Diffusion tensor imaging and disability progression in multiple sclerosis : a 4-year follow-up study

B ain and Beha io . 2019;9:e01194.   | 1 o 10 h ps://doi.o g/10.1002/b b3.1194 wileyonlinelib a y.com/jou nal/b b3 Recei ed:10Oc obe 2018 | Re ised:26No embe 2018 | Accep ed:5Decembe 2018 DOI:10.1002/b b3.1194 ORIGINAL RESEARCH Di usion enso imaging and disabili y p og ession in mul iple scle osis: A 4‐yea ollow‐up s udy Ma cin Kolasa1,2  | Ullama i Hakulinen2,3,4 | An i B ande 2 | Sanna Hagman1 | P asun Das ida 2 | I ina Elo aa a1 | Ma ja‐Liisa Sumelah i1 Thisisanopenaccessa icleunde  he e mso  heC ea i eCommonsA ibu ionLicense,whichpe mi suse,dis ibu ionand ep oduc ioninanymedium, p o ided he o iginal wo k is p ope ly ci ed. ©2018TheAu ho s. B ain and Beha io publishedbyWileyPe iodicals,Inc. 1Facul yo MedicineandLi e Sciences,Tampe eUni e si y,Tampe e, Finland 2Depa men o Radiology,Medical ImagingCen e o Pi kanmaaHospi al Dis ic ,Tampe eUni e si yHospi al, Tampe e,Finland 3Facul y o Biomedical Sciences and Enginee ing,Tampe eUni e si yo  Technology,Tampe e,Finland 4Depa men o MedicalPhysics,Medical ImagingCen e ,Tampe eUni e si y Hospi al,Tampe e,Finland Co espondence Ma cinKolasa,Depa men o Radiology, MedicalImagingCen e o Pi kanmaa Hospi alDis ic ,Tampe eUni e si y Hospi al,Tampe e,Finland. Email: ma cin.kolasa@u a. i Funding in o ma ion Suomen Kul uu i ahas o; Suomen Ai osää iö;Compe i i eResea chFundingo  Tampe eUni e si yHospi al Abs ac Objec i es: Di usion enso  imaging (DTI) is sensi i e echnique o de ec  wide‐ sp eadchangesinwa e di usi i yin heno mal‐appea ingwhi ema e (NAWM) ha appea s una ec ed in con en ional magne ic esonance imaging. We aimed o in es iga e hep ognos ic alueands abili y o DTIindicesin heNAWMo  he b ain in an assessmen o disabili y p og ession in pa ien s wi h a elapsing‐onse mul iplescle osis(MS). Me hods:Fo y‐sixMSpa ien swe es udied o DTIindices( ac ionalaniso opy (FA),meandi usi i y(MD), adial(RD),andaxial(AD)di usi i y)in heNAWMo  he co puscallosum(CC)and hein e nalcapsulea  baselineand a 1yea a e . DTI analysis o 10heal hycon olswasalsope o meda baseline.Simul aneously, ocal b ain lesion olume and a ophy measu emen s we e done a baseline o MS pa‐ ien s.Associa ionsbe weenDTIindices, olume icmeasu emen s,anddisabili y p og ession o e 4 yea s we e s udied by mul i a ia e logis ic eg ession analysis. Resul s:A baseline,mos DTIme icsdi e edsigni ican lybe weenMSpa ien s andheal hycon ols.The ewas endency o associa ionsbe weenbaselineDTIin‐ dices in he CC and disabili y p og ession (p<0.05). Changes in DTI indices o e  1yea we eobse edonlyin heCC(p<0.008),and hosechangeswe eno  ound o p edic clinical wo sening o e 4 yea s. Clea ‐cu associa ion wi h disabili y p o‐ g ession was no de ec ed o baseline olume ic measu emen s. Conclusion:Abe an di usi i ymeasu esin heNAWMo  heCCmayp o