to as dementia pugilistica , which reflected the prevailingnotion that this condition was restricted to boxers –athletes who engaged in a sport with purposeful repeatedblows to the head. Recent research, however, has demon-strated neuropathological evidence of CTE in retiredAmerican football players, a professional wrestler, aprofessional hockey player and a soccer player [4], as wellas in nonathletes [5]. It is probable that many individualsare susceptible to CTE, including those who experiencefalls, motor vehicle accidents, assaults, epileptic seizures,or military combat, and that repeated mild closed headtrauma of diverse srcin is capable of instigating theneurodegenerative cascade leading to CTE.Although neuropathologically distinct, the clinical pre-sentation of CTE may be very similar to AD or Abstract Recently, it has become clear that head trauma canlead to a progressive neurodegeneration known aschronic traumatic encephalopathy. Although themedical literature also implicates head trauma as arisk factor for Alzheimer’s disease, these  ndings arepredominantly based on clinical diagnostic criteria thatlack speci  city. The dementia that follows head injuriesor repetitive mild trauma may be caused by chronictraumatic encephalopathy, alone or in conjunctionwith other neurodegenerations (for example,Alzheimer’s disease). Prospective longitudinal studiesof head-injured individuals, with neuropathologicalveri  cation, will not only improve understanding of head trauma as a risk factor for dementia but will alsoenhance treatment and prevention of a variety of neurodegenerative diseases. © 2010 BioMed Central Ltd Mild traumatic brain injury: a risk factor forneurodegeneration Brandon E Gavett 1,2 , Robert A Stern 1,2 , Robert C Cantu 2,3,4 , Christopher J Nowinski 2,3 and Ann C McKee 1,2,5,6 * COMMENTARY *Correspondence:; 5 Geriatric Research Education Clinical Center, Edith Nourse Rogers Memorial VAHospital, 200 Springs Road, Bedford, MA 01730, USAFull list of author information is available at the end of the article Gavett et al  .  Alzheimer’s Research & Therapy  2010, 2 :18 © 2010 BioMed Central Ltd  frontotemporal lobar degeneration, especially inadvanced disease [4]. Individuals may meet clinicalcriteria for AD or frontotemporal lobar degeneration,even though the age of onset for CTE is generally youngerthan that for AD and the course of the disease is typically slower than that of AD or frontotemporal lobardegeneration.  ese similarities bring into question thespecificity of the clinical diagnostic criteria for AD usedin the multitude of case–control studies that haveestablished TBI as a risk factor for AD. Withoutneuropathological verification, the prevalence of CTEneuropathology in a demented sample is unknown. The link between head trauma, Alzheimer’s diseaseand other neurodegenerations Multiple epidemiological studies have shown that mildTBI is a risk factor for late-life dementia, especially AD[1]. Although the evidence is not without its detractors(for example [6]), meta-analytic studies support thenotion that AD risk is increased after TBI, at least formen [7]. In almost all of the studies investigating TBI andAD risk, AD was diagnosed based on clinical criteria forprobable or possible AD, without neuropathological verification. Only one study has evaluated the risk of ADfollowing TBI using standardized neuropathologicalcriteria for AD [8] – finding that a history of TBI was arisk factor for AD, particularly in individuals without theapolipoprotein e4 allele. As the majority of reports werebased on clinical diagnostic criteria that may lack thespecificity to rule out other causes of dementia [9], it ispossible that the increased incidence of dementia follow-ing head injuries is due to CTE, alone or in conjunctionwith other neurodegenerative conditions such as AD.Multiple studies have also indicated that a history of trauma to the central nervous system is a risk factor forother neurodegenerative conditions, including PD [2,10]and amyotrophic lateral sclerosis [3,11,12]. WidespreadTAR DNA-binding protein 43 (TDP-43)-positive inclu-sions have been reported in the neocortex in cases of CTE [13]. We recently also found TDP-43 immuno-reactive inclusions and neurites in the frontal andtemporal cortices, medial temporal lobe, basal ganglia,diencephalon, and brainstem in 10 out of 12 cases of CTE.  ree of these athletes with CTE also had aprogressive motor neuron disease characterized by profound weakness, atrophy, spasticity, and fascicula-tions, and abundant TDP-43-positive inclusions werefound in the spinal cord, as well as tau neurofibrillary changes, upon postmortem examination [14].  