long-term consequences of repetitive brain...
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a:
Concussion Supplement
Long-term Consequences of Repetitive Brain TraumChronic Traumatic EncephalopathyRobert A. Stern, PhD, David O. Riley, BS, Daniel H. Daneshvar, MA,
Christopher J. Nowinski, BA, Robert C. Cantu, MD, Ann C. McKee, MDpation inecline ofcontrol,
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Abstract: Chronic traumatic encephalopathy (CTE) has been linked to particicontact sports such as boxing and American football. CTE results in a progressive dmemory and cognition, as well as depression, suicidal behavior, poor impulseaggressiveness, parkinsonism, and, eventually, dementia. In some individuals, itated with motor neuron disease, referred to as chronic traumatic encephalomywhich appears clinically similar to amyotrophic lateral sclerosis. Results of neuropresearch has shown that CTE may be more common in former contact sports athlpreviously believed. It is believed that repetitive brain trauma, with or possiblysymptomatic concussion, is responsible for neurodegenerative changes highliaccumulations of hyperphosphorylated tau and TDP-43 proteins. Given the myouth, high school, collegiate, and professional athletes participating in contact spinvolve repetitive brain trauma, as well as military personnel exposed to repeatrauma from blast and other injuries in the military, CTE represents an importahealth issue. Focused and intensive study of the risk factors and in vivo diagnosis ofpotentially allow for methods to prevent and treat these diseases. Research also wilpolicy makers with the scientific knowledge to make appropriate guidelines regaprevention and treatment of brain trauma in all levels of athletic involvement as wmilitary theater.
PM R 2011;3:S
INTRODUCTION
There has been increased attention given to the recognition, diagnosis, and managsports-related concussion. Participants in popular sports such as American footballwrestling, rugby, soccer, and lacrosse all risk exposure to brain injury that ranasymptomatic subconcussive blows to symptomatic concussion to more moderatetraumatic brain injury (TBI). In addition, military service and many other aincluding, but not limited to, downhill skiing, martial arts, horse riding, parachuother adventure sports have been associated with TBI [1-3]. An estimated 1.6-3.sports- and recreation-related concussions occur in the United States each year,the true figure is unknown because most concussions are not recognized and reportIn addition to symptomatic concussions, players in collision sports such as Afootball may experience many more subconcussive impacts throughout a season anAthletes at certain positions (eg, linemen) may sustain up to 1400 impacts per seahigh school players who play both offense and defense potentially sustain closerimpacts [7-10].
A mild TBI (mTBI) or concussion is a brain injury that results from a force transthe head that leads to a collision between the brain and skull or to a strain on the tvasculature of the brain [11,12]. This injury can lead to a variety of physical, psycand cognitive symptoms, and, when these deficits do not resolve, can result in possion syndrome (PCS) [13]. Common symptoms include fatigue, dizziness, headacand noise sensitivity, mental fogginess, depression, irritability, and impairmentstive functioning and concentration. Because a concussion and its symptoms res
temporary, reversible cytoskeletal and metabolic derangements that involve shifts inPM&R © 2011 by the American Ac1934-1482/11/$36.00
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R.A.S. Center for the Study of Trcephalopathy, Boston UniversitMedicine, Boston University, 72 ESt, 7380, Boston, MA 02118; DNeurology and Neurosurgery; Alzhease Center Clinical Core, BostoSchool of Medicine, Boston, Mcorrespondence to: R.A.S.; e-maibu.eduDisclosure: nothing to disclose
D.O.R. Center for the Study of Trcephalopathy, Department of Neuton University School of MedicineDisclosure: nothing to disclose
D.H.D. Department of Neurology,versity School of Medicine, BostoDisclosure: nothing to disclose
C.J.N. Center for the Study of Trcephalopathy, Boston UniversitMedicine, Boston, MA, Sports LegWaltham, MADisclosure: nothing to disclose
R.C.C. Center for the Study of Trcephalopathy, and the Departmesurgery, Boston University SchoolBoston, MA; Sports Legacy InstituMA; Neurosurgery Service, andment of Surgery, Emerson HospiMA; and Sports Medicine, EmersConcord, MADisclosure: nothing to disclose
A.C.M. Center for the Study oEncephalopathy; Neurology andBoston University School of MedicMADisclosure: nothing to disclose
Disclosure Key can be found onContents and at www.pmrjourna
Research support: This work waby the Boston University AlzheimCenter NIA P30 AG13846,0572063345-5; NIH R01NS078from the National Operating CoStandards for Athletic Equipmen
ionLegacy Institute; and an unrestricted gift fromthe National Football League
ademy of Physical Medicine and RehabilitationVol. 3, S460-S467, October 2011
DOI: 10.1016/j.pmrj.2011.08.008
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S461PM&R Vol. 3, Iss. 10S2, 2011
channels and energy imbalance, the majority of deficiated with a concussive injury resolve within a mdays, weeks, or months [13-16]. In some instances,persist for months or years after the initial injury. Hois believed that no more than 15% of individualhistory of mTBI still experience symptoms 1 year af[13,17,18].