idead‐ di ional in o ma ion o indi idual disabili y p og ession o e 4 yea s in MS wi h he elapsing‐onse disease.CCmaybeagood a ge  o DTImeasu emen sinmoni o ‐ ingdiseaseac i i yinMS,andmo es udiesa eneeded oassess he ela edp og‐ nos ic po en ial. KEYWORDS di usion enso imaging,longi udinals udy,mul iplescle osis 2 o 10 | KOLASA e AL. 1 | INTRODUCTION In mul iple scle osis (MS), demyelina ion and axonal inju y in he cen al ne ous sys em a e esponsible o neu ological disabili y. Con en ionalmagne ic esonanceimaging(MRI)de ec ingT1andT2 ocalb ainlesionsisno speci ic o heunde lyingpa hology,andi  lacks sensi i i y o he mic os uc u al di use damage in he no mal‐ appea ingwhi e ma e (NAWM)(Filippi,Absin a,&Rocca,2013). Con en ional MRI ma ke s co ela e only mode a ely wi h clinical disabili y(Tin o ee al.,2015),and hei p ognos ic aluein heas‐ sessmen  o disabili yp og essionin de ini e MSislimi ed(Filippi e al.,2013).Consequen ly,b aina ophy ha hasbeen ela ed o long‐ e m disabili y in MS (De S e ano e  al., 2016) exp esses he unde lying pa hological p ocesses only nonspeci ically. Con ounding ac o s,suchasdisease‐modi ying he apiesandcausesun ela ed o MS,complica ein e p e a iono MRIma ke sanda ophyinclinical p ac ice(Kaunzne &Gau hie ,2017;Wa jese al.,2015). Di usion enso  imaging (DTI) quan i ies he magni ude and di ec ion o  wa e  di usion, and i  is sensi i e o di use mic o‐ s uc u al abno mali ies in he b ain ha appea s una ec ed on con‐ en ionalMRIs(Ro a ise al.,2005).DTI‐de i edme ics,including ac ional aniso opy (FA), mean di usi i y (MD), adial (RD), and axial(AD)di usi i ies,seem op o ideabe e speci ici y odemy‐ elina ionandaxonalinju y hancon en ionalMRIs(Sune al.,2006). Inc eased MD and dec eased FA in he NAWM o  di e en  b ain egions,including heco puscallosum(CC),ha ebeen ypicallyde‐ ec edinMS(Banaszek,Bladowska,Pok yszko‐D agan,Podemski, &Sasiadek,2015;P eziosae al.,2011;Sigal,Shmuel,Ma k,Gil,& Ana ,2012).Howe e ,inconsis en  esul s ega ding heco ela ion be weendisabili yandDTIindicesin heCCand hepy amidal ac  ha e been epo ed in c oss‐sec ional s udies using di e en me h‐ odso DTIanalysisandclinicalscaleso disabili y(Lin,Yu,Jiang,Li, &Chan,2007;Llu iue al.,2012;Pok yszko‐D agane al.,2018; Roosendaale al.,2009;To o ellae al.,2014).Theco ela ionbe‐ weenRDandseconda yp og essioninMShasbeenobse edina 50‐yea clinical ollow‐ups udyindica ing hepo en ial oleo DTIin hep edic iono ou comesinMS(Ande sene al.,2018). P e iously,dec easedFAandinc easedRDmos lyin heCCo  MS we e obse ed in a 2‐yea  longi udinal s udy (Ha ison e  al., 2011).Incon as , nochangesin di usi i ywe e obse edin he NAWMo MSo e 2–4yea s(On anedae al.,2017;Rashide al., 2008).Mo eo e , ews udieswi hasho (1–2yea s) ollow‐upha e applieda egionalandwhole‐b ainDTIanalysis olongi udinalmea‐ su emen s o di usi i y aiming o e alua e he p ognos ic alue o DTIin