ese findings support epidemiologic evidence that therepetitive head trauma experienced in sports might alsobe associated with the development of a motor neurondisease [3,11,14]. TBI could conceivably trigger multiplemolecular pathways that result in the overproductionand aggregation of a number of key proteins that formpathological aggregates in neurodegenerative diseases.TBI may not only provoke the accumulation of hyper-phosphorylated tau protein, as CTE, but also of A β , α -synuclein, and TDP-43, possibly increasing the likelihoodof developing AD, PD, and motor neuron disease.Experimental evidence indicates that A β neurotoxicity isenhanced in the presence of tau [15]. It is conceivablethat tau deposition provoked by repetitive head traumaaccelerates A β toxicity in individuals with age-related A β  plaques [16], triggering the more rapid onset of AD.Furthermore, aggregates of  α -synuclein and A β havebeen described after experimental TBI in animals andafter acute brain trauma in humans [17]. The need for future chronic traumaticencephalopathy research  ere is clearly a need for improved accuracy of clinicaldiagnostic criteria in the di ff  erential diagnosis of CTEand AD, which will require new prospective longitudinalstudies terminating in autopsy. Equally important is theneed for standardized criteria to diagnose CTE neuro-pathologically, either alone or as mixed disease.Although the evidence suggests that central nervoussystem trauma is a risk factor for CTE, as well as for AD,PD, and motor neuron disease, very little is known aboutwhat type, frequency, or amount of trauma is necessary to induce the accumulation of these pathological proteins.Future prospective studies will be necessary to answerthese questions as well as to determine at what age thenervous system is most susceptible to the deleteriouse ff  ects of trauma and whether proper management of acute head injuries is e ff  ective in reducing the incidenceof late-life neurodegenerative dementias.Accurate di ff  erential diagnosis in the preclinical orearly phases of CTE and AD may have important thera-peutic implications as well. For example, therapeuticsselectively targeting A β will be misguided if thepredominant neuropathological abnormality is hyper-phosphorylated tau protein, as in CTE. Furthermore, useof experimental models of head injury to provokeneurodegeneration in genetically modified animals may ultimately serve to identify key components of the patho-genetic molecular cascades as well as susceptibility genesfor a variety of neurodegenerative diseases. Abbreviations A β , β -amyloid; AD, Alzheimer’s disease; CTE, chronic traumaticencephalopathy; PD, Parkinson’s disease; TBI, traumatic brain injury; TDP-43, TAR DNA-binding protein 43. Competing interests RAS has been a paid consultant for Elan Pharmaceuticals and OutcomeScience. He also receives royalties from Psychological Assessment Resources,Inc., as a co-developer of the Neuropsychological Assessment Battery. Theother authors declare they have no competing interests. Gavett et al  .  Alzheimer’s Research & Therapy  2010, 2 :18 2 of 3  Acknowledgements  The present work was supported by NIA P30AG13846 (supplement0572063345-5), the National Operating Committee on Standards for AthleticEquipment and the Department of Veterans A   airs. This work was alsosupported by an unrestricted gift from the National Football League. Thefunding sources were not involved in the preparation, review, or approval of this manuscript. Author details 1 Department of Neurology, Boston University School of Medicine, 72 EastConcord St., B-7800, Boston, MA 02118, USA. 2 Center for the Study of TraumaticEncephalopathy, Boston University, 72 East Concord St., B-7800, Boston, MA02118, USA. 3 Sports Legacy Institute, 230 3rd Ave., Waltham, MA 02451, USA. 4 Department of Neurosurgery, Emerson Hospital, 131 ORNAC Suite 820, JohnCuming Building, Concord, MA, 01742, USA. 5 Geriatric Research EducationClinical Center, Edith Nourse Rogers Memorial VA Hospital, 200 Springs Road,Bedford, MA 01730, USA. 6 Department of Pathology and Laboratory Medicine,Boston University School of Medicine, 670 Albany Street – 4th Floor, Boston,MA 02118, USA. Published: 25 June 2010 References 1. Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A,Jorm AF, Kokmen E, Kondo K, Rocca WA: Head trauma as a risk factor forAlzheimer’s disease: a collaborative re-analysis of case–control studies.EURODEM Risk Factors Research Group.   Int J Epidemiol  1991, 20: S28-S35.2. Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW: Head injury and Parkinson’s disease risk in twins.    Ann Neurol  2006, 60: 65-72.3. Chen H, Richard M, Sandler DP, Umbach DM, Kamel F: Head injury andamyotrophic lateral sclerosis.    Am J Epidemiol  2007, 166: 810-816.4. McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE,Santini VE, Lee HS, Kubilus CA, Stern RA: Chronic traumatic encephalopathyin athletes: progressive tauopathy after repetitive head injury.    J    Neuropathol Exp Neurol  2009, 68: 709-735.5. Roberts GW, Whitwell HL, Acland PR, Bruton CJ: Dementia in a punch-drunk wife.   Lancet  1990, 335: 918-919.6. Fratiglioni L, Ahlbom A, Viitanen M, Winblad B: Risk factors for late-onsetAlzheimer’s disease: a population-based, case–control study.    Ann Neurol  1993, 33: 258-266.7. Fleminger S: Head injury as a risk factor for Alzheimer’s disease: theevidence 10 years on; a partial replication.    J Neurol Neurosurg Psychiatr  2003, 74: 857-862.8. Jellinger KA, Paulus W, Wrocklage C, Litvan I:  Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsycohorts with evaluation of ApoE genotype.   BMC Neurol  2001, 1: 3-6.9. Kukull WA, Larson EB, Rei  er BV, Lampe TH, Yerby MS, Hughes JP:  The validityof 3 clinical diagnostic criteria for Alzheimer’s disease.   Neurology  1990, 40: 1364-1369.10. Ben-Shlomo Y:  The epidemiology of Parkinson’s disease.   Baillieres Clin Neurol  1997, 6: 55-68.11. Schmidt S, Kwee LC, Allen KD, Oddone EZ: Association of ALS with headinjury, cigarette smoking and APOE genotypes.    J Neurol Sci  2010, 291: 22-29.12. Chen H, Richard M, Sandler DP, Umbach DM, Kamel F: Head injury andamyotrophic lateral sclerosis.  Am J Epidemiol  2007, 166: 810-816.13. King A, Sweeney F, Bodi I, Troakes C, Maekawa S, Al-Sarraj S: Abnormal TDP-43 expression is identi  ed in the neocortex in cases of dementiapugilistica, but is mainly con  ned to the limbic system when identi  ed inhigh and moderate stages of Alzheimer’s disease.   Neuropathology  2010.[Epub ahead of print]14. McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP,Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee H, Kubilus CA, DanshevarDH, Wul   M, Budson AE:  TDP-43 proteinopathy and motor neuron diseasein chronic traumatic encephalopathy.    J Neuropathol Exp Neurol  2010[manuscript accepted for publication].15. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, YuGQ, Mucke L: Reducing endogenous tau ameliorates amyloid beta-induced de  cits in an Alzheimer’s disease mouse model. Science 2007, 316: 750–754.16. Mann DM, Brown AM, Prinja D, Jones D, Davies CA: A morphological analysisof senile plaques in the brains of non-demented persons of di   erent agesusing silver, immunocytochemical and lectin histochemical stainingtechniques.   Neuropathol Appl Neurobiol  1990, 16: 17-25.17. Uryu K, Chen XH, Martinez D, Browne KD, Johnson VE, Graham DI, Lee VM, Trojanowski JQ, Smith DH: Multiple proteins implicated inneurodegenerative diseases accumulate in axons after brain trauma inhumans.   Exp Neurol  2007, 208: 185-192. doi:10.1186/alzrt42 Cite this article as : Gavett BE, et al  .: Mild traumatic brain injury: a risk factorfor neurodegeneration.  Alzheimer’s Research & Therapy  2010, 2: 18. Gavett et al  .  Alzheimer’s Research & Therapy  2010, 2 :18 3 of 3
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