Change in the Cortical Complexity of Spinocerebellar Ataxia Type 3 Appears Earlier than Clinical ...

18 Pages·2015·1.13 MB·English

RESEARCHARTICLE
Change in the Cortical Complexity of
Spinocerebellar Ataxia Type 3 Appears Earlier
than Clinical Symptoms
Tzu-YunWang1☯,Chii-WenJao1,2☯,Bing-WenSoong3,4,Hsiu-MeiWu5,Kuo-KaiShyu6,
Po-ShanWang3,4,7,8*,Yu-TeWu1,8*
1 DepartmentofBiomedicalImagingandRadiologicalSciences,NationalYang-MingUniversity,Taipei,
Taiwan,ROC,2 DepartmentofRecreationSportsandHealthPromotion,Asia-PacificInstituteofCreativity,
Tao-Fen,Taiwan,ROC,3 TheNeurologicalInstitute,TaipeiVeteransGeneralHospital,Taipei,Taiwan,
ROC,4 DepartmentofNeurology,NationalYang-MingUniversitySchoolofMedicine,Taipei,Taiwan,ROC,
5 DepartmentofRadiology,TaipeiVeteransGeneralHospital,Taipei,Taiwan,ROC,6 Departmentof
ElectricalEngineering,NationalCentralUniversity,Chung-Li,Taiwan,ROC,7 TheNeurologicalInstitute,
TaipeiMunicipalGan-DauHospital,Taipei,Taiwan,ROC,8 InstituteofBiophotonics,NationalYang-Ming
University,Taipei,Taiwan,ROC
☯Theseauthorscontributedequallytothiswork.
* [email protected](YTW); [email protected](PSW)
OPENACCESS
Citation:WangT-Y,JaoC-W,SoongB-W,WuH-M,
Abstract
ShyuK-K,WangP-S,etal.(2015)Changeinthe
CorticalComplexityofSpinocerebellarAtaxiaType3
AppearsEarlierthanClinicalSymptoms.PLoSONE Patientswithspinocerebellarataxiatype3(SCA3)haveexhibitedcerebralcorticalinvolve-
10(4):e0118828.doi:10.1371/journal.pone.0118828
mentandvariousmentaldeficitsinpreviousstudies.Clinically,conventionalmeasure-
AcademicEditor:RalfKrahe,UniversityofTexas ments,suchastheMini-MentalStateExamination(MMSE)andelectroencephalography
MDAndersonCancerCenter,UNITEDSTATES
(EEG),areinsensitivetocerebralcorticalinvolvementandmentaldeficitsassociatedwith
Received:July17,2014 SCA3,particularlyattheearlystageofthedisease.Weappliedathree-dimensionalfractal
Accepted:November24,2014 dimension(3D-FD)method,whichcanbeusedtoquantifytheshapecomplexityofcortical
folding,inassessingcorticaldegeneration.Weevaluated48geneticallyconfirmedSCA3
Published:April21,2015
patientsbyemployingclinicalscalesandmagneticresonanceimagingandusing50healthy
Copyright:©2015Wangetal.Thisisanopen
participantsasacontrolgroup.AccordingtotheScalefortheAssessmentandRatingof
accessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense,whichpermits Ataxia(SARA),theSCA3patientswerediagnosedwithcorticaldysfunctioninthecerebellar
unrestricteduse,distribution,andreproductioninany cortex;however,nosignificantdifferenceinthecerebralcortexwasobservedaccordingto
medium,providedtheoriginalauthorandsourceare thepatients’MMSEratings.Usingthe3D-FDmethod,wedeterminedthatcorticalinvolve-
credited.
mentwasmoreextensivethaninvolvementoftraditionalolivopontocerebellarregionsand
DataAvailabilityStatement:Allrelevantdataare
thecorticocerebellarsystem.Moreover,thesignificantcorrelationbetweendecreased3D-
withinthepaper.
FDvaluesanddiseasedurationmayindicateatrophyofthecerebellarcortexandcerebral
Funding:ThisworkwassupportedbytheNational
cortexinSCA3patients.ThechangeofthecerebralcomplexityintheSCA3patientscanbe
ScienceCouncilsupportedfortheCenterfor
detectedthroughoutthediseaseduration,especiallyitbecomessubstantialatthelate
DynamicalBiomarkersandTranslationalMedicine,
NationalCentralUniversity,Taiwan(NSC102-2911-I- stageofthedisease.Furthermore,wedeterminedthatatrophyofthecerebralcortexmay
008-001),BrainResearchCenter,NationalYang- occurearlierthanchangesinMMSEscoresandEEGsignals.