heassessmen o disabili yp og essioninMS(Rashide al., 2008;Samanne al.,2012;Schmie e e al.,2004).Inoneo  hese s udies, heinc easeo MDin hewhi ema e o  on allobeo e  1 yea was associa ed wi h clinical impai men in p ima y‐p og es‐ si e MS (Schmie e  e  al., 2004), while in ano he  s udy, in ea ly elapsing‐ emi ingMS,nodi usi i ychangeswe ede ec edo e  2yea s(Rashide al.,2008). The in es iga ion o  he p ognos ic alue o  DTI in his c oss‐ sec ional and 4‐yea longi udinal s udy aims o assess whi e ma e di usion change and i s s abili y in he elapsing‐onse MS coho conside ing he a iable a e o disease p og ession. 2 | MATERIALS AND METHODS The s udy was app o ed by he local e hics commi ee in he Hospi al Dis ic  o  Pi kanmaa (R05157). All subjec s p o ided in‐ o med w i en consen . 2.1 | Subjec s In o al,56indi iduals,46pa ien swi h elapsing‐onse MS,and10 heal hysubjec swe e en olledin his4‐yea  ollow‐ups udy (be‐ ween2006and2012)a  heTampe eUni e si yHospi al,Finland. TheMSdiagnosiswasbasedon he e isedMcDonaldc i e ia om 2005(Polmane al.,2005)and hediseasecou seclassi ica ionon LublinandReingoldc i e ia(Lubline al.,2014).Theinclusionc i e‐ iawe eadiagnosiso  elapsing‐ emi ingMS(RRMS)o seconda y‐ p og essi eMS(SPMS),nos e oid ea men a leas 8weeksbe o e clinical and adiological assessmen s, and an Expanded Disabili y S a usScale(EDSS)sco ebo ha  hes udyen yanda e 4yea s. Heal hysubjec sconsis edo  i e emalesand i emales,and he meanageo  hesubjec swas39.7yea s( ange26–61).Heal hysub‐ jec s we e ec ui ed om he hospi al s a o hei ela i es wi h no his o y o neu ological o psychia ic illness. Du ing he ollow‐up,MSpa ien sunde wen aclinicalexamina‐ ionby hesameneu ologis a baselineandannually o 4yea s(in o al i eexamina ions).Clinicalp og essionwasde e minedas he di e encebe ween hebaselineEDSSandEDSS4yea sa e  he baseline. P og ession o disabili y du ing he ollow‐up was de ined asanEDSSsco einc ease≥1.0when hebaselineEDSSwas<6.0o  aninc easeo EDSS≥0.5when hebaselineEDSS≥6.0,and hese subjec swe eassigned oap og essiong oup(Ro a ise al.,2003). All heo he pa ien swe eincludedin hes ableg oup. 2.2 | MR imaging acquisi ion MRI olume yincludedT1andFLAIRb ainlesion olumeandb ain a ophy measu emen s, and i  was ca ied ou  a  baseline o  42 MSpa ien s.DTIin46caseswaspe o meda baselineand1yea  a e  hebaseline isi .Heal hycon olswe eassessedwi hDTIa  baseline. Thepa ien sunde wen MRIon hesamedayasaclinicalex‐ amina ion. The pa ien s and con ols unde wen a whole‐b ain imaging by using a 1.5‐Tesla MR scanne  (Magne om A an o SQ, SiemensMedicalSolu ions,E langen,Ge many),and heMRIacqui‐ si ion and p o ocol we e as ollows: T1‐weigh ed heade ollowed byanaxial h ee‐dimensional(3D)T1‐weigh edmagne iza ionp e‐ pa ed apid g adien  echo (MPRAGE), 3D T2‐weigh ed u bo spin echo, luid‐a enua ed in e sion eco e y (FLAIR), T1‐weigh ed spin echo wi h magne iza ion ans e  con as s, mul idi ec ional di usion‐weigh edecho‐plana imaging,andgadolinium‐enhanced | 3 o 10 KOLASA e AL. T1‐weigh edMPRAGEwhenneeded.TheDTIp o ocolconsis edo  a single‐sho spin‐echo‐based echo‐plana di usion‐weigh ed imag‐ ingwi h h eea e agesand12g adien encodingdi ec ions,wi hb alueso 0and1,000s/mm2. The imaging pa ame e s a e p esen ed in Table 1. 