To date, the resulting progressive tauopathy, kchronic traumatic encephalopathy (CTE), has ofound in individuals with a history of repetitive brai[3,7]. Despite the recent increase in attention onterm effects of repetitive brain trauma, including CTbeen known for some time that contact sports mayciated with neurodegenerative disease. In 1928,[19] described a symptom spectrum in boxers, wtermed “punch drunk,” that appeared to resultrepeated blows experienced in the sport, particularlging boxers who took significant head punishmenttheir fighting style. In 1937, Millspaugh [20] introdterm dementia pugilistica to describe the syndromterized by motor deficits and mental confusion in b1973, a neuropathologic report, by Corsellis et aldementia pugilistica in 15 boxers concluded that,similar to other neurodegenerative diseases, demenlistica is a neuropathologically distinct disorder.
After its initial description, evidence emergedclinical symptoms and neuropathology associatedmentia pugilistica were not solely limited to thpopulation. As a result, the term CTE surfaced in tand is now the term used to describe the neurologicration that results from repetitive brain trauma [3,22research results have demonstrated neuropatholdence of CTE in participants of many sports oboxing, including American football, professionaland professional wrestling. CTE also has been foundwith a history of repetitive brain trauma aside fromincluding a victim of physical abuse, a person wself-injurer, a person with epilepsy, and a circu[3,7,23-28].
Although CTE is associated with a history of rbrain trauma, the exact relationship between the acmatic injury and CTE is unclear. It has been hypothat a neurodegenerative cascade is triggered by raxonal stretching and deformation induced by trauticularly in individuals with previous unresolved coand/or subconcussive injuries [14,29]. It also is uwhether CTE is more likely to occur after extendedto repetitive brain trauma or whether a single tinjury can initiate this neurodegenerative cascade intible individuals. Given the current understanding oseems likely that trauma type and frequency playCTE development [30]. An athlete’s specific sportcompetition (eg, professional versus collegiate),
and playing career duration may all confer different degrso-ofay, it
ary
asen
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of CTE risk [30]. Other factors, such as age, gengenetic predisposition, may contribute to CTE’sment in susceptible individuals, although theserequire further investigation [3].
To date, there has been no randomized neuropastudy of CTE, and, as a result, there is a selection bireported cases. Fourteen of the 15 professional Afootball players examined neuropathologically at thans Affairs Center for the Study of Traumatic Enceph(VA CSTE) Brain Bank have been diagnosed with CTa biased sample, which overrepresents the actual incCTE in professional American football players, becailies are more likely to consider neuropathologic examif they suspect that their loved one has symptoms rCTE or another neurodegenerative disease. Futureperhaps in vivo studies that use biologic markers oand new clinical diagnostic criteria for CTE, wilimproved understanding of the incidence, prevalerisk factors for CTE.
