AJOURNALOFNEUROLOGYThespectrumofdiseaseinchronictraumaticAnnC.ThorD.Ch - PDF document

AJOURNALOFNEUROLOGYThespectrumofdiseaseinchronictraumaticAnnC.ThorD.ChristopherJ.RobertA.DanielH.VictorE.SydneyM.ChristineM.DavidO.CarolineA.KerryA.MatthewA.BrettR.CarmelaR.RobertRossBenjaminL.AndrewE.LeeE.NeilW.*andRobertC.1UnitedStatesDepartmentofVeteransAffairs,VABostonHealthcareSystem,Boston,MA02130,USA2CenterfortheStudyofTraumaticEncephalopathy,BostonUniversitySchoolofMedicine,Boston,MA02118,USA3Alzheimer’sDiseaseCenter,BostonUniversitySchoolofMedicine,Boston,MA02118,USA4DepartmentofNeurology,BostonUniversitySchoolofMedicine,Boston,MA02118,USA5DepartmentofPathology,BostonUniversitySchoolofMedicine,Boston,MA02118,USA6SportsLegacyInstitute,Waltham,MA02451,USA7DepartmentofNeurosurgery,BostonUniversitySchoolofMedicine,Boston,MA02118,USA8DepartmentofBiologicalSciences,UniversityofMassachusetts,Lowell,MA01854,USA9DataCoordinatingCenter,BostonUniversitySchoolofPublicHealth,BostonMA02118,USA10DepartmentofBiochemistry,BostonUniversitySchoolofMedicine,Boston,MA02118,USA11DepartmentofPharmacology,BostonUniversitySchoolofMedicine,Boston,MA02118,USA12DepartmentofPathology,MayoClinic,Rochester,MN55905,USA13DepartmentofPsychiatry,BostonUniversitySchoolofMedicine,Boston,MA02118,USA14DepartmentofOpthamology,BostonUniversitySchoolofMedicine,Boston,MA02118,USA15DepartmentofBiomedicalEngineering,BostonUniversitySchoolofMedicine,Boston,MA02118,USA16DepartmentofNeurosurgery,EmersonHospital,Concord,MA01742,USA*Theseauthorscontributedequallytothiswork.Correspondenceto:AnnC.McKee,MD,VABostonHealthCareSystem,150SouthHuntingtonAvenue,151-CMA02130,E-mail:ann.mckee@va.gov;amckee@bu.eduChronictraumaticencephalopathyisaprogressivetauopathythatoccursasaconsequenceofrepetitivemildtraumaticbraininjury.Weanalysedpost-mortembrainsobtainedfromacohortof85subjectswithhistoriesofrepetitivemildtraumaticbraininjuryandfoundevidenceofchronictraumaticencephalopathyin68subjects:allmales,ranginginagefrom17to98years(mean59.5years),including64athletes,21militaryveterans(86%ofwhomwerealsoathletes)andoneindividualwhoengagedinself-injuriousheadbangingbehaviour.Eighteenage-andgender-matchedindividualswithoutahistoryofrepetitivemildtraumaticbraininjuryservedascontrolsubjects.Inchronictraumaticencephalopathy,thespectrumofhyperphosphory-latedtaupathologyrangedinseverityfromfocalperivascularepicentresofneuroÞbrillarytanglesinthefrontalneocortextoseveretauopathyaffectingwidespreadbrainregions,includingthemedialtemporallobe,therebyallowingaprogressivestagingofpathologyfromstagesIÐIV.MultifocalaxonalvaricositiesandaxonallosswerefoundindeepcortexandsubcorticalwhiteBrain2012:Page1of22 ReceivedJuly2,2012.RevisedSeptember1,2012.AcceptedOctober1,2012.TheAuthor(2012).PublishedbyOxfordUniversityPressonbehalfoftheGuarantorsofBrain.Allrightsreserved.ForPermissions,pleaseemail:journals.permissions@oup.com matteratallstagesofchronictraumaticencephalopathy.TARDNA-bindingprotein43immunoreactiveinclusionsandneuriteswerealsofoundin85%ofcases,rangingfromfocalpathologyinstagesIÐIIItowidespreadinclusionsandneuritesinstageIV.SymptomsinstageIchronictraumaticencephalopathyincludedheadacheandlossofattentionandconcentration.AdditionalsymptomsinstageIIincludeddepression,explosivityandshort-termmemoryloss.InstageIII,executivedysfunctionandcognitiveimpairmentwerefound,andinstageIV,dementia,word-ÞndingdifÞcultyandaggressionwerecharacteristic.Dataonathleticexposurewereavailablefor34Americanfootballplayers;thestageofchronictraumaticencephalopathycorrelatedwithincreaseddurationoffootballplay,survivalafterfootballandageatdeath.Chronictraumaticencephalopathywasthesolediagnosisin43cases(63%);eightwerealsodiagnosedwithmotorneurondisease(12%),sevenwithAlzheimerÕsdisease(11%),11withLewybodydisease(16%)andfourwithfrontotemporallobardegeneration(6%).Thereisanorderedandpredictableprogressionofhyperphosphorylatedtauabnormalitiesthroughthenervoussysteminchronictraumaticencephalopathythatoccursincon-junctionwithwidespreadaxonaldisruptionandloss.ThefrequentassociationofchronictraumaticencephalopathywithotherneurodegenerativedisorderssuggeststhatrepetitivebraintraumaandhyperphosphorylatedtauproteindepositionpromotetheaccumulationofotherabnormallyaggregatedproteinsincludingTARDNA-bindingprotein43,amyloidbetaproteinandalpha-synuclein.axonalinjury;braintrauma;frontotemporallobardegeneration;neurodegenerativedisorders;traumaticbraininjuryCTE=chronictraumaticencephalopathy;FTLD=frontotemporallobardegeneration;MND=motorneurondiseaseRepetitivemildtraumaticbraininjurycantriggerthedevelopmentofchronictraumaticencephalopathy(CTE),aprogressiveneuro-degenerationcharacterizedbythewidespreaddepositionofhyperphosphorylatedtau(p-tau)asneurobrillarytanglesCorsellisandBrierley,1959etal.,1973etaletal.,1999etal.,2005etal.,2009etal.,2010etal.,2011etal.,2011etal.,2011etal.,2012etal.,2012).CTEwasoriginallyreportedin1928byHarrisonMartland,aNewJerseypathologist,whodescribedtheclinicalaspectsofaprogressiveneurologicaldeterioration(‘punchdrunk’)thatoccurredafterrepetitivebraintraumainboxers(Martland,1928).Althoughoriginallytermed‘dementiapugilistica’(Millspaugh,1937),therecognitionthatactivitiesotherthanboxingwereassociatedwithitsdevelopmentleadtothepreferreduseoftermssuchasprogressivetraumaticencephalopathyandlater,CTE(Critchley,1949CTEisclinicallyassociatedwithsymptomsofirritability,impul-sivity,aggression,depression,short-termmemorylossandheigh-tenedsuicidalitythatusuallybegin8–10yearsafterexperiencingrepetitivemildtraumaticbraininjury(etal.,2009).Withadvancingdisease,moresevereneurologicalchangesdevelopthatincludedementia,gaitandspeechabnormalitiesandparkinsonism.Inlatestages,CTEmaybeclinicallymistakenforAlzheimer’sdis-easeorfrontotemporaldementia(etal.,2010).AsubsetofcaseswithCTEisassociatedwithmotorneurondisease(MND)(etal.,2010TheneuropathologicalchangesofCTEaredistinctiveandeas-ilydistinguishedfromothertauopathies,includingAlzheimer’sdisease.TheneuropathologicalfeaturesofCTEincludegeneralizedatrophyofthecerebralcortex,medialtemporallobe,dienceph-alonandmammillarybodieswithenlargedventricles;cavumseptumpellucidum,oftenwithfenestrations;extensivep-tau-immunoreactiveneurobrillarytanglesandastrocytictanglesinthefrontalandtemporalcortices,particularlyaroundsmallcere-bralvesselsandatthedepthsofcerebralsulci;extensivep-tau-immunoreactiveneurobrillarytanglesinlimbicregions,di-encephalonandbrainstemnuclei;extensivedegenerationofaxonsandwhitematterbrebundles;TARDNA-bindingprotein43(TDP-43)immunoreactiveintraneuronalandintraglialinclusionsandneuritesinmostcasesandarelativeabsenceofamyloid-peptidedeposits(CorsellisandBrierley,1959etaletal.,1991etal.,1999etaletal.,2009etaletal.,2011etal.,2011etal.,2011etal.,2012etal.,2012In2008,theCenterfortheStudyofTraumaticEncephalopathy(CSTE)atBostonUniversitySchoolofMedicineestablishedtheCSTEbrainbankattheBedfordVAHospitaltoanalysethebrainandspinalcordsafterdeathofathletes,militaryveteransandcivilianswhoexperiencedrepetitivemildtraumaticbraininjury.Throughthiseffort,wecomprehensivelyanalysedthebrainandspinalcordof85donorsforevidenceofCTE,aswellasforallotherneurodegenerativediseases,includingAlzheimer’sdisease,frontotemporallobardegeneration(FTLD),Parkinson’sdisease,Lewybodydiseaseandmultiplesystematrophy.WereportthespectrumofCTEandneurodegenerativepathologyfoundinthebrainandspinalcordofthesedonors,comparethepathologicalndingswith18cognitivelynormalage-andgender-matchedcontrolsubjectswithoutknownhistoryofmildtraumaticbraininjury,andcorrelatetheclinicalndingstotheneuroanatomicalregionsofp-taupathology.Althoughabraindo-nationstudyandautopsydirectedcaseserieswillneverestablishtheincidenceorprevalenceofadisordersuchasCTEowingtoascertainmentbiases,systematicclinicopathologicalanalysisallowsinsightintothespectrumofclinicalandneuropathologicalalter-ationsassociatedwiththedisorderandlaysthefoundationforfutureprospectivelongitudinalstudies. Brain2012:Page2of22A.C.McKeeetal