Repetitive Traumatic Brain Injury and Development of Chronic Traumatic Encephalopathy: A Potential Role for Biomarkers in Diagnosis, Prognosis, and Treatment?

1.4 MB·English

by  Turner, Ryan C.

REVIEWARTICLE
published:17January2013
doi:10.3389/fneur.2012.00186
Repetitive traumatic brain injury and development of

chronic traumatic encephalopathy: a potential role for

biomarkers in diagnosis, prognosis, and treatment?

RyanC.Turner1,2*,BrandonP.Lucke-Wold1,2,MatthewJ.Robson3,BennetI.Omalu4,AnthonyL.Petraglia5
andJulianE.Bailes6,7

1DepartmentofNeurosurgery,SchoolofMedicine,WestVirginiaUniversity,Morgantown,WV,USA

2CenterforNeuroscience,SchoolofMedicine,WestVirginiaUniversity,Morgantown,WV,USA

3DepartmentofBasicPharmaceuticalSciences,SchoolofPharmacy,WestVirginiaUniversity,Morgantown,WV,USA
4DepartmentofPathology,UniversityofCalifornia,Davis,CA,USA
5DepartmentofNeurosurgery,UniversityofRochesterMedicalCenter,Rochester,NY,USA
6DepartmentofNeurosurgery,NorthShoreUniversityHealthSystem,Evanston,IL,USA
7SectionofNeurosurgery,DepartmentofSurgery,UniversityofChicagoMedicalCenter,Chicago,IL,USA

Editedby: Thediagnosisofchronictraumaticencephalopathy(CTE)uponautopsyinagrowingnumber
RonaldL.Hayes,BanyanBiomarkers, of athletes and soldiers alike has resulted in increased awareness, by both the scien-
Inc.,USA
tific/medicalandlaycommunities,ofthepotentialforlastingeffectsofrepetitivetraumatic
Reviewedby: brain injury. While the scientific community has come to better understand the clini-
StefaniaMondello,Universityof
Florida,USA cal presentation and underlying pathophysiology of CTE, the diagnosis of CTE remains

RonaldL.Hayes,BanyanBiomarkers, autopsy-based,whichpreventsadequatemonitoringandtrackingofthedisease.Thelack
Inc.,USA of established biomarkers or imaging modalities for diagnostic and prognostic purposes
*Correspondence: alsopreventsthedevelopmentandimplementationoftherapeuticprotocols.Inthiswork
RyanC.Turner,Departmentof
the clinical history and pathologic findings associated with CTE are reviewed, as well as
Neurosurgery,SchoolofMedicine,
WestVirginiaUniversity,OneMedical imagingmodalitiesthathavedemonstratedsomepromiseforfutureuseinthediagnosis

CenterDrive,Suite4300,Health and/or tracking of CTE or repetitive brain injury. Biomarkers under investigation are also

SciencesCenter,POBox9183, discussed with particular attention to the timing of release and potential utility in situa-
Morgantown,WV26506-9183,USA.
tionsofrepetitivetraumaticbraininjury.Furtherinvestigationintoimagingmodalitiesand
e-mail:[email protected]
biomarkerelucidationforthediagnosisofCTEisclearlybothneededandwarranted.

Keywords:chronictraumaticencephalopathy,CTE,TBI,biomarkers,imaging

INTRODUCTION conflicts in Iraq and Afghanistan and consequently, has been

Increasing awareness by both medical professionals and the describedasthe“signatureinjuryof war”(Shentonetal.,2012).

lay community concerning the potential long-term effects of The diagnosis of mTBI remains particularly challenging due to

repetitive traumatic brain injury, such as chronic traumatic theusuallackofabnormalfindingsonconventionalCTandMR

encephalopathy (CTE) and cognitive impairment (Guskiewicz imaging(Shentonetal.,2012).LackofadiagnostictestformTBI

et al., 2005; Gavett et al., 2010; Daneshvar et al., 2011), has led isproblematicconsideringthepotentialforbothenduringcere-

totheidentificationofaneedforimproveddiagnosticandprog- bral effects (cognitive, neurophysiological, and clinical) and for

nostic tests. Investigators have focused primarily on the use of identificationofthoseatriskfordevelopmentofCTElaterinlife.

variousimagingmodalitiesanddevelopment of blood-orCSF- Chronic traumatic encephalopathy represents a progressive

basedbiomarkers.Inthefollowingsectionsweattempttobriefly neurodegenerativediseasecurrentlydiagnosedonlyuponautopsy

reviewfindingsassociatedwithCTEdiagnosis,proposeddisease and subsequent neuropathological examination (Saulle and

pathophysiology,andhowthesefindingsmaypotentiallyrelateto Greenwald, 2012). Despite the lack of specific diagnostic crite-

imagingand/orbiomarkerdiscovery. ria required for pre-mortem clinical diagnosis,patients afflicted

withCTEdiagnosedpost-mortemareoftendescribedassuffer-

EPIDEMIOLOGYANDCLINICALPRESENTATION ingbehavioral,cognitive,andemotionalchangesorimpairments

Exposure to repetitive mild traumatic brain injury (mTBI) is a priortodeath(Gavettetal.,2011b;Omaluetal.,2011b;Saulleand

commonoccurrenceinathletesontheplayingfieldandsoldiers Greenwald,2012).Notably,symptomdevelopmentoccursfollow-

onthebattlefield.Infact,playingAmericanfootballathigherlevels ing a prolonged latency in most cases, although exceptions do

resultsindocumentedexposureofupto1400impactsperseason exist(Gavettetal.,2011a;Omaluetal.,2011b).Thetendencyfor

for select positions such as linemen with some players involved a latent period creates a clear distinction between initial symp-

inbothoffenseanddefensesustainingnearly2000impacts(Stern tomsassociatedwithtraumaticbraininjury(TBI)andthepersis-

etal.,2011).Similarly,mTBIhasbeenidentifiedasthemostcom- tent,long-termdegeneration,muchlikeotherneurodegenerative

moncombat-relatedinjuryinsoldiersreturningfrompresent-day diseasessuchasAlzheimer’sdisease(AD).