MingUniversityandagrantfromMinistryof
Education,AimfortheTopUniversityPlan,and
NationalScienceCouncil(103-2221-E-010-003-MY3
and101-2314-B-733-001-MY2).Thefundershadno
roleinstudydesign,datacollectionandanalysis,
decisiontopublish,orpreparationofthemanuscript.
PLOSONE|DOI:10.1371/journal.pone.0118828 April21,2015 1/18
ChangeintheCorticalComplexityofSCA3
CompetingInterests:Theauthorshavedeclared Introduction
thatnocompetinginterestsexist.
Spinocerebellarataxiatype3(SCA3)isahereditaryneurodegenerativedisordercausedby
CAGexpansioninthecodingregionofchromosome14q32.1[1,2].Clinically,SCA3patients
arecharacterizedbyprominentandprogressivecerebellarataxiacombinedwithdegeneration
ofthecerebellumanditsafferentandefferentconnections[3].Recentstudieshaveindicated
thatSCA3patientsexhibitmentaldeficits,suchascognitiveimpairmentinexecutivefunctions,
verbalandvisualmemory,visuoconstruction,visualattention,andemotionaldeficits[4–6].
Currently,anincreasingamountofevidencehasindicatedtheinvolvementofthecerebral
cortexinSCA3[7,8].Mutantataxin-3proteinshavebeenobservedincerebralcortexand
couldcontributetothedegenerationofnervecells[9].Moreover,subclinicalabnormalitiesin
thecerebralcortexhavebeenidentifiedinfunctional[10,11]andneuropathologicalstudies
[12].Voxel-basedmorphometry(VBM)haveindicatedinvolvementofvariousregionsofthe
cerebrum,includingthefrontalandtemporallobes[13];temporalgyrus,bilateralinferiortem-
poralgyrus,andcingulategyrus[14];putamen,cingulum,precentral,andparietallobe[15];
andbilateralputamenandpallidum[16].However,thesitesofcerebralinvolvementinSCA3
wereinconsistentintheseVBMstudies[17,18].
Measuringthecorticalshapecanprovideanalternativetothevolumetricmethodforassess-
ingmorphologicalchangesinthebrain.Fractalanalysis,gyrificationindexandcurvedness
havebeenproposedtoquantifythestructuralcomplexityofthecortexandselectabnormalities
inthecorticalstructureinpatientswithmovementdisorders[19–31].Fractalanalysishas
showndecreasedcorticalcomplexityinpatientswithmentaldisorderscomparingtonormal
controls[32–35].Inaddition,fractalanalysishasbeenusedtoinvestigaterelationshipbetween
corticalcomplexityandintelligenceaswellascognitiveability[36–38].
InSCA3patients,motor-relateddysfunctionhasgenerallybeenassessedusingtheSARA
[39];however,noreliableandeasilyimplementedmeasureofmentaldeclineinSCA3patients
hasbeendeveloped.TheextracerebellarsymptomsofSCA3wererecentlyassessedusingthe
InventoryofNon-AtaxiaSymptoms(INAS)[40].However,theINASscoreisadimensionless
valueandcannotbeusedtomeasuretheseverityofSCA3[16].Previousstudieshaveshown
thatthedegreeofcorticaldegeneration,whichwasquantifiedusingfractaldimension(FD)
analysis,canindicatetheseverityofneurodegenerativedisorders[22,23].AFDanalysisthat
condensesallofthestructuraldetailsofanirregularobjectintoasinglenumericvalueisadvan-
tageousforproducingresultswithsmallerstandarddeviationsandsexeffectscomparedwith
thetraditionalvolumetricmethod[21,23].Thismethodcanbeusedforeffectivelymeasuring
structuralcorticalchangesinboththecerebellarandextracerebellarregionsandfacilitated
evaluatingtheseverityofthecorticalatrophyinthisSCA3study.
