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REVIEWOpenAccessClinic,neuropathologyandmoleculargeneticsoffrontotemporaldementia:amini-reviewXiao-dongPan1,2,3andXiao-chunChen1,2,3*AbstractFrontotemporallobardegeneration(FTLD)representsagroupofclinically,neuropathologicallyandgeneticallyheterogeneousdisorderswithplentyofoverlapsbetweentheneurodegenerativemechanismandtheclinicalphenotype.
FTLDispathologicallycharacterizedbythefrontalandtemporallobaratrophy.
Frontotemporaldementia(FTD)clinicallypresentswithabnormalitiesofbehaviorandpersonalityandlanguageimpairmentsvariants.
TheclinicalspectrumofFTDencompassesdistinctcanonicalsyndromes:behaviouralvariantofFTD(bvFTD)andprimaryprogressiveaphasia.
Thelaterincludesnonfluent/agrammaticvariantPPA(nfvPPAorPNFA),semanticvariantPPA(svPPAorSD)andlogopenicvariantPPA(lvPPA).
Inaddition,thereisalsooverlapofFTDwithmotorneurondisease(FTD-MNDorFTD-ALS),aswellastheparkinsoniansyndromes,progressivesupranuclearpalsy(PSP)andcorticobasalsyndrome(CBS).
TheFTLDspectrumdisordersarebaseduponthepredominantneuropathologicalproteins(containinginclusionsofhyperphosphorylatedtauorubiquitinprotein,e.
gtransactiveresponse(TAR)DNA-bindingprotein43kDa(TDP-43)andfusedin-sarcomaproteininneuronsandglialcells)intothreemaincategories:(1)microtubule-associatedproteintau(FTLD-Tau);(2)TARDNA-bindingprotein-43(FTLD-TDP);and(3)fusedinsarcomaprotein(FTLD-FUS).
TherearefivemaingenesmutationsleadingclinicalandpathologicalvariantsinFTLDthatidentifiedbymoleculargeneticstudies,whicharechromosome9openreadingframe72(C9ORF72)gene,granulin(GRN)gene,microtubuleassociatedproteintaugene(MAPT),thegeneencodingvalosin-containingprotein(VCP)andthechargedmultivesicularbodyprotein2B(CHMP2B).
Inthisreview,recentadvancesonthedifferentclinicvariants,neuroimaging,genetics,pathologicalsubtypesandclinicopathologicalassociationsofFTDwillbediscussed.
Keywords:bvFTD,Nonfluent/agrammaticvariant,Semanticvariant,Logopenicvariant,Moleculargenetics,MAPT,GRN,C9ORF72IntroductionFrontotemporaldementia(FTD)representsagroupofclinically,neuropathologicallyandgeneticallyhetero-geneousdisorders.
Itisarangeofprogressivedementiasyndromesassociatedwithfocalatrophyoftheorbitomesialfrontalandanteriortemporallobes.
Andthetermfrontotemporallobardegeneration(FTLD)todescribethepathologicalsyndrome.
In1892,ArnoldPickdescribedapatientwithprogressiveaphasiaandlobaratrophy[1].
In1911,AloisAlzheimerdescribedthehistopathologicalstatusrelatedtothesepatients,pointingtheabsenceofsenileplaquesandneuro-fibrillarytangles,andthepresenceofargyrophilicneuronalinclusions(latercalled"Pickbodies")andswollencells(latercalled"Pickcells")atneuropathologicalexamination[2].
However,duringthe20thcentury,thesepatientswithfrontotemporallobardegenerationweregenericallyreferredtoaspatientswithdementia,beingoftendiagnosedwithAlzheimerdisease(AD)[2].
In1994,twomajorresearchgroupsfromLundandManchesterproposedclinicalandneuropathologicalcriteriaforthediagnosisofFTD[3].
In1998,Nearyetal[4]reportedaconsensusonclinicaldiagnosticcriteriaoffrontotemporallobardegenerationintheAmericanAcademyofNeurology(AAN).
FTDoftenbeginswhenthepatientisinthefifthtoseventhdecades.
Epidemiologicalstudiessuggestthat*Correspondence:chenxc998@163.
com1DepartmentofNeurology,UnionHospitalofFujianMedicalUniversity,29XinquanRoad,Fuzhou350001,China2KeyLaboratoryofBrainAgingandNeurodegenerativeDisease;FujianInstituteofGeriatrics,UnionHospitalofFujianMedicalUniversity,29Xinquan,Road,Fuzhou350001,ChinaFulllistofauthorinformationisavailableattheendofthearticleTranslationalNeurodegeneration2013PanandChen;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
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0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
PanandChenTranslationalNeurodegeneration2013,2:8http://www.
translationalneurodegeneration.
com/content/2/1/8FTDisthesecondmostcommoncauseofdementiainindividualsyoungerthan65andisjustlesscommonthanAlzheimer'sdisease(AD)withinthisagegroup[2,5].
Ofover65yearsolddementia,theincidenceofFTDranksfourth,thetopthreeisAlzheimer'sdisease,Lewybodydementiaandvasculardementia[5-7].
Theredonotappeartobeanycleargenderdifferencesinsus-ceptibility[8-11].
AmongtheFTDclinicalsyndromes,sexdistributionappearstovaryfromonesubtypetothenext.
SeveralstudiesreportamalepredominanceinbvFTDandSD,andafemalepredominanceinPNFA[5,12].
Thereisawiderangeindurationsofillness(2-20years)partlyreflectingdifferentunderlyingpathologies.
Inthepastfewyears,significantadvanceshavebeenseenintheetiology,pathogenesis,andgenetics,pathologyandclinicalphenotypeofFTD,andmanynewterminologyandclassificationofFTDhaveemerged.
Inthisreview,recentadvancesonthedifferentclinicalvariantphenotypes,neuroimaging,hereditaryforms,pathologicalsubtypesandclinicopathologicalassociationsofFTDwillbediscussed.
FTLDclinicalpresentation:classificationandcharacteristicsFrontotemporallobardegeneration(FTLD)includesagroupofprogressivedegenerativedisorderscharacterisedbyprogressivebehaviouralchange,executivedysfunctionandlanguagedifficulties[13].
UnlikeAD,behavioralsymptomspredominateintheearlystagesofFTLD.
TheclinicalheterogeneityinfamilialandsporadicformsofFTDisremarkable,withpatientsdemonstratingvariablemixturesofdisinhibition,dementia,PSP,CBD,andmotorneurondisease[13,14].
Earlysymptomsaredividedamongcognitive,behavioral,andsometimesmotorabnor-malities,reflectingdegenerationoftheanteriorfrontalandtemporalregions,basalganglia,andmotorneurons[13,14].
FTLDisapowerfulmodeltostudyemotion,socialcognitionandlanguageorganizationinthebrain.
Behavioralvariantfrontotemporaldementia(bvFTD)bvFTDhasthehighestprevalenceamongsttheFTDclinicalsyndromes,accountingforapproximately70%ofallFTDcases[2,5].
TheonsetofbvFTDistypicallybeforetheageof65years,withanaverageonsetageof58years[12,15].
Patientswiththisclinicalvariantpresentwithmarkedchangesinpersonalityandbehaviourandwithrelativepreservationofthecognitivefunctionspraxis,gnosiaandmemory[13,16].
Commonbehavioraldeficitsincludeapathy,disinhibition,weightgain,foodfetishes,compulsions,euphoria,andanabsenceofinsightintotheircondition.
Poorbusinessdecisionsanddifficultyorganizingworktasksarecommon.
Cognitivetestingtypicallyrevealssparedmemorybutimpairedexecutivefunctions[3,13,17].
bvFTDhasbeenassociatedwithsymmetricalventromedialfrontal,orbitalfrontal,andinsularatrophyandleftanteriorcingulateatrophy[18].
BehaviouralassessmentisatthecoreofassessmentinpatientswithpotentialbvFTDandseemstobemoresensitiveindistinguishingbvFTDfromADthanstandardcognitivetesting.
The'InternationalBehavioralVariantFTDCriteriaConsortium'developedinternationalconsensuscriteriaforbvFTD.
Subclassifi-cationsweremadeinpossiblebvFTDdefinedbyclinicalcriteria,probablebvFTDsupportedbyneuroimagingdata,anddefinitebvFTDconfirmationbyneuropathologicalevidenceorapathogenicmutation[17].
Primaryprogressiveaphasia(PPA)PPAisalanguagedisorderthatinvolveschangesintheabilitytospeak,read,writeandunderstandwhatothersaresaying.