In the sections below, we will provide (1) an ovethe neuropathologic findings of CTE (including gmicroscopic pathology) and a related variant, chromatic encephalomyelopathy that is associated witneuron disease; (2) descriptions of the early and latepresentations and course of CTE; and (3) a descriptipossible risk factors for CTE, in addition to the nrepetitive brain trauma.
GROSS NEUROPATHOLOGY
The gross changes of CTE are typically observed in ldisease (Table 1). Advanced cases of CTE demonsteralized atrophy, most prominent in the frontal antemporal lobes; enlargement of the lateral and thircles; cavum septum pellucidum; and septal fene(Figure 1). There also may be thinning of the hypo
Table 1. Gross neuropathology of chronic traumaticalopathy
OverallDecrease in brain massCavum septum pellucidumSeptal fenestrations
VentriclesEnlarged lateral ventriclesEnlarged third ventricle
AtrophyGeneralized atrophy, particularly of the frontal andtemporal lobesAtrophy of the medial temporal lobesMammillary body atrophyThalamic atrophy
PallorLocus coeruleus
eesSubstantia nigra
hy of].
roscooreactT), a
s (Figutauo
cluste, andthereralim
s found, and thebinding
ortantly,relative
ivity, the-43 pro-read andienceph-
insularindivid-clusionsinal cordt degen-
ord, andgressive
o amyo-by pro-
ascicula-found informs of
ephalo, showrtex afootb
atholond III
the mof t
raumatic
S462 Stern et al CHRONIC TRAUMATIC ENCEPHALOPATHY
floor, shrinkage of the mammillary bodies, and atrophippocampus, entorhinal cortex, and amygdala [3,7
MICROSCOPIC NEUROPATHOLOGY:GENERAL DESCRIPTION
CTE is characterized by a unique pattern of micchanges (Table 2). There are extensive tau-immunneurofibrillary tangles (NFT), neuropil neurites (Nglial tangles (GT) in the frontal and temporal cortice2). Unlike Alzheimer disease (AD) or many otherthies, the tau immunoreactive abnormalities tend tothe depths of sulci, around small blood vesselssuperficial cortical layers [3,7]. In advanced cases,tau-immunoreactive inclusions in the limbic and pa
Figure 1. Gross pathology of chronic traumatic encathy (CTE). The coronal section of normal brain (top)the expected size and relationship of the cerebral coventricles. The brain from a retired professionalplayer (bottom), showing the characteristic gross pof CTE with severe dilatation of ventricles II (1) acavum septum pellucidum (3), marked atrophy ofdial temporal lobe structures (4), and shrinkagemammillary bodies (5).
regions, diencephalon, brainstem, and subcortical wh
the
picivendre
pa-r atin
arebic
matter. The specific soluble and insoluble tau isoformin CTE are indistinguishable from those found in ADratio of tau isoforms with 4 versus 3 microtubulerepeats is approximately 1 in both diseases [31]. Impthese changes seen in CTE usually occur in theabsence of beta-amyloid (A�) deposits [3,7].
In addition to the widespread tau immunoreactmajority of CTE cases also are marked by TDPteinopathy. The TDP-43 inclusions can be widespare typically found in the brainstem; basal ganglia; dalon; medial temporal lobe; frontal, temporal, andcortices; and subcortical white matter. In a subset ofuals with CTE, abundant TDP-43 immunoreactive inand neurites are found in the anterior horns of the spand motor cortex, combined with corticospinal-traceration, loss of anterior horn cells of the spinal cventral root atrophy. These individuals develop a promotor neuron disease that appears very similar ttrophic lateral sclerosis (ALS) and is characterizedfound weakness, muscular atrophy, spasticity, and ftions [32]. The fact that an ALS-like condition issome individuals with CTE suggests that someclinical ALS may be associated with TBI [33,34].