MaterialsandmethodsAtotalof85brainsfromformerathletes,militaryveteransorcivilianswithahistoryofrepetitivemildtraumaticbraininjurywerecompre-hensivelyevaluated.EighteenadditionalbrainsfromcognitivelyintactindividualswithouthistoryofmildtraumaticbraininjurywereobtainedfromtheBostonUniversityAlzheimer’sDiseaseCenterBrainBankthatincludedsomesubjectsfromtheFraminghamHeartStudy.Nextofkinprovidedwrittenconsentforparticipationandbraindonation.InstitutionalreviewboardapprovalforbraindonationwasobtainedthroughtheBostonUniversityAlzheimer’sDiseaseCenter,CSTEandtheBedfordVAHospital.Institutionalreviewboardapprovalforpost-mortemclinicalrecordreview,interviewswithfamilymembersandneuropathologicalevaluationwasobtainedthroughBostonUniversitySchoolofMedicine.ClinicalassessmentConcussionandmildtraumaticbraininjuryhistory,historyofcognitiveandbehaviouralchangesandclinicalstatusleadinguptodeathweredeterminedthroughpost-morteminterviewswithnextofkinper-formedbyaneuropsychologist(R.A.S.)whowasblindtotheresultsoftheneuropathologicalexaminationatthetimeofinterview.Informantswereinterviewedbeforereceivingtheresultsoftheneuro-pathologicalexamination.Theinterviewwassemi-structuredandcon-ductedbytelephone.Areasqueriedincludeddemographics,athletichistory,militaryservice,concussionandbraintraumahistory,medicalhistory(includingneurological,psychiatricandsubstanceuse),familyhistory,social/occupationalhistory,andreported/observedchangesinmood,behaviour,motorfunctions,cognitionandactivitiesofdailyliving.Tosemi-quantifycognitive,moodandfunctionalchanges,modicationsofstandardmeasures/interviewswereadmin-isteredtotheinformanttoassesstheirperceptionofthesubjectinthemonthsoryearsbeforedeath(etal.,1982etalBrownandSchinka,2005etal.,2005).Medicalrecordreviewwasalsoperformed(R.A.S.andA.C.M.).InanalysisoftheclinicalsymptomsassociatedwithCTE,caseselec-tionwasrestrictedtothosecaseswithpost-mortemsemi-structuredfamilyinterviewsandpathologicaldiagnosisofCTEorCTEplusMND(CTE-MND),withoutotherco-morbidities.DurationofexposuretoAmericanfootballandpositionplayedToexaminetherelationshipbetweenexposureandstageofCTE,analyseswereperformedonthesubsetofathleteswhoplayedAmericanfootball.Onlyfootballplayedatthehighschoollevelorhigherwasconsideredfortheseanalyses.Ofthe85braindonors,58playedAmericanfootballastheirprimarysport.Ofthose,16sub-jectswereexcludedowingtocomorbiddisease(Alzheimer’sdisease,Parkinson’sdisease,Lewybodydisease,FTLDandmultiplesystematrophy),andsevenwereexcludedowingtoincompleteathleticinformation.Footballplayerswerealsogroupedbyprimarypositionplayed:offensiveanddefensivelinemen,quarterbacks,widere-ceivers,allotheroffensivebacks,defensivelinebackersanddefensiveNeuropathologicalexaminationTheneuropathologicalprocessingfollowedtheprocedurespreviouslyestablishedfortheBostonUniversityAlzheimer’sDiseaseCenterBrainBank(etal.,1995).Parafn-embeddedsectionswerestainedwithLuxolfastblue,haematoxylinandeosin,Bielschowsky’ssilver,AT8,alpha-synuclein,amyloid-ß,TDP-43,phosphorylatedTDP-43(pTDP-43),SMI-31andSMI-34usingmethodsdescribedpre-viously(etal.,2009).Inaddition,multiplelargecoronalslabsofthecerebralhemisphereswerecutat50monasledgemicrotomeandstainedasfree-oatingsectionsusingAT8,amyloid-ß,TDP-43,pTDP-43,CP13andPHF-1(etal.,2009SupplementaryTable1).Neuropathologicaldiagnosesweremadewithoutanyknowledgeofthesubjects’clinicalhistories(A.C.M.)andconrmedbytwootherneuropathologists(T.D.S.andV.E.A.).NeuropathologicaldiagnosesDeÞnitionofchronictraumaticencephalopathyBasedonourpreviousstudiesandreviewoftheliteratureonCTEetal.,1973etal.,1991etal.,1999etal.,2005etal.,2009etaletal.,2012),thediagnosisofCTEwasdenedbythepresenceofthefollowingcriteria(Table1Figs.1):(i)perivascularfociofp-tauimmunoreactiveastrocytictanglesandneurobrillarytangles;(ii)irregularcorticaldistributionofp-tauimmu-noreactiveneurobrillarytanglesandastrocytictangleswithapredi-lectionforthedepthofcerebralsulci;(iii)clustersofsubpialandperiventricularastrocytictanglesinthecerebralcortex,diencephalon,basalgangliaandbrainstem;and(iv)neurobrillarytanglesinthecerebralcortexlocatedpreferentiallyinthesuperciallayers.DeÞnitionofchronictraumaticencephalopathyÐmotorneurondiseaseThediagnosisofCTE-MNDrequiredaclinicaldiagnosisofdeniteamyotrophiclateralsclerosisusingtherevisedElEscorialcriteriaforthediagnosisofamyotrophiclateralsclerosis(etal.,1994),andthepathologicaldiagnosisofCTE,asdenedabove,inadditiontothefollowingcriteria(etal.,2010):(i)degenerationoflateralandventralcorticospinaltractsofthespinalcord;(ii)markedlossofanteriorhorncellsfromcervical,thoracicandlumbarspinalcordwithgliosis;and(iii)TDP-43orpTDP-43positiveneuronal,glial,neur-iticorintranuclearinclusionsinanteriorhorncellsandwhitemattertractsofthespinalcord.CriteriaforAlzheimerÕsdiseaseThecriteriaforAlzheimer’sdiseasewerebasedonthepresenceofamyloid-ßneuriticplaquesandp-tauneurobrillarytanglesaccordingtotheNIA–ReagancriteriaforintermediateandhighlikelihoodAlzheimer’sdiseaseandtherecentNIAAlzheimerAssociation’sguide-lines(etal.,1999etal.,2012).TheNIA–ReagancriteriatakeintoaccountboththeBraakandBraakstagingofneuro-brillarytangles(BraakandBraak,1991)andtheoveralldensityofneuriticplaquesbasedonCERADcriteria(etal).Thenature,patternanddistributionofp-tauneurobrillarydegenerationinCTEaredistinctivefromAlzheimer’sdisease(Table1Fig.1etal.,2011CriteriaforParkinsonÕsdiseaseandLewybodydiseaseThediagnosisofParkinson’sdiseaseorLewybodydiseasewasbasedonthepresenceanddistributionofalpha-synuclein-positiveLewy ThespectrumofdiseaseinCTEBrain2012:Page3of22 bodiesandwasconsideredbrainstem-predominant(Parkinson’sdis-ease),limbicortransitionalLewybodydisease,andneocorticalordiffuseLewybodydiseaseasdenedbyMcKeithcriteria(etal.,1996)andBraakstaging(DelTredicietal.,2002BraakandDelTredici,2008CriteriaforfrontotemporallobardegenerationNeuropathologicaldiagnosisofFTLDwasbasedonpredominantin-volvementofthefrontalandtemporallobesandcharacteristicimmu-nohistochemistryforp-tau,TDP-43andp-TDP-43usingestablishedcriteriaforFTLD(etal.,2007Bigio,2008etal).ThemostcommonFTLD,FTLDwithTDP-43-positiveinclu-sions,FTLD-TDP,wasdenedbyTDP-43-positiveneuronalcytoplas-micandintranuclearinclusions,dystrophicneuritesandglialcytoplasmicinclusionsinthesuperciallayersofcerebralcortexanddentategyrus.ThediagnosisofFTLD-tau,whichincludesprogressivesupranuclearpalsy,corticobasaldegenerationandPick’sdisease,wasdenedbythespecicpatternsofp-tauglialandneuronalpathologyandneuroanatomicalareasofinvolvementaccordingtoconsensuscriteria(etal.,1996etal.,2007Dickson,2009Ifcriteriaformorethanoneneurodegenerativediseasewerepre-sent,thecasewasconsideredtobemixeddisease.Diagnosisofmultiplesystematrophywasbasedonpublishedcriteria(etal.,2009Semi-quantitativeassessmentofneuropathologicalThedensityofneurobrillarytangles,astrocytictangles,diffuseandneuriticamyloid–plaquesandvascularamyloidwasratedsemi-quantitativelyusingAT8oramyloid-ßimmunostainedparafn-embedded10msectionsaccordingtomethodspreviouslyreportedetal.,2006ApolipoproteinEgenotypingApolipoproteinE(ApoE)genotypingwasconductedusingrestrictionisotypingfordeterminingApoEisoformsbasedonbraintissuesamples.StatisticalanalysisStageofCTEwastreatedasaninexactordinalvariable;Spearman’srankordercorrelationwasusedtodeterminethestatisticaldepend-encebetweenCTEstageandalllinearvariablesofinterest(e.g.age,yearsofeducation,totalnumberofreportedconcussions,totalnumberofyearsofAmericanfootballplayedandnumberofyearsbetweenretirementanddeath).Fornon-linearindependentvariables,theWilcoxon–Mann–Whitneytwo-samplerank-sumtestwasusedfor Table1DistinctionsinhyperphosphorylatedtaupathologybetweenAlzheimerÕsdiseaseandCTEPathologicalfeaturesAlzheimerÕsdiseaseCTETauproteinSixisoformsAllsixisoformspresentAllsixisoformspresent3or4repeattau3repeatand4repeattaupresent3repeatand4repeattaupresentCelloriginNeuronalNFTsandpre-tanglesNFTsandpre-tanglesAstrocyticNotpresentProminentastrocytictanglesNeuronaldomainCellbodyProminentProminentDendriteProminentProminentAxonSparseProminentCellPatternPerivascularNotpresentProminentNFTsandastrocytictanglesFociatdepthsofcerebralsulciNotpresentProminentNFTsandastrocytictanglesIrregular,patchycorticaldistributionNotpresentProminentCorticallaminaeNFTspredominantlyinlaminaeIIIandVNFTspredominantlyinlaminaeII–IIISubpialastrocytictanglesNotpresentProminentPeriventricularastrocytictanglesNotpresentPresentMildpathologyBraakstagesI–III:CTEstagesI–II:NFTsinentorhinalcortex,amygdalaandNFTsinfocalepicentresincerebralcortex,usuallyfrontallobeAdvancedpathologyBraakstagesIV–VI:CTEstagesIII–IV:HighdensityofNFTsinwidespreadcorticalareasandmedialtemporallobe,uniformHighdensityofNFTsinwidespreadcorticalareasandmedialtemporallobe,patchyirregularLowdensitiesofNFTsinbasalgangliaandbrainstem;noneinmammillarybodies.Whitemattertractsrelativelyuninvolved.HighdensitiesofNFTsinthalamus,hypothalamus,mammillarybodies,brainstem.ModeratedensitiesofNFTsinbasalganglia,especiallynucleusaccumbens.Prominentp-taupathologyinwhitemattertracts.etal.,2001bLowdensitiesof4Rimmunoreactive‘thorn-shapedastrocytes’arefoundinthetemporallobeofsomeoldersubjectsandoldersubjectswithAlzheimer’sdisease(etal.,2012etal.,2012NFT=neurobrillarytangles. Brain2012:Page4of22A.C.McKeeetal Figure1Distinctivep-taupathologyofCTEcomparedwithAlzheimer’sdisease.