Itisassociatedwithearlytemporallobeatrophyorbrainlesionsaroundthelateralfissure.
PPArepresentsaspectrumofselectivelanguagedisordersandthevariantofPPAmightprovidecluestotheunder-lyingpathology[19].
Currentlycerebrospinalfluid(CSF)biomarkershavelimitedabilitytoidentifyPPAreliably,whichmightbeexplainedbythepathologicalheterogeneity.
AnindicationoflowerAβ1-40levelsorthelowerT-tautoAβ1-42ratioinFTD,mightbeusefultodistinguishpatientsfromsubjectsADandcontrolsubjects[20,21].
In2011,criteriawereadoptedfortheclassificationofPPAintothreeclinicalsubtypes:nonfluent/agrammaticvariantPPA(nfvPPAorPNFA),semanticvariantPPA(svPPAorSD)andlogopenicvariantPPA(lvPPA)[22].
TheproposalisanimportantstepforwardinestablishingtheconsistencyofterminologyandclassificationofPPA.
Thediagnosticrecommendationsincludetwosteps.
First,thepatientshouldmeetthebasicstandardofPPA,whichisaninitialpresentationofsignificantdamagetolanguageandaccompaniedbylimiteddailylivingskillsandothercognitiveimpairment.
Second,weneedtoassessthemainlanguagedomains,includingverbalgeneration,repeat,andunderstandingofwordsandsyntax,naming,semanticknowledgeandreading/spellingcharacteristics.
Finally,clinicalvariantswillbedividedbasingonspecificspeechandlanguagefeaturescharacteristicofeachsubtype.
Classificationcanthenbefurtherspecifiedas"imaging-supported"iftheexpectedpatternofatrophyisfoundand"withdefinitepathology"ifpathologicorgeneticdataareavailable.
Therefore,thenewproposalhasaclearpracticalsignificance.
nfvPPAorPNFAisthesecondmostprevalentpres-entationofFTLD,accountingforalarge25%[12].
ThefeatureofnfvPPAincludesgrammaticalerrormakingagrammatismand/orlaboriousspeech,butrelativelypreservedlanguagecomprehension.
Apraxiaofspeech(AOS)ororofacialapraxiaisfrequentlyaccompanyingtheaphasia[15].
SemanticvariantPPA(svPPA)orSDpresentsin20–25%oftheFTLDpatients[12].
svPPAPanandChenTranslationalNeurodegeneration2013,2:8Page2of9http://www.
translationalneurodegeneration.
com/content/2/1/8presentsasignificantlyimpairednamingabilityandwordcomprehension,whilespeechproductionisspared[22,23].
LvPPAorlogopenicprogressiveaphasia[24]ismarkedbyimpairedwordfindinganddifficultrepetition.
lvPPAshowesanimpairedabilitytorepeatsentencesorphrases,spontaneousspeechandasinglewordextractingwhennaming.
UnlikeotherFTDsubtypes,lvPPAgenerallydoesnotproducechangesinbehaviororpersonalityuntillaterstagesofthedisease.
Mostpeoplewithprogressiveaphasiamaintaintheabilitytocareforthemselves,keepupoutsideinterestsand,insomeinstances,remainemployedforafewyearsafteronsetofthedisorder.
LPAismostlyassociatedwithaneuro-pathologicaldiagnosisofAD[25].
ClinicaldistinctionbetweenbvFTD,nfvPPAandsvPPAisoftencomplicatedforthatoverlapoftheclinicalsyndromesbetweenthemcanoccurinadvancedstagesofdisease.
FTLDoverlapswithotherclinicalsyndromeThesubcorticalnucleiandmotorsystemsareinvolvesinFTLDvariants.
Motorneurondysfunction(MND)hasbeendescribedin40%oftheFTLDpatients,referredtoasFTLD-MND.
ThecommoncomorbidityofAmyotrophiclateralsclerosis(ALS)withbehaviorabnormality,cognitiveimpairmentordementiahasbeennoticed[26,27].
FTLDmayprecede,followorcoincidewiththeonsetofmotorsymptoms[28].
OtherdisordersarecloselyrelatedtoFTLD,includingprogressivesupranuclearpalsy(PSP)syndromes,corticobasalsyndrome(CBS),FTDwithparkinsonism(FTDP)andargyrophilicgraindisease(AGD).
PSPandCBSaretwocommonatypicalparkinsoniansyndromesdemonstratingcognitiveandbehaviourdisordersthatoverlapwithFTD.
Ofthem,behavioralandcognitivedysfunctionpromotesthedevelopmentofdementia.
Andextrapyramidalsystemsymptomspresentasbradykinesia,abnormalposture,rigidity,buttremoruncommon.
Theco-occurrenceofAGDinALSisnotuncommon,andcomparablewiththatinanumberofdiseasesbelongingtothetauopathiesorα-synucleinopathies[29].
Motionsystemdamagepresentsasmuscleatrophy.
FTDP-17showinggeneticlinkagetochromosome17,presentswithaclinicalsyn-dromeofautosomaldominantdisinhibition,dementia,parkinsonism,andamyotrophy[30].
TheclinicalpictureresemblesbvFTD,whilecognitivedeficitsincludean-terogradememorydysfunctioninanearlystage,laterthedeteriorationofvisuospatialfunction,orientationandglobalmemoryaregraduallypresented.
Motorsignstypicallyincludethesymmetricalbradykinesiawithoutrestingtremor,incombinationwithaxialrigidityandposturalinstability.
TheearlyclinicalpresentationofAGDissimilartoADbutitislessaggressive,withpatientsmaintainmildcognitiveimpairment(MCI)formanyyears[31].
NeuroimaginginFTLDNeuroimagingplaysacriticalroleindiagnosisofFTD.
NeuroimaginginvestigationscanreliablydifferentiateFTLDsubtypesfromotherdementias,andcanhelpclinicaldiagnosticsbasedonneuropsychiatricsymptoms.
Differentclinicalvariatentshavedifferentformsofbrainatrophy,whichcanbeusedforsomeimportantcluesforearlyclinicaldifferentialdiagnosis.
DTIcandetectwhitematterdamage,differentsubtypesofwhitematterinjuryalsohelpclinicalearlydifferentialdiagnosisofclinicalsubtypesofFTLD[32].
Functionalneuroimagingtechniques,suchas[99mTc]-hexamethylpropyleneamineoximesingle-photonemissioncomputedtomography(SPECT)[33]or[18F]-fluorodeoxyglucose(FDG)-PETareincreasinglybeingusedtohelpwiththediagnosisofFTLD[34].
Arterialspinlabelingimaging(ASL)likeFDG-PETcanbeusedforshowingthehypometabolisminbrainregions.
HypometabolismonFDG-PETisdetectedconsistentlyandreliablyinfrontalbrainregionsinpatientswithbvFTDcomparedwiththosewithAD,whoshowposteriorcingulatehypometabolismearlyinthediseaseprocess[34].
However,inpatientsshowingclearbrainatrophyonstructuralMRI,littleadditionaldiagnosticbenefitisgainedbydoingaPETscan,becausefocalatrophyisapositivepredictivemarkerofFTD.
Theimagingpresen-tationofnfvPPAindicatesthatpredominantleftposteriorfronto-insularatrophyonMRIorpredominantleftposteriorfronto-insularhypoperfusionorhypometabolismonSPECTorPET.
Imaging-supportedsvPPAshowpredominantanteriortemporallobeatrophyand/orthesebrainregionshypoperfusionorhypometabolismonSPECTorPET.
TheimagingoflvPPAmustshowatleastoneofpredominantleftposteriorperisylvianorparietalatrophyonMRIand/orhypoperfusionorhypometabolismonSPECTorPET[22,25,35-37].
FutureinFTLDareverysimilartoimaginginAD–earlydetection,moleculardiagnosis,monitordiseaseprogressionandvalidateandimplementdiseasemodifyingtherapies.
SpecificanatomicpatternsinFTLD,andanamyloid-PETneuroimaging,whichusestheamyloid-β-detecting11C-PittsburghcompoundB,hasshownpromisingresultsindiscriminatingorrule-outatypicalADandFTDcases[38,39]particularlythosepresentingwithlanguagedeficitsratherthanbehaviouralchanges.
MicroPETwith18F-THK523inTautransgenicmicehavebeenreported[40].
Tauspecificimagingscannerthatusesthe18F-THK523maybeapromisingtechniquecomingsooninfuture[40].