2.3 | MR imaging pos p ocessing The DTI da awe eanalyzedwi h comme cialNeu o3Dso wa e (Siemens Heal hca e, Mal e n, USA) a  an o line wo ks a ion. Mul idi ec ional di usion da a we e assessed isually o he p es‐ ence o dis o ions and a i ac s. The e we e no signi ican eddy cu ‐ en dis o ions due o he di usion g adien s. Six eehand egions o  in e es  (ROI) o  app oxima ely 26–48mm2 (depending on he ana omical egion)we eposi ionedon hele and igh pos e io  limbso  hein e nalcapsule(IC),CCgenu,le and igh CCbody, andCCsplenium(Figu e1).TheROIswe emanuallyplacedexac ly he same way a bo h ime poin s on axial images o he colo ‐coded FAmapsandwe eau oma ically ans e edon heMD,eigen al‐ ues,andnon‐di usion‐weigh edb0maps.TheROIswe ecen e ed on he ana omical s uc u e in he mos  homogeneous a ea, wi h guidance om con en ional T2 images o exclude ocal lesions om heROIandpa ial olumee ec  ombo de a eas.Thesizeo ROI was educedi a ocallesionwasiden i iedin heROI.Thedi e ‐ enceinROIsizebe ween hebaselineand1‐yea  ollow‐upwas e y small,<9%( ange1.8%–8.8%)inallROIs.The alueso  he ollowing DTIpa ame e swe eob ained:FA,MD,AD,andRD. Thewholeb ain olumeo  heT1hypoin ense,FLAIRhype in‐ ense lesions, and b ain pa enchymal ac ion (BPF) we e assessed blindlyusing hesemi‐au oma icsegmen a ionso wa eAna oma ic™ 2.23(Heinonene al.,1998)by hesame eade .BPFwasde inedas a a io o b ain pa enchymal olume o he o al olume wi hin he b ainsu acecon ou (Rudick,Fishe ,Lee,Simon,&Jacobs,1999). 2.4 | S a is ical analysis Means and s anda d de ia ions we e gi en o no mally dis ibu ed a iables and medians and anges o skewed dis ibu ed da a. Fo hedemog aphicand olume icda a,g oupswe ecompa edusing independen sample es s o no mally dis ibu ed con inuous a i‐ ablesandMann–Whi neyU es s o skewed dis ibu ed con inuous a iables. Spea man's ank co ela ions we e de e mined o co ela‐ ionsbe weenclinicalandMRIpa ame e s.TheWilcoxon es was used ope o mcompa isonsbe weenDTI aluesa baselineand 1yea .Toin es iga eassocia ionbe weenDTIme ics, olume ic measu emen s,and disabili yp og ession o e 4yea s, ase ieso  logis ic eg ession models we e c ea ed. The p esence o absence o disabili y p og ession was used as a dependen a iable in all models.Inlogis ic eg essionModel1, heage and ime om he onse ( i s symp oms) obaselinewe ese asco a ia es.InModel 2, heco a ia eswe eas ollows:sex,diseasedu a ion( ime om MSdiagnosis obaseline),baselineEDSS,numbe o  elapsesup o 3yea sp eceding hebaseline,immunomodula o ymedica ions a‐ us,and olume icmeasu emen s(T1/FLAIRlesion olume,BPF). A esul ing odds a io (OR) is gi en wi h 95% con idence in e al (CI),and hep‐ alue<0.05wasconside eds a is icallysigni ican . The Bon e oni‐co ec ed p‐ alues o sixcompa isons(p<0.008) we ealsoin es iga edin heanalysesconce ningDTI.As a is ical analysis was pe o med using SPSS S a is ics o Windows e sion 22(IBMCo p.,A monk,NY,USA). 