()Alzheimer’sdisease.()Doubleimmunos-tainedsectionsforamyloid-ß(red)andPHF-1(brown)showdiffusecorticaldistributionofneurobrillarytanglespreferentiallyinvolvinglaminaeIIIandVandwithoutaccentuationatdepthsofsulci.()Smallbloodvesselsatsulcaldepthsshownoclusteringofneurobrillarypathologyperivascularly.()SectionsimmunostainedforAT8demonstratediffusecorticaldistributionofp-taupathologywithoutaccumulationsatsulcaldepths.()NeurobrillarytanglesarepreferentiallydistributedinlaminaeIIIandV.(Smallbloodvesselsatbottomofcorticalsulcusshownoclusteringofneurobrillarypathologyaroundvasculature(AT8immunostain).(Subpialregionatdepthofsulcusshowsnop-taupositiveastrocytictangles(AT8immunostain).()Periventricularregionofthirdventricleshowsnoependymalimmunostainingforp-tauandlowdensitiesofp-tauneurites(AT8immunostain).()Doubleimmunostainedsectionshowingabundantamyloid-ßplaques(red)andinterspersedPHF-1neurobrillarytangles(brown).()ModerateneurobrillarychangeinsubstantianigraparscompactatypicalofsevereAlzheimer’sdisease(AT8immunostain).()AbsenceofastrocytictanglesorneurobrillarytanglesinmammillarybodyinAlzheimer’sdisease(AT8immunostain).()CTE.()Sectionsimmunos-tainedforAT8showingirregularcorticaldistributionofp-taupathologywithprominentsubpialclustersofp-tauastrocytictangles,focalaccentuationatdepthsofsulcianddistributionofneurobrillarytanglesinsupercialcorticallaminaeII–III.()Smallbloodvesselsatbottomofcorticalsulcusprominentperivasculardistributionofastrocytictanglesandneurobrillarytangles(AT8).()SubpialregionatdepthofsulcusshowsprominentclusterofAT8positiveastrocytictangles.()Periventricularregionofthirdventricleshows ThespectrumofdiseaseinCTEBrain2012:Page5of22 independentvariableswithonlytwogroups(e.g.lifetimehistoryofsteroiduse,presenceofatleastoneApoEe4allele),whereastheKruskall–Wallistestwasusedforvariableswithmorethantwogroup-ings(e.g.positionplayed).Additionally,todeterminewhethertheproportionofindividualswithatleastoneApoEe4allelewashigherinindividualsdiagnosedwithCTE,aChi-squaregoodnessofttestwasperformedcomparingallCTEcases(=65)withtheexpectedproportionintheUSpopu-lation(etal.,1993The85braindonorswithahistoryofmildtraumaticbraininjuryincluded80athletes(22ofwhomwerealsomilitaryveterans),threemilitaryveteranswithnohistoryofcontactsports,oneci-vilianwhohadexperiencedmultiplefallsandoneindividualwhoengagedinself-injuriousrepetitivehead-bangingbehaviour(84males,onefemale,agerange14–98years,mean54.1years)(Table2).Wealsoanalysedthebrainsof18cognitivelyintactsubjectswithoutknownhistoryofrepetitivemildtraumaticbraininjury(17males:onefemale,agerange18–88years,mean17.4years),sevenofwhomweremilitaryveteransandthreeofwhomwereathletes(skiing,sailing,golfandtrapshoot-ing)withnoknownhistoryofmildtraumaticbraininjury.PathologicalÞndingsSevenofthe18controlbrainswerecompletelynegativeforp-tauneurobrillarytangles(meanage48.119.8years),11controlbrainsshowedAlzheimer’s-typeneurobrillarypathologylimitedtothehippocampusandentorhinalcortexconsistentwithBraakneurobrillarystagesIandII(meanage70.87.8years).Threecontrolsubjectsshowedsmallamountsofamyloid-ßdepositionasdiffuse,neuriticplaquesorvascularamyloid(mean69.7years).Nocontrolcaseshowedevidenceofperivascularclustersofneurobrillarytanglesorastrocytictangles,neurobrillarytangleslocalizedtothedepthsofthecerebralsulciorneurobril-larytanglesprimarilylocalizedtothesupercialcorticallaminaeTable2,Cases1–18).Brainsfrom17ofthe85individualswithahistoryofrepetitivemildtraumaticbraininjury(16males:onefemale;meanage22.4years,20%ofthemildtraumaticbraininjurysample)didnotshowanychangesofCTE(Table2,Cases19–35).Oneindividualwhoplayedhighschoolfootball(Case32)wasdiagnosedwithmultiplesystematrophy.Thebrainsof68ofthe85subjectsshowedp-tauimmunoreactiveneurobrillarytanglesandastrocytictanglesinapatternandneuroanatomicaldistribu-tiondiagnosticofCTE(68males,0females;meanage20.4years,80%ofthemildtraumaticbraininjurysample).The68included50footballplayers[34ofwhomplayedprofessionallyincluding33NationalFootballLeagueplayers(twoathletesalsoplayedintheCanadianFootballLeagueandonealsoplayedintheUnitedFootballLeague)andoneCanadianFootballLeagueplayer],onesemi-professionalfoot-ballplayer,ninecollegefootballplayers,sixhighschoolfootballplayers,vehockeyplayers(fourNationalHockeyLeagueplayersandoneamateurhockeyplayer),sevenprofessionalboxers,oneamateurboxerandoneprofessionalwrestler.FourindividualswithoutahistoryofcontactsportsalsodevelopedCTEincludingthreeveteransandoneindividualwhodisplayedself-injuriousheadbangingbehaviour.CTEorCTE-MNDwasdiagnosedin51cases(51males,0females,meanage55.321.8years;60%ofthemildtraumaticbraininjurysample,75%ofallCTEcases).CTE-MNDwasdiagnosedineightcases(includingthreecasespreviouslyreported,etal.,2010;9.4%ofmildtraumatic Figure1intenseependymalimmunostainingforAT8andabundantpericapillaryneurites.()Doubleimmunostainedsectionforamyloid-ß(red)andPHF-1(brown)showsdenseneurobrillarytangleswithoutamyloid-ßdeposition.()DenseAT8immunostainedastrocytictanglesandneurobrillarytanglesinsubstantianigraparscompactaofsevereCTE(AT8).()DenseAT8immunostainedastrocytictanglesandneurobrillarytanglesinmammillarybodytypicalofCTE.()DenseCP-13immunostainedaxonalvaricositiesandneuropilthreadsintheanteriorcommissureinCTE.()AT8immunostainedaxonalvaricositiesandneuropilthreadsintheexternalcapsuleinCTE.(Alzheimer’sdisease:lowdensitiesofAT8immunostainedneuropilthreadsinsubcorticalwhitematter.()CTE:AT8immunos-tainedastrocytictangles(openarrowheads),neurobrillarytangles(arrowheads)andpre-tangles(asterisk)characteristicofCTE.Somesectionscounter-stainedwithcresylviolet;allscalebars=100 Figure2Patternsof3Rand4RTauinCTE.()3RimmunostainingshowsscatteredRD3immunoreactiveneuronsinmiddlefrontalcortexandCA1hippocampus.()4RimmunostainingshowsmanyET3immunoreactiveneuronsandastrocytictanglesinthesubpialregionofthemiddlefrontalcortexandatthedepthofthesulcus.()4RimmunostainingshowsmanyET3immunoreactiveneuronsinCA1hippocampus.)AT8immunostainingshows3Rand4Rimmuno-positiveneuronsandastrocytictanglesinmiddlefrontalcortexandCA1hippocampus.Allare10-mparafn-embeddedsec-tions,scalebars=50 Brain2012:Page6of22A.C.McKeeetal Table2Demographics,pathologicaldiagnosesandimmunoreactivityofthecontrolsandmildtraumaticbraininjurycohortCaseMTBIexposure(sport/military)RaceSexApoECauseofdeathCTEAmyloid-§SYNTDP-43OtherdiagnosesDPNPCAA1Noathletics10–19HMn/aCerebralaneurysm02Noathletics20–29CM34Suicide03Noathletics,Vet50–59CMn/aKidneyfailure04Noathletics,Vet60–69CM33Malignancy05Noathletics50–59CM23Malignancy06Noathletics60–69CFn/aMalignancy07Noathletics60–69CM33Malignancy08Sailing,skiing60–69CM23Malignancy09Trapshooting,Vet60–69CM33MVA010Skiing,hiking,golng,Vet60–69CM33Malignancy011Noathletics60–69CM24ICH0+++++12Noathletics,Vet60–69CM34Cardiac0+++13Noathletics,Vet70–79CM23Malignancy014Noathletics70–79CM23Malignancy015Noathletics,Vet70–79CM33ICH0+++++16Noathletics,Vet70–79CM33Cardiac017Noathletics70–79CM33Respiratoryfailure0+18Noathletics80–89CM23Cardiac019MSsoccer10–19CM33Cerebraloedema020HSAFB10–19CM33Overdose021HSAFB10–19CM33Overdose022HSAFB10–19CM34Suicide023Collegehockey10–19CM33Overdose024HSAFB10–19CM33Cardiac025Proicehockey20–29CMn/aMetabolicencephalopathy026HSAFB20–29CMn/aGSW027ProAFB20–29CM33GSW028HSAFB20–29CM33Suicide029MMA20–29CM33Suicide030Prowrestling30–39CM33Suicide031Compskiing30–39CF34Suicide032HSAFB40–49CMn/aSuicide033HSbaseball,hockey,Vet60–69CMn/aMalignancy034Youthbox70–79CM23Cardiac035Fireghter80–89CM34Respiratoryfailure036HSAFB,HSbasketball10–19CMSISI+37HSAFB,rugby10–19CM33CerebraloedemaI+38IED/explosives,HSAFB,Vet20–29HM33ICHI39ProAFB20–29AAM33SuicideI+40HSAFB,Vet20–29CM34SuicideI41ProAFB30–39CM33CardiacI+42ProAFB50–59CM34MalignancyI43CollegeAFB20–29CM34SuicideII+44Prowrestling20–29CM33OverdoseII45Proicehockey20–29CM33OverdoseII+46CollegeAFB,HSwrestling30–39CM33RespiratoryfailureII++++CTE-MND ThespectrumofdiseaseinCTEBrain2012:Page7of22 