p-ingndallgy
(2),e-
he
Table 2. Microscopic neuropathology of chronic tencephalopathy
Neurofibrillary tangles, frequentOlfactory bulbDorsolateral frontal cortexOrbital frontal cortexSubcallosal frontal cortexInsular cortexSuperior and/or middle temporal gyriInferior temporal gyrusEntorhinal cortexHippocampusAmygdalaMammillary bodiesSubstantia nigraLocus coeruleus
Neurofibrillary tangles, commonHypothalamusSubstantia innominataMedullaThalamus
Neurofibrillary tangles, rareCingulate gyrusInferior parietal cortexOccipital lobe
�-Amyloid depositsDiffuse plaques in 45%Sparse neuritic plaques
White matterLoss of myelinated fibersPerivascular macrophages
iteCribriform state
thologic-age fromho haveposed tothologistl historyxposure)mpletedl historyxt of kinhologistlogic re-ere com-ur previ-
and/orprisinglyentation
n of CTEssion orms fromike otherssive de-neuronalf normals) of thaturrentlythan 50concus-E beginimpair-
ely abates. In stillmptomsorsen at
lly yearsve brainave seenE in thenclear ifhat time
atic en-
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aticau (Arain (leyer w
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epths�60).in bo
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T8 immtz cel
agnificFTs are
characteristic feature of CTE (original magnification �15
S463PM&R Vol. 3, Iss. 10S2, 2011
CLINICAL PRESENTATION
To date, we have found more than 50 neuropaconfirmed cases of CTE, with patients ranging inteens to their 80s, and occurring in individuals wplayed contact sports as well as military personnel exblast injuries. During diagnosis, the neuropa(A.C.M.) remained blinded to the patient’s clinica(eg, medical, behavioral, cognitive, brain trauma euntil after the neuropathologic examination was coand the pathologic diagnosis was made. This clinicawas obtained from semistructured interviews with neand by review of medical records by the neuropsyc(R.A.S.) who remained blinded to the neuropathosults until after all aspects of the clinical history wpleted. The results of this experience, along with oously published review of the literature of CTEdementia pugilistica as of 2009, resulted in a surconsistent description of the clinical course and presof CTE [3].
It is important to note that the clinical presentatiois distinct from the long-term sequelae of a concufrom PCS. CTE is not the accumulation of symptothe earlier injuries. Rather, the symptoms of CTE, lneurodegenerative diseases, results from the progrecline in functioning of neurons or of the progressivedeath. That is, when there is sufficient disruption oneuronal functioning, symptoms specific to the area(disruption will begin to exhibit. Based on our cunpublished observations from our series of morecases, there may have been no earlier symptoms ofsion or PCS, and, therefore, the symptoms of CTinsidiously and are apparently unrelated to earlierment. In other cases, PCS symptoms may completmonths or years before the onset of CTE symptomother cases, there may be overlap; that is, the PCS symay begin to abate but CTE symptoms gradually wthe same time.
Typically, CTE symptoms present in midlife, usuaor decades after the end of exposure to repetititrauma (ie, retirement from sports). Although we hthe earliest stages of neuropathologic changes of CTbrains of individuals in their teens or early 20s, it is uany cognitive, mood, or behavioral symptoms at t
Table 3. Early clinical presentation of chronic traumcephalopathy
Short-term memory problemsExecutive dysfunction (eg, planning, organization,multitasking)
Depression and/or apathyEmotional instabilityImpulse control problems (eg, disinhibition, having afuse”)
en-T8)ft)ith
aryc),ofre
auof