Inaddition,researchershavedelineatedthediseaseprogressionofcorticaldysfunctionin
SCA3patients[3,16,41,42].However,fewstudieshavereportedtheassociationbetweenthe
diseaseprogressionofcerebraldysfunctionandcorticalabnormalityinSCA3patients.D'Ab-
reu,Franca,etal.(2012)couldnotdeterminetheprogressionofatrophywithinashortdura-
tionbyusingmagneticresonancespectroscopy,andReetz,Costa,etal.(2013)reportedthat
diseaseprogressionwaslimitedintheputamenandcaudatenucleus,inadditiontocerebellum
[16,42].
Inthisstudy,wecombinedtheclinicalfeaturesofSCA3andtheFDmethodto(1)identify
thepatternofaffectedregionsinthecortexofSCA3patientsbymeasuringtheregionalcorti-
calchangesthatoccurinsupratentorialregions,(2)distinguishwhethercorticalcomplexityis
associatedwiththeclinicalsymptoms,suchasMMSEandEEGsignals,observedinSCA3,
and(3)investigatethecorrelationbetweentheprogressionofcerebraldysfunctionand
cerebellardysfunction.
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ChangeintheCorticalComplexityofSCA3
MaterialsandMethods
1.Participants
TheInstitutionalReviewBoardofTaipeiVeteransGeneralHospitalapprovedthisstudy.All
participantsprovidedwritteninformedconsentbeforeparticipating.Forty-eightSCA3patients
wererecruitedfrom2005to2012.Agroupof50healthyvolunteerswerematchedaccordingto
age,sex,andyearsofeducation,servingasacontrolgroup.Anataxialclinicalassessmentofall
ofthepatientswasconductedusingSARAscoresandmodifiedHoehnandYahrstaging[43].
Inaddition,17patientsreceivedroutineelectroencephalography(EEG)examinationsand14
patientswereassessedusingtheMMSE[44].Table1showsthedemographic,clinical,andMRI
dataforbothgroups.SCA3patientswhoexperiencedprogressiveandotherwiseunexplained
ataxiaandtestedpositivefortheSCAtype3genotypewereincludedinthisstudy.Thedisease
durationoftheSCA3patientswas8.89±6.432years.Tofurtherinvestigatethedifferencein
corticalchangeaccordingtodiseaseduration,weseparatedtheSCA3patientsintotwogroups:
anearlystagegroup(23patientsofwhomthediseasedurationwasshorterthan8years)anda
latestagegroup(25patientsofwhomthediseasedurationwaslongerthan8years).
Themembersofthecontrolgrouphadnocentralnervoussystemdiseaseandexhibitedno
neurologicalabnormalitiesduringthestudyperiod.Anexperiencedneuroradiologistexam-
inedtheT1-andT2-weightedimagesofthecontrolgrouptoensuretheabsenceoflatentneu-
rologicaldiseasesorunexpectedabnormalities.
2.Electroencephalography
2.1Recording. TheEEGdatawerecollectedwhentheparticipantsweresittingrelaxed
andwiththeireyesclosed.Alertnesswascontinuallymonitoredtopreventdrowsiness.The
EEGswererecordedusinga19-channeldigitalportableEEGmachine(NicoletBiomedical
Inc.,Madison,WI)for5minutes.Allelectrodeswereplacedbasedontheconfigurationofthe
international10–20systemwithalinkedearreference(meanEEGsignalofelectrodesatbilat-
eralears).Electrodeskinimpedancewasusuallylessthan3kO.Thesignalsweredigitizedata
rateof256Hzbyusinga12-bitanalogue-to-digitalconverterandprocessedusingananalo-
gousband-passfilter(0.05−70Hz)anda60-Hznotchfilter.
Table1. Thedemographic,clinical,andMRimagedataofcontrolandpatientgroups.
Characteristic Group
Controls(N=50) SCA3Patients(N=48) pvalue
Sex(F/M) 25/25 21/27 0.535a
Age(years)† 48.24±13.956 48.13±11.747 0.516b
Duration(years)† — 8.89±6.432 —
SARA† — 14±8.103 —
H&Ystaging† — 2.88±1.19 —
MMSE† — 28.5±1.61 —
EEGsignalsobservation(abnormal/normal) — 5/12 —
Cerebralatrophyobservedviavisualinspection — 9 —
Cerebellaratrophyobservedviavisualinspection — 39 —
SARA=ScalefortheAssessmentandRatingofAtaxia;MMSE=Mini-MentalStateExamination;H&Ystaging=HoehnandYahrStagingScale
aPearson'schisquaretest(χ2=0.384);
btwo-tailedtwo-samplet-test;
†Continuousvariablesareexpressedasmean±standarddeviation(SD);
doi:10.1371/journal.pone.0118828.t001
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ChangeintheCorticalComplexityofSCA3
2.2CriteriaoftheabnormalityinEEG. AbnormalEEGpatternsoftheSCA3patients
wereidentifiedbyexperiencedneurologists,whichincludedspikes,intermittentslowactivity,
diffusebackgroundslowingandfrontalandoccipitalintermittentrhythmicdeltaactivity.Ex-
periencedneurologistsexaminedalltheEEGrecordingswithoutpriorinformingthatthesere-
cordingscollectedfromSCA3patientsorotherparticipants.