Table2CaseMTBIexposure(sport/military)RaceSexApoECauseofdeathCTEAmyloid-§SYNTDP-43OtherdiagnosesDPNPCAA47IED,HSAFB,Prisonguard,Vet30–39CM33OverdoseII+48CollegeAFB40–49AAM33RespiratoryfailureII++++CTE-MND49IED,MVA,Vet40–49CM33CerebralaneurysmII050Proicehockey40–49CM33CardiacII+51ProAFB40–49CM33CardiacII052HSAFB40–49CM33SuicideII+53ProAFB40–49AAM34RespiratoryfailureII++++CTE-MND54CollegeAFB50–59CM33MalignancyII+++55Proicehockey50–59CM34CardiacII+56ProAFB,Vet80–89CM33CardiacII++++++57ProAFB30–39CM33SuicideIII058Probox40–49CM33SuicideIII+59HSbasketball,collegeAFB,amateurbox,Vet40–49CM33RespiratoryfailureIII+++CTE-MND60CollegeAFB40–49CM33OverdoseIII+61ProAFB40–49CM44GSWIII062ProAFB40–49CM44OverdoseIII+063ProAFB50–59AAM34SuicideIII+64ProAFB50–59CM34CardiacIII+65Self-injury50–59CMn/aRespiratoryfailureIII066ProAFB60–69CM23RespiratoryfailureIII++++CTE-MND67ProAFB60–69AAM33OverdoseIII+68ProAFB60–69CM33CardiacIII+69ProAFB60–69CM33RespiratoryfailureIII+++CTE-MND70TBI,PTepilepsy,Vet70–79CM33PneumoniaIII++++++++71MVA,altercation,Vet80–89CM33PneumoniaIII++72Probox50–59AAM33RespiratoryfailureIV+73Probox60–69CM34RespiratoryfailureIV+++++CTE-MND74Probox60–69CM33CardiacIV++++++CTE-MND75Probox,Vet70–79CM33FTTIV+++76ProAFB70–79AAM34MalignancyIV+++77ProAFB70–79CM23CardiacIV++78ProAFB,Vet80–89AAM44RespiratoryfailureIV++++++++79Probox,Vet70–79AAM33FTTIV++++++80ProAFB,Vet70–79CM33RespiratoryfailureIV+++++++81Probox80–89AAM34SepsisIV+++++++82ProAFB80–89CM33FTTIV+83ProAFB,Vet80–89AAM33FTTIV++++++84SemiProAFB,Vet80–89CM33FTTIV+++++++++85Amateurbox,Vet90–99CMn/aFTTIV++++++++++86ProAFB,Vet90–99CM33FTTIV+++++87CollegeAFB60–69CM44FTTIV++++++++++++Alzheimer’sdisease88ProAFB,Vet60–69CM23FTTIV++++++++++Alzheimer’sdisease89CollegeAFB60–69CM33FTTIV+++++++++++++Alzheimer’sdisease90ProAFB,Vet70–79CM34FTTIV++++++++++Alzheimer’sdisease91ProAFB60–69CM33FTTIV+++++++++++Alzheimer’sdisease,Parkinson’sdisease Brain2012:Page8of22A.C.McKeeetal braininjurysample,11.8%ofCTEcases)(Table2).ThebrainsofsevensubjectsfullledcriteriaforCTEplusAlzheimer’sdisease(meanage69.96.5years,8.2%ofmildtraumaticbraininjurysample,10.3%CTEcases);11werediagnosedwithCTEplusLewybodydisease(meanage73.46.2years;12.9%ofthemildtraumaticbraininjurysample,16.2%ofCTEcases),eitherasParkinson’sdisease,transitionalordiffuseLewybodydisease;andfour(meanage75.55.0years;4.7%ofthemildtraumaticbraininjurysample,5.9%ofCTEcases)werediagnosedwithCTEplusFTLD[FTLD-TDPintwo,FTLD-tauintwo(progressivesupra-nuclearpalsyandPick’sdiseaseinoneeach)](Table2andLewybodiesAmyloid-ßdeposition,eitherasdiffuseplaques,neuriticplaquesorvascularamyloid,wasfoundin30brains(35.3%ofthemildtrau-maticbraininjurysample,44.1%ofCTEcases)and14(27.4%)pureCTEcases.SubjectswithCTEandpureCTEwhosebrainsshowedamyloid-ßdepositsweresignicantlyolderthanthosewithoutamyloid-ß(0.0001).Alpha-synuclein-positiveLewybodieswerefoundin15oftheCTEcases(22.0%).IntwocaseswithCTE,Lewybodieswererestrictedtotheolfactorybulbandmedulla,andintwocaseswithCTEplusAlzheimer’sdisease,Lewybodieswererestrictedtotheamygdala.SubjectswithLewybodiesweresignicantlyolderthanthosewithout(NeuropathologyofchronictraumaticInindividualswithCTEorCTE-MND,13haddiffuseplaques(25.5%),10hadmodestnumbersofneuriticplaques(19.6%)andsevenhadsmallamountsofvascularamyloid(13.7%).These51brainsshowedapredictablerangeofuniquep-taupathologythatcouldbedividedintofourdistinctstagesofdisease(Figs1–3CTEdiseaseseverityrangedfromverymild(stageI/IV,7,agerange17–56years,mean28.3years13.5),mild(stageII/IV,14,agerange21–87years,mean44.3years16.7),moderate(stageIII/IV,=15,agerange38–82years,mean56.014.2)tosevere(stageIV/IV,15,agerange51–98years,mean77.4years11.7)(Table2Tables3).Thep-tauneurobrillarytanglesatallstageswereimmunoreactiveforboth3Rand4Rtau,andastrocytictan-gleswerepredominantlyimmunoreactivefor4Rtau(Fig.2StageIchronictraumaticSevenbrainsshowedstageICTE(Table2,Cases36–42,Figs.3SupplementaryTables2).Mildlateralventricularenlargementwasfoundinthreeoftheveintactbrainspecimens.Thegrossneuropathologicalfeaturesandbrainweightswereotherwiseunremarkable(meanbrainweight1463.3179.0g).Microscopically,stageIwascharacterizedbyfocalepicentresofperivascularp-tauneurobrillaryandastrocytictangles,mostprominentinthesulcaldepthsandtypicallyaffectingsuperioranddorsolateralfrontalcortices(Figs1–3).Thecortexsurrounding Table2CaseMTBIexposure(sport/military)RaceSexApoECauseofdeathCTEAmyloid-§SYNTDP-43OtherdiagnosesDPNPCAA92ProAFB70–79CM34FTTIV+++++++++++Alzheimer’sdisease,LewyBodydisease93Amateuricehockey,Vet80–89CM33FTTIV++++++++++++Alzheimer’sdisease,Parkinson’sdisease94CollegeAFB,collegerugby,Vet60–69CM33FTTIV+++++++++Parkinson’sdisease95ProAFB60–69CM24RespiratoryfailureII++++++++LewyBodydisease96ProAFB70–79CM33CardiacIII++++++++++LewyBodydisease97Proicehockey70–79CM34FTTIII+++++++++LewyBodydisease98ProAFB,Vet70–79CM44CardiacIV++++++Parkinson’sdisease99ProAFB,Vet80–89CM33MalignancyIII+++++++++LewyBodydisease100ProAFB70–79CM33CardiacIII+++++++++Parkinson’sdisease,101CanadianAFB70–79CM23RespiratoryfailureII++Parkinson’sdisease,102ProAFB60–69AAM33FTTI++Pick’s103ProAFB80–89AAM34FTTIV++++++++++FTLD-TDPAFB=Americanfootball;SYN=alpha-synuclein;AA=AfricanAmerican;Box=Boxing;C=Caucasian;CAA=cerebralamyloidangiopathy;Comp=competitive;DP=diffuseamyloidßplaques;F=female;FB=football;FTT=failuretothriveassociatedwithdementia;GSW=gunshotwound;H=Hispanic;HS=highschool;ICH=intracerebralhaemorrhage;IED=improvisedexplosivedeviceblastexposure;LBD=Lewybodydisease;M=male;MS=middleschool;MTBI=mildtraumaticbraininjury;MVA=motorvehicleaccident;MSA=multiplesystematrophy;n/a=notavailable;NP=neuriticamyloidßplaques;Pick’s=Pick’sdisease;PT=post-traumatic;PSP=progressivesupranuclearpalsy;Pro=professional;SIS=secondimpactsyndrome;TBI=traumaticbraininjury;TDP43=TARDNA-bindingprotein;Vet=militaryveteran.Scoringscale:+=mild,++=moderate,+++=severe,++++=verysevere. ThespectrumofdiseaseinCTEBrain2012:Page9of22 theepicentreswasunremarkableexceptforrareisolatedneuro-brillarytanglesinsuperciallaminae.Lowdensitiesofneuro-brillarytangleswerefoundinthelocuscoeruleusintwocases.Onecaseshowedsparseneurobrillarytanglesinthehippocam-pus,entorhinalcortexandsubstantianigra;anothercasedisplayedp-tauneurobrillarytanglesanddistortedaxonalprolesinthemedulla(Case37).Phosphorylatedneurolamentimmunohisto-chemistryshowedscattereddistortedaxonalvaricositiesinfrontalcortex,subcorticalwhitematteranddeepwhitemattertractsofthediencephalon,whichwerealsooccasionallyimmunoreactiveforp-tau(Fig.4).TDP-43immunopositiveneuriteswerefoundinfourofthesevencases(57%)inthefrontalsubcorticalwhitematterandfornix.ClinicalsymptomsFamilyinterviewandmedicalrecordreviewwereavailableinsixofthesevensubjectswithstageICTE.Onesubjectwasasymptom-atic.Fourofthesixreportedheadacheandlossofattentionandconcentration,threereportedshort-termmemorydifculties,ag-gressivetendenciesanddepressionandtworeportedexecutivedysfunctionandexplosivity.Twosubjectswerediagnosedwithpost-traumaticstressdisorder(Tables3StageIIchronictraumaticFourteenbrainsshowedstageIIpathology(Table2,Cases43–56).Grossly,therewasnoevidenceofcerebralatrophywithameanbrainweightof1463.3100.1g.Therewasmildenlargementofthefrontalhornofthelateralventriclesorthirdventriclein6ofthe11intactspecimens,andasmallcavumseptum(0.2–0.7cm)wasfoundinfour;thethirdventriclewasenlargedandsharplyconcaveinthree.Threecasesshowedpallorofthelocuscoeruleusandsubstantianigra.Therewasseveregliosisandatrophyofonemammillarybodyinonecase(Case45).P-taupathologywasfoundinmultiplediscretefociofthecortex,mostcommonlysuperior,dorsolateral,lateral,inferiorandsubcallosalfrontal,anterior,inferiorandlateraltemporal,inferiorparietal,insularandseptalcortices.Neurobrillarytangleswerealsofoundinthesuperciallayersofcortex(Figs.1and).Moderatedensitiesofneurobrillarytangleswerealsofoundinthelocuscoeruleus,nucleusbasalisofMeynertandamygdalaevenintheyoungerindividuals(Fig.4andSupple-mentaryTable3).Lowdensitiesofp-tauneurobrillarytanglesand Figure3ThefourstagesofCTE.InstageICTE,p-taupath-ologyisrestrictedtodiscretefociinthecerebralcortex,mostcommonlyinthesuperior,dorsolateralorlateralfrontalcor-tices,andtypicallyaroundsmallvesselsatthedepthsofsulci(blackcircles).InstageIICTE,therearemultipleepicentresatthedepthsofthecerebralsulciandlocalizedspreadofneurobrillarypathologyfromtheseepicentrestothesuper-ciallayersofadjacentcortex.Themedialtemporallobeis Figure3sparedneurobrillaryp-taupathologyinstageIICTE.InstageIII,p-taupathologyiswidespread;thefrontal,insular,temporalandparietalcorticesshowneurobrillarydegenerationwithgreatestseverityinthefrontalandtemporallobe,concentratedatthedepthsofthesulci.AlsoinstageIIICTE,theamygdala,hippocampusandentorhinalcortexshowneurobrillarypath-ology.InstageIVCTE,thereisseverep-taupathologyaf-fectingmostregionsofthecerebralcortexandthemedialtemporallobe,sparingcalcarinecortexinallbutthemostseverecases.Allimages,CP-13immunostained50-mtissue Brain2012:Page10of22A.C.McKeeetal