FTLDNeuropathologyandcliniconeuropathologicalcorrelationsNeuropathologyThesubtypesofunderlyingpathologicalchangesinpatientswithFTDareclassifiedonthebasisofthePanandChenTranslationalNeurodegeneration2013,2:8Page3of9http://www.
translationalneurodegeneration.
com/content/2/1/8patternofproteindeposition,andarereferredtocollectivelyasfrontotemporallobardegeneration.
Underamicroscope,commonpathologicchangesofFTLDareatrophybrainregionpresentingneuronalloss,spongychangeandgliosisincorticesofatrophiedfrontalandtemporallobes[41,42].
FTDhaveidentifiednovelgeneticdefectsandachromosomallocusinhereditaryformsofFTLD,aswellasnovelclinicneuropathologicalassociations.
Immunohistochemistryallowssubcategorizationofthesedisordersintospecificproteinopathiesbasedonthemajorconstituentoftheinclusions.
(1)FTLD-tau:Onesubtypeispresentedasneuronsandglialcellscontaininginclusionsofhyperphosphorylatedtauprotein,referredtoasFTLD-tau[43].
TaupathologywasassociatedwithFTDwithparkinsonism,PSPsyndromes[44],CBS[45]andAGD[31].
(2)FTLD-UbiquitinorFTLD-U:Over50%oftheFTLDpatientspresentedwithtau-negativeubiquitinstaininginclusions,referredtoasFTLD-UbiquitinorFTLD-U[46].
In80–95%ofthisgroup,inclusionswerefoundtobecomposedoftransactiveresponse(TAR)DNA-bindingprotein43kDa(TDP-43)[47-49],referredtoasFTLD-TDP[50],orTDP-43-negativeFTLD-Ucaseshavinginclusionsoffusedin-sarcomaprotein(FUS),referredtoasFTLD-FUS[43,49,51,52].
However,inasmallnumberofFTLD-Upatients,theinclusionproteinremainsunclear.
ThisgroupisreferredtoasFTLD-ubiquitinproteasomesystem(FTLD-UPS)[46,53].
(3)Dementialackingdistinctivehistopathology(DLDH)[54,55].
(4)Otherraretypes:dementiawithbasophilicinclusionbody,neuronalintermediatefilamentinclusiondisease[52].
AssociationbetweenpathologyandclinicalphenotypeAssociationswerenotedbetweentheclinicalFTLDsubtypesandunderlyingproteinopathies,butastrictonetoonerelationshipislacking.
bvFTDismostlyassociatedwithFTLD-TDP43,somecasesarealsocorrelatedwithFTLD-tau(PiDsubtype).
AnFTLD-FUSproteinopathyisinvariantlyassociatedwithaclinicaldiagnosisofbvFTD,eitherwithorwithoutthesignsofMND.
MicroscopicassessmentofnfaPPAatautopsyoftenrevealsFTLDasso-ciatedwithatauopathy(FTLD-tau).
nfaPPAiscommonlyassociatedwithtaupathology,especiallywhenAOSororofacialapraxiaispresent.
Inmostcases,thepathologyunderlyingnfaPPAwasmixed,includingFTLD-tauandFTLD-TDP43,butwithapredominanceofFTLD-taupathology.
SvPPAis,inmostcases,linkedwithTDP-43-immunoreactivepathology,althoughtaupathologyissometimesobserved.
Somepatientswithpredominantlyrighttemporallobeatrophy(RTLA)areusuallydiagnosedclinicallywitheitherbvFTDorsvPPA[56].
IthasbeensuggestedthatpatientswithbvFTDandRTLAhaveFTLD-taupathology,whereaspatientswithsvPPAandRTLAhaveFTLD-TDP43pathology[56].
svPPApatientswhooftenpresentwithacalculiaisassociatedwithFTLD-tau[57].
LvPAispredominantlyassociatedwithADpathology.
ManypatientswithlvPPAoftenhaveunderlyingADpathology[58-60].
CSFtau:amyloid-βratio[37]andPiBPETimaging[25]studiescanbehelpfulintheidentificationofpatientswhoaremorelikelytohavelvPPAthannfaPPA.
Arecentstudyshowedthat93%ofpatientswithlvPPAonamyloidPETimagingwasfoundPiBpositive,butsvPPAonly9%,nfvPPAis13%,whichsuggeststhatthereissomecommonpathologicalfeaturesbetweenlvPPAandAD[59].
TaupathologywasalsoassociatedwithFTLDwithparkinsonism,PSP,CBD,AGDandPickbodies(PiD)[30,44,61].
Similarly,TDP-43andFUSproteinopathiesarealsocommonlyfoundinMNDwithorwithoutFTLD[52].
Althoughthesearerelativelystrongassociations,theyarenotabsolute,anditiscurrentlynotpossibletopredictwithcertaintytheunderlyingpathologyofspecificFTLDsyndromes.
ExtrapyramidalsystemsymptomsaccompaniedwithapraxiaindicatesthepresenceofCBS,whichmostlyattributestoTaudisease.
WhiledementiawithFTLD-MNDsyndromemostlyattributestoTDP-43pathology[15,45,57].
ThesesuggestthatitiscontributingtotherapeuticstrategyforFTLDthroughelucidatingtherelationshipbetweenpathologicalandclinicalpresentation.
MoleculargeneticsApproximately40%ofpatientswithFTDhaveafamilyhistory[8].
bvFTDisthemostprominentsubtypewithfamilyhistory,especiallywhenconcomitantsymptomsofMNDarepresent(60%),whileSvPPAappearedtobetheleasthereditaryFTLDsubtype(<20%)[62].
Moleculargen-eticstudieshaveidentifiedseveralcommon(MAPT,GRN)andrare(VCP,CHMP2B,TARDBP,FUS)geneticfactorsinhereditaryFTLDoverrecentyears.
In1998microtubuleassociatedproteintau(MAPT)genewasfound,whichlocatedonchromosome17q21.
32,inwhich13%ofthecasesisFTDP-17,thosewhohaveparkinson-likesymptoms[63].
In2004,thegeneencodingvalosin-containingprotein(VCP)genewasfound,locatedonchromosome9p13.
3,whichisassociatedwiththegenesthatcauseFTLDinasso-ciationwithinclusionbodymyopathyandPaget'sdisease[64,65].
In2005,thechargedmultivesicularbodyprotein2B(CHMP2B,alsoknownaschromatin-modifyingprotein2B)genemutations,locatedonchromosome3p11.
2,wasdiscoveredinalargeDanishcohortwithfamilialFTLD[66,67].
In2006,amutatedgenelocatedonchromosomePanandChenTranslationalNeurodegeneration2013,2:8Page4of9http://www.
translationalneurodegeneration.
com/content/2/1/8Table1Clinicalphenotypes,pathologicalandmoleculargeneticspectruminFTLD[13,19,22,35,72,77,78]CoreclinicalfeaturePraxiologicalobstacleLogopathyExtrapyramidalsymptoms+praxiologicalobstacleDyskinesia+praxiologicalobstacleClinicalsyndromeBehavioralvariantFrontotemporaldementia(bvFTD)Primaryprogressiveaphasia(PPA)Corticobasaldegeneration(CBD)progressivesupranuclearpalsy(PSP)FTD-MND/ALSnonfluent/agrammaticvariantPPA(nfvPPA)Semanticsvariation(svPPA)logopenicvariantPPA(lvPPA)BrainmorphologicallyaffectedpartsPrefrontallobeandtemporallobeLeftposteriorfrontallobe,insulaThefront/ventraltemporallobeleftposteriorsuperiortemporallobeandmedialparietallobeFrontalandtemporallobe,BasalgangliaBasalgangliaandbrainstemCortexandmotorneuronBiochemistryandNeuropathologyFTLD-Tau(Picktype,3R-tau)FTLD-TDP43FTLD-TaumorethanFTLD-TDP43,ADlikepathologicalvisibleMostbelongstoFTLD-TDP43;ADlikepathologicalrareAD-likepathologicalcommon;FTLD-TDP43visibleFTLD-Tau(CBDtype,4R-tau)commonFTLD-Tau(PSPtype,4R-tau)commonFTLD-TDP43,FTLD-FUSCausativeandAssociatedGenesC9ORF72PGRN,C9ORF72PGRNMAPTC9ORF72PGRNC9ORF72PGRNMAPTPGRNFUSMAPTMAPTMAPTPGRNC9ORF72C9ORF72VCPVCPVCPVCPVCPVCPCHMP2BCHMP2BCHMP2BCHMP2BCHMP2BNote:3Rtau:threemicrotubulebindingrepeats;4Rtau:fourmicrotubule-bindingrepeats.