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Figure 2. Microscopic pathology of chronic traumcephalopathy (CTE). Top panel: Phosphorylated timmunostained coronal hemisections of a normal band a brain from a retired professional football plaCTE (right). The brain with CTE, showing severe neurdegeneration of the amygdala (a), entorhinal cotemporal cortex, insular cortex (ins), nucleus bMeynert (nbM), and frontal cortex. The cortical chamost severe at the depths of the sulci. Lower panelneurofibrillary tangles (NFT) are often prominent at dthe sulci (AT8 immunostain, original magnificationSubpial tau immunoreactive tangles are foundneurons and astrocytes (double immunostained seGFAP [red] and AT8 [brown], showing colocalizatioand GFAP; original magnification �350). (C) Edense NFTs are found in the medial temporal lobe stincluding CA1 of the hippocampus, shown herplaques are absent (AT8 immunostain, original mtion �150). (D) NFTs and astrocytic tangles tencentered around small blood vessels and in subpia(AT8 immunostain, original magnification �150).characteristically involve cortical layers II and III (Anostain, original magnification �150). (F) NFT in a Beprimary motor cortex (AT8 immunostain, original mtion �350). (G) Perivascular tau immunoreactive N
Suicidal behavior
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S464 Stern et al CHRONIC TRAUMATIC ENCEPHALOPATHY
were directly the result of the mild neuronal dcaused by the disease. When symptoms begin, theearlier than that of sporadic AD and usually earlierof frontotemporal lobar degeneration or frontotemmentia (FTD). Symptom progression is slow andoften over several decades. Early symptoms (Tabconsistent with those expected from the neuropchanges observed at autopsy. These include impaircognition (eg, from medial temporal and dorsolaterdegeneration), mood (eg, amygdala degeneration),havior (eg, amygdala and orbitofrontal degeneratthough the cognitive difficulties (including short-terory problems and executive dysfunction) are similarseen in other neurodegenerative diseases, the mbehavioral symptoms may be the most concerning, eto family members and coworkers [35]. These incpressed mood and/or apathy, emotional instabilityideation and behavior, and problems with impulseespecially having a “short fuse.” Substance abuse (sofatal) and suicide are not uncommon.
As the disease progresses, symptoms become moand their scope broadens. The primary clinical feworsening CTE are listed in Table 4, including wmemory impairment (although it may not resemble trapid forgetting typical of the hippocampal episodicimpairment of AD), worsening executive dysfunctionplanning, organization, multitasking, judgment), langficulties (including speech output), aggressive and irrhavior (including physical aggression), apathy (sometfound and in contrast to the outward aggressive behavmotor disturbance (most frequently parkinsonism, adifficulties with gait and falling). As the condition prinstrumental activities of daily living worsen and the sare severe enough to impair social and/or occupationaling, with eventual dementia.
RISK FACTORS
Repetitive brain trauma appears to be a necessary vathe development of CTE but may not be sufficient.ropathologically confirmed cases of CTE have hadof brain trauma exposure but not all individuals wsure to brain trauma develop CTE. A major goa
Table 4. Later clinical presentation of chronic traumcephalopathy
Worsening memory impairmentWorsening executive dysfunctionLanguage difficultiesAggressive and irritable behaviorApathyMotor disturbance, including parkinsonismDementia (ie, memory and cognitive impairment se
enough to impair social and/or occupational func
research must be epidemiologic and prospective studies
iont ishatde-al,aregicintal
be-Al-m-osendlly
de-dalol,es
ereof
ingereoryorif-
be-ro-ndases,msn-
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TE
identify the specific risk factors for the developmenneurodegenerative disease.
An important potential risk factor for CTE may bpredisposition. There have been preliminary studlinked the apolipoprotein E (APOE) gene, specifiAPOE �4 allele, to worse cognitive functioning in boprofessional football players, and to prolonged recova single TBI [36-38]. In our case series of 12 profootball players and boxers with neuropathologicafirmed CTE, 5 were APOE �4 carriers, and 2 of thhomozygous for the �4 allele [32]. Although thesetaken together suggest that APOE may be a suscgene for CTE, much more research is required. Mbecause of the presence of TDP-43 in CTE brainssimilar clinical presentations between CTE and FTtional genes associated with familial FTD, and perhmay prove to play a role in CTE risk.