3 | RESULTS 3.1 | Clinical and adiological assessmen a baseline and o e he ollow‐up In o al,22o 46(48%)pa ien sshoweddisabili yp og essiono e  4yea s.Themeanageo pa ien sa baselinewas39.6yea s( ange 18–61). The demog aphic and clinical cha ac e is ics a e summa‐ izedinTable2.Se enpa ien shadonedemyelina ingplaquein he IC, ou pa ien shadonedemyelina ingplaquein heCC,andone pa ien hadse e alplaquesin heCC. Inciden al indingsin heb ainwhi ema e we e oundin ou  heal hy subjec s om con ol g oup; h ee subjec s had one o wo punc a e whi e ma e  hype in ensi ies, one subjec  had se e al punc a e whi e ma e  hype in ensi ies, and none o  heal hy sub‐ jec s p esen ed clinical signs o demyelina ing disease. InMS,compa ed oheal hysubjec s, hes onges di e ences (p<0.001)we e oundin heCC o FA,MD,andRD(Suppo ing In o ma ionFigu eS1). The FLAIR lesion olumes we e signi ican ly highe  (p<0.05) in he disabili y p og ession g oup compa ed o he s able disabil‐ i yg oup(Table2).Nosigni ican co ela ionswe e oundbe ween baselineDTIandage,diseasedu a ion,baselineEDSS,andnumbe  o  elapsesbe o ebaseline(da ano shown). A  baseline, signi ican  co ela ions (p<0.008, >0.4) we e oundbe weenMRI olume icmeasu emen sandDTIindices.The s onges co ela ions we e ound in he CC genu be ween he T1 b ain lesion olume and FA (p=0.001, =−0.48), MD (p<0.001, =0.52), RD (p<0.001, =0.52) and be ween FLAIR lesion ol‐ umeandFA(p<0.001, =−0.6),MD(p<0.001, =0.54),andRD TABLE 1 Imagingpa ame e s Axial T1WI Axial FLAIR Axial DTI Slice hickness (mm) 0.9 5 5 In e slicegap(mm) 0 0 1.5 Fieldo  iew(mm) 230 × 230 230 × 230 230 × 230 Ma ix 256×256 256×256 128 × 128 Echo ime(ms) 4.2 100 96 Repe i ion ime (ms) 1,160 8,500 3,500 In e sion ime(ms) 600 2,500 No e. DTI: di usion enso  imaging; FLAIR: luid‐a enua ed in e sion eco e y;T1WI:T1‐weigh edimaging. 4 o 10 | KOLASA e AL. (p<0.001, =0.6).Rega dingb aina ophy, hes onges co ela‐ ionswe e oundbe weenBPFandRD(p=0.002, =−0.46)in he igh  CC body, RD (p=0.007, =−0.41) in he le  CC body, MD (p=0.004, =−0.44)andAD(p=0.001, =−0.49)in he igh IC, andMD(p<0.001, =−0.53)andAD(p=0.002, =−0.47)in he le IC(Suppo ingIn o ma ionTableS1). Du ing he1‐yea  ollow‐up,FAsigni ican ly(p<0.05)inc eased in4/6ROIs,andRDdec easedin4/6ROIs(CCgenu,body,and he CCsplenium).ADshowedasigni ican inc easein3/6ROIs( heCC genu,CCbody).The esul s emainedsigni ican excep  o RDin heCCgenuandADinle CCbodya e  heBon e onico ec ions (p<0.008).In heIC, hechangeswe enonsigni ican (Table3). Nog oupdi e encesexis ed ega dingDTIchangeo e 1yea  inanyROIsbe weendisabili yp og essionands ableg oups(da a no shown). Toassess hein a‐obse e  epea abili yo DTImeasu emen s, he in aclass co ela ions (ICCs) we e calcula ed o  20 pa ien s. Thesameobse e (U.H.) epea ed hemeasu emen s o  hesame scanswi ha imein e alo app oxima ely3mon hs.InallROIs, he ICCswe egoodandexcellen andwe e0.77–0.98(mean0.91) o  FA,0.75–0.96(mean0.84) o MD,0.64–0.93(mean0.85) o AD, and0.85–0.95(mean0.91) o RD. 3.2 | Associa ion be ween MRI ma ke s and disabili y p og ession Inlogis ic eg essionModel1wi hco a ia eso ageand ime om heonse  obaseline(Table4),alowe baselineFAandhighe RDin heCCgenu, igh CCbody,and heCCspleniumwe eassocia ed wi h disabili y p og ession (p˂0.05). Mo eo e , a highe  baseline MD in he igh  CC body and highe  MD and AD in he CC sple‐ nium we e associa ed wi h disabili y p og ession. The esul s did no emain signi ican a e he Bon e oni co ec ions. The e we e no signi ican associa ionsbe weenbaselineDTIindicesin heICand disabili y p og ession o e he ollow‐up. The age and symp om ime hadnoe ec inanyo  heanalyzedROIs. InModel2,whichcon ainedbaselineEDSSand elapsenumbe  be o ebaseline,anassocia ionbe weenDTIanddisabili yp og es‐ siondisappea edin heCCgenu,body,and hesplenium eg ading se e aldi usi i ypa ame e s;howe e ,noneo  heseexplana o y a iables eached s a is ical signi icance (Suppo ing In o ma ion Tables S2 and S3). Medica ion, disease du a ion, and sex had no e ec  on disabili y p og ession (da a no  shown). T1, FLAIR, and BPF we e no  explana o y o  disabili y p og ession (Suppo ing In o ma ion Table S4). Howe e , he associa ion be ween disabil‐ i yp og essionandDTIdisappea edin heCCgenu,ands a is ical powe  sligh ly dec easedin heo he  CC a eas in he models,in‐ cludingFLAIRlesion olumeandBPF.TheT1lesion olumehadno e ec inany eg essionmodel(da ano shown). DTIchange o e 1yea  didno  ela e odisabili y p og ession o e 4yea sinanyROIs(da ano shown). 4 | DISCUSSION The p ognos ic assessmen o clinical disabili y accumula ion by usingcon en ionalMRIiss illsubop imal(Filippie al.,2013),whe e addi ional challenges conce n he indi idual and he e ogenous dis‐ abili y p og ession. In he p esen  s udy, he elapsing‐onse  MS pa ien coho showedal e edDTIindicesa baselinecompa ed o heal hycon ols,especiallyin heCCand oalesse deg eein he IC.Theana omicalloca iono  heobse eddi e ences mayindi‐ ca e ha DTIissensi i e omic os uc u alabno mali iesoccu ing in heNAWM ac s esponsible o cogni i eandlocomo o  unc‐ ions.Ou  indingco obo a eso he  epo sshowing ha ADisless a ec edwhencompa ed oRDin heCCand hepy amidal ac , FIGURE 1 F eehandROIplacemen on hecolo ‐coded ac ionalaniso opyaxialmaps.