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Chronic traumatic encephalopathy has been diagnosed in a whetheritbeintheformofneurofibrillarytangles(NFTs),neu-
broad spectrum of individuals with a history of head trauma, ropil threads (NTs), or glial tangles (GTs), is a defining feature
althoughthenumberofandseverityofimpactsisoftenunclear, of CTE.While other neurodegenerative diseases such asAD are
rangingfromathletesplayingAmerican football,soccer,hockey, also frequently defined and/or described by the presence of tau,
boxers, and wrestlers to soldiers who have received battlefield CTE is clearly unique based on the topographic distribution of
injuries(Omaluetal.,2005,2006,2010a,b,c,2011b;McKeeetal., tauopathy(Gavettetal.,2011b).ADischaracterizedbyarelatively
2009; Baugh et al., 2012; Goldstein et al., 2012; Lakhan and uniformdistributionof tauNFTsinlayerscontaininglargepro-
Kirchgessner, 2012). Due to the variety of individuals afflicted jectionneurons,suchaslayersIIIandV(Gavettetal.,2011b).In
byCTE,emergingevidenceindicatesthatCTEislikelymorecom- contrast,CTEisexemplifiedbyanirregulardistributionoftauin
mon than previously thought (Stern et al., 2011; Baugh et al., more superficial cortical layers such as II and III. Similarly, the
2012). Based on the experience of one group of investigators,a progressive topographic involvement of regions of the brain as
conservativeestimateoflifetimeprevalenceofCTEinAmerican seeninCTEdiffersfromwhatisseeninotherneurodegenerative
footballplayersisatleast3.7%(SaulleandGreenwald,2012).Esti- diseaseslikeAD.WhileneuriticamyloidplaquesareseeninAD,
matesofCTEprevalenceinretiredprofessionalboxershavebeen neuriticamyloidplaquesarenotdefiningfeaturesofCTE,andare
ashighas20%(LakhanandKirchgessner,2012).Consideringthe lessfrequentlyseeninCTE(Gavettetal.,2011b).
numberofindividualsactivelyengagedincontactsportssuchas AnotherdelineatingfactorbetweenADandCTEisthepresence
football or exposed to explosive devices on the battlefield, it is ofneuriticbetaamyloid(Aβ)plaques.Foundextensivelythrough-
clearthatCTErepresentsaclearpublic-healthrisk.Muchofthe outthebrainsofthoseafflictedwithAD,neuriticamyloidplaques
earlyworkinvolvingCTEdiagnosisfocusedonconcussionhistory arefoundinaminorityofCTEsufferers.Diffuseandneuriticamy-
butrecentstudieshavedocumentedapotentialroleofrepetitive loidplaquesarefoundinlessthan40–45%ofindividualswithCTE
subconcussive blows as well (Omalu et al., 2010b; Baugh et al., (Blaylock and Maroon,2011;Gavett et al.,2011b).Additionally,
2012). whenfoundinCTE,amyloidplaquesaremorelikelytobediffuse
plaquesandnotthetypicalneuriticplaquesthatarediagnosticof
NEUROPATHOLOGICFINDINGSOFCTE AD(Gavettetal.,2011b).TheroleAβplaysinCTEpathophysiol-
Gross ogy,andwhyitispresentinsomebrainsbutnotothers,remains
Gross neuropathologic examination of the brain in individuals tobeelucidated.Interestingly,amyloidprecursorprotein(APP),
afflictedwithCTEmayproducearangeoffindings.Thebrainmay which can undergo cleavage to form Aβ,accumulates following
appeargrosslynormalormayshowminimallobarcorticalatrophy axonalinjury,andlikelyplaysaroleinplaqueformation(Gavett
foragewithoutremotecorticalcontusionsorlacerations(Omalu etal.,2011b).
et al., 2005). There may be other non-specific gross pathologic Chronic traumatic encephalopathy has been recently associ-
changes like fenestrations of the septi pellucidi,communicating ated, in greater than 80% of cases, with accumulation of yet
ventriculomegaly,subcorticalganglionicatrophy,cerebellarfolial anotherphosphorylatedproteinaggregate,TDP-43(Gavettetal.,
atrophy,andpallorofthesubstantianigra(Gavettetal.,2011b).In 2011b).Insomecases,TDP-43hasbeenfoundextendingintothe
general,however,theCTEbrainofnon-boxersisgrosslynormal anteriorhornsofthespinalcord,particularlyinpatientsexhibiting
withoutevidenceoffocaltraumaticbraininjury. motorneurondiseasesymptomssimilartothoseofamyotrophic
Thefrequentlackofgrossneuroanatomicalchangesobserved lateralsclerosis(Gavettetal.,2011b;Sternetal.,2011).WhileTDP-
in CTE is in striking contrast to dementia pugilistica, believed 43proteinopathyoccursasaprimaryorsecondaryproteinopathy
to represent a more severe form of CTE observed in boxers inavarietyofneurodegenerativediseases,thesignificanceofTDP-
(Millspaugh,1937;Corsellisetal.,1973;AdamsandBruton,1989; 43 proteinopathy in CTE is presently not clear. The presence of
Casson et al., 2006). Dementia pugilistica, described originally anotherphosphorylatedproteininaggregateformmayindicatea
as “punch drunk” by Martland (1928), was characterized neu- sharedprocessresultinginneurodegenerationfollowingrepetitive
ropathologically by Corsellis et al. (1973) based on a tetrad of braintrauma(Gavettetal.,2011b).BeingthatTDP-43hasbeen
findings: (1) abnormalities of the septum pellucidum; (2) cere- suggested to mediate the response of the neuronal cytoskeleton
bellar and other scarring of the brain; (3) degeneration of the followinginjury,braintrauma,andsubsequentaxonalinjurymay
substantia nigra; and (4) the presence of neurofibrillary tangles triggeraTDP-43-mediatedprocessinvolvedinneurodegeneration
(NFTs)inaregionalmanner.Whilesomecontroversyexistscon- (Costanzaetal.,2011).
cerningidentificationofCTE,theworkofCorsellisandcolleagues ThediversityofpathologicalfindingsassociatedwithCTE,as
isnotableinthatatnopointisencephalopathydefinedbythepres- representedbythevariedfindingspresentedabove,hasbeguntobe
ence of a fenestrated or cavum septum pellucidum and equally describedwithfourdistinctphenotypesemerging(Table1;Omalu
important,thecompletetetradwasnotobservedinathirdofthe etal.,2011a).Thesignificanceof thesephenotypeswithregards
casescharacterizedasdementiapugilistica(Cassonetal.,2006). to clinical correlate remains to be elucidated but it is becoming
increasinglyclearthatCTErepresentsadiversespectrumofdis-
Microscopic ease,afindingconsistentwiththeheterogeneousnatureofinjury
MicroscopicinvestigationofCTEhasfocusedprimarilyonseveral history,geneticpredisposition,andavarietyofotherfactors.
factors:thepresenceoftau,amyloid,andpresenceofTARDNA-
bindingprotein43proteinopathyaswellaslowgradediffusewhite CTEPATHOGENESISANDPATHOPHYSIOLOGY
matter rarefaction, microglial activation, and presence of reac- The pathogenesis and pathophysiology of CTE remain unclear,
tiveastrocytes(Gavettetal.,2011b).Thepresenceofatauopathy, as with many neurodegenerative diseases, but is believed to be
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Table1|ThediversityofpathologicalfindingsinCTEhasleadtotheemergenceoffourdistinctphenotypes.

Phenotype Cerebralcortex Subcorticalnuclei/basalganglia Brainstem Cerebellum

#1 +SparsetofrequentNFTsandNTs +WithorwithoutNFTsandNTs +SparsetofrequentNFTsandNTs +NoNFTsandNTs

+Nodiffuseamyloidplaques

#2 +SparsetofrequentNFTsandNTs +WithorwithoutNFTsandNTs +SparsetofrequentNFTsandNTs +NoNFTsandNTs
+Sparsetofrequentdiffuseamyloid
plaques
#3 +NonetosparseNFTsandNTs +NonetosparseNFTsandNTs +ModeratetofrequentNFTsandNTs +NoNFTsandNTs
+Nodiffuseamyloidplaques

#4 +NonetosparseNFTsandNTs +NonetosparseNFTsandNTs +NonetosparseNFTsandNTs +NoNFTsandNTs
+Nodiffuseamyloidplaques

Howeachphenotypecorrelatestotheclinicalconditionremainsunclearbutthevarieddiseasefindingsareconsistentwiththediversityofclinicalexposureand

disease-relatedfactors.

a multifactorial process initiated by brain trauma. The develop- phenotype switching occurs, this pro-inflammatory state can

ment of CTE begins with subconcussive or concussive injury. be maintained for prolonged periods, consistent with neu-

The damage is progressive and often accelerated by the num- rodegenerative processes and emergence of hyperphosphory-

ber of brain injuries that occur in an individual. Initially,mTBI lated tau. Similarly, mild injury has been demonstrated to

causes diffuse axonal injury (DAI), which results in disruption damage axons due to degenerative processes, resulting in a

ofaxonaltransportandsubsequentaxonalswelling.Theswelling progressive deterioration, rather than rapidly occurring axonal

causesadisconnectionoftheaxonsandlaterWalleriandegener- shearing. This furthers the notion of CTE as a chronic neu-

ation(Johnsonetal.,2012).Thisdegenerativeprocess,aportion rodegenerative process, clearly distinct from the immediate

of which is referred to in the literature as immunoexcitotoxic- sequelae often associated with TBI (Blaylock and Maroon,

ity,mayleadtothedevelopmentof CTE(BlaylockandMaroon, 2011).