There are many other nongenetic variables towhen evaluating an individual’s risk of developing Cble 5). As stated above, all confirmed cases of CTE ha history of repetitive brain trauma. However, thenature of the brain trauma exposure necessary for thopment of the disease is not yet known. For examunknown if CTE is any more likely to manifest afsevere TBIs versus numerous repetitive subconcuspacts. Further complications arise when comparinexposure and type both between and within spoexample, although boxing and American football bohigh incidence of head impacts, results of a study havthat boxers are exposed to a greater amount of rforces, whereas American football players receive moblows [39]. More recently, a study that used an accter-based system in the helmets of 3 college Ameriball teams throughout a season found that head-imposure differed significantly based on position [9].(both offensive and defensive) and linebackers receivimpacts per practice and game than other positionman, linebackers, and defensive backs received moreto the front of the head than the back, whereas quarhad a higher percentage of impacts to the back ofcompared with the front [9]. Future implementatioilar technology will help clarify the type and voimpacts in American football and other sports, whicextrapolated to estimate total impacts received overeer duration and may translate to information on thdeveloping CTE based on the sport and position.
Age at the time of head injury also may affect anual’s risk of developing CTE later in life, althoughtionship is not yet understood. It has been suggestedincreased plasticity of a younger brain may allow aindividual to better compensate and recover afterjury [40]. However, current literature indicatesyounger brain may be more susceptible to diffu
en-
g)
to injury, which leads to more pronounced and prolonged
at expincre
ough tgirls a
sion an parteportbles mpectrummatnd heT formtial reropathifestatropatherve me dise
ct disdic Ases. Nto th
tletiesnt yea
eases,rationogic (oimagal neuspectrn for
in CSFr for ADoup hasiomark-
stitute oftitute onHuman
develop-ble to bees to thelzheimermptomsdence oftion andges and,heoreti-
vene, thebe. If ae devel-
file, thenn such ald be de
s of CTEhat wass is nowepetitiveall levelsoverage,ublishedwe knowow com-
minimum
ithoutamount
play thelater in
tangles
S465PM&R Vol. 3, Iss. 10S2, 2011
cognitive deficits [41,42]. Therefore, it is possible thsure to repetitive brain trauma at an early age maythe risk of CTE more than exposure later in life, althhas yet to be proven. Gender also may play a role, aswomen appear to be at greater risk for concusPCS-related symptoms, although this may be due igirls and women being more forthcoming when rtheir symptoms [43,44]. Other health-related variaaffect the neurodegeneration and clinical symptom sassociated with CTE. For example, chronic inflaassociated with obesity, hypertension, diabetes, adisease may exacerbate neurodegeneration and NFtion in AD [45-48]. Cognitive reserve (ie, differenience to the clinical presentation of underlying neulogic disease) also may play a role in the clinical manof CTE neuropathology. That is, given identical neulogic severity, individuals with greater cognitive resbe less likely to display the clinical symptoms of ththan individuals with less cognitive reserve [49].
ONGOING AND FUTURE RESEARCH
As stated above, CTE is a neuropathologically distinder, different in many ways from AD, FTD, sporaParkinson disease, or other neurodegenerative diseaertheless, its clinical presentation can be similardiseases, especially in the later stages when subpresentation are less likely to be delineated. In receresearch to investigate other neurodegenerative disexample, AD, has been moving toward the integclinical (eg, neurologic, neuropsychological), biolcerebrospinal fluid [CSF] and/or functional neurmeasurements of proteins), anatomical (eg, structurimaging), biochemical (eg, magnetic resonancecopy), and genetic (eg, APOE genotype) informatio
Table 5. Potential additional risk factors for chronic
Potential General Risk Factor
Genetics APOE �4Family history First- andType of brain trauma exposure Symptom
gravitaAge and duration of brain trauma
exposureSusceptib
Frequency of brain trauma exposure Minimumany adof “res
Chronic inflammation Obesity,neurod
Cognitive reserve Greaterclinicathe ne
Gender Are womRace Are there
CTE � chronic traumatic encephalopathy; NFT � neurofibrillary
purposes of early detection, differential diagnosis, treatme
o-asehisndndto
ingaym
ionarta-
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iono-ay
ase
or-LS,ev-eseinrs,forof
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and prevention [50]. In addition, recent advancesbiomarkers have resulted in a “signature” biomarkeof low CSF A� and elevated CSF tau [51]. Our grrecently begun investigations aimed at developing bers for CTE through funding from the National InNeurological Disorders and Stroke, the National InsAging, and the National Institute of Child Health andDevelopment. Through this research on biomarkerment for CTE, accurate diagnostic criteria will be aproposed and validated by using similar approachrecently published revised diagnostic criteria for Adisease [52-55]. This approach includes clinical syand history combined with objective biomarker evithe disease. This method will allow for the detecdiagnosis of the CTE in the early symptomatic stapossibly, in the preclinical stages of the disease. Tcally, the earlier in the disease process one can intermore effective disease-modifying agents will likelydisease-modifying agent (eg, a tau antagonist) can boped, proven effective, and has an adequate risk propreclinical intervention with the drug could result ilong delay in symptom presentation that there woufacto prevention of the clinical disorder or CTE.