PanandChenTranslationalNeurodegeneration2013,2:8Page5of9http://www.
translationalneurodegeneration.
com/content/2/1/817q21.
31areidentifiedasthegranuleproteinprecursor(PGRN),only1.
7MnucleotideawayfromtheMAPT[68,69].
Approximately10%ofpatientswithFTLDisassociatedwiththisgene.
In2011,chromosome9openreadingframe72(C9ORF72)genewasnewlyidentifiedinFTLD[70,71].
Overall,patientswithmutationsinGRN,MAPTandC9ORF72togetheraccountforatleast17%oftotalFTDcases[53,72].
SummedC9ORF72,GRNandMAPTmutationfrequencieswere32-40%[70,73].
MutationsinVCPandCHMP2Barerare,eachexplaininglessthan1%ofthefamilialFTLD.
TheMAPTgenemutationsoftenleadtoFTLD-Taupathologicalchanges.
TheBothPGRNandC9ORF72muta-tionscancauseFTLD-TDP-43.
ThesymmetryfrontallobeatrophyinbvFTDpatientsisassociatedwithC9ORF72andMAPTgenemutations,whereastheasymmetryoffrontallobeatrophyinbvFTDpatientsisassociatedwithPGRNgenemutations[74].
Thelargehexanucleotiderepeatexpansionlocatedwithinthenon-codingportionofC9ORF72isthecauseofchromosome9-linkedALSandFTLD[70].
Thesesuggestthatspecificgenemutationsmayaffectthepatternsofneuroanatomicinjuryinthedevelopmentoffrontallobaratrophy.
C9ORF72isexpressedasthreemajortranscriptsandtheexpandedG4C2repeatislocatedintheproximalregulatoryregionofC9ORF72[70,73],upstreamofoneandinthefirstintronofthetwoothertranscripts.
Repeatexpansionresultsinnearcompletelossofexpressionofthemajorgenetranscripts.
Thepathogenicexpansionwasnon-penetrantinindividualsyoungerthan35years,50%penetrantby58years,andalmostfullypenetrantby80years.
Innormalpopulation,thesizeoftheG4C2repeatrangesfrom3to25units,whichisexpandedtoatleast60unitsinFTLDpatients[70,71,73].
TheclinicalphenotypeofC9ORF72mutationoftenpresentsasbvFTDorALSorFTDco-morbiditiesALS.
InpatientswithbvFTD,C9ORF72mutationismorecommonthanMAPTorPGRN.
Anxietyoragitation,andmemorydysfunction(oftenepisodicmemory)isacommonclinicalfeature.
Thosecasesunderlinesthatthehexanucleotiderepeatexpansioninchromosome9couldbealsoassociatedwithearlyonsetpsychiatricpresentations[75].
Overexpressedp-62inclusionbodylesionsinthecere-bellumisoneofpathologicalfeatures[76].
Neuroimagingpresentsasthesymmetricalfrontaland/ortemporallobeatrophy,andparietal,occipitalandcerebellaratrophycanalsoappear.
Therefore,C9ORF72mutationisnotonlyas-sociatedwithcorticalanatomicsitebutalsowithsub-corticalstructures.
However,itisunclearfortheexactmechanismofactionofthis"repeatamplificationC9ORF72gene".
TheclinicalandpathologicalheterogeneityinFTLDcausesachallengefordiagnosisofFTLD.
AhelpfulTable2TheprofileofmaingenesmutationanditspossiblediseasemechanismsinFTLDGenesymbolMAPTC9ORF72PGRNVCPCHMP2BFullnameMicrotubule-associatedproteintauChromosome9openreadingframe72ProgranulinValosincontainingproteinChromatinmodifyingprotein2BChromosomallocalization17q21.
329p21.
217q21.
329p13.
33p11.
2.
MAPTgivesrisetosixisoforms:threeisoformscontainingthreeamino-acidrepeats(3R),andthreeisoformswithfourrepeats(4R)[79].
expressedasthreemajortranscripts,theexpandedG4C2repeatislocatedintheproximalregulatoryregionofC9ORF72[70,73].
encodesprogranulin,aubiquitouslyexpressedgrowthfactorprecursorconsistingof7.
5granulinpeptides.
EncodesaubiquitouslyexpressedmemberofafamilyofATPasesassociatedwithawiderangeofcellularfunctions[85].
EncodesacomponentoftheheteromericESCRT-IIIcomplexwithfunctionsintheendosomal-lysosomalandtheautophagicproteindegradationpathway.
FunctionsandpossibleroleinthediseasemechanismMutationsresultinachangeinratioof3Rto4Rtauisoforms.
Mutationsaffectthenormalfunctionofthetauproteintostabilisemicrotubules,increasethetendencyoftautoformneurotoxicaggregatesanddisturbneuronalplasticityandaxonaltransport[80].
Repeatexpansionresultsinnearcompletelossofthemajorgenetranscripts.
AndaccumulationoftranscriptsharboringtheexpandedG4C2repeatinnuclearRNAfoci[70].
awiderangeofbiologicalprocessessuchasinflammationandwoundrepair,orinpathologicalconditionsincludingtumorigenesis[82].
mutationsresideattheinterfacebetweentheD1ATPaseandtheN-domainoftheCDC48-likeprotein[85].
Expressedinneuronsofallmajorbrainregions.
Itiscriticalfordevelopment,sexualdifferentiation[88]andneuronalsurvival[89].
G4C2repeatleadstoneuronalcytoplasmicinclusionsthroughouttheentirecorticalthickness[81].
Neurotrophicfunctioninvolvedinneuronalsurvivalandneuriteoutgrowth[83,84].
mutationsdisturbubiquitin-proteasomemediatedproteindegradation,autophagy,orboth[86,87].
MutationsaffecttheC-terminalendoftheproteinduetoaberrantsplicing[78].
unidentifiedmechanismsexist.
Estimatedmutationfrequency[69,72,79,81,90]0-50%14-48%3–26%<1%<1%PanandChenTranslationalNeurodegeneration2013,2:8Page6of9http://www.
translationalneurodegeneration.
com/content/2/1/8supplementforclinicalevaluationusinggeneticsandbiologicalmarkerstestingcansignificantlyimprovetheforecastofpotentialhistopathologyinvivo.
Wesummarizeclinicalphenotypes,molecularpathologicalandgeneticspectruminFTLDinTable1.
Andtheprofileofmaingenesmutationsanditspossiblediseasemecha-nismsinFTLDisshowninTable2.
ConclusionInthisreview,wehavesystematicallyupdatedcurrentunderstandingonclinical,genetic,neuropathological,andneuroimagingperspectivesofFTD.
ThisreviewaimstoarouseawarenessofFTDamongclinicians,inpar-ticularwhentheoverlappingclinicalandneuroimagingcharacteristicfeaturesamongdementiaanddifferentsubtypesofFTDremaingreatchallengesforclinicians.
IdentificationofbiomarkersforclinicaldiagnosisanddifferentiationFTDfromotherdementiaiswarrantedforfuturestudies.
Genediagnosistestshouldbecon-sideredforfamilialcasessuspectedwithFTDinclinicpractice.
Longitudinalclinicopathologicalcorrelationstudieswillfurtherelucidatethenetworkfunctionsofhumanbraininthiscomplexdisorderwithbehaviour,speechandmotorabnormality.
Withfurtherunder-standingofthegenetics,clinicalandneuropathologicalbasisofFTD,wecanvisualisethatFTDwillbefurtherclinicallydefined.
Andnewconsensuswillbedevelopedforbetterguidanceinclinicalpractice.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsXdPcollectedthereferencematerialsanddraftedthemanuscript.
XcCrevisedthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsThisworkwassupportedbythegrantsfromtheNationalNaturalScienceFoundationofChina(81200991),OutstandingYoungPersons'ResearchProgramforHigherEducationofFujianProvince,China(JA10123),MajorProjectofFujianScienceandTechnologyBureau(2009D061).
Authordetails1DepartmentofNeurology,UnionHospitalofFujianMedicalUniversity,29XinquanRoad,Fuzhou350001,China.
2KeyLaboratoryofBrainAgingandNeurodegenerativeDisease;FujianInstituteofGeriatrics,UnionHospitalofFujianMedicalUniversity,29Xinquan,Road,Fuzhou350001,China.