2011).Itisinterestingtonotethattheabnormaltauandamyloid

accumulations,whichareseeninCTEarepeptidederivativesof IMAGINGMODALITIESFORREPETITIVEBRAININJURYAND

bothmembraneandcytoskeletalproteins,whichareinvolvedin CHRONICTRAUMATICENCEPHALOPATHY

traumaticaxonalinjuryfollowingconcussiveandsubconcussive A major concern for clinicians and researchers is how to detect

injury.Thisprocessisstillrelativelypoorlyunderstoodclinically small but important brain changes prior to the development of

with post-mortem studies on young adults revealing that repet- CTE symptoms so that preventative measures can be taken or

itive head injury is associated with the formation of NFTs and treatmentsimplemented,onceavailable(Baughetal.,2012;Saulle

tau-based pathology surrounding vascular elements within the and Greenwald, 2012). The obvious short term deficits seen in

cortex (Geddes et al., 1999). Consequently, it is perhaps likely concussiveinjuriessuchaslossof consciousness,post-traumatic

thatmicrovasculardamageplaysaroleinformationof theclas- amnesia,andalteredmentalstatushavebeenhistoricallyhardto

sicalneuropathologyassociatedwithCTE.Thisisconsistentwith quantifyusingtraditionalimagingmodalitiessuchascomputed

findingsfromclassicalliteratureexploringdementiapugilisticain tomography(CT)andmagneticresonanceimaging(MRI;Difiori

which a large percentage of ex-boxers experienced perivascular and Giza, 2010; McCrory, 2011; Prichep et al., 2012). The dif-

hemorrhageswithevidenceofmeningealand/orsubpialsiderosis ficulties and shortcomings of more commonly utilized imaging

(AdamsandBruton,1989).Inadditiontorepetitivebraininjury, techniqueshaveledresearchersandclinicianstodefineconcussion

there may be other identified factors that may contribute to or asabiomechanicallyinducedbraininjurywithnogrossanatomic

alterdiseasedevelopment,suchaspresenceof certaingenotypes lesions(Signorettietal.,2011).Despitethelackof grosslesions,

(Omalu et al., 2010b). Notably, anabolic steroid use had been itisstillnecessarytolookatdiffuseandmicroscopicalterations

previously suggested as a potential contributing factor to CTE inthebrain.Untilrecently,imagingtechniqueswerenotsophis-

developmentbuttheuseofexogenousanabolicsteroidshasbeen ticatedenoughtodetectthesubtlechangesthatarethehallmark

shownexperimentallytonotworsenmTBI(Millsetal.,2012). of DAI. Clinicians have previously been forced to rely on post-

While the precise pathway or mechanism via which repet- mortemtissueanalysistodiscovermechanismsofCTEpathology

itive brain trauma predisposes to CTE development is poorly (LakhanandKirchgessner,2012).Withtheinventionandappli-

elucidated, Blaylock and Maroon (2011) posit a logical process cation of new imaging modalities,it is now possible to identify

viawhichimmunoexcitotoxicitymediatesthetransition.Aspart andinvestigatemoreof thepathologicalchangesthatareacon-

of this process, microglia are primed by initial impacts and sequence of mTBI. The following sections will highlight several

with sustained trauma as well as aging, undergo phenotypic ofthenewimagingmodalitiesthatarebeingusedsuccessfullyto

conversion from a non-destructive to destructive mode (Blay- studyvariousphenomenaassociatedwithmTBIandalsopromis-

lock and Maroon, 2011; Saulle and Greenwald, 2012). Once ingmodalitiesforfurtherinvestigationofCTE.Thesemodalities

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andpotentialstrengths,aswellaschallenges,associatedwitheach FUNCTIONALMAGNETICRESONANCEIMAGING
aresummarizedinTable2. Functionalmagneticresonanceimaging(fMRI)isuniqueamongst
the various imaging modalities discussed within this work due
DIFFUSIONTENSORIMAGING to the ability to provide insight into functional alterations,par-
Diffusiontensorimaging(DTI)representsoneofthemorethor- ticularly working memory, and anatomic or structural changes
oughly investigated techniques for detecting axonal injury clini- simultaneously. The capability to measure brain-behavior rela-
cally(MacDonaldetal.,2007;Smitsetal.,2011;Shahetal.,2012; tionships has proved useful in other neurodegenerative diseases
Shentonetal.,2012)andhasevenbeenshowntocorrelatewith and appears promising for further investigation of CTE-related
long-termoutcomeinpreclinicalrodentsmodelsofTBI(Maller changes(Gavettetal.,2011a).Basedonbloodoxygenleveldepen-
etal.,2010).Perhapsmostnotably,preliminarystudiesinretired dent (BOLD) signal, fMRI is advantageous in that serial scans
professionalathletessubjectedtorepeatheadtraumademonstrate canbeadministeredwithoutexposuretoharmfulionizingradi-
a correlation between history of concussion and DTI measures, ation (Sanchez-Carrion et al., 2008). This is particularly useful
particularly in the callosal white matter (Gavett et al., 2011a). forfMRI-basedstudiesasbaselinemeasurementsarerequiredfor
HowDTI-basedfindingsarealteredwithageandwhetherthese comparison due to inter-individual variability (Rosenbaum and
findingscorrelatewithneurodegenerativeandbehavioralchanges Lipton, 2012). Following exposure to head trauma, deficits on
associated with CTE remains to be seen (Tremblay et al.,2012). fMRI are apparent in both concussive and subconcussive injury
Regardless,DTIappearstobeapromisingtechniquefordetect- groups with concussive injury producing a more severe deficit
ing and tracking structural correlates of repetitive brain injury (Talavageetal.,2010;McDonaldetal.,2012).Importantly,studies
(Chappelletal.,2008;Bazarianetal.,2012;Bennettetal.,2012; utilizingbothfMRIandImPACTforneuropsychologicaltesting
Hutchinsonetal.,2012;Lietal.,2012),includingthosebelieved (NPT)haverevealeddeficitsinworkingmemory,eveninthegroup
tobespecifictoCTE. sustainingonlysubconcussiveimpacts,andthesedeficitsappear

Table2|NumerousimagingmodalitiesmayprovideinsightintothedevelopmentortrackingofCTE.

Imagingmodality Potentialstrengths Potentialweaknesses Referencesofinterest

Diffusiontensorimaging(DTI) +Radiologicandclinicaldeficitsmay +Maybetime-intensiveif Henryetal.(2011a),Gavettetal.
correlatewell tractographyrequired (2011a),andRutgersetal.(2008)
+Correlationbetweenconcussionhistory
andDTImeasures

Functionalmagneticresonance +Real-timeassessmentofbrainactivity +Likelyrequiresbaseline Gavettetal.(2011a),Talavageetal.

imaging(fMRI) andfunction scanforcomparison (2010),McDonaldetal.(2012),

+Showndeficitsinsubconcussiveinjury Breedloveetal.(2012),and

Henningeretal.(2007)

Magneticresonance +InsightintopathophysiologyofCTE +Difficultydistinguishing Henryetal.(2010),Kleindienstetal.
spectroscopy(MRS) +Shownpersistentchangesinprofessional betweennaturalchangeswith (2005),Linetal.(2010,2012);Gavett
athletes agingandthoseofinjury etal.(2011a),andTremblayetal.
+Metabolitesmaycorrelatewithpathology (2012)
andfunction

Positronemissiontomography +Identificationofbrainregionsexhibiting +Exposuretoradioactive Vennetietal.(2007),Provenzano

(PET) decreasedmetabolism isotopesmaylimitrepeat etal.(2010),Wagner(2012),and

+MaymeasuretaudepositioninCTE scans Smalletal.(2006)

Singlephotonemission +Abnormalitiesinperfusionvisualizedin +SPECTfailstopredict Kempetal.(1995)andLinetal.
computertomography(SPECT) boxerswithrepeattraumaexposure neuropsychologicaldeficits (2012)

Susceptibilityweightedimaging +Canmapblood-brainbarrierdisruption +Predictiveabilitylimitedin Baughetal.(2012),Kouetal.

(SWI) andtaudeposition adults (2009),Ashwaletal.(2006),and

+Showntopredictoutcomeinpediatric Gavettetal.(2011a)

patientspost-injury

+CandetectmicrohemorrhageswithDTI

Electroencephalography(EEG) +ComponentsofP300suchasP3a/P3b +Minimalinvestigation Costanzaetal.(2011)andGavett
alteredchronicallypost-concussion outsideofboxing etal.(2011a)
+Lowcost +Analysisdifficult