3.Magneticresonanceimagingscan
3.1Dataacquisition. AxialMRbrainimagesencompassingtheentirecerebrumandcere-
bellumwereacquiredusinga1.5-TVisionSiemensscanner(Erlangen,Germany).Thepartici-
pantswerescannedusingacircularlypolarizedheadcoiltoobtaintheT1-weightedimages
(TR,14.4ms;TE,5.5ms;matrixsize:256×256;1.5-mmaxialslices;FOV=256mm×256
mm;voxelsize,1.0×1.0×1.5mm).
3.2Dataprocessing. TheacquiredT1-weightedimageofeachparticipantwasreformatted
intoanaxialimageandconvertedtotheAnalyzeformatbyusingMRIcrosoftware(ChrisRor-
den,UniversityofNottingham,UK;www.sph.sc.edu/comd/rorden/mricro.html).Fig1shows
thedata-processingflowchart.Toimprovetheaccuracyofbraintissueextraction,anautomatic
skull-strippingfunctionwasappliedtotheimagevolumesbyusingthebrainextractiontoolin
theMRIcrosoftware(Fig1a).Fig1bshowsthenormalizationprocess,whichwasconducted
usingDiffeoMap(Li,X.;Jiang,H.;andMori,S.;JohnsHopkinsUniversity,www.MriStudio.org).
Inthisprocedure,a12-parameteraffinetransformation(AIR;Woods,Grafton[45])wasusedto
normalizeeachT1-weightedimagetowardtheJHU_MNI_SS_T_ssT1template.
3.3Atlasextraction. ImagedataprocessingwasconductedusingtheSPM5
toolbox(WelcomeDepartmentofCognitiveNeurology,InstituteofNeurology,University
CollegeLondon,London,UK,http://www.fil.ion.ucl.ac.uk/spm/)andtheIndividualBrainAt-
lasesusingStatisticalParametricMapping(IBASPM;http://www.thomaskoenig.ch/Lester/
ibaspm.htm)toolboxinMATLAB7.0software(Mathworks,Natick,MA,USA).Thisprocess
consistedofthefollowingsteps:(1)thenormalizedimagevolumewassegmentedintogray
matter,whitematter,andcerebralspinalfluidinnativespace(Fig1c),and(2)thegraymatter
imagewastransformedintoMontrealNeurologicalInstitutespace[46],andeachvoxelofgray
matterwasanatomicallyassignedtooneofthe116automaticanatomicallabelstructuresby
usingIBASPM[46](Fig1d).The26regionsofthecerebellumwerethenmergedinto7regions
Fig1.Procedureforimagepreprocessing.EachvoxelofgraymatterineveryT1-weightedimagewas
anatomicallyassignedtotheresulting97labeledbrainregions,whichweredisplayedindifferentcolorsinthe
lowerrightpanel.
doi:10.1371/journal.pone.0118828.g001
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ChangeintheCorticalComplexityofSCA3
accordingtotheiranatomicalstructures,andthevolumesof97labeled(45foreachcerebral
hemisphere;Table2)brainstructureswereextractedforeachparticipant(Fig1e).
3.4Three-dimensionalbox-countingmethodforfractalanalysis. Mandelbrotoriginally
proposedfractalanalysistoquantifytheshapecomplexityofobjectsintoasinglenumerical
value[47].Becausefractalanalysisinvolvestopologicallymeasuringcomplexity,ahighFD
valuerepresentsahighdegreeoftopologicalcomplexityintheexaminedtissue[48].Inthis
study,weadoptedthe3Dbox-countingmethodbecauseitcanbeusedtoevaluatetheFDof
structureswithorwithoutself-similarity[26,48].Thus,weobtainedthe3D-FDvaluesof97re-
gionsofgraymatterfromtheentirebrainforeachparticipant.Thealgorithmofbox-counting
methodwasillustratedinourpreviousstudies[22].