3CentreofNeurobiology,FujianMedicalUniversity,88JiaotongRoad,Fuzhou350001,China.
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doi:10.
1186/2047-9158-2-8Citethisarticleas:PanandChen:Clinic,neuropathologyandmoleculargeneticsoffrontotemporaldementia:amini-review.
TranslationalNeurodegeneration20132:8.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
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FTLDispathologicallycharacterizedbythefrontalandtemporallobaratrophy.
Frontotemporaldementia(FTD)clinicallypresentswithabnormalitiesofbehaviorandpersonalityandlanguageimpairmentsvariants.
TheclinicalspectrumofFTDencompassesdistinctcanonicalsyndromes:behaviouralvariantofFTD(bvFTD)andprimaryprogressiveaphasia.
Thelaterincludesnonfluent/agrammaticvariantPPA(nfvPPAorPNFA),semanticvariantPPA(svPPAorSD)andlogopenicvariantPPA(lvPPA).
Inaddition,thereisalsooverlapofFTDwithmotorneurondisease(FTD-MNDorFTD-ALS),aswellastheparkinsoniansyndromes,progressivesupranuclearpalsy(PSP)andcorticobasalsyndrome(CBS).
TheFTLDspectrumdisordersarebaseduponthepredominantneuropathologicalproteins(containinginclusionsofhyperphosphorylatedtauorubiquitinprotein,e.
gtransactiveresponse(TAR)DNA-bindingprotein43kDa(TDP-43)andfusedin-sarcomaproteininneuronsandglialcells)intothreemaincategories:(1)microtubule-associatedproteintau(FTLD-Tau);(2)TARDNA-bindingprotein-43(FTLD-TDP);and(3)fusedinsarcomaprotein(FTLD-FUS).
TherearefivemaingenesmutationsleadingclinicalandpathologicalvariantsinFTLDthatidentifiedbymoleculargeneticstudies,whicharechromosome9openreadingframe72(C9ORF72)gene,granulin(GRN)gene,microtubuleassociatedproteintaugene(MAPT),thegeneencodingvalosin-containingprotein(VCP)andthechargedmultivesicularbodyprotein2B(CHMP2B).
Inthisreview,recentadvancesonthedifferentclinicvariants,neuroimaging,genetics,pathologicalsubtypesandclinicopathologicalassociationsofFTDwillbediscussed.
Keywords:bvFTD,Nonfluent/agrammaticvariant,Semanticvariant,Logopenicvariant,Moleculargenetics,MAPT,GRN,C9ORF72IntroductionFrontotemporaldementia(FTD)representsagroupofclinically,neuropathologicallyandgeneticallyhetero-geneousdisorders.
Itisarangeofprogressivedementiasyndromesassociatedwithfocalatrophyoftheorbitomesialfrontalandanteriortemporallobes.
Andthetermfrontotemporallobardegeneration(FTLD)todescribethepathologicalsyndrome.
In1892,ArnoldPickdescribedapatientwithprogressiveaphasiaandlobaratrophy[1].
In1911,AloisAlzheimerdescribedthehistopathologicalstatusrelatedtothesepatients,pointingtheabsenceofsenileplaquesandneuro-fibrillarytangles,andthepresenceofargyrophilicneuronalinclusions(latercalled"Pickbodies")andswollencells(latercalled"Pickcells")atneuropathologicalexamination[2].
However,duringthe20thcentury,thesepatientswithfrontotemporallobardegenerationweregenericallyreferredtoaspatientswithdementia,beingoftendiagnosedwithAlzheimerdisease(AD)[2].
In1994,twomajorresearchgroupsfromLundandManchesterproposedclinicalandneuropathologicalcriteriaforthediagnosisofFTD[3].
In1998,Nearyetal[4]reportedaconsensusonclinicaldiagnosticcriteriaoffrontotemporallobardegenerationintheAmericanAcademyofNeurology(AAN).
FTDoftenbeginswhenthepatientisinthefifthtoseventhdecades.
Epidemiologicalstudiessuggestthat*Correspondence:chenxc998@163.
com1DepartmentofNeurology,UnionHospitalofFujianMedicalUniversity,29XinquanRoad,Fuzhou350001,China2KeyLaboratoryofBrainAgingandNeurodegenerativeDisease;FujianInstituteofGeriatrics,UnionHospitalofFujianMedicalUniversity,29Xinquan,Road,Fuzhou350001,ChinaFulllistofauthorinformationisavailableattheendofthearticleTranslationalNeurodegeneration2013PanandChen;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
PanandChenTranslationalNeurodegeneration2013,2:8http://www.
translationalneurodegeneration.
com/content/2/1/8FTDisthesecondmostcommoncauseofdementiainindividualsyoungerthan65andisjustlesscommonthanAlzheimer'sdisease(AD)withinthisagegroup[2,5].
Ofover65yearsolddementia,theincidenceofFTDranksfourth,thetopthreeisAlzheimer'sdisease,Lewybodydementiaandvasculardementia[5-7].
Theredonotappeartobeanycleargenderdifferencesinsus-ceptibility[8-11].
AmongtheFTDclinicalsyndromes,sexdistributionappearstovaryfromonesubtypetothenext.
SeveralstudiesreportamalepredominanceinbvFTDandSD,andafemalepredominanceinPNFA[5,12].
Thereisawiderangeindurationsofillness(2-20years)partlyreflectingdifferentunderlyingpathologies.
Inthepastfewyears,significantadvanceshavebeenseenintheetiology,pathogenesis,andgenetics,pathologyandclinicalphenotypeofFTD,andmanynewterminologyandclassificationofFTDhaveemerged.
Inthisreview,recentadvancesonthedifferentclinicalvariantphenotypes,neuroimaging,hereditaryforms,pathologicalsubtypesandclinicopathologicalassociationsofFTDwillbediscussed.
FTLDclinicalpresentation:classificationandcharacteristicsFrontotemporallobardegeneration(FTLD)includesagroupofprogressivedegenerativedisorderscharacterisedbyprogressivebehaviouralchange,executivedysfunctionandlanguagedifficulties[13].
UnlikeAD,behavioralsymptomspredominateintheearlystagesofFTLD.
TheclinicalheterogeneityinfamilialandsporadicformsofFTDisremarkable,withpatientsdemonstratingvariablemixturesofdisinhibition,dementia,PSP,CBD,andmotorneurondisease[13,14].
Earlysymptomsaredividedamongcognitive,behavioral,andsometimesmotorabnor-malities,reflectingdegenerationoftheanteriorfrontalandtemporalregions,basalganglia,andmotorneurons[13,14].
FTLDisapowerfulmodeltostudyemotion,socialcognitionandlanguageorganizationinthebrain.
Behavioralvariantfrontotemporaldementia(bvFTD)bvFTDhasthehighestprevalenceamongsttheFTDclinicalsyndromes,accountingforapproximately70%ofallFTDcases[2,5].
TheonsetofbvFTDistypicallybeforetheageof65years,withanaverageonsetageof58years[12,15].
Patientswiththisclinicalvariantpresentwithmarkedchangesinpersonalityandbehaviourandwithrelativepreservationofthecognitivefunctionspraxis,gnosiaandmemory[13,16].
Commonbehavioraldeficitsincludeapathy,disinhibition,weightgain,foodfetishes,compulsions,euphoria,andanabsenceofinsightintotheircondition.
Poorbusinessdecisionsanddifficultyorganizingworktasksarecommon.
Cognitivetestingtypicallyrevealssparedmemorybutimpairedexecutivefunctions[3,13,17].
bvFTDhasbeenassociatedwithsymmetricalventromedialfrontal,orbitalfrontal,andinsularatrophyandleftanteriorcingulateatrophy[18].
BehaviouralassessmentisatthecoreofassessmentinpatientswithpotentialbvFTDandseemstobemoresensitiveindistinguishingbvFTDfromADthanstandardcognitivetesting.
The'InternationalBehavioralVariantFTDCriteriaConsortium'developedinternationalconsensuscriteriaforbvFTD.
Subclassifi-cationsweremadeinpossiblebvFTDdefinedbyclinicalcriteria,probablebvFTDsupportedbyneuroimagingdata,anddefinitebvFTDconfirmationbyneuropathologicalevidenceorapathogenicmutation[17].
Primaryprogressiveaphasia(PPA)PPAisalanguagedisorderthatinvolveschangesintheabilitytospeak,read,writeandunderstandwhatothersaresaying.
Itisassociatedwithearlytemporallobeatrophyorbrainlesionsaroundthelateralfissure.