Eachmodalityexhibitspotentialstrengthsandweaknesses,presentedhere,affectingitsviabilityforfurtherCTE-relatedresearch.
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to be related to the number of impacts rather than the magni- POSITRONEMISSIONTOMOGRAPHY
tudeofanyoneimpact(Breedloveetal.,2012).Furthermore,in Positronemissiontomography(PET)canbeusedtodetectmeta-
apreclinicalmodelofTBI,fMRIresponsewasdiminishedacutely bolic rates in a variety of tissues of interest,including the brain
andcorrelatedwithfunctionaldeficitsbasedontheforepawplace- (PriceandJones,1995).WhilePEThastraditionallybeenusedin
menttest(Henningeretal.,2007).TheuseoffMRIforassessing casesof moresevereinjury,recentevidenceindicatesapotential
the more subtle deficits produced by repetitive subconcussive role in mTBI (Mase et al., 2004; Venneti et al., 2007). In box-
impactswarrantsfurtherinvestigation,andinparticular,longitu- ers, hypometabolism was observed in regions likely affected by
dinalstudiesinvestigatingthepersistenceofdeficitsonfMRIand impactstothesideoftheheadsuchastheportionofthefrontal
thelikelihoodof furtherdevelopmentfordetecting,diagnosing, lobeanteriortoBroca’sarea(Provenzanoetal.,2010).Similarly,
andtrackingCTE. hypometabolism was observed in the posterior cingulate cortex
and posterior parietal lobes (Provenzano et al., 2010). In other
MAGNETICRESONANCESPECTROSCOPY patients afflicted with TBI, hypometabolism may be seen com-
Magneticresonancespectroscopy(MRS)isanon-invasivemethod monlyintheanteriortemoporallobeandorbitofrontallobedue
thatmeasuresbrainchemistryassociatedwithDAIandneuronal torapidacceleration-decelerationmechanisms(Provenzanoetal.,
injury(Gavettetal.,2011a;Shentonetal.,2012).Itissensitivefor 2010). Other promising developments in PET imaging include
changesoccurringwithage,mTBI,andmildcognitiveimpairment the development of ligands specific for disease states such as
(MCI;Tshibandaetal.,2009).Asanimagingmodality,1HMRS AD. For example, Pittsburgh compound B selectively binds Aβ
isusedtodetectchangesinN-acetylaspartate(NAA),myoinositol whereasothersunderdevelopmentnon-selectivelybindbothAβ
(mI),choline,lactate,andadenosinetriphosphate(ATP)produc- andtau(Gavettetal.,2011a).WhileAβisnotdiagnosticforCTE,
tioninspecificROI.NAAisaneuronalmarkerandisreportedas thistechnologyappearspotentiallypromisingfortheimagingof
a NAA:creatinine ratio. Other markers that may prove useful in CTEshouldtau-specificcompoundsbeidentified.Furthermore,
neuralinjuryincludemI,aglialmarker(Signorettietal.,2010), recent studies using F18 DDNP glucose-PET, conducted by Dr.
choline-basedcompounds,indicativeofmembraneintegrity,and Gary Small at UCLA, show promise for identifying tau protein
lactate,an indirect marker for ischemia (Signoretti et al.,2010). deposition in the form of NFT’s in subjects with potential CTE
Themetabolitelevelsinaninjuredbrainarecomparedtolevels (Wagner, 2012). F18 DDNP glucose-PET allows for labeling of
inahealthybrainforanalysis(Vagnozzietal.,2010).Adecrease bothplaquesandtangles,ashasbeenshownincasesof MCIas
in NAA and ATP is indicative of reversible neuronal and mito- wellasAD,makingthistechniqueexceptionallypromisinginiden-
chondrialdysfunction(Henryetal.,2011b).Anelevationof the tifyingcharacteristicpathologicalfeaturesofCTEastheydevelop
NAA:creatinineratioindicatespersistentdamagefollowingmTBI pre-mortem(Smalletal.,2006).Thiseffortissignificantinthat
(Signoretti et al., 2011). H2O is often measured as an internal itcouldpotentiallyallow,forthefirst-timeever,thediagnosisof
controlinthepatientduringimaging(Tremblayetal.,2012).By CTEpre-mortem(Small,2012).Similarly,identificationofNFT’s
monitoringthemetabolitesandH2O,theprogressofapatientcan followingbraininjurywouldprovidesubstantialinsightintothe
be tracked longitudinally (Bigler and Maxwell,2012). It is even timingofdevelopmentandpathophysiologyofCTE.
possible to detect changes in the brain prior to onset of symp-
tomssuchasinsubconcussiveinjuries(Henryetal.,2010).Fur- SINGLEPHOTONEMISSIONCOMPUTERTOMOGRAPHY
thermore,metabolite levels remain altered long after symptoms Single photon emission computer tomography (SPECT), simi-
subside,whichgivescredencetotheideaoflong-termdegenera- lar to PET in the use of radionuclides, can be used for mea-
tionoccurringandpresenceofalatentperiod(Kleindienstetal., surement of cerebral perfusion and has been shown to detect
2005). As MRS utilizes current clinical MR scanners and does abnormalities in 41% of amateur boxers in comparison to 14%
not administer ionizing radiation to the patient,MRS may rep- of controls. Furthermore, abnormalities were generally singu-
resentanidealimagingmodalityforlong-termstudiesrequiring lar in the control group yet multiple in the group of boxers
repeated measurements. Furthermore,a preliminary study con- subjected to repetitive brain trauma (Kemp et al., 1995). While
ductedbyLinandcolleaguesdemonstratedpersistentchangesin SPECT has not been utilized in studies of CTE, CTE is asso-
ChoandGlxin5professionalathletes,aged31–54years.Specifi- ciated with amyloid protein deposition in a significant number
cally,bothChoandGlxweresignificantlyincreasedascompared of cases and amyloid is notably largely perivascular in depo-
to controls (Lin et al., 2010, 2012; Gavett et al., 2011a). Addi- sition, particularly in regions of abnormal vasculature, which
tionally,studieshavedemonstratedchangesinmIconsistentwith could account for abnormal findings on SPECT (Kemp et al.,
MCIliteraturethatcorrelatewithNFTcountinADbrainsupon 1995).Ithasalsobeencorrelatedwithfunctionaldeficitsrevealed
pathological examination (Tremblay et al.,2012). Consequently, on NPT. Specifically, NPT strongly predicts diminished perfu-
understandingtheeffectof repetitivebraininjuriesonmIlevels sion on SPECT but the inverse is not true (Lin et al., 2012).
over time may be of interest for future investigation due to the The reasons for this mismatch are currently unknown but may
strongcorrelationwithepisodicmemorydeficitsobservedinfor- be due to SPECT being obtained at a resting state while NPT
merly concussed athletes (Tremblay et al., 2012). Based on this requiresneuralactivityandprocessing(Linetal.,2012).Inspite
evidence,MRSappearspromisingfornotonlyelucidationofCTE of thislackof correlationandlackof specificitywhenconsider-
pathophysiology but also tracking the effects of repetitive brain ing other disease conditions,SPECT has clear value in recovery
traumalongitudinally.Inthismanner,MRSmayalsobeusefulfor prognosticationbasedonpreviouslyreportedfindings(Linetal.,
thediagnosisofCTEineffectedindividuals. 2012).
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Turneretal. BiomarkerandimagingadvancesforCTE
SUSCEPTIBILITYWEIGHTEDIMAGING BIOMARKERSFORCTE:ANEWFRONTIER
Susceptibilityweightedimaging(SWI)isusedtodetectmicrohem- Asdiscussedinprevioussectionsmodernimagingtechniquesare
orrhages,theintactstructureofthevenoussystem,andoxygensat- onewaybywhichdiagnosingandtrackingtheprogressionofCTE
urationfollowingneurotrauma(Shenetal.,2007).Microhemor- maybefeasibleinthenearfuture.Unfortunately,accessandeco-
rhages,venousthrombosis,andischemiaarecommonsecondary nomicissuesassociatedwithimagingtechniquesmaysomewhat
injuries following mTBI (Aiken and Gean, 2010). Furthermore, limittheirultimateusefulnessinthediagnosisofCTE,especially
theextentofblood-brainbarrier(BBB)disruptionandperivascu- duringtheacutephasesof injury.WithCTEpotentiallybeinga
lartaudepositioncanbemappedwithSWI(Baughetal.,2012). large public-health issue, a simple and cost effective manner to
TauaccumulatesinthebrainduringtheprogressionofCTE(Stern diagnose and possibly track progression of the disease is crucial
etal.,2011).Theimagingtechniqueworksbytakingphasedata (Baughetal.,2012).
fromaT2∗ weightedMRIandcreatingasecondmappedimage. BiomarkersrepresentonemethodbywhichCTEmayoneday
This image allows both blood oxygen levels and the amount of be diagnosed. Additionally, it may be possible to track disease
deoxyhemoglobin to be measured (McCrea et al.,2008). It also severityandprogressionthroughtheuseofabiomarker(s).Ideally,
localizes concentrations of paramagnetic iron and detects areas apotentialbiomarkerforCTEwouldbeminimallyinvasive,have
of iron translocation (Cheng et al., 2010). Iron deposition may diagnosticpotentialandwouldcorrelatetodiseaseseverity,allow-
playaroleinCTEsymptommanifestation(Zhangetal.,2010). ingcareproviderstotrackprogressionofthedisease.Itshouldbe
The images produced with SWI are highly functional, velocity- sensitiveenoughtodetectthediseaseandwhenusedinconjunc-
compensated,andgradientechoed(Meodedetal.,2012).When tionwithclinicalevidenceofCTEsymptomsandapasthistoryof
used with DTI, SWI can accurately show which areas of white repeatedheadinjuries,allowforadiagnosis.Asdescribedabove,
matteraredamagedbymicrohemorrhages(Kouetal.,2009).This there is currently no accepted method of diagnosing CTE until
modalityoffersauniquetooltodetectareasof injuryearly,and post-mortem pathological analysis has been conducted (Baugh
providesclinicianswithinformationonhowtomanagethecareof et al., 2012). A readily available biomarker with the aforemen-
thepatient,particularlyinchildreninwhichSWIhasbeenshown tionedtraitswouldgivepractitionersausefultoolforthediagnosis
topredictfutureoutcomesfollowinginjury(Ashwaletal.,2006; andtrackingofpatientssufferingfromCTE.
Gavettetal.,2011a).Unfortunately,thepredictiveabilityismore Currentlythereisapaucityofstudiesaimedatdetermininga
limitedinadultsatpresentbutnecessitatesfurtherstudy(Gavett biomarker(s) specifically for CTE. Many studies aimed at eluci-
etal.,2011a). datingbiomarkersforTBIandothertypesofneurotraumahave
beenconducted.OnedifficultaspectofsearchingforaCTEbio-
ELECTROENCEPHALOGRAPHY markeristhatCTEsymptomologycanbesimilartoavarietyof
Electroencephalography (EEG) has been used to demonstrate other neurologic disorders. This may add a layer of complexity
mentalprocessingimpairmentin12professionalconcussedbox- to conducting human clinical studies in an attempt to discover
ersbasedonincreasedP300latencyandlessenedamplitude.P300 suitablebiomarkers.TheneuropathologyofCTE,however,isnot
has been identified as a cognitive event-related potential (ERP) distinctlydifferent,ashyperphosphorylatedtauandTDP-43depo-