4.Statisticalanalysis
ThenormalityofeachdatagroupwasverifiedusingtheJarque-Beratest[49].Thesexandage
differencesbetweenthegroupsweremeasuredusingthePearsonchi-squaretest(χ2=0.384,
p=0.535)andthe2-tailed2-samplettest(p=0.516),respectively.
WeusedPearson’srmeasurementtoinvestigatethecorrelationsbetweendiseaseduration
andSARAscoresandbetweendiseasedurationandMMSEscores.The2-tailedttestwasused
todeterminewhetherthe3D-FDvaluesofeachcorticalregiondifferedsignificantlybetween
thecontrolgroupandtheSCA3group.Thesignificanceoftheresultswascorrectedaccording
tothefalsediscoveryrate(thresholdof0.05)[50].
Table2. Corticalandsub-corticalregionsdefinedinAutomatedAnatomicalLabelingtemplateimageinstandardstereotaxicspace(Eachregion
isdivideintoleftandright).
Regionname Abbreviation Regionname Abbreviation
Precentralgyrus PreCG Lingualgyrus LIN
Superiorfrontalgyrus SFG Superioroccipitalgyrus SOG
Orbitofrontalcortex(superior) ORBsup Middleoccipitalgyrus MOG
Middlefrontalgyrus MFG Inferioroccipitalgyrus IOG
Orbitofrontalcortex(superior-medial) ORBsupmed Fusiformgyrus FUG
Inferiorfrontalgyrus(opercular) IFGoper Postcentralgyrus PostCG
Inferiorfrontalgyrus(triangular) IFGtraing Superiorparietalgyrus SPG
Orbitofrontalcortex(inferior) ORBinf Inferiorparietalgyrus IPG
Rolandicoperculum ROL Supramarginalgyrus SM
Supplementarymotorarea SMA Angulargyrus ANG
Olfactorycortex OLF Precuneus PCUN
Superiorfrontalgyrus(medial) SFGmed Paracentrallobule PL
Orbitofrontalcortex(middle) ORBmid Caudatenucleus CAU
Gyrusrectus REG Lenticularnucleus,putamen PUT
Insula INS Lenticularnucleus,pallidum PAL
Anteriorcingulategyrus ACC Thalamus THA
Middlecingulategyrus MCC Heschlgyrus HES
Posteriorcingulategyrus PCC Superiortemporalgyrus STG
Hippocampus HIP Temporalpole(superior) TPOsup
Parahippocampalgyrus PHIP Middletemporalgyrus MTG
Amygdala AMY Temporalpole(middle) TPOmid
Calcarinefissureandsurroundingcortex CAL Inferiortemporalgyrus ITG
Cuneus CUN
doi:10.1371/journal.pone.0118828.t002
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ChangeintheCorticalComplexityofSCA3
Themagnitudeoftheassociationbetweenthe3D-FDvalueofindividualbrainregionsand
clinicalfeatures,suchasdiseaseduration,SARAscores,andMMSEscores,wasdetermined
usingPearson’srmeasurement.Weconductedmultiplelinearregressionstoverifytheassocia-
tionbetweendiseasedurationand3D-FDvalues(asadependentvariable),withagecontrolled.
Inaddition,weexploredthedifferencesintheprogressionrateineachparcellatedregionof
thecerebralcortexbyusinganANOVA(withaBonferronitestforposthocanalyses).These
analyseswereconductedusingtheStatisticsToolboxinMATLAB7.0.
Results
SCA3patientsexhibitedcorticaldysfunctioninthecerebellarcortex
(SARA),butnosignificantdifferenceinthecerebralcortex(MMSE)
Fig2showsthevariationintheSARAandMMSEscoresof14SCA3patientswithrespectto
thedurationofdisease.TheresultsindicatedthattheSARAscoresofSCA3patientssignifi-
cantlyincreasedasthedurationofthediseaseincreased(r=0.5672;p=0.0344).TheSCA3pa-
tientsexhibitednocorrelationbetweenMMSEscoresanddiseaseduration(r=-0.2138;
p=0.4100),andonlyoneoftheSCA3patientsmetthecriteriafordementia(MMSE<26).