Figure4HyperphosphorylatedtaupathologyinthefourstagesofCTE.InstageICTE(rstcolumn),p-taupathologyisfoundinlimiteddiscreteperivascularfoci(),typicallyatthedepthsofsulcioraroundsmallvessels.Thereismildp-taupathologyincerebralcorticesneighbouringtheepicentres().Thereisnoorminimalp-taupathologyintheamygdala()orCA1ofhippocampus().Occasionalp-tauneuritesarefoundinthenucleusbasalisofMeynert()andsubstantianigra();isolatedneurobrillarytanglesarepresentinthelocuscoeruleus()instageI.InstageIICTE(secondcolumn),thereisspreadofpathologyfromfocalepicentres()tothesuperciallayersofadjacentcortex().Themedialtemporallobeshowsonlymildneurobrillarypathology,includingamygdala()andCA1hippocampus).NucleusbasalisofMeynert()andlocuscoeruleus()demonstratemoderatep-taupathologyasneurobrillarytanglesandneurites;thesubstantianigra()showsonlymodestpathology.InstageIII,p-taupathologyissevereandwidespreadthroughoutthefrontal,insular,temporalandparietalcortices.Thecorticalepicentresanddepthsofthesulcioftenconsistofconuentmassesofneurobrillarytanglesandastrocytictangles().Theinterveningcorticesshowadvancedneurobrillarydegeneration().Theamygdala(),hippo-campus()andentorhinalcortexdemonstratemarkedneurobrillarypathology.ThenucleusbasalisofMeynertshowsdenseneuro-brillarytangles();thelocuscoeruleus()showsadvancedneurobrillarypathology,andthesubstantianigraismoderatelyaffected)instageIIICTE.InstageIVCTE,thereiswidespreadp-taupathologyaffectingmostregionsofthecerebralcortexandmedialtemporallobewithrelativesparingofthecalcarinecortex.Astrocytictanglesareprominent,andthereismarkedneuronallossinthecortex,amygdalaandhippocampus.Phosphorylated-tauneurobrillarytanglesarereducedinsizeanddensity.Thecorticalepicentresshowsevereneuronallossandprominentastrocytictangles();similarchangesarefoundthroughoutthefrontal,temporalandparietalcortices().Theamygdalademonstratesintensegliosisandp-tauneuronalandglialdegeneration().Thehippocampusisscleroticwithmarkedneuronalloss,gliosis,ghostneurobrillarytanglesandastrocytictangles().ThenucleusbasalisofMeynertshowsmarkedneurobrillarypathologyandgliosis();thesubstantianigra()andlocuscoeruleus()showadvancedneurobrillarypathology.Allimages:CP-13immunostained50-mtissuesections,somecounterstainedwithcresylviolet,allscalebars=100 ThespectrumofdiseaseinCTEBrain2012:Page11of22 Table3ClinicalsymptomsassociatedwithstagesofCTECaseYearsofFamilyhistoryofneurologicaldiseaseAgeofHeadacheDepressionImpulsivityExplosivityAggressionStageICTE3611None17HA++3712None18HA++3812None20HA++++++++3914None26ATT,STM,LANG+++4116None30HA,STM+++++++4216Mother:Alzheimer’sdiseasen/aNoneStageIICTE4315Nonen/aNone+4411None26HA,STM++++++++4511None26HA,STM,MS++++++++++4616None30MND+++++++4713None31STM,DEP,PTSD++++4817None40MND++++++4916None42HA,DEP,ATT++++5011None41STM,ATT,EXP,EXEC++++++5120None46HA+++5216Father:possibleAlzheimer’sdisease,bipolardisease47STM,ATT,EXEC,DEP++++5312Father:possibleundiagnosed48MND++++5414None52HA,STM++++++++++5513Nonen/aNone5618Nonen/aNoneStageIIICTE5714.5None34HA,MS,PAR++++++++5815None37HA,psychosis,STM++++++++++5916None27MND+6016None38STM,DEP,EXP++++++++6114None40STM,ATT,EXEC,EXP++6216Father:bipolardisease42ATT,EXEC+6318Father:Alzheimer’sdisease45HA,EXP+++++++++6416None53STM,ATT,EXEC++++6616None56STM,apathy++++6716Brother:mentalillness63STM,EXEC,ATT+6815Nonen/aNone+++6918Father:depression52HA,STM,DEP,IMP++++++StageIVCTE7212None42AGG,DEP,PAR+++++7315None46EXEC,IMP,PAR,AGG++++++++7412Sibling:ALS64STM,EXEC,PAR++++++ Brain2012:Page12of22A.C.McKeeetal pretangleswerepresentinthehypothalamus,CA1ofhippocampus,entorhinalcortex,thalamus,substantianigraanddorsalandmedianraphenucleiofthemidbrain.Distortedaxonalvaricosities,somep-tauimmunoreactive,werefoundinfrontalandtemporalcorticesaswellaswhitemattertracts(Figs.1and).Elevenofthe14subjectswithstageIICTEalsoshowedTDP-43immunopositivity(79%).TDP-43immunopositivityconsistedofrareneuritesorinclu-sionsinthecerebralsubcorticalwhitematter,brainstemormedialtemporallobeineightcases,ofteninasubpial,periventricularorperivasculardistribution(Fig.6).ThreesubjectsshowedsevereTDP-43abnormalitiesasneuronalandglialinclusionsandneuritesinwidespreadregionsoftheCNS,includingthecerebralhemi-spheres,basalganglia,diencephalon,brainstem,anteriorhorncellsandwhitemattertractsofthespinalcord(Fig.6).Thesecasesalsodemonstrateddegenerationoflateralandventralcorticospinaltractsofthespinalcordandmarkedlossofanteriorhorncellsfromthespinalcord;featuresthatsupportthediagnosisofCTE-MND.ClinicalsymptomsElevenofthe14individualswithstageIICTEweresymptomatic;commonpresentingsymptomsweredepressionormoodswings,headachesandshort-termmemoryloss.ThreesubjectspresentedwithsymptomsofMND.SymptomsinstageIIsubjectsincludeddepressionormoodlability,explosivity,lossofattentionandcon-centration,short-termmemorylossandheadache.Lesscommonsymptomsincludedexecutivedysfunction,impulsivity,suicidalityandlanguagedifculties(Tables3StageIIIchronictraumaticFifteenbrainsshowedstageIIIpathology(Table2,Cases57–71).Grossly,mostbrainsshowedmildcerebralatrophywithdilationofthelateralandthirdventricles;meanbrainweightwas106.7g.Septalabnormalitieswerefoundin5ofthe12intactbrainspecimens(42%)rangingfromcavumseptum,septalperforationsorcompleteabsenceoftheseptum.Sevenbrainsshowedmoderatedepigmentationofthelocuscoeruleus(58%);sixshowedmilddepigmentationofthesubstantianigra(42%).Othercommongrosspathologicalfeatureswereatrophyofthemammillarybodiesandthalamus,sharplyconvexcontourofthemedialthalamus,thinningofthehypothalamicoorandthinningofthecorpuscallosum.Microscopically,neurobrillarytangleswerewidespreadthroughoutsuperiorfrontal,dorsolateralfrontal,inferiororbital,septal,insular,temporalpole,superiormiddleandinferiortemporalandinferiorparietalcortices.Therewerealsoextensiveneurobrillarytanglesinthehippocampus,entorhinalcortex,amygdala,nucleusbasalisofMeynertandlocuscoeruleusSupplementaryTable3).Neurobrillarytangleswerefrequentinolfactorybulbs,hypothalamus,mammillarybodies,substantianigraanddorsalandmedianraphenuclei.SparseneurobrillarytangleswerefoundinRolandic,cingulatecortices,thalamus,nu-cleusaccumbens,dorsalmotornucleusofthevagus,dentatenu-cleusofthecerebellumandspinalcord.Severeaxonallossanddistortedaxonalproleswerefoundinthesubcorticalwhitematter,particularlyaffectingthefrontalandtemporalcorticesFig.5).TDP-43immunoreactiveneuriteswereevidentinthe Table3CaseYearsofFamilyhistoryofneurologicaldiseaseAgeofHeadacheDepressionImpulsivityExplosivityAggression7512None56STM,DEP,AGG,EXP+++++++7612None35PAR,IMP,BIZ++++++++7716Mother:bipolardisease58DEP,AGG++++++++7818None60STM,EXEC,BIZ8016None76STM,EXEC,LANG++++8112Brother:Alzheimer’sdisease35STM,ATT,Falls++++++8218None49ATT,AGG,EXP++++++++8310None65AP,EXEC,EXP++++8416None74PAR++++8616None83STM,EXECAGG=aggression;ALS=amyotrophiclateralsclerosis;ATT=attentionloss;BIZ=bizarrebehaviours;DEP=Depression;EXEC=executivedysfunction;EXP=explosivity;HA=headaches;IMP=impulsivity;LANG=languagedisturbance;MS=moodswings;n/a=notapplicable;PAR=paranoia;PTSD=post-traumaticstressdisorder;STM=short-termmemoryloss. ThespectrumofdiseaseinCTEBrain2012:Page13of22 cerebralcortex,medialtemporallobeorbrainstemofmostcases.Widespread,moresevereTDP-43neuronalandglialinclusionsandneuriteswerefoundinthreecaseswithstageIIICTEdiagnosedwithCTE-MND.ClinicalsymptomsFamilyinterviewandmedicalrecordreviewwereavailablefor12subjectswithstageIIICTE;oneindividualwasasymptomatic(Case68).Themostcommonpresentingsymptomswerememoryloss,executivedysfunction,explosivityanddifcultywithattentionandconcentration.OthersymptomsfrequentlyfoundinstageIIIsub-jectsweredepressionormoodswings,visuospatialdifcultiesandaggression.Lesscommonsymptomsincludedimpulsivity,apathy,headachesandsuicidality.Seventy-vepercentofsubjectswereconsideredcognitivelyimpaired.Twosubjectsdevelopedsymp-tomsofMNDaftertheonsetofcognitiveorbehaviouralabnorm-alities,anotherdevelopedcognitivechangesaftertheonsetofMND(Tables3 Table4ClinicalsymptomsassociatedwithstagesofCTECaseAttentionParanoiaExecutiveSuicidalMemoryLanguageVisuospatialApathyDementiaGaitDysarthriaParkinsonianPTSDStageICTE36+38++++PTSD39++++++++41+++StageIICTE43++44+++45+++++++++++46+++++aa47+++++++++PTSD48++aa49++50++++++++++52+++++++++54+++++++StageIIICTE57++++++++++58+++++++++++++++++59++60++++61+++++++++62+++++++63++++++++++++64++++++66+++++++++aa67+++++++++69+++++++aaStageIVCTE72++++++++++++++++73++++++++++++++aa74+++++++++++++aa+75+++++++++++++++++++76+++++++++77+++++++++++++78++++++++++++++++++++80++++++++81+++++++++++++++++82+++++++++++++++83++++++++++++++++84++++++++++++++86++++++++++++aGaitandspeechdifcultiesassociatedwithMND.PTSD=post-traumaticstressdisorder. Brain2012:Page14of22A.C.McKeeetal StageIVchronictraumaticFifteenindividualswereconsideredtohavestageIVCTE(Table2Cases72–86).Macroscopicbrainchangesincludedatrophyofthecerebralcortexandwhitematterandmarkedatrophyofthemedialtemporallobe,thalamus,hypothalamusandmammillarybody.MeanbrainweightwassignicantlysmallerthanlowerstageCTE(1208168.1g;0.001).Mostbrainsshowedven-tricularenlargement,asharplyconcavecontourofthethirdven-tricle,cavumseptumpellucidumranginginsizefrom0.5to1.0cm,andseptalperforationsorseptalabsence.Pallorofthelocuscoeruleusandsubstantianigrawerefoundinallinstanceswhereitcouldbeassessed.Microscopically,therewasstrikingneuronallossinthecortex,hippocampalsclerosisaffectingCA1andsubiculumandastrocyticp-taupathology.Severep-tauabnormalitieswerefoundwidelydistributedthroughoutthecere-brum,diencephalon,basalganglia,brainstemandspinalcord().Primaryvisualcortexwasrelativelyspared.Subcorticalwhitemattertractsshowedmarkedaxonallossanddistortedaxonalproles(Fig.5).TDP-43immunoreactivitywassevereinmostcasesconsistingofdenseTDP-43positiveroundedandthreadlike Figure5TheaxonalpathologyofCTE.