withanovelamplitudeandlatency,makingitapotentiallysuit- sitionarefoundinavarietyofneurodegenerativediseasesoutside
able measure of brain processing ability. Similarly, investigators CTE(McKeeetal.,2010;Baughetal.,2012;SaulleandGreenwald,
havedemonstratedalteredcomponentsofP300,suchasP3a/P3b, 2012).Additionally,recentreportsindicatethatCTEmaybeasso-
decades after concussion in older athletes with a history of past ciated with symptomology similar to ALS,further complicating
concussion compared to controls (Costanza et al., 2011; Gavett thelikelihoodof clinicaldiagnosiswithoutimproveddiagnostic
et al.,2011a). Based on these findings,EEG may have utility in tests(McKeeetal.,2010).Thesereportsemphasizetheneedfora
assessing long-term cognitive effects associated with concussion biomarkerwithhighspecificitythatcandelineateCTEfromother
andtherefore,maybeusefulinidentifyingthosepredisposedto neurologicdisorders.
CTEdevelopment. There are two primary body fluids where readily attainable
biomarkers of CTE may be located. These include the cerebral
FUTUREDIRECTIONS spinalfluid(CSF)andtheblood.Bloodorplasmasampleshave
Advances in imaging technology and improved access provide the distinct advantage of being minimally invasive and easy to
nearlylimitlessopportunitiesforbothunderstandingthepatho- obtain.CSFsamples,however,areinmoredirectcontactwiththe
physiologyanddiagnosisofCTEpre-mortem.Assuch,itmaybe CNS and may confer an advantage in this regard to the deter-
possibletoinitiatebothtreatmentsandpreventivemeasuresprior minationofsuitablebiomarkersforCTE.RoutineuseofCSFin
toemergenceofCTE.Manychallengesremainsuchasclarifying thediagnosisortrackingof CTEpresentsseveralobviousprob-
the role of subconcussive injury in CTE development and how lems associated with obtaining CSF samples. Therefore, ideally
to most readily identify suspected subconcussive injuries on the a biomarker aimed at detecting CTE in the periphery would be
athletic or battlefield. By utilizing techniques such as MRS and found in serum or plasma samples obtained via venipuncture.
fMRI, pathology can be correlated with functional deficits and As discussed above, currently there is a lack of primary studies
hopefullyleadtomoreappropriateidentificationandmonitoring aimed at the elucidation of biomarkers in either one of these
ofthosewithsuspectedinjuries,regardlessofseverity.Otherchal- body fluids for CTE. However, several studies have been con-
lengessuchastheneedforbaselinemeasurementsremaintobe ductedintherealmofTBIandmTBIandthesewillbediscussed
overcomeaswellbutclearlywarrantadditionalinvestigation. herein.
FrontiersinNeurology|Neurotrauma January2013|Volume3|Article186|6
Turneretal. BiomarkerandimagingadvancesforCTE
It may be possible that biomarkers in development for TBI CSF and the serum of rats exposed to a model of this type of
maybeusefulduringtheacuteinjuryphaseofpatientsatriskfor TBI.Additionally,this group showed that the expression of five
CTE.Therepeatedconcussiveandsubconcussiveblowsthatresult microRNA’s were altered post-blast TBI in the serum of these
inCTEmayalterlevelsofparticularbiomarkersstudiedforTBI animals(Balakathiresanetal.,2012).Theseincludedlet-7i,miR-
immediately following these events. The tracking of these acute 122,miR-200b,miR-340-5p,andmiR-874(Balakathiresanetal.,
changes,althoughnotspecifictoCTE,maygivehealthcareprofes- 2012).Furtherstudyisneededinbothanimalmodels,aswellas
sionalsinsightintothosepatientsatthegreatestriskfordeveloping humans,tovalidatethepotentialforusingmicroRNA’saspoten-
CTElaterinlife.Equallyimportantthough,isthepotentialutility tial biomarkers for TBI and possibly CTE. Although this study
for biomarker surveillance in patients with known or suspected was conducted using a blast TBI animal model, a recent report
post-concussionsyndrome. hasshownthatthismodelproducespathologysimilartothatseen
Manystudiesthathavebeenconductedaimedatdetermining in CTE and models similar to this may be viable animal mod-
a biomarker for TBI or mTBI in the plasma or serum. A study elsforthestudyofCTE(Goldsteinetal.,2012).Theproduction
conductedbyMondelloetal.hasdeterminedthatglialneuronal of validatedanimalmodelscouldgreatlyaidinthediscoveryof
ratio (GNR), characterized as the ratio between glial fibrillary biomarkersaimedatdetectingCTEandtheproductionofpoten-
acidicprotein(GFAP)andubiquitincarboxy-terminalhydrolase- tial clinical therapies for treating CTE. Other studies have also
L1(UCH-L1)intheserumofTBIpatientsischaracteristicofthe successfullyidentifiedRNA-basedbiomarkersformTBIbasedon
typeofTBIinjury,focalvs.diffuse(Mondelloetal.,2012).Itwas bothmicro-andsnoRNAinperipheralbloodmononuclearcells
notedbyMondelloetal.(2012)thattheirstudiesmayhaveimpli- (PBMCs). Using a panel of three markers,veterans that experi-
cationsfordiagnosisinTBIpatientsintheearlyacutephasesof enced mTBI were detected with 89% accuracy, 82% selectivity,
injury,howeverwhethertheseresultswouldhaveimplicationsfor and78%specificity(Pasinettietal.,2012).Futurestudiesutilizing
CTEpatientshasyettobedetermined.Itispossiblethataftermul- both animalmodels aswell asclinical samplesmay revealaddi-
tipleconcussiveorsubconcussiveblowstotheheadthattheGNR tional RNA-based molecules that may be viable biomarkers for
maybealteredandmayofferinsightintotheextentofinjuryand detectingandpossiblytrackingCTE.
potentialforlaterdevelopmentofCTE. One particularly interesting report recently published, stud-
Severalotherstudiesaimedatelucidatingvaluablebiomarkers iedavarietyof biomarkersaimedatdetectingTBIandmTBIin
forTBIintheserumhavebeenconductedandmayofferinsight Olympicboxerswithanextendedhistoryofmanybouts(Neselius
intotheproductionofabiomarker(s)specifictoCTE.Ithasbeen etal.,2012).Thisstudydeterminedextentofincreasesinneurofil-
reportedthatplasmabilirubinlevelsinTBIpatientsareelevated amentlightprotein(NFL),totaltau(T-tau),tauphosphorylated
ondayssubsequenttoinjury(Dohietal.,2005).Unfortunately, at threonine 181 (P-tau181),H-FABP,GFAP,S-100B,and the 42
thisstudyonlydeterminedbilirubinlevelsupto4dayspost-injury. aminoacidformofamyloidβ(Aβ1–42)inOlympicboxersbothin
Thedeterminationastowhethertheincreasesinplasmabilirubin theacutephaseafteraboutandanextendedphaseof2weekspost-
remain elevated for a significant amount of time post-injury or boutandcomparedthemtonon-boxingcontrols.Itwasfoundthat
whetheritisspecifictotheacuteinjuryphasehasyettobemade. bothNFLandGFAPlevelswithintheCSFweresignificantlydiffer-
Additionally,thedeterminationastowhetherbilirubinconcentra- entfromcontrolsinboththeacuteandextendedphaseoftesting
tionsintheplasmawouldbeelevatedinpatientsatriskforCTE (Neseliusetal.,2012).Thedeterminationastowhethereitherof
hasalsoyettobemade. these correlated to injury severity was unable to be conclusively
AnotherintriguingpotentialserumbiomarkerforCTEmaybe madeinthisstudy(Neseliusetal.,2012).
theproteinneuron-specificenolase.Zetterbergetal.(2009)have However,apreviousstudyhasshownthattheremaybeapoten-
shownthatthisproteinisincreasedintheserumofboxersascom- tialcorrelationbetweenNFLlevelsintheCSFandinjuryseverity
paredtohealthycontrolsaftertheboxersabstainedfromboxing (Zetterbergetal.,2006).Zetterbergetal.(2006)showedthatNFL,
foraperiodof2months.Interestingly,elevatedlevelsofneuron- T-tau, and GFAP were increased in the CSF of boxers and the
specificenolaseweredetected2monthsafteranon-participatory levels appear to be correlated to injury severity, as boxers who
period of boxing,however other biomarker candidates for CTE receivedmorehitsinnumberorseverityhadincreasedlevelsof
such as S-100B,brain-derived neurotrophic factor (BDNF),and thesemarkers.OnlyNFLinthesestudieshowever,wasincreased
heart-typefattyacidbindingprotein(H-FABP)werefoundtobe foranextendedtimeperiod(testedat3months)ascomparedto
unchanged (Zetterberg et al., 2009). These results indicate that controls(Zetterberg etal.,2006). Theextendedincrease inNFL
neuron-specific enolase may be one protein biomarker that has levelswithintheCSFpost-injurymaymakeitaviablecandidate
thepotentialforuseasadiagnostictool.Itispossiblethatneuron- for a biomarker for mTBI and CTE however whether levels of
specific enolase remains elevated for an extended time period NFLwithintheCSFcorrelatetolaterdiseaseseverityinthecaseof
after injury and may be a useful tool for diagnostic purposes in CTEormTBIhasyettobeconclusivelymade.NFLlevelshowever,
athletesandpatientswhohavesufferedmultipleconcussiveand havebeenshowntobealteredinothertypesofneurologictrauma
subconcussiveblowstothehead. anddisorderssothismayultimatelydecreaseitsviabilityasatool
Anareaofbiomarkerresearchthathasreceivedmuchattention for detecting,diagnosing,and tracking CTE disease progression
is the field of microRNA. It is possible that potential biomark- (Avsaretal.,2012;Tortellietal.,2012).
ers for CTE may not only be protein-based in nature. A recent AlthoughlevelsofproteinssuchasNFLandtaumaynotbespe-
report by Balakathiresan et al. (2012) has shown that levels of cificwithregardstoCTE,abatteryofvariousbiomarkerproteins
microRNAlet-7iareelevatedpost-blast-inducedTBIinboththe combined with patient history and imaging studies (discussed
www.frontiersin.org January2013|Volume3|Article186|7
Turneretal. BiomarkerandimagingadvancesforCTE
in previous sections) may result in the ability to make a pre- LINKINGPATHOPHYSIOLOGYTOIMAGINGANDBIOMARKER
mortem diagnosis of CTE via a reference fractional laboratory DISCOVERY
indexusingahighthroughputanalyticalsystem.Inthisrespect, Perhaps the greatest challenge concerning development of bio-
a combined battery of proteins such as tau, GFAP, NFL, S100- markers or imaging modalities for prevention, diagnosis, and
B,and bilirubin may offer more accurate quantitative data with prognosis of CTE is the current lack of well-elucidated disease
regardstoapatientsriskfordevelopingCTEandwhencombined pathophysiology. Consequently,few clearly identifiable and spe-
with other modalities of relevant clinical data, may be used as cific disease markers have been identified. Without first under-
even more accurate diagnostic indicators at some point in the standingdiseasedevelopmentmoreclearly,likelyviabothclinical
future. research and utilization of animal models of repetitive brain