Inaddition,5of17SCA3patientsexhibitedabnormalEEGsignalsinthecerebralhemi-
sphere.Specifically,3of5SCA3patientswithabnormalEEGrecordingshowintermittent
slowing,and2of5SCA3patientswithabnormalEEGrecordingexhibiteddiffusebackground
slowing.WeaccordinglyclassifiedtheSCA3patientsinto2groups:SCA3patientswithabnor-
malEEGsignals(5cases)andSCA3patientswithnormalEEGsignals(12cases).Thedisease
durationsofSCA3patientswithabnormalEEGsignalshasthetrendtobelongerthanthatof
SCA3patientswithnormalEEGsignals(durationforSCA3patientswithabnormalEEGsig-
nals:13.3±5.57;durationforSCA3patientswithnormalEEGsignals:6.71±3.51).
Fig2.ThecorticaldysfunctionofSCA3patientsincerebellarcortex(SARA;leftverticalaxis)andin
cerebralcortex(MMSE;reightverticalaxis)wereincoherent.Theresultshowssignificantlyincreasing
SARAscoresthroughoutdurationofdisease(r=0.5672;p=0.0344),butnonsignificantcorrelationbetween
MMSEscoresanddurationofdisease(r=-0.2138;p=0.4100).(SARA:Y=0.72494x+7.6755;MMSE:
Yp=-0.0182x+28.6531).
doi:10.1371/journal.pone.0118828.g002
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ChangeintheCorticalComplexityofSCA3
Significantcorrelationbetweendecreased3D-FDvaluesanddisease
durationinSCA3
The3D-FDvaluesofthecerebellarcortexandcerebralcortexoftheSCA3patientsexhibited
significantdecreasescomparedwiththoseofthecontrolparticipants(Fig3aandFig4a).We
observedasignificantcorrelationbetweendecreased3D-FDvaluesofboththecerebraland
cerebellarcorticesanddiseasedurationintheSCA3patients(Fig3bandFig4b).
ChangeofthecerebralcortexinSCA3patientswasmoresubstantialat
thelatestageofthedisease
TheSCA3patientsexhibitedasignificantcorrelationbetweenthe3D-FDvaluesofthecerebel-
larcortexandSARAscores(r=−0.3346;p=0.023).However,thecorrelationbetweenthe
Fig3.CerebralcortexofSCA3patients.(a)significantdecreasein3D-FDvaluesincomparisonwiththat
ofnormalsubjects.(b)Asignificantcorrelationwasobservedbetweendecreased3D-FDvaluesanddisease
durationincerebralcortexofSCA3(r=-0.0330,p=0.0287).
doi:10.1371/journal.pone.0118828.g003
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ChangeintheCorticalComplexityofSCA3
Fig4.CerebellarcortexofSCA3patients.(a)significantdecreasein3D-FDvaluesincomparisonwiththat
ofnormalsubjects.(b)Asignificantcorrelationwasobservedbetweendecreased3D-FDvaluesanddisease
durationincerebellarcortexofSCA3(r=-0.0318,p=0.0354).
doi:10.1371/journal.pone.0118828.g004
3D-FDvaluesofthecerebralcortexandMMSEscoresintheSCA3patientswasnonsignificant.
Whenweusedthe3D-FDmethod,theSCA3patientsexhibitedsignificantlydecreasedFDval-
ues,evenattheearlystage.Themean3D-FDvaluesoftheSCA3patientsattheearlystage
weregreaterthanthoseatthelatestageofthedisease(Fig5aandFig5b).Thisresultsuggested
thatcorticalatrophyismoreapparentatthelatestagethanattheearlystageofthedisease.
WidespreadinvolvementofthesupratentorialregionsinSCA3patients
3D-FDanalysisindicatedthat37parcellatedregionsofthecerebralandcerebellarcorticesex-
hibitedsignificantregionalvariationintheSCA3patientscomparedwiththecontrols(Table3).