PPArepresentsaspectrumofselectivelanguagedisordersandthevariantofPPAmightprovidecluestotheunder-lyingpathology[19].
Currentlycerebrospinalfluid(CSF)biomarkershavelimitedabilitytoidentifyPPAreliably,whichmightbeexplainedbythepathologicalheterogeneity.
AnindicationoflowerAβ1-40levelsorthelowerT-tautoAβ1-42ratioinFTD,mightbeusefultodistinguishpatientsfromsubjectsADandcontrolsubjects[20,21].
In2011,criteriawereadoptedfortheclassificationofPPAintothreeclinicalsubtypes:nonfluent/agrammaticvariantPPA(nfvPPAorPNFA),semanticvariantPPA(svPPAorSD)andlogopenicvariantPPA(lvPPA)[22].
TheproposalisanimportantstepforwardinestablishingtheconsistencyofterminologyandclassificationofPPA.
Thediagnosticrecommendationsincludetwosteps.
First,thepatientshouldmeetthebasicstandardofPPA,whichisaninitialpresentationofsignificantdamagetolanguageandaccompaniedbylimiteddailylivingskillsandothercognitiveimpairment.
Second,weneedtoassessthemainlanguagedomains,includingverbalgeneration,repeat,andunderstandingofwordsandsyntax,naming,semanticknowledgeandreading/spellingcharacteristics.
Finally,clinicalvariantswillbedividedbasingonspecificspeechandlanguagefeaturescharacteristicofeachsubtype.
Classificationcanthenbefurtherspecifiedas"imaging-supported"iftheexpectedpatternofatrophyisfoundand"withdefinitepathology"ifpathologicorgeneticdataareavailable.
Therefore,thenewproposalhasaclearpracticalsignificance.
nfvPPAorPNFAisthesecondmostprevalentpres-entationofFTLD,accountingforalarge25%[12].
ThefeatureofnfvPPAincludesgrammaticalerrormakingagrammatismand/orlaboriousspeech,butrelativelypreservedlanguagecomprehension.
Apraxiaofspeech(AOS)ororofacialapraxiaisfrequentlyaccompanyingtheaphasia[15].
SemanticvariantPPA(svPPA)orSDpresentsin20–25%oftheFTLDpatients[12].
svPPAPanandChenTranslationalNeurodegeneration2013,2:8Page2of9http://www.
translationalneurodegeneration.
com/content/2/1/8presentsasignificantlyimpairednamingabilityandwordcomprehension,whilespeechproductionisspared[22,23].
LvPPAorlogopenicprogressiveaphasia[24]ismarkedbyimpairedwordfindinganddifficultrepetition.
lvPPAshowesanimpairedabilitytorepeatsentencesorphrases,spontaneousspeechandasinglewordextractingwhennaming.
UnlikeotherFTDsubtypes,lvPPAgenerallydoesnotproducechangesinbehaviororpersonalityuntillaterstagesofthedisease.
Mostpeoplewithprogressiveaphasiamaintaintheabilitytocareforthemselves,keepupoutsideinterestsand,insomeinstances,remainemployedforafewyearsafteronsetofthedisorder.
LPAismostlyassociatedwithaneuro-pathologicaldiagnosisofAD[25].
ClinicaldistinctionbetweenbvFTD,nfvPPAandsvPPAisoftencomplicatedforthatoverlapoftheclinicalsyndromesbetweenthemcanoccurinadvancedstagesofdisease.
FTLDoverlapswithotherclinicalsyndromeThesubcorticalnucleiandmotorsystemsareinvolvesinFTLDvariants.
Motorneurondysfunction(MND)hasbeendescribedin40%oftheFTLDpatients,referredtoasFTLD-MND.
ThecommoncomorbidityofAmyotrophiclateralsclerosis(ALS)withbehaviorabnormality,cognitiveimpairmentordementiahasbeennoticed[26,27].
FTLDmayprecede,followorcoincidewiththeonsetofmotorsymptoms[28].
OtherdisordersarecloselyrelatedtoFTLD,includingprogressivesupranuclearpalsy(PSP)syndromes,corticobasalsyndrome(CBS),FTDwithparkinsonism(FTDP)andargyrophilicgraindisease(AGD).
PSPandCBSaretwocommonatypicalparkinsoniansyndromesdemonstratingcognitiveandbehaviourdisordersthatoverlapwithFTD.
Ofthem,behavioralandcognitivedysfunctionpromotesthedevelopmentofdementia.
Andextrapyramidalsystemsymptomspresentasbradykinesia,abnormalposture,rigidity,buttremoruncommon.
Theco-occurrenceofAGDinALSisnotuncommon,andcomparablewiththatinanumberofdiseasesbelongingtothetauopathiesorα-synucleinopathies[29].
Motionsystemdamagepresentsasmuscleatrophy.
FTDP-17showinggeneticlinkagetochromosome17,presentswithaclinicalsyn-dromeofautosomaldominantdisinhibition,dementia,parkinsonism,andamyotrophy[30].
TheclinicalpictureresemblesbvFTD,whilecognitivedeficitsincludean-terogradememorydysfunctioninanearlystage,laterthedeteriorationofvisuospatialfunction,orientationandglobalmemoryaregraduallypresented.
Motorsignstypicallyincludethesymmetricalbradykinesiawithoutrestingtremor,incombinationwithaxialrigidityandposturalinstability.
TheearlyclinicalpresentationofAGDissimilartoADbutitislessaggressive,withpatientsmaintainmildcognitiveimpairment(MCI)formanyyears[31].
NeuroimaginginFTLDNeuroimagingplaysacriticalroleindiagnosisofFTD.
NeuroimaginginvestigationscanreliablydifferentiateFTLDsubtypesfromotherdementias,andcanhelpclinicaldiagnosticsbasedonneuropsychiatricsymptoms.
Differentclinicalvariatentshavedifferentformsofbrainatrophy,whichcanbeusedforsomeimportantcluesforearlyclinicaldifferentialdiagnosis.
DTIcandetectwhitematterdamage,differentsubtypesofwhitematterinjuryalsohelpclinicalearlydifferentialdiagnosisofclinicalsubtypesofFTLD[32].
Functionalneuroimagingtechniques,suchas[99mTc]-hexamethylpropyleneamineoximesingle-photonemissioncomputedtomography(SPECT)[33]or[18F]-fluorodeoxyglucose(FDG)-PETareincreasinglybeingusedtohelpwiththediagnosisofFTLD[34].
Arterialspinlabelingimaging(ASL)likeFDG-PETcanbeusedforshowingthehypometabolisminbrainregions.
HypometabolismonFDG-PETisdetectedconsistentlyandreliablyinfrontalbrainregionsinpatientswithbvFTDcomparedwiththosewithAD,whoshowposteriorcingulatehypometabolismearlyinthediseaseprocess[34].
However,inpatientsshowingclearbrainatrophyonstructuralMRI,littleadditionaldiagnosticbenefitisgainedbydoingaPETscan,becausefocalatrophyisapositivepredictivemarkerofFTD.
Theimagingpresen-tationofnfvPPAindicatesthatpredominantleftposteriorfronto-insularatrophyonMRIorpredominantleftposteriorfronto-insularhypoperfusionorhypometabolismonSPECTorPET.
Imaging-supportedsvPPAshowpredominantanteriortemporallobeatrophyand/orthesebrainregionshypoperfusionorhypometabolismonSPECTorPET.
TheimagingoflvPPAmustshowatleastoneofpredominantleftposteriorperisylvianorparietalatrophyonMRIand/orhypoperfusionorhypometabolismonSPECTorPET[22,25,35-37].
FutureinFTLDareverysimilartoimaginginAD–earlydetection,moleculardiagnosis,monitordiseaseprogressionandvalidateandimplementdiseasemodifyingtherapies.
SpecificanatomicpatternsinFTLD,andanamyloid-PETneuroimaging,whichusestheamyloid-β-detecting11C-PittsburghcompoundB,hasshownpromisingresultsindiscriminatingorrule-outatypicalADandFTDcases[38,39]particularlythosepresentingwithlanguagedeficitsratherthanbehaviouralchanges.
MicroPETwith18F-THK523inTautransgenicmicehavebeenreported[40].
Tauspecificimagingscannerthatusesthe18F-THK523maybeapromisingtechniquecomingsooninfuture[40].