()PhosphorylatedneurolamentimmunostainingforSMI-34(red)incontrolsubcorticalwhitemattershowsregularalignmentandlinearmorphologyofmostaxonalproles.()AxonsincontrolcerebralcortexstainedwithBielschowsky’ssilvermethodshowanelinearpatternandregularity.()Phosphorylatedneurolamentimmunostaining(SMI-34)incontrolcerebralcortexalsoshowsregularalignmentandlinearmorphologyofaxonsevenaroundsmallvessels.()PhosphorylatedneurolamentimmunostainingincerebralcortexofstageIICTEdemonstratesalterationsinalignmentandnumerousroundedaxonalvaricositiesaroundsmallvessels(asterisks).()BielschowskysilvermethodinstageICTEshowsneurobrillarytangles(arrows)andsilverpositiveaxonalvaricosities(asterisks)aroundsmallarteriole.()SMI-34immunostainingofsamecorticalfocusasinHandIalsoshowsaxonalvaricosities(asterisks)aroundcorticalarteriole.()SMI-34immunostainingincerebralcortexofstageIIICTEshowsmarkedreductioninaxonalstainingandnumerouslarge,irregularaxonalvaricosities.Asmallarterioleshowsmarkedinltrationwithhaemosiderin-ladenmacrophages(arrow).()AxonalvaricositiesandirregularitiesarealsofoundinstageICTE.()CTEstageIIdoubleimmunostainedforphosphorylatedtau(PHF-1,brown)andphosphorylatedneurolament(SMI-34,red)showsaxonalswellingsincontinuitywithphosphorylatedtauneuriticabnormalities.()Doubleimmunouorescencestainingforphosphorylatedneurolament,SMI-34(red)andPHF-1(green)inthesubcorticalwhitematterofCTEstageIIIdemonstratescontiguousaxonalvaricosities(red)aswellasp-tau(green)(arrowheads)intheaxon.()SMI-34immunostaininginsubcorticalwhitematterofstageIVCTEshowssevereaxonallossandmultiplelarge,irregularaxonalvaricosities.()Phosphorylatedtau(AT8,brown)immunoreactiveirregularaxonalprolesfoundindeepwhitemattertractsCTEstageI.()Denseaxonalvaricosities,distortedaxonalprolesandneurobrillarytangles(arrows)characterizethecerebralcortexofCTEstageIVimmunostainedwithphosphorylatedneurolament(SMI-34).Imagesfrommtissuesections,scalebars=100m,except=10 ThespectrumofdiseaseinCTEBrain2012:Page15of22 neurites,intraglialandintraneuronalinclusionsincerebralcortex,medialtemporallobe,diencephalon,basalganglia,brainstemand,lessfrequently,spinalcord.Subpial,periventricularandperivascularTDP-43immunoreactiveneuriteswerealsopresentFig.6).Inthemostseverelyaffectedcases,thereweredensecorticalTDP-43inclusionsandneuritesinallneocorticallayers,particularlylayerII,aswellasoccasionalTDP-43-positiveinclu-sionsinthedentatefasciaofthehippocampus.ClinicalsymptomsFamilyinterviewandmedicalrecordreviewwereavailableon13subjectswithstageIVCTE;allweresymptomatic.Executive Figure6ThephosphorylatedTDP43pathologyofCTEandCTE-MND.()pTDP-43immunostainedneuritesfoundinperiventricularregionofthethirdventricleinCTEII.()CTEstageIIdemonstratingpTDP-43immunostainedneuritesinaperivasculardistribution.(pTDP-43immunoreactiveinclusioninlocuscoeruleusinCTEstageII.()ClustersofpTDP-43immunoreactiveneuritesinthesubpialregionofthebrainsteminstageIIICTE.()PerivascularpTDP-43neuritesinstageIIICTE.()SubpialpTDP-43neuritesinthecorpuscallosumofstageIVCTE.()DensepTDP-43abnormalitiesinthetemporalcortexofstageIVCTE-MND.()DensepTDP-43pathologyofCA1hippocampusinstageIVCTE.()perivascularfocusatsulcaldepthpTDP-43abnormalitiesarewidespreadthroughouttheCNSinCTEassociatedwithMND(CTE-MND)(,corpuscallosum;,cerebralpeduncle;,fornix;,subpialregionoffrontalcortex;perivascularregionfrontalcortex;,Rolandiccortex).Allimages:50-mtissuesections,allscalebars=100 Brain2012:Page16of22A.C.McKeeetal dysfunctionandmemorylosswerethemostcommonsymptomsatonset,andalldevelopedseverememorylosswithdementiaduringtheircourse.Mostsubjectsalsoshowedprofoundlossofattentionandconcentration,executivedysfunction,languagedif-culties,explosivity,aggressivetendencies,paranoia,depression,gaitandvisuospatialdifculties.Lesscommonsymptomswereimpulsivity,dysarthriaandparkinsonism;31%weresuicidalatsomepointintheircourse.Twoofthe13subjectsdevelopedsymptomsofMNDyearsafterdevelopingcognitiveandbehav-iouralabnormalities.ProfessionalAmericanfootballplayersOfthe35formerprofessionalAmericanfootballplayers(34NationalFootballLeagueandoneCanadianFootballLeague),oneshowednodisease(Case27,age26years),threehadstageI/IVdisease,threehadstageII/IV,ninehadstageIII/IVdisease,sevenhadstageIV/IVdisease,twohadCTEplusAlzheimer’sdisease,fourhadCTEplusLewybodydisease,twohadCTEplusAlzheimer’sdiseaseandLewybodydisease,fourhadCTEplusFTLDandthreehadCTE-MND.OneNationalFootballLeagueplayerhadaprimarydiagnosisofPick’sdiseasewithonlymodestevidenceofCTE(Case102),onehadaprimarydiagnosisofLewybodydiseasewithstageIICTE(Case95)andanotherhadaprimarydiagnosisofprogressivesupranuclearpalsywithstageIICTE(Case101).Thirty-oneofthe34formerprofessionalAmericanfootballplayershadstageIII–IVCTEorCTEplusco-morbiddisease(89%).SixteenformerNationalFootballLeagueplayershadpureCTEstageIII–IV(47%),94%weresymptomatic;themostcommonpresentingsymptomswereshort-termmemoryloss,executivedysfunctionandattentionandconcentrationloss.Meanageatsymptomonsetwas54.114.1years(range34–83years).PositionsplayedbyNationalFootballLeagueplayerspositiveforCTEincludedoffensivelinemen(26%),runningbacks(20%),defensivelinemen(14%),linebackers(14%),quarterbacks(6%),defensivebacks(6%),tightends(6%)andwidereceivers(6%).MeanageatdeathforformerNationalFootballLeagueplayersdiagnosedwithCTEwas67.116.6years(range38–98years).ProfessionalhockeyplayersOftheveformerprofessionalhockeyplayers,thebrainofoneyoungplayershowednosignsofCTE(age20years).ThreeofthefourformerNationalHockeyLeagueplayershadstageIICTE(75%),onehadstageIIICTE+Lewybodydisease(25%)(meanage51.3years,range28–73years);onlythreeofthefourweresymptomaticatthetimeofdeath.Exposuretofootball,steroiduse,positionplayedandApoEgenotypeOfthe103subjects,58playedfootballastheirprimarysport.Ofthose,42subjectswerediagnosedwithCTEorCTE-MND;thefamiliesof35wereavailableforstructuredinterviewregardingathleticexposure.These35braindonors(meanage50.3years,range17–98years)playedfootballforameanof6.5years(range2–24years).Thenumberofyearsplayed(Spearman’stest,=0.805,0.0001),yearssincere-tirement(Spearman’stest,=0.753,0.0001)andageatdeath(Spearman’stest,=0.806,0.0001)weresignicantlycorrelatedwithpathologicalstageofCTE.Familyreportednumberofconcussions(Spearman’stest,=0.259,0.184);yearsofeducation(Spearman’stest,=0.258,0.134),lifetimesteroiduse(Wilcoxon–Mann–Whitneytest,0.731)andpositionplayed(Kruskall–Wallistest,0.407)werenotsignicantlyrelatedtoCTEstage.Furthermore,ofthe68individualsdiagnosedwithCTE,theproportionofthesamplecarryingatleastoneApoEe4allelewasnotsignicantlydifferentthanthatobservedinthegeneralpopulation(Chi-squaregoodnessoft,MilitaryveteransSixteenofthe21militaryveteranswithCTEwerealsoathletes,includingeightNationalFootballLeagueplayers.Nineveteranssawcombat:fourintheIraqandAfghanistanconicts,oneintheGulfWar,twoinVietnamandtwoinWorldWarII.ThreeveteranswithCTEexperiencedamoderate-to-severetraumaticbraininjurywhileinservice(onecontusion,oneintraparenchymaltraumaticbraininjurywithpersistent,poorlycontrolledpost-traumaticepilepsy,onespinalcordinjury).Threewereexposedtoblastfromimprovizedexplosivedevicesandexplosivemunitions;oneathletewasalsoexposedtoexplosivemunitionsinVietnam.ThreeveteransoftheconictsinIraqandAfghanistanwerediagnosedwithpost-traumaticstressdisorder,twoofwhomwereexposedtoblastfromimprovizedexplosivedevicesandonewhoexperiencedrepetitiveconcussiveinjuriesduringcombatandincivilianlife[fourveteransoftheIraqandAfghanistanconictswerealsoreportedinGoldsteinetal.