FIGURE1|Imagingandbiomarkerstudiesmaybeusefulinimprovingunderstandingoftheroleofrepetitiveconcussiveandsubconcussiveinjuryin

diseasedevelopment.Twoexperimentalparadigmsarepresentedrepresentingapotentiallymoreideal,butcostly,scenario(A)andthemorecost-conscious

approach(B).

FrontiersinNeurology|Neurotrauma January2013|Volume3|Article186|8
Turneretal. BiomarkerandimagingadvancesforCTE
trauma, logical discovery of CTE-associated markers appears Understanding this issue warrants further investigation as neu-
unlikely.RecentworkhasdemonstratedthepresenceofCTE-like ropathologicchangesassociatedwithCTEhavebeenfoundinan
neuropathologyinwild-typemicefollowingsingle-blastexposure asymptomatic18-year-oldhighschoolfootballplayerandconse-
and increased formation of NFTs in a transgenic mouse model quently,age at time of first head injury may contribute to CTE
followingrepetitiveinjury(Yoshiyamaetal.,2005;Goldsteinetal., incidence(SaulleandGreenwald,2012).
2012).Inasingle-injuryexperiment,againusingtransgenicmice
utilized in AD models, tau and amyloid-β accumulation was CONCLUSION
accelerated(Tranetal.,2011).Similarly,studieshaveshownthe Chronictraumaticencephalopathyisanemergingpublic-health
presenceofphosphorylatedtauandamyloid-βmonthsafterinitial concern due to disease prevalence likely higher than previously
fluidpercussioninjuryinthegeneticallyunmodifiedrat(Hoshino recognizedandcontinuedpopularityofcontactsportsaswellas
etal.,1998). involvement in military combat that places soldiers at risk for
Despitethepresentlackofclearelucidationofdiseasepatho- explosive blasts and subsequent TBI. As CTE represents a dev-
physiology,certain imaging techniques such as MRS,fMRI,and astating deterioration of neurologic function, a clear need for
tau-specificlabelingcompoundsinPET,havebegunandwilllikely improveddiagnosticandprognostictestsexists.Toaccommodate
continuetoprovideinsightintoCTEdevelopmentvialongitudinal this need, as well as more clearly elucidate disease pathophys-
changesinneurologicfunctionandhealthviaavarietyofmarkers. iology, imaging, and/or biomarker-based tests are required. We
Similarly,workinotherdiseaseconditionsthatallowsforimaging proposeapotentialwork-flowforimplementationofbothimag-
ofactivatedmicroglia,consistentwiththenotionofimmunoex- ingandbiomarker-basedstudiesforimprovingtheunderstanding
citotoxicity,mayprovidefurtherinsightintodiseasedevelopment of the role concussive and subconcussive impacts play in long-
andprogression(Vennetietal.,2007). termdiseasedevelopment(Figure1).Whilethespecificsremain
In addition to assisting in the diagnosis and prognosis of open to interpretation,obtaining pre-injury exposure studies as
patients suffering from CTE,continued improvements in imag- wellasafterasuspectedorconfirmedinjuryparametersislikely
ingandbiochemicalassaysassociatedwithCTEidentificationmay to provide further insight into the effects of TBI. It is only by
promoteriskfactoridentificationandprovideinsightintoperiods more accurately identifying CTE pre-mortem and studying dis-
of increasedrisk.Forexample,theroleof ageattimeof impact easeprogressionandmechanismsthatwecanestablishimproved
and associated brain trauma in disease development is unclear. therapeuticapproaches.