FTLDNeuropathologyandcliniconeuropathologicalcorrelationsNeuropathologyThesubtypesofunderlyingpathologicalchangesinpatientswithFTDareclassifiedonthebasisofthePanandChenTranslationalNeurodegeneration2013,2:8Page3of9http://www.
translationalneurodegeneration.
com/content/2/1/8patternofproteindeposition,andarereferredtocollectivelyasfrontotemporallobardegeneration.
Underamicroscope,commonpathologicchangesofFTLDareatrophybrainregionpresentingneuronalloss,spongychangeandgliosisincorticesofatrophiedfrontalandtemporallobes[41,42].
FTDhaveidentifiednovelgeneticdefectsandachromosomallocusinhereditaryformsofFTLD,aswellasnovelclinicneuropathologicalassociations.
Immunohistochemistryallowssubcategorizationofthesedisordersintospecificproteinopathiesbasedonthemajorconstituentoftheinclusions.
(1)FTLD-tau:Onesubtypeispresentedasneuronsandglialcellscontaininginclusionsofhyperphosphorylatedtauprotein,referredtoasFTLD-tau[43].
TaupathologywasassociatedwithFTDwithparkinsonism,PSPsyndromes[44],CBS[45]andAGD[31].
(2)FTLD-UbiquitinorFTLD-U:Over50%oftheFTLDpatientspresentedwithtau-negativeubiquitinstaininginclusions,referredtoasFTLD-UbiquitinorFTLD-U[46].
In80–95%ofthisgroup,inclusionswerefoundtobecomposedoftransactiveresponse(TAR)DNA-bindingprotein43kDa(TDP-43)[47-49],referredtoasFTLD-TDP[50],orTDP-43-negativeFTLD-Ucaseshavinginclusionsoffusedin-sarcomaprotein(FUS),referredtoasFTLD-FUS[43,49,51,52].
However,inasmallnumberofFTLD-Upatients,theinclusionproteinremainsunclear.
ThisgroupisreferredtoasFTLD-ubiquitinproteasomesystem(FTLD-UPS)[46,53].
(3)Dementialackingdistinctivehistopathology(DLDH)[54,55].
(4)Otherraretypes:dementiawithbasophilicinclusionbody,neuronalintermediatefilamentinclusiondisease[52].
AssociationbetweenpathologyandclinicalphenotypeAssociationswerenotedbetweentheclinicalFTLDsubtypesandunderlyingproteinopathies,butastrictonetoonerelationshipislacking.
bvFTDismostlyassociatedwithFTLD-TDP43,somecasesarealsocorrelatedwithFTLD-tau(PiDsubtype).
AnFTLD-FUSproteinopathyisinvariantlyassociatedwithaclinicaldiagnosisofbvFTD,eitherwithorwithoutthesignsofMND.
MicroscopicassessmentofnfaPPAatautopsyoftenrevealsFTLDasso-ciatedwithatauopathy(FTLD-tau).
nfaPPAiscommonlyassociatedwithtaupathology,especiallywhenAOSororofacialapraxiaispresent.
Inmostcases,thepathologyunderlyingnfaPPAwasmixed,includingFTLD-tauandFTLD-TDP43,butwithapredominanceofFTLD-taupathology.
SvPPAis,inmostcases,linkedwithTDP-43-immunoreactivepathology,althoughtaupathologyissometimesobserved.
Somepatientswithpredominantlyrighttemporallobeatrophy(RTLA)areusuallydiagnosedclinicallywitheitherbvFTDorsvPPA[56].
IthasbeensuggestedthatpatientswithbvFTDandRTLAhaveFTLD-taupathology,whereaspatientswithsvPPAandRTLAhaveFTLD-TDP43pathology[56].
svPPApatientswhooftenpresentwithacalculiaisassociatedwithFTLD-tau[57].
LvPAispredominantlyassociatedwithADpathology.
ManypatientswithlvPPAoftenhaveunderlyingADpathology[58-60].
CSFtau:amyloid-βratio[37]andPiBPETimaging[25]studiescanbehelpfulintheidentificationofpatientswhoaremorelikelytohavelvPPAthannfaPPA.
Arecentstudyshowedthat93%ofpatientswithlvPPAonamyloidPETimagingwasfoundPiBpositive,butsvPPAonly9%,nfvPPAis13%,whichsuggeststhatthereissomecommonpathologicalfeaturesbetweenlvPPAandAD[59].
TaupathologywasalsoassociatedwithFTLDwithparkinsonism,PSP,CBD,AGDandPickbodies(PiD)[30,44,61].
Similarly,TDP-43andFUSproteinopathiesarealsocommonlyfoundinMNDwithorwithoutFTLD[52].
Althoughthesearerelativelystrongassociations,theyarenotabsolute,anditiscurrentlynotpossibletopredictwithcertaintytheunderlyingpathologyofspecificFTLDsyndromes.
ExtrapyramidalsystemsymptomsaccompaniedwithapraxiaindicatesthepresenceofCBS,whichmostlyattributestoTaudisease.
WhiledementiawithFTLD-MNDsyndromemostlyattributestoTDP-43pathology[15,45,57].
ThesesuggestthatitiscontributingtotherapeuticstrategyforFTLDthroughelucidatingtherelationshipbetweenpathologicalandclinicalpresentation.
MoleculargeneticsApproximately40%ofpatientswithFTDhaveafamilyhistory[8].
bvFTDisthemostprominentsubtypewithfamilyhistory,especiallywhenconcomitantsymptomsofMNDarepresent(60%),whileSvPPAappearedtobetheleasthereditaryFTLDsubtype(<20%)[62].
Moleculargen-eticstudieshaveidentifiedseveralcommon(MAPT,GRN)andrare(VCP,CHMP2B,TARDBP,FUS)geneticfactorsinhereditaryFTLDoverrecentyears.
In1998microtubuleassociatedproteintau(MAPT)genewasfound,whichlocatedonchromosome17q21.
32,inwhich13%ofthecasesisFTDP-17,thosewhohaveparkinson-likesymptoms[63].
In2004,thegeneencodingvalosin-containingprotein(VCP)genewasfound,locatedonchromosome9p13.
3,whichisassociatedwiththegenesthatcauseFTLDinasso-ciationwithinclusionbodymyopathyandPaget'sdisease[64,65].
In2005,thechargedmultivesicularbodyprotein2B(CHMP2B,alsoknownaschromatin-modifyingprotein2B)genemutations,locatedonchromosome3p11.
2,wasdiscoveredinalargeDanishcohortwithfamilialFTLD[66,67].
In2006,amutatedgenelocatedonchromosomePanandChenTranslationalNeurodegeneration2013,2:8Page4of9http://www.
translationalneurodegeneration.
com/content/2/1/8Table1Clinicalphenotypes,pathologicalandmoleculargeneticspectruminFTLD[13,19,22,35,72,77,78]CoreclinicalfeaturePraxiologicalobstacleLogopathyExtrapyramidalsymptoms+praxiologicalobstacleDyskinesia+praxiologicalobstacleClinicalsyndromeBehavioralvariantFrontotemporaldementia(bvFTD)Primaryprogressiveaphasia(PPA)Corticobasaldegeneration(CBD)progressivesupranuclearpalsy(PSP)FTD-MND/ALSnonfluent/agrammaticvariantPPA(nfvPPA)Semanticsvariation(svPPA)logopenicvariantPPA(lvPPA)BrainmorphologicallyaffectedpartsPrefrontallobeandtemporallobeLeftposteriorfrontallobe,insulaThefront/ventraltemporallobeleftposteriorsuperiortemporallobeandmedialparietallobeFrontalandtemporallobe,BasalgangliaBasalgangliaandbrainstemCortexandmotorneuronBiochemistryandNeuropathologyFTLD-Tau(Picktype,3R-tau)FTLD-TDP43FTLD-TaumorethanFTLD-TDP43,ADlikepathologicalvisibleMostbelongstoFTLD-TDP43;ADlikepathologicalrareAD-likepathologicalcommon;FTLD-TDP43visibleFTLD-Tau(CBDtype,4R-tau)commonFTLD-Tau(PSPtype,4R-tau)commonFTLD-TDP43,FTLD-FUSCausativeandAssociatedGenesC9ORF72PGRN,C9ORF72PGRNMAPTC9ORF72PGRNC9ORF72PGRNMAPTPGRNFUSMAPTMAPTMAPTPGRNC9ORF72C9ORF72VCPVCPVCPVCPVCPVCPCHMP2BCHMP2BCHMP2BCHMP2BCHMP2BNote:3Rtau:threemicrotubulebindingrepeats;4Rtau:fourmicrotubule-bindingrepeats.