(2012)CauseofdeathandsuicideAmongthe51subjectswithCTEandCTE-MND,thereweresevendeathsfromsuicide;sixothersclearlyexpressedsuicidalideationsatsomepointduringtheirlife(26%suicidaltendenciesorcom-pletedsuicide,14%completedsuicide).Thereweresixdeathsfromdrugoralcoholoverdose(12%).Themostcommoncausesofdeathwererespiratoryfailure(60%associatedwithCTE-MND),cardiacdisease,suicide,overdose,failuretothriveasso-ciatedwithend-stagedementiaandmalignancy.CTEisaprogressivetauopathywithdistinctiveclinicalandpatho-logicalfeaturesthatoccursafterrepetitivemildtraumaticbraininjury.Althoughhistorically,CTEhasbeenprimarilyassociatedwithboxing,CTEmayalsooccurasaconsequenceofAmericanfootball,hockey,wrestling,rugbyandexposuretoblastorcon-cussiveinjuryassociatedwithmilitaryservice(CorsellisandBrierley,1959etal.,1973etal.,1991etal.,1996etal.,1999etal.,2005etal.,2009etal.,2010etal.,2011etal.,2011etal.,2011etal.,2012etal.,2012etal.,2012).We ThespectrumofdiseaseinCTEBrain2012:Page17of22 analysedthebrainsof85individualswithahistoryofrepetitivemildtraumaticbraininjuryandfoundevidenceofCTEin80%;allmales,ranginginagefrom17to98years(mean=59.5years),including64athletes,21militaryveterans(mostofwhomwerealsoathletes)andoneindividualwhoengagedinself-injurioushead-bangingbehaviour.ThedevelopmentofCTEinoneindivid-ualinthisseriesandtwoothersintheliteratureinwhomself-injuriousheadbangingwasthesoleenvironmentalexposuresuggeststhatrepetitivemildtraumaticbraininjuryaloneissuf-cienttotriggerCTEinsomepeople(etal.,1991etal.,1999).AthleteswithCTEincluded50footballplayers(33NationalFootballLeague,oneCanadianFootballLeague,onesemi-professional,ninecollege,sixhighschool),fourNationalHockeyLeagueplayers,oneamateurhockeyplayer,sevenprofes-sionalboxers,oneamateurboxerandoneprofessionalwrestler.VeteranswithCTEincludedmarines,soldiersandsailorsfromWorldWarII,Vietnam,GulfWar,IraqandAfghanistan.NeuropathologicalstagingofchronictraumaticencephalopathyTheevidencesuggeststhatCTEbeginsfocally,usuallyperivascu-larly,atthedepthsofthesulciinthecerebralcortexandspreadsslowlyoverdecadestoinvolvewidespreadregionsofneocortex,medialtemporallobe,diencephalon,basalganglia,brainstemandspinalcord.Theearly,focalchangesofCTEdemonstratedhereandbyothers(etaletal.,1999)aredistinctivefromp-taupathologyoftheAlzheimertypereportedinsomecognitivelynormalyoungadults(BraakandDelTredici,2011)andinassociationwithotherenvironmentalexposures(etal.,2010).ThetauisoformproleandphosphorylationstateinCTEissimilartoAlzheimer’sdisease(etal.,2001),andtheneuronaltaupathologyshowsimmunoreactivitytoboth3Rand4Rtau.Theastrocyticp-taupathologyinCTEispredomin-antly4Rtauimmunopositive;however,itistopographicallydis-tinctfromthe4Rtauimmunoreactivethorn-shapedastrocytesthathavebeenreportedinthemedialtemporallobeinageingandAlzheimer’sdisease(etal.2012etal.,2012Wedividedthetopographicallypredictablepatternofp-taupathologyofCTEintofourstages.StageIwascharacterizedbyperivascularp-tauneurobrillarytanglesinfocalepicentresatthedepthsofthesulciinthesuperior,superiorlateralorinferiorfron-talcortexandwasclinicallyassociatedwithheadacheandlossofattentionandconcentration.InstageIICTE,neurobrillarytangleswerefoundinsupercialcorticallayersadjacenttothefocalepi-centresandinthenucleusbasalisofMeynertandlocuscoeruleus.IndividualswithstageIICTEexperienceddepressionandmoodswings,explosivity,lossofattentionandconcentration,headacheandshort-termmemoryloss.StageIIICTEshowedmacroscopicevidenceofmildcerebralatrophy,septalabnormalities,ventriculardilation,asharplyconcavecontourofthethirdventricleandde-pigmentationofthelocuscoeruleusandsubstantianigra.Therewasdensep-taupathologyinmedialtemporallobestructures(hippocampus,entorhinalcortexandamygdala)andwidespreadregionsofthefrontal,septal,temporal,parietalandinsularcortices,diencephalon,brainstemandspinalcord.MostindividualswithstageIIICTEdemonstratedcognitiveimpairmentwithmemoryloss,executivedysfunction,lossofattentionandconcen-tration,depression,explosivityandvisuospatialabnormalities.StageIVCTEwasassociatedwithfurthercerebral,medialtem-porallobe,hypothalamic,thalamicandmammillarybodyatrophy,septalabnormalities,ventriculardilationandpallorofthesubstan-tianigraandlocuscoeruleus.Microscopically,p-taupathologyinvolvedwidespreadregionsoftheneuraxisincludingwhitematter,withprominentneuronallossandgliosisofthecerebralcortexandhippocampalsclerosis.SubjectswithstageIVCTEwereuniformlydementedwithprofoundshort-termmemoryloss,ex-ecutivedysfunction,attentionandconcentrationloss,explosivityandaggression.Mostalsoshowedparanoia,depression,impulsiv-ityandvisuospatialabnormalities.Advancingpathologicalstagewasassociatedwithasignicantdecreaseinbrainweightandincreasedseverityofcognitiveabnormalitiessupportingthevalid-ityofthepathologicalstagingscheme.Inaddition,pathologicalstagecorrelatedwithdurationofexposuretoAmericanfootball,survivalafterfootballandageatdeathinthosewhoplayedSpreadoftaupathologyUndernormalconditionsinthematurehumanCNS,tauisprimar-ilyassociatedwithmicrotubulesinaxons,whereitisneithertoxicnorassociatedwithneurobrillarypathology.Braintraumacausessometautobecomedissociatedfrommicrotubulesinaxonsviamechanismsthatmostlikelyincludeintracellularcalciuminux,glutamatereceptor-mediatedexcitotoxicityandkinaseactivationmediatinghyperphosphorylationofintracellulartau(etaletal.,2009etal.,2010etal.,2011etal.,2012).Taudissociatedfrommicrotubulesmaybecomeabnormallyphosphorylated,misfolded,aggregatedandproteolyticallycleavedbycalpainsandcaspases,allofwhichareassociatedwithneurotoxicity(etal.,2006etal.,2006etal.,2006).Directandindirectevidenceforinterneuronaltautransferinanimalmodelshasrecentlysuggestedthatinterneuronalspreadingoftaupathologymaybeduetotransferoftoxictauspeciesbetweenneurons(etaletal.,2010etal.,2012etal.,2012Thismightbemediatedbyeitheraprion-liketemplatedmisfoldingoftau(etal.,2011etal.,2012etal.,2012reviewedbyHallandPatuto,2012)orbycalciumdysregulatoryeffectsofoligomericortoxicN-terminaltauinthereceivingneuron(ParkandFerreira,2005etal.,2009).Althoughspreadingoftaupathologyisgenerallythoughttooccurinasso-ciationwithneuronalsynapses,glialtoglialspread,periventricularanddiffuseextracellulartaumigrationpatterns.CSFuidentersthebrainparenchymaalongtheVirchow–Robinspacessurround-ingpenetratingarteries,andbraininterstitialuidisclearedalongparavenousdrainagepathwayssuggestingapossiblespreadoftaupathologythroughthisroute,similartotheclearanceofamyloid-ßpeptide.Recentstudieshavedemonstratedthatamyloid-ßpeptideetal.,2012).ClearancethroughparavenousowandtheCSFmightalsoregulateextracellularlevelsofp-tauandTDP-43 Brain2012:Page18of22A.C.McKeeetal andexplainthefrequentperivascular,subpialandperiventricularlocalizationoftheseproteins.AxonalinjuryandTDP-43Inadditiontop-taupathology,axonalinjurywasapparentinallstagesofCTE,rangingfrommultifocal,oftenperivascular,axonalvaricositiesinthecortexandsubcorticalwhitematterinstagesI–IItosevere,diffuseaxonallossinthecortexandwhitematterinCTEstagesIII–IV.TDP-43abnormalitieswerealsofoundinthemajorityofCTEcases.InCTEstagesI–III,sparseTDP-43neuriteswerefoundinvariousregionsofthecortex,medialtemporallobeandbrainstem.InstageIVCTE,TDP-43immunoreactivitywassevere,withintraneuronalandintraglialinclusions,roundedandthreadlikeneuritesinthecortex,whitematter,diencephalon,basalgangliaandbrainstem.Althoughitiswell-establishedthatp-taupathologycorrelateswiththeseverityofcognitiveimpairmentinothertauopathies,suchasAlzheimer’sdisease(WilcockandEsiri,etal.,1991etal.,1992),thecontribu-tionofTDP-43proteinopathytosymptomsofCTEcannotbeoverlooked,especiallyinlatestagedisease.Aswithfrontotem-poraldementia,CTEusuallybeginswithbehaviourandpersonalitychangesatmid-life(meanageofonset44.3years,range17–12.1years).But,unlikeAlzheimer’sdiseaseorfrontotem-poraldementia,theclinicalcourseofCTEisslow,progressingatarateof11–14yearsbetweenpathologicalstages.Inaddition,itislikelythataxonaldysfunctionandlosscontributetotheproduc-tionofclinicalsymptoms,especiallyintheearlystagesofCTEwhentaupathologyisfocalandunlikelytoaccountforthehead-ache,attentionandconcentrationloss,andmemorydifcultiesexperiencedbysubjectswithstageIorIIdisease.AlthoughthedatasuggestthatCTEpathologyisprogressive,itremainstobedeterminedwhethersomeindividualsarerelativelyresilientwithstaticorevenreversiblepathology.ElevenpercentofindividualswithCTEwereasymptomatic,withameanageatdeathof59years(range26–87years)andmostwithstageIIdisease,suggest-ingthatCTEmaynotprogressormaynotprogressatthesamerateinallpatients.ChronictraumaticencephalopathypluscomorbidneurodegenerativediseaseOfthe68caseswithCTE,37%hadco-morbidneurodegenerativedisease,includingMND,Parkinson’sdiseaseorLewybodydisease,Alzheimer’sdiseaseandFTLD.Repetitivetraumaticbraininjuryandaxonalinjurymighttriggermolecularpathwaysthatresultintheoverproductionandaggregationofotherproteinspronetopathologicalaccumulationinneurodegenerativediseaseincluding-synucleinandamyloid-ß,therebyincreasingthelikeli-hoodofMND,FTLDLewybodydiseaseorAlzheimer’sdisease.Multipleepidemiologicalstudieshaveshownthattraumaisariskfactorfordementia,especiallyAlzheimer’sdisease,aswellasforamyotrophiclateralsclerosisandParkinson’sdisease(etal.,2000etal.,2006etal.,2010etal.,2012).Inaddition,CTEandtheaccumulationofmisfoldedtauaggregatesmaypromotetheaggregationofpathologicalpro-teinsthroughcross-seeding(etal.,1998etal).Cross-seedingmightexplaintheaccumulationofTDP-43inthelargemajorityofCTEcases,itspartialimmunohistochemicalco-locationwithtauandtheparticularlyseveredepositionofTDP-43foundinadvancedCTE.ChronictraumaticencephalopathywithmotorneuronMostsubjectswithCTE-MND(63%)presentedwithsymptomsofMND,developingcognitiveandbehaviouralsymptomsseveralyearsaftertheonsetofmotorweakness,atrophyandfascicula-tions.Theminoritypresentedwithapathy,depression,memoryloss,cognitivedecline,paranoia,impulsivityorexecutivedysfunc-tion1–8yearsbeforethedevelopmentofmotorneuronsymp-toms.TherewasatendencyforsubjectswithCTE-MNDtodiefromrespiratoryinsufciencyatanearlierage(53.014.3years)thanthosewithoutMND(55.823.0years),althoughthedif-ferencewasnotsignicant.IndividualswithMNDandCTE,inde-pendentofthestageofp-taupathology,demonstratedsevereTDP-43pathologyasneuronal,glialandneuriticinclusionsinvol-vingwidespreadregionsoftheCNSincludingmotorcortexandspinalcord.ClinicopathologicalcorrelationNeuroanatomicalareasthatarepreferentiallyaffectedinCTEin-cludesuperior,dorsolateralandlateralfrontalcortices.Pathologyintheseregionsmayunderlietheclinicalfeaturesofdisinhibition,lackofinsightandpoorexecutivefunctionfoundinsubjectsevenatearlystagesofCTE.Pathologicalinvolvementoftheinferiortemporallobeandamygdalamightcontributetothefrontalsymptomsandtotheirritability,impulsivity,explosivityandout-burstsofaggressionsocommonlyexperiencedasearlymanifest-ationsofCTE.PathologyofthenucleusbasalisofMeynertandseptalnucleimightcontributetothecognitivesymptoms.Moreover,pathologyinthesubcallosalandinferiororbitalfrontalcortexandbrainstem,especiallythelocuscoeruleusandmedianraphe,mightberelatedtothecommonsymptomsofdepressionandmoodlability.Mammillarybody,anteriorthalamicandhippo-campalpathologymostlikelyplayamajorroleinproducingmemoryloss,cognitiveimpairmentandeventualdementia.Eventhoughthebraindonorswerenotscreenedforcognitiveimpairments,anautopsy-basedcaseseriesislimitedbysignicantascertainmentbias,asfamiliesofindividualsshowingbehaviouralorcognitivesymptomsaremuchmorelikelytoinitiateandpar-ticipateinabraindonationprogrammethanfamiliesofnormallyfunctioningindividuals.Consequently,nogeneralizationsregard-ingtheincidenceandprevalenceofCTEinlivingathletesandveteranscanbemade.Furthermore,inseveralofthecases,theclinicalsymptomswereconfoundedbydrugandalcoholabuse;therefore,thedegreetowhichtheextensivep-tau,TDP-43andaxonalpathologyandneurodegenerationisresponsibleforthesubject’sclinicalpresentationisunclear.Inclusionofmorerigorouscontrolsubjects,suchasindividualswhoexperiencedrepetitivemildtraumaticbraininjuryanddidnotdevelopbehaviouralorcognitiveabnormalities,willbeextremelyusefulinfuturestudiesdesignedtodelineatecriticalaspectsofthetraumaticexposureandsusceptibilitytotrauma-induced ThespectrumofdiseaseinCTEBrain2012:Page19of22 Futureprospectivelongitudinalstudiesareplannedtoaddresstheselimitations.Forinstance,bystudyingalargenumberofretiredNationalFootballLeagueathletesprospectivelyandconductingneuropathologicalanalysesatdeath,acontrolgroupmatchedonage,education,athletichistory,medicalcomorbiditiesandcauseofdeathcanbeusedtoexaminedifferencesbetweenindividualswithandwithoutclinicalandneuropathologicalevi-denceofSimilarly,currentstudiesfocusedonalargecohortofIraqandAfghanistanveteranswithhistoriesofblastandconcus-sivetraumaticbraininjuriesandpost-traumaticstressdisorderwillshedlightontheoverlapbetweentraumaticbraininjury,CTEandpost-traumaticstressdisorder,aswellastheroleofcombat-associatedinjuryinproducingCTE(etal).ClinicalcriteriaforthediagnosisofCTEneedtobeestab-lishedandtested.AlthoughApoEdoesnotappeartobeariskfactorforthedevelopmentofCTEortheseverityofCTEpath-ologyinthisautopsyseries,largeprospectivepopulation-basedstudiesneedtobeimplementedtoaddressthisdenitivelyGandyandDeKosky,2012).Thecurrentresultsestablishthatadistinctivepatternofneuropathologicalchanges,previouslyre-portedprimarilyinboxers,canalsobefoundinotherathletesandmilitaryveteransandprovideaclearimpetusforfutureCTEisauniqueneurodegenerativeconditionthatisassociatedwithrepetitivemildtraumaticbraininjury.Althoughtherearemanyissuesthatrequiremorethoroughinvestigation,suchashowmuchheadtraumaiscausative,whattype,andhowfre-quent,theagewhenplayersaremostsusceptibleandwhethersomeindividualsaregeneticallymorepronethanothers,thisstudyclearlyshowsthatforsomeathletesandwarghters,theremaybesevereanddevastatinglong-termconsequencesofrepetitivebraintraumathathastraditionallybeenconsideredonlymild.Theauthorsgratefullyacknowledgetheuseofresourcesandfacil-itiesattheEdithNourseRogersMemorialVeteransHospital(Bedford,MA),LisaMcHaleandDr.DavidHemmyfortheirexpertlogisticalassistance,Dr.PeterDavies(AlbertEinsteinCollegeofMedicine)andDr.RohandeSilva(QueensSquare,London)forantibodies.Theyalsogratefullyacknowledgethein-dividualsandfamilieswhoseparticipationandcontributionsmadethisworkpossible.DepartmentofVeteransAffairs;VeteransAffairsBiorepositoryCSP501);TranslationalResearchCenterforTraumaticBrainInjuryandStressDisorders(TRACTS)VeteransAffairsRehabilitationResearchandDevelopmentTraumaticBrainInjuryCenterofExcellencetoA.M.);NationalInstituteofAgingBostonUniversityAlzheimer’sDiseaseCenterCenterP30AG13846toN.W.K.;supplementtoA.C.M.,NationalInstituteofAgingBostonUniversityFraminghamHeartStudyR01R01AG1649];NationalInstituteofNeurologicalDisordersandStroke,NationalInstituteofAging,NationalInstituteofChildHealthandHumanDevelopmentDevelopmentNS078337toR.A.S.];SportsLegacyInstitute;NationalOperatingCommitteeonStandardsforAthleticEquipment,andthere-sourcesanduseoffacilitiesattheEdithNourseRogersMemorialVeteransHospitalinBedford,MA.ThisworkwasalsosupportedbyanunrestrictedgiftfromtheNationalFootballLeague.Thefundingsourceswerenotinvolvedinthepreparation,revieworapprovalofthismanuscript.SupplementarymaterialSupplementarymaterialisavailableatAmadoroG,CiottiMT,CostanziM,CestariV,CalissanoP,CanuN.NMDAreceptormediatestau-inducedneurotoxicitybycalpainandERK/MAPKactivation.ProcNatlAcadSciUSA2006;103:2892–7.AnthonyIC,NorrbyKE,DingwallT,CarnieFW,MillarT,ArangoJC,etal.PredispositiontoacceleratedAlzheimer-relatedchangesinthebrainsofhumanimmunodeciencyvirusnegativeopiateabusers.Brain2010;133:3685–98.ArriagadaPV,GrowdonJH,Hedley-WhyteET,HymanBT.Neurobrillarytanglesbutnotsenileplaquesparalleldurationandse-verityofAlzheimer’sdisease.Neurology1992;42:631–9.BaughCM,StammJM,RileyDO,GavettBE,ShentonME,LinA,etal.Chronictraumaticencephalopathy:neurodegenerationfollowingre-petitiveconcussiveandsubconcussivebraintrauma.BrainImagingBehav2012;2:244–54.BigioEH.UpdateonrecentmolecularandgeneticadvancesinFTLD.JNeuropatholExpNeurol2008;67:635–48.BraakH,BraakE.NeuropathologicalstagingofAlzheimer-relatedchanges.ActaNeuropathol1991;82:239–59.BraakH,BraakE,BohlJ.StagingofAlzheimer-relatedcorticaldestruc-tion.EurNeurol1993;33:403–8.BraakH,BraakE.MorphologicalcriteriafortherecognitionofAlzheimer’sdiseaseandthedistributionpatternofcorticalchangesrelatedtothisdisorder.NeurobiolAging1994;15:355–6.BraakH,DelTrediciK.NervoussystempathologyinsporadicParkinsondisease.Neurology2008;70:1916–25.BraakH,DelTrediciK.ThepathologicalprocessunderlyingAlzheimer’sdiseaseinindividualsunderthirty.ActaNeuropathol2011;121:BrooksBR.ElEscorialWorldFederationofNeurologycriteriaforthediagnosisofamyotrophiclateralsclerosis.SubcommitteeonMotorNeuronDiseases/AmyotrophicLateralSclerosisoftheWorldFederationofNeurologyResearchGrouponNeuromuscularDiseasesandtheElEscorial‘Clinicallimitsofamyotrophiclateralsclerosis’work-shopcontributors.JNeurolSci1994;124:96–107.BrooksBR,MillerRG,SwashM,MunsatTL.ElEscorialrevisited:revisedcriteriaforthediagnosisofamyotrophiclateralsclerosis.AmyotrophLateralSclerOtherMotorNeuronDisord2000;1:293–9.BrownLM,SchinkaJA.Developmentandinitialvalidationofa15-iteminformantversionoftheGeriatricDepressionScale.IntJGeriatrPsychiatry2005;20:911–8.Ca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