REFERENCES Lin,A.,etal.(2012).Chronictrau- neurophysiological impairment in encephalopathyintheelderly:clin-
Adams,C.W.,andBruton,C.J.(1989). maticencephalopathy:neurodegen- highschoolfootball.J.Biomech.45, ical expression and structural sub-

Thecerebralvasculatureindemen- eration following repetitive con- 1265–1272. strates. Neuropathol. Appl. Neuro-

tiapugilistica.J.Neurol.Neurosurg. cussive and subconcussive brain Casson,I.R.,Pellman,E.J.,andViano, biol.37,570–584.
Psychiatr.52,600–604. trauma. Brain Imaging Behav. 6, D. C. (2006). Chronic traumatic Daneshvar,D.H.,Riley,D.O.,Nowin-
Aiken,A.H.,andGean,A.D.(2010). 244–254. encephalopathyinaNationalFoot- ski, C. J., McKee, A. C., Stern, R.
Imaging of head trauma. Semin. Bazarian,J.J.,Zhu,T.,Blyth,B.,Borrino, ballLeagueplayer.Neurosurgery58, A.,andCantu,R.C.(2011).Long-
Roentgenol.45,63–79. A., and Zhong, J. (2012). Subject- E1003;authorreplyE1003;discus- termconsequences:effectsonnor-

Ashwal, S., Babikian, T., Gardner- specific changes in brain white sionE1003. maldevelopmentprofileaftercon-
Nichols,J.,Freier,M. C.,Tong,K. matter on diffusion tensor imag- Chappell, M. H., Brown, J. A., cussion.Phys.Med.Rehabil.Clin.N.
A., and Holshouser, B. A. (2006). ingaftersports-relatedconcussion. Dalrymple-Alford,J.C.,Ulug,A.M., Am.22,683–700,ix.
Susceptibility-weightedimagingand Magn.Reson.Imaging30,171–180. and Watts, R. (2008). Multivariate Difiori,J.P.,andGiza,C.C.(2010).New
proton magnetic resonance spec- Bennett,R.E.,MacDonald,C.L.,and analysis of diffusion tensor imag- techniques in concussion imaging.

troscopy in assessment of out- Brody,D.L.(2012).Diffusionten- ingdataimprovesthedetectionof Curr.SportsMed.Rep.9,35–39.

comeafterpediatrictraumaticbrain sorimagingdetectsaxonalinjuryin microstructural damage in young Dohi,K.,Satoh,K.,Ohtaki,H.,Shioda,
injury.Arch.Phys.Med.Rehabil.87, amousemodelofrepetitiveclosed- professional boxers. Magn. Reson. S., Miyake, Y., Shindo, M., et al.
S50–S58. skull traumatic brain injury. Neu- Imaging26,1398–1405. (2005). Elevated plasma levels of
Avsar, T., Korkmaz, D., Tutuncu, rosci.Lett.513,160–165. Cheng,J.L.,Yang,Y.J.,Li,H.L.,Wang,J., bilirubin in patients with neuro-
M., Demirci, N. O., Saip, S., Bigler,E.D.,andMaxwell,W.L.(2012). Wang,M.H.,andZhang,Y.(2010). trauma reflect its pathophysiologi-

Kamasak, M., et al. (2012). Pro- Neuropathology of mild traumatic In vivo tracing of superparamag- cal role in free radical scavenging.

tein biomarkers for multiple scle- brain injury: relationship to neu- neticironoxide-labeledbonemar- Invivo19,855–860.
rosis: semi-quantitative analysis of roimaging findings. Brain Imaging rowmesenchymalstemcellstrans- Gavett,B.E.,Cantu,R.C.,Shenton,M.,
cerebrospinal fluid candidate pro- Behav.6,108–136. planted for traumatic brain injury Lin,A.P.,Nowinski,C.J.,McKee,A.
teinbiomarkersindifferentformsof Blaylock,R.L.,andMaroon,J.(2011). by susceptibility weighted imaging C.,etal.(2011a).Clinicalappraisal
multiplesclerosis.Mult.Scler. Immunoexcitotoxicity as a cen- inaratmodel.Chin.J.Traumatol. of chronic traumatic encephalopa-

Balakathiresan,N.,Bhomia,M.,Chan- tral mechanism in chronic trau- 13,173–177. thy:currentperspectivesandfuture

dran,R.,Chavko,M.,McCarron,R. matic encephalopathy – a unify- Corsellis, J. A., Bruton, C. J., and directions. Curr. Opin. Neurol. 24,
M.,andMaheshwari,R.K.(2012). inghypothesis.Surg.Neurol.Int.2, Freeman-Browne, D. (1973). The 525–531.
MicroRNA let-7i is a promising 107. aftermathof boxing.Psychol.Med. Gavett,B.E.,Stern,R.A.,andMcKee,
serumbiomarkerforblast-induced Breedlove, E. L., Robinson, M., 3,270–303. A. C. (2011b). Chronic traumatic
traumatic brain injury. J. Neuro- Talavage, T. M., Morigaki, K. Costanza, A., Weber, K., Gandy, S., encephalopathy: a potential late

trauma29,1379–1387. E., Yoruk, U., O’Keefe, K., et al. Bouras,C.,Hof,P.R.,Giannakopou- effect of sport-related concussive
Baugh,C.M.,Stamm,J.M.,Riley,D. (2012). Biomechanical correlates los, P., et al. (2011). Review: con- and subconcussive head trauma.
O., Gavett, B. E., Shenton, M. E., of symptomaticandasymptomatic tactsport-relatedchronictraumatic Clin.SportsMed.30,179–188,xi.

www.frontiersin.org January2013|Volume3|Article186|9
Turneretal. BiomarkerandimagingadvancesforCTE
Gavett,B.E.,Stern,R.A.,Cantu,R.C., Johnson,V.E.,Stewart,W.,andSmith, metabolisminpatientswithcogni- chronic traumatic encephalopathy
Nowinski,C. J.,and McKee,A. C. D.H.(2012).Axonalpathologyin tiveimpairmentsafterminortrau- inAmericanathletes.Neurosurgery
(2010).Mildtraumaticbraininjury: traumaticbraininjury.ExpNeurol. maticbraininjury:PETstudyina 69,173–183;discussion183.

ariskfactorforneurodegeneration. doi:10.1016/j.expneurol.2012.01.013 chronicstate.Int.Congr.Ser.1259, Omalu, B., Hammers, J. L., Bailes, J.,
AlzheimersRes.Ther.2,18. Kemp,P.M.,Houston,A.S.,MacLeod, 365–369. Hamilton, R. L., Kamboh, M. I.,
Geddes, J. F., Vowles, G. H., Nicoll, M.A.,andPethybridge,R.J.(1995). McCrea,R.P.,Harder,S.L.,Martin,M., Webster,G.,etal.(2011b).Chronic
J. A., and Revesz, T. (1999). Neu- Cerebralperfusionandpsychomet- Buist,R.,andNichol,H.(2008).A traumatic encephalopathy in an
ronal cytoskeletal changes are an rictestinginmilitaryamateurboxers comparisonofrapid-scanningX-ray Iraqiwarveteranwithposttraumatic

early consequence of repetitive and controls. J. Neurol. Neurosurg. fluorescencemappingandmagnetic stressdisorderwhocommittedsui-

head injury. Acta Neuropathol. 98, Psychiatr.59,368–374. resonanceimagingtolocalizebrain cide.Neurosurg.Focus31,E3.
171–178. Kleindienst, A., Tolias, C. M., Cor- irondistribution.Eur.J.Radiol.68, Omalu, B. I., Bailes, J., Hammers, J.
Goldstein,L. E.,Fisher,A. M.,Tagge, win, F. D., Muller, C., Marmarou, S109–S113. L.,andFitzsimmons,R.P.(2010a).
C.A.,Zhang,X.L.,Velisek,L.,Sul- A., Fatouros, P., et al. (2005). McCrory,P.(2011).Sportsconcussion Chronictraumaticencephalopathy,
livan, J. A., et al. (2012). Chronic Assessment of cerebral S100B lev- andtheriskofchronicneurological suicidesandparasuicidesinprofes-

traumaticencephalopathyinblast- els by proton magnetic resonance impairment.Clin.J.SportMed.21, sional American athletes: the role

exposed military veterans and a spectroscopy after lateral fluid- 6–12. of the forensic pathologist. Am. J.
blast neurotrauma mouse model. percussioninjuryintherat.J.Neu- McDonald, B. C., Saykin, A. J., and ForensicMed.Pathol.31,130–132.
Sci.Transl.Med.4,134ra160. rosurg.102,1115–1121. McAllister,T.W.(2012).Functional Omalu,B.I.,Fitzsimmons,R.P.,Ham-
Guskiewicz, K. M., Marshall, S. W., Kou,Z.,Benson,R.R.,Gattu,R.,and MRIofmildtraumaticbraininjury mers, J., and Bailes, J. (2010b).
Bailes,J.,McCrea,M.,Cantu,R.C., Haacke, E. M. (2009). Susceptibil- (mTBI): progress and perspectives Chronic traumatic encephalopathy