PanandChenTranslationalNeurodegeneration2013,2:8Page5of9http://www.
translationalneurodegeneration.
com/content/2/1/817q21.
31areidentifiedasthegranuleproteinprecursor(PGRN),only1.
7MnucleotideawayfromtheMAPT[68,69].
Approximately10%ofpatientswithFTLDisassociatedwiththisgene.
In2011,chromosome9openreadingframe72(C9ORF72)genewasnewlyidentifiedinFTLD[70,71].
Overall,patientswithmutationsinGRN,MAPTandC9ORF72togetheraccountforatleast17%oftotalFTDcases[53,72].
SummedC9ORF72,GRNandMAPTmutationfrequencieswere32-40%[70,73].
MutationsinVCPandCHMP2Barerare,eachexplaininglessthan1%ofthefamilialFTLD.
TheMAPTgenemutationsoftenleadtoFTLD-Taupathologicalchanges.
TheBothPGRNandC9ORF72muta-tionscancauseFTLD-TDP-43.
ThesymmetryfrontallobeatrophyinbvFTDpatientsisassociatedwithC9ORF72andMAPTgenemutations,whereastheasymmetryoffrontallobeatrophyinbvFTDpatientsisassociatedwithPGRNgenemutations[74].
Thelargehexanucleotiderepeatexpansionlocatedwithinthenon-codingportionofC9ORF72isthecauseofchromosome9-linkedALSandFTLD[70].
Thesesuggestthatspecificgenemutationsmayaffectthepatternsofneuroanatomicinjuryinthedevelopmentoffrontallobaratrophy.
C9ORF72isexpressedasthreemajortranscriptsandtheexpandedG4C2repeatislocatedintheproximalregulatoryregionofC9ORF72[70,73],upstreamofoneandinthefirstintronofthetwoothertranscripts.
Repeatexpansionresultsinnearcompletelossofexpressionofthemajorgenetranscripts.
Thepathogenicexpansionwasnon-penetrantinindividualsyoungerthan35years,50%penetrantby58years,andalmostfullypenetrantby80years.
Innormalpopulation,thesizeoftheG4C2repeatrangesfrom3to25units,whichisexpandedtoatleast60unitsinFTLDpatients[70,71,73].
TheclinicalphenotypeofC9ORF72mutationoftenpresentsasbvFTDorALSorFTDco-morbiditiesALS.
InpatientswithbvFTD,C9ORF72mutationismorecommonthanMAPTorPGRN.
Anxietyoragitation,andmemorydysfunction(oftenepisodicmemory)isacommonclinicalfeature.
Thosecasesunderlinesthatthehexanucleotiderepeatexpansioninchromosome9couldbealsoassociatedwithearlyonsetpsychiatricpresentations[75].
Overexpressedp-62inclusionbodylesionsinthecere-bellumisoneofpathologicalfeatures[76].
Neuroimagingpresentsasthesymmetricalfrontaland/ortemporallobeatrophy,andparietal,occipitalandcerebellaratrophycanalsoappear.
Therefore,C9ORF72mutationisnotonlyas-sociatedwithcorticalanatomicsitebutalsowithsub-corticalstructures.
However,itisunclearfortheexactmechanismofactionofthis"repeatamplificationC9ORF72gene".
TheclinicalandpathologicalheterogeneityinFTLDcausesachallengefordiagnosisofFTLD.
AhelpfulTable2TheprofileofmaingenesmutationanditspossiblediseasemechanismsinFTLDGenesymbolMAPTC9ORF72PGRNVCPCHMP2BFullnameMicrotubule-associatedproteintauChromosome9openreadingframe72ProgranulinValosincontainingproteinChromatinmodifyingprotein2BChromosomallocalization17q21.
329p21.
217q21.
329p13.
33p11.
2.
MAPTgivesrisetosixisoforms:threeisoformscontainingthreeamino-acidrepeats(3R),andthreeisoformswithfourrepeats(4R)[79].
expressedasthreemajortranscripts,theexpandedG4C2repeatislocatedintheproximalregulatoryregionofC9ORF72[70,73].
encodesprogranulin,aubiquitouslyexpressedgrowthfactorprecursorconsistingof7.
5granulinpeptides.
EncodesaubiquitouslyexpressedmemberofafamilyofATPasesassociatedwithawiderangeofcellularfunctions[85].
EncodesacomponentoftheheteromericESCRT-IIIcomplexwithfunctionsintheendosomal-lysosomalandtheautophagicproteindegradationpathway.
FunctionsandpossibleroleinthediseasemechanismMutationsresultinachangeinratioof3Rto4Rtauisoforms.
Mutationsaffectthenormalfunctionofthetauproteintostabilisemicrotubules,increasethetendencyoftautoformneurotoxicaggregatesanddisturbneuronalplasticityandaxonaltransport[80].
Repeatexpansionresultsinnearcompletelossofthemajorgenetranscripts.
AndaccumulationoftranscriptsharboringtheexpandedG4C2repeatinnuclearRNAfoci[70].
awiderangeofbiologicalprocessessuchasinflammationandwoundrepair,orinpathologicalconditionsincludingtumorigenesis[82].
mutationsresideattheinterfacebetweentheD1ATPaseandtheN-domainoftheCDC48-likeprotein[85].
Expressedinneuronsofallmajorbrainregions.
Itiscriticalfordevelopment,sexualdifferentiation[88]andneuronalsurvival[89].
G4C2repeatleadstoneuronalcytoplasmicinclusionsthroughouttheentirecorticalthickness[81].
Neurotrophicfunctioninvolvedinneuronalsurvivalandneuriteoutgrowth[83,84].
mutationsdisturbubiquitin-proteasomemediatedproteindegradation,autophagy,orboth[86,87].
MutationsaffecttheC-terminalendoftheproteinduetoaberrantsplicing[78].
unidentifiedmechanismsexist.
Estimatedmutationfrequency[69,72,79,81,90]0-50%14-48%3–26%<1%<1%PanandChenTranslationalNeurodegeneration2013,2:8Page6of9http://www.
translationalneurodegeneration.
com/content/2/1/8supplementforclinicalevaluationusinggeneticsandbiologicalmarkerstestingcansignificantlyimprovetheforecastofpotentialhistopathologyinvivo.
Wesummarizeclinicalphenotypes,molecularpathologicalandgeneticspectruminFTLDinTable1.
Andtheprofileofmaingenesmutationsanditspossiblediseasemecha-nismsinFTLDisshowninTable2.
ConclusionInthisreview,wehavesystematicallyupdatedcurrentunderstandingonclinical,genetic,neuropathological,andneuroimagingperspectivesofFTD.
ThisreviewaimstoarouseawarenessofFTDamongclinicians,inpar-ticularwhentheoverlappingclinicalandneuroimagingcharacteristicfeaturesamongdementiaanddifferentsubtypesofFTDremaingreatchallengesforclinicians.
IdentificationofbiomarkersforclinicaldiagnosisanddifferentiationFTDfromotherdementiaiswarrantedforfuturestudies.
Genediagnosistestshouldbecon-sideredforfamilialcasessuspectedwithFTDinclinicpractice.
Longitudinalclinicopathologicalcorrelationstudieswillfurtherelucidatethenetworkfunctionsofhumanbraininthiscomplexdisorderwithbehaviour,speechandmotorabnormality.
Withfurtherunder-standingofthegenetics,clinicalandneuropathologicalbasisofFTD,wecanvisualisethatFTDwillbefurtherclinicallydefined.
Andnewconsensuswillbedevelopedforbetterguidanceinclinicalpractice.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsXdPcollectedthereferencematerialsanddraftedthemanuscript.
XcCrevisedthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsThisworkwassupportedbythegrantsfromtheNationalNaturalScienceFoundationofChina(81200991),OutstandingYoungPersons'ResearchProgramforHigherEducationofFujianProvince,China(JA10123),MajorProjectofFujianScienceandTechnologyBureau(2009D061).
Authordetails1DepartmentofNeurology,UnionHospitalofFujianMedicalUniversity,29XinquanRoad,Fuzhou350001,China.
2KeyLaboratoryofBrainAgingandNeurodegenerativeDisease;FujianInstituteofGeriatrics,UnionHospitalofFujianMedicalUniversity,29Xinquan,Road,Fuzhou350001,China.
3CentreofNeurobiology,FujianMedicalUniversity,88JiaotongRoad,Fuzhou350001,China.
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