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ChangeintheCorticalComplexityofSCA3
Fig5.Significantdifferencesof3D-FDvaluesbetweenSCA3patientsandnormalsubjectsatearly
stageandlatestageofdisease.(a)Thecerebralcortex.(b)Thecerebellarcortex.SCA3showssignificant
decreased3D-FDvaluesatboththeearlyandlatestageofdisease.Comparingthemeanvaluesof3D-FD
valuesatearlystageofdiseasewiththatatlatestage,thecorticalatrophyinSCA3patientwasmore
substantialatthelatestageofdisease.
doi:10.1371/journal.pone.0118828.g005
Amongtheparcellatedregions,32werelocatedinthecerebralcortexand5werelocatedinthe
cerebellarcortex(Fig6).Notably,theposteriorlobeofthecerebellarcortexshowsignificantde-
creaseinSCA3patients.Inaddition,unlikepreviousstudiesbasedonthevolumetricmethodor
postmortemanalysis[51],ourstudyrevealednosignificantdifferenceinthe3D-FDvaluesof
thebilateralthalamusbetweentheSCA3patientsandthehealthyparticipants.Wespeculated
thatthethalamusmayshrinkbutretainitsshape,andthatthetopologicalcomplexityofanat-
rophiedthalamusmaynotchange.Consequently,atrophyofthethalamusmightnotbede-
tectedusingtheFDmethod.
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ChangeintheCorticalComplexityofSCA3
Table3. Brainregionswithsignificantdifferencein3D-FDvaluesbetweennormalcontrolandSCA3patients.
Regionname Side Mean±std Mean±std p-value
Cerebellarcortex
Entirecerebellarcortex — 2.558±0.024 2.531±0.035 <0.001*
anterior_lobeofcerebellarcortex L 2.168±0.037 2.110±0.069 <0.001*
R 2.152±0.04 2.030±0.08 <0.001*
posterior_lobe_upperofcerebellarcortex L 2.472±0.025 2.452±0.04 0.004*
R 2.481±0.03 2.441±0.036 <0.001*
Vermis — 2.154±0.048 2.118±0.043 <0.001*
Cereberalcortex
Entirecerebralcortex — 2.536±0.024 2.506±0.025 <0.001*
Frontallobe
Precentralgyrus L 2.146±0.066 2.067±0.07 <0.001*
Superiorfrontalgyrus L 2.078±0.033 2.045±0.051 <0.001*
R 2.132±0.04 2.099±0.057 0.001*
Middlefrontalgyrus L 2.278±0.035 2.247±0.04 <0.001*
Orbitofrontalcortex(superior-medial) L 2.109±0.039 2.084±0.054 0.009*
R 2.138±0.04 2.101±0.047 <0.001*
Inferiorfrontalgyrus(opercular) R 2.099±0.05 2.067±0.05 0.002*
Inferiorfrontalgyrus(triangular) L 2.266±0.042 2.229±0.047 <0.001*
Supplementarymotorarea L 2.187±0.049 2.135±0.047 <0.001*
Superiorfrontalgyrus(medial) L 2.173±0.041 2.124±0.061 <0.001*
R 2.087±0.05 2.057±0.067 0.014*
Paracentrallobule L 2.044±0.067 1.996±0.075 0.001*
R 1.978±0.07 1.921±0.08 <0.001*
Parietallobe
Postcentralgyrus L 2.173±0.054 2.100±0.057 <0.001*
Superiorparietalgyrus L 2.095±0.055 2.028±0.063 <0.001*
R 2.075±0.06 2.038±0.072 0.007*
Inferiorparietalgyrus L 2.193±0.066 2.093±0.078 <0.001*
Supramarginalgyrus L 2.111±0.054 2.044±0.062 <0.001*
Angulargyrus L 2.123±0.073 2.000±0.09 <0.001*
Precuneus L 2.212±0.033 2.169±0.049 <0.001*
R 2.137±0.04 2.100±0.044 <0.001*
Occipitallobe
Calcarinefissureandsurroundingcortex L 2.249±0.039 2.217±0.038 <0.001*
Cuneus L 2.129±0.038 2.109±0.043 0.013*
Lingualgyrus L 2.202±0.038 2.168±0.045 <0.001*
Superioroccipitalgyrus L 1.950±0.064 1.891±0.076 <0.001*
Middleoccipitalgyrus L 2.191±0.045 2.124±0.068 <0.001*
Temporallobe
Superiortemporalgyrus L 2.181±0.051 2.120±0.053 <0.001*
Middletemporalgyrus L 2.336±0.034 2.303±0.048 <0.001*
Limbicsystem
Posteriorcingulategyrus L 1.989±0.054 1.945±0.05 <0.001*
Parahippocampalgyrus R 2.142±0.03 2.157±0.031 0.011*
Subcorticalregions
Amygdala R 1.944±0.04 1.968±0.042 0.005*
(Continued)
PLOSONE|DOI:10.1371/journal.pone.0118828 April21,2015 10/18