(1)Genuo  heco puscallosum(sizeo ROI means26mm2, ange13–71),(2)pos e io limbo  hein e nalcapsule(48mm2,13–81),(3)spleniumo  heco puscallosum(32mm2, 13–81),(4)bodyo  heco puscallosum(26mm2,19–84).Pixelsize1.8×1.8mm | 5 o 10 KOLASA e AL. includingIC(Hen y,Oh,Nelson,&Pelle ie ,2003;Line al.,2007; Roosendaale al.,2009). In heNAWMo MS,FAis ypicallydec eased,whe easMDis inc eased,exp essing helosso whi ema e  ac sdi ec ionali y and heinc easeino e allwa e di usi i y, espec i ely(Alexande , Lee,Laza ,&Field,2007).Inc easedRD,ameasu eo pe pendicu‐ la di usi i y o he ibe s,isusuallylinked odemyelina ion(Fink e  al., 2010). Di usionpa allel o he ibe s, ha  is,AD,ama ke  o axonalin eg i y,is ypicallydec easedandco ela esclea lywi h axonaldamagea  heea lys ageso MS.A  hech onics ageo MS, ADmaycon e selyinc ease, ep esen ing hecon oundinge ec o  epa a i ep ocesses,suchasgliosisandcellula in il a ion(Aung, Ma ,&Benzinge ,2013).In hiscon ex , henonsigni ican di e ‐ ence be ween heal hy con ols and MS pa ien s in ou s udy may esul  omdi e en di ec ionso changeinAD ep esen ingcom‐ pe ing pa hological p ocesses a di e en p og ession s ages in MS. Theco ela ionbe weenbaselineb ainlesion olume,b aina ophy, and DTI measu emen s in ou  MS g oup sugges s ha  di usi i y abno mali iesmaybeseconda y op og ession,bo hWalle iande‐ gene a ion o he axons passing h ough emo e mac oscopic b ain TABLE 2 Demog aphic,clinicaland adiologicalda a o MSpa ien s Whole g oup S able g oup P og ession g oup p‐Valuea No.o pa ien s 46 24 22 Female:male 31:15 17:7 14:8 0.6 Meanagea baseline,yea s,mean( ange) 39.6(18–61) 39.1(20–61) 40.2(18–58) 0.3 Median ime omonse symp om obaseline, yea s( ange) 9(0.7–32.2) 7.6(1.4–32.2) 12.3(0.7–31.2) 0.6 Mediandiseasedu a ion,yea s( ange) 4.2(0–31.2) 2.3(0–27.2) 5.9(0–31.2) 0.1 EDSS,median( ange) Baseline 2(0–7) 1.5(0–6) 3.0(0–7) 0.2 Yea 1 2(0–7.5) 1.5(0–6) 3.5(0–7.5) Yea 2 2.5(0–8) 1.5(0–6) 5.5(0–8) Yea 3 2(0–8) 1.5(0–6) 5.5(0–8) Yea 4 2(0–8) 1.5(0–6) 6.0(1–8) <0.001 Di e encebe weenEDSSo e 4yea s, median( ange) 0.5(–1.5 o4) 0(0.5 o−1.5) 1.5(0.5–4) No.o  elapsesup o h eeyea sbe o ebaseline,no.o pa ien s(%) 015(33) 5(21) 10(45) 0.07 1–2 24(52) 14(58) 10(45) 3–5 7(15) 5(21) 2(10) No.o  elapsesdu ing he ollow‐up,no.o pa ien s(%) 024(52.2) 12(50) 12(54.5) 1.00 1–2 12(26.1) 7(29.2) 5(22.7) 3–6 10(21.7) 5(20.8) 5(22.7) Du a iono  ea men a baseline,mon hs, median( ange) 18.5(1–122) 18.5(1–70) 15.5(1–122) 0.9 T ea men a baseline,no.o pa ien s(%)b18(39) 12(50) 6(27) 0.2 T ea men a  heendo  he ollow‐up, no.o pa ien s(%)b 20(43.4) 12(50) 8(36) 0.3 T1 b ain lesion load a baseline cm3, median( ange)c 1.7(0.1–28.5) 1(0.1–28.5) 2.2(0.1–14.7) 0.1 FLAIRb ainlesionloada baselinecm3, median( ange)c 5.8(1–39) 2.8(1–39) 8.2(1–33) 0.03 B ainpa enchymal ac iona baseline, median( ange)c 0.72(0.6–0.81) 0.73(0.64–0.8) 0.68(0.6–0.81) 0.2 No e.EDSS,ExpandedDisabili yS a usScale;Rangewasde inedasminimumandmaximum alues. aCompa isonbe weens able e susp og essiong oups,Mann‐Whi neyU es  o median alues,  es  o mean alues,andchi‐squa e es  o de‐ sc ip i eda a;inbold,p<0.05.bFi s ‐line ea men (be a‐in e e on,gla i ame ace a e).cValuescalcula ed o 42MSpa ien s(23pa ien sins able g oup,19pa ien sinp og essiong oup); he ewe enosigni ican di e ences ega dingclinicalanddemog aphicda abe weeng oupo pa ien swi h DTI(n=46)and he olume icanalysis. 