Randolph, C., et al. (2005). Asso- ityweightedimagingcomplements from the first decade of studies. inaprofessionalAmericanwrestler.

ciation between recurrent concus- todiffusiontensorimagingintrau- BrainImagingBehav.6,193–207. J.ForensicNurs.6,130–136.
sionandlate-lifecognitiveimpair- maticbraininjury.Neuroimage 47, McKee,A.C.,Cantu,R.C.,Nowinski, Omalu, B. I., Hamilton, R. L., Kam-
mentinretiredprofessionalfootball S68. C. J., Hedley-Whyte, E. T., Gavett, boh, M. I., Dekosky, S. T., and
players. Neurosurgery 57, 719–726; Lakhan, S. E., and Kirchgessner, B. E.,Budson,A. E.,et al. (2009). Bailes,J.(2010c).Chronictraumatic
discussion719–726. A. (2012). Chronic traumatic Chronic traumatic encephalopathy encephalopathy(CTE)inaNational

Henninger, N., Sicard, K. M., Li, Z., encephalopathy: the dangers of in athletes: progressive tauopathy FootballLeaguePlayer:casereport
Kulkarni,P.,Dutzmann,S.,Urbanek, getting “dinged”. SpringerPlus 1. afterrepetitiveheadinjury.J.Neu- andemergingmedicolegalpractice
C.,etal.(2007).Differentialrecovery doi:10.1186/2193-1801-1-2 ropathol.Exp.Neurol.68,709–735. questions.J.ForensicNurs.6,40–46.
ofbehavioralstatusandbrainfunc- Li,S.,Sun,Y.,Shan,D.,Feng,B.,Xing, McKee,A. C.,Gavett,B. E.,Stern,R. Omalu, B. I., Dekosky, S. T., Hamil-
tionassessedwithfunctionalmag- J.,Duan,Y.,etal.(2012).Temporal A., Nowinski, C. J., Cantu, R. C., ton,R.L.,Minster,R.L.,Kamboh,

neticresonanceimagingaftermild profiles of axonal injury following Kowall,N.W.,et al. (2010). TDP- M. I.,Shakir,A. M.,et al. (2006).

traumatic brain injury in the rat. impactaccelerationtraumaticbrain 43 proteinopathy and motor neu- Chronic traumatic encephalopathy
Crit.CareMed.35,2607–2614. injuryinrats–acomparativestudy ron disease in chronic traumatic inanationalfootballleagueplayer:
Henry, L. C., Tremblay, J., Tremblay, with diffusion tensor imaging and encephalopathy.J.Neuropathol.Exp. partII.Neurosurgery59,1086–1092;
S., Lee, A., Brun, C., Lepore, N., morphologicalanalysis.Int.J.Legal. Neurol.69,918–929. discussion1092–1083.
et al. (2011a). Acute and chronic Med.doi:10.1007/s00414-012-0712- Meoded,A.,Poretti,A.,Northington,F. Omalu,B. I.,Dekosky,S. T.,Minster,

changesindiffusivitymeasuresafter 8 J.,Tekes,A.,Intrapiromkul,J.,and R. L., Kamboh, M. I., Hamilton,

sports concussion. J. Neurotrauma Lin,A.P.,Liao,H.J.,Merugumala,S.K., Huisman,T.A.(2012).Susceptibil- R. L., and Wecht, C. H. (2005).
28,2049–2059. Prabhu,S.P.,Meehan,W.P.IIIand ityweightedimagingoftheneonatal Chronic traumatic encephalopathy
Henry, L. C., Tremblay, S., Leclerc, Ross,B.D.(2012).Metabolicimag- brain.Clin.Radiol.67,793–801. inaNationalFootballLeagueplayer.
S.,Khiat,A.,Boulanger,Y.,Ellem- ingofmildtraumaticbraininjury. Mills, J. D., Bailes, J. E., Turner, Neurosurgery 57, 128–134; discus-
berg, D., et al. (2011b). Metabolic BrainImagingBehav.6,208–223. R. C., Dodson, S. C., Sakai, J., sion128–134.

changes in concussed American Lin,A.P.,Ramadan,S.,Box,H.,Stan- and Maroon, J. C. (2012). Ana- Pasinetti,G.M.,Ho,L.,Dooley,C.,Abbi,

footballplayersduringtheacuteand well,P.,Stern,R.,and Mountford, bolicsteroidsandheadinjury.Neu- B.,andLange,G.(2012).Selectnon-
chronic post-injury phases. BMC C. (2010). Neurochemical Changes rosurgery 70, 205–209; discussion codingRNAinbloodcomponents
Neurol. 11:105. doi:10.1186/1471- in Athletes with Chronic Traumatic 209–210. provide novel clinically accessible
2377-11-105 Encephalopathy.Chicago,IL:Radio- Millspaugh, J. A. (1937). Dementia biological surrogates for improved
Henry,L. C.,Tremblay,S.,Boulanger, logicalSocietyofNorthAmerica. pugilistica.U.S.Nav.Med.Bull.35, identification of traumatic brain

Y., Ellemberg, D., and Lassonde, MacDonald,C.L.,Dikranian,K.,Song, 297–303. injuryinOEF/OIFVeterans.Am.J.
M.(2010).Neurometabolicchanges S.K.,Bayly,P.V.,Holtzman,D.M., Mondello,S.,Jeromin,A.,Buki,A.,Bul- Neurodegener.Dis.1,88–98.
in the acute phase after sports andBrody,D.L.(2007).Detection lock,R.,Czeiter,E.,Kovacs,N.,et Price, P., and Jones, T. (1995). Can
concussions correlate with symp- oftraumaticaxonalinjurywithdif- al. (2012). Glial neuronal ratio: a positron emission tomography
tom severity. J. Neurotrauma 27, fusion tensor imaging in a mouse novelindexfordifferentiatinginjury (PET)beusedtodetectsubclinical

65–76. model of traumatic brain injury. type in patients with severe trau- responsetocancertherapy?TheEC

Hoshino, S., Tamaoka, A., Takahashi, Exp.Neurol.205,116–131. maticbraininjury.J.Neurotrauma PET Oncology Concerted Action
M., Kobayashi, S., Furukawa, T., Maller, J. J., Thomson, R. H., Lewis, 29,1096–1104. andtheEORTCPETStudyGroup.
Oaki,Y.,etal.(1998).Emergenceof P.M.,Rose,S.E.,Pannek,K.,and Neselius, S., Brisby, H., Theodorsson, Eur.J.Cancer31A,1924–1927.
immunoreactivitiesforphosphory- Fitzgerald, P. B. (2010). Traumatic A., Blennow, K., Zetterberg, H., Prichep, L. S., McCrea, M., Barr,
latedtauandamyloid-betaprotein braininjury,majordepression,and and Marcusson, J. (2012). CSF- W., Powell, M., and Chabot, R.

inchronicstageoffluidpercussion diffusion tensor imaging: making biomarkers in Olympic boxing: J. (2012). Time course of clin-

injury in rat brain. Neuroreport 9, connections. Brain Res. Rev. 64, diagnosis and effects of repetitive ical and electrophysiological
1879–1883. 213–240. headtrauma.PLoSONE 7:e33606. recovery after sport-related con-
Hutchinson,E.B.,Rutecki,P.A.,Alexan- Martland,H.S.(1928).Punchdrunk. doi:10.1371/journal.pone.0033606 cussion. J. Head Trauma Rehabil.
der,A.L.,andSutula,T.P.(2012). JAMA91,1103–1107. Omalu, B., Bailes, J., Hamilton, R. doi:10.1097/HTR.0b013e318247b54e
Fisherstatisticsforanalysisofdiffu- Mase, M., Nagai, H., Kabasawa, H., L., Kamboh, M. I., Hammers, J., Provenzano,F.A.,Jordan,B.,Tikofsky,

siontensordirectionalinformation. Ogawa, T., Iida, A., and Yamada, Case, M., et al. (2011a). Emerg- R.S.,Saxena,C.,VanHeertum,R.

J.Neurosci.Methods206,40–45. K.(2004).Cerebralbloodflowand inghistomorphologicphenotypesof L.,andIchise,M.(2010).F-18FDG

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