DISCUSSION
There has been a tremendous growth in the awarenesin both scientific and lay circles in recent years. Wbelieved to be a very rare disease only seen in boxercommonly discussed as a potential consequence of rbrain trauma seen in multiple different sports and atof play. In contrast to the rapid increase in media cnew policies, and culture change, the rate of new presearch on CTE has been relatively slow. Althoughmuch more about certain aspects of the disease n
tic encephalopathy
Specific Examples and/or Questions
; GRN; TARDPcond-degree relatives with history of dementiaoncussions; asymptomatic subconcussive blows; blast wave;force; degree of axonal injury and/or microhemorrhageseriod during youth; years of overall exposure
er of injuries (eg, can one moderate-severe TBI lead to CTE, wal repetitive concussions or subconcussive exposure history?);
overall time interval) between injuriesension, diabetes, and heart disease may exacerbate
eration and NFT formationive reserve (or brain reserve capacity) may be less likely to distoms associated with the neurodegeneration or exhibit themthologic processgreater risk if they had the same exposure as men?l differences in risk?
; TBI � traumatic brain injury.
trauma
; MAPT/or seatic ctionalility p
numbdition
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cognitl sympuropaen atracia
nt, pared with just 5 years ago, especially the neuropathology
in inover 1ainsof A
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S466 Stern et al CHRONIC TRAUMATIC ENCEPHALOPATHY
and clinical history associated with CTE, we remafancy in the study of CTE. Because it has been wellyears since AD was first described, and there remconsensus as to the underlying causal mechanismno highly accurate method of in vivo AD diagnosisavailable Alzheimer disease–modifying intervenshould not be surprising that many critical questionregarding CTE. These questions include the followiis the underlying mechanism of disease? What arefactors for disease (including susceptibility genetrauma exposure variables, and others)? What is thetion prevalence of CTE? What is the incidence of Ccommon is the disease among individuals with speletic and/or military histories? How can CTE be detediagnosed accurately during life? How can CTEvented? What interventions can result in successfumodification?
Only through further study (including animal mbasic and translational investigations, and clinical anmiologic research) can these questions be answeredCTE move from a disease only diagnosed postmortethat can be identified in life and eventually be treavented, and cured. In addition, by addressing thesquestions, new research findings will provide policwith urgently needed scientific knowledge to make aate guidelines regarding the prevention and requirment of brain trauma in all levels of athletic involvwell as the military theater.
CONCLUSION
CTE has been linked to participation in contact sporboxing, American football, and hockey, and has beeindividuals with non–sports-related histories of rhead injuries. It is believed that repetitive brain trauor without symptomatic concussion, sets off a caevents that results in neurodegenerative changes maunique tauopathy and TDP-43 proteinopathy. Symay begin years or decades after the cessation of braiexposure although earlier than most other neurodegdiseases. Early symptoms include a decline of memexecutive functioning, depression, suicidal ideation ahavior, and poor impulse control. Disease progrrelatively slow and eventually leads to dementia.individuals, CTE may lead to a motor neuron diseasto ALS. Recent neuropathologic research suggestsmay be more widespread than previously believed. Gmillions of athletes participating in contact sportsvolve repetitive brain trauma, as well as militarexposed to repetitive brain trauma from blast ainjuries and others in society who experience repeti
injuries, CTE represents an important public health issuein-00noD,noit
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