6 o 10 | KOLASA e AL. lesions(Gee al.,2004;Line al.,2007)andb aina ophydue o he pa ial olumee ec wi hin oxels(Roosendaale al.,2009). The main obse a ion in ou s udy is he endency o baseline DTIme ics’associa ionin heCCwi hdisabili yp og essiono e  4 yea s wi h he mos consis en and s able co ela ion obse ed in heCCsplenium.Weobse edaninc easedbaselineADandRD, indi ec ly ep esen ing axonal in eg i y and demyelina ion, which is associa ed wi h disabili y p og ession e en a e co ec ing o ocal lesion olume. This esul co obo a es obse a ions in a p e‐ iouss udyanalyzingonlyFAmapswhe edec easedFAin heCC spleniuminp ima y‐p og essi eMS(Bodinie al.,2013)wasasso‐ cia ed wi h EDSS p og ession o e  5yea s; howe e , longi udinal s abili yo DTIindiceshasno beenanalyzedin hiss udy.Aswe in es iga edlongi udinalchangesinbo hADandRDindices,which a emo especi ically ela ed oMSpa hology,wecanspecula e ha  in lamma o y ac i i y and axonal degene a ion a e esponsible o clinicalwo seninginou MScoho .Simila  oou  esul s,inc eased RDin heCCbodyhasbeenassocia edwi hmo o impai men ex‐ p essedby he9‐holepeg es (NHPT)ina1‐yea  ollow‐ups udy wi hasmallnumbe (n=22)o pa ien swi hRRMS(Ke n,Sa cona, TABLE 3 DTIindicesa baselineanda e 1yea o  he ollow‐upinMSpa ien s Relapsing‐onse MS pa ien s, n = 46 DTI me ics Baseline Yea 1 Annual change p‐Valuea Median Min Max Median Min Max Median Min Max Co pus callosum genu FA 0.78 0.48 0.88 0.81 0.48 0.93 0.03 −0.08 0.14 <0.001 MD 0.80 0.62 1.31 0.82 0.67 1.07 −0.01 −0.34 0.20 0.891 AD 1.73 1.47 2.25 1.84 1.40 2.23 0.10 −0.62 0.43 0.006 RD 0.34 0.17 0.84 0.32 0.12 0.66 −0.04 −0.25 0.14 0.009 Co pus callosum body igh FA 0.56 0.30 0.87 0.68 0.32 0.89 0.06 −0.17 0.30 <0.001 MD 0.83 0.58 1.08 0.81 0.70 1.11 0.01 −0.17 0.24 0.797 AD 1.47 1.07 1.84 1.63 1.13 1.95 0.12 −0.37 0.65 0.003 RD 0.53 0.20 0.92 0.44 0.20 0.75 −0.08 −0.33 0.11 <0.001 Co pus callosum body le FA 0.58 0.29 0.85 0.68 0.37 0.88 0.10 −0.18 0.31 0.001 MD 0.82 0.67 1.39 0.83 0.68 1.11 0.01 −0.42 0.24 0.589 AD 1.46 1.06 2.08 1.64 1.08 2.00 0.12 −0.37 0.65 0.027 RD 0.52 0.23 1.14 0.45 0.20 0.74 −0.09 −0.40 0.15 <0.001 Co pus callosum splenium FA 0.79 0.52 0.94 0.82 0.58 0.94 0.02 −0.07 0.20 0.004 MD 0.75 0.56 1.28 0.75 0.58 1.11 −0.02 −0.20 0.21 0.215 AD 1.67 1.23 2.13 1.69 1.42 2.07 0.04 −0.27 0.30 0.157 RD 0.28 0.11 0.86 0.25 0.09 0.69 −0.04 −0.31 0.14 0.003 In e nalcapsule igh FA 0.72 0.62 0.83 0.71 0.55 0.85 0.00 −0.16 0.07 0.304 MD 0.74 0.66 0.79 0.74 0.67 0.83 0.01 −0.05 0.10 0.245 AD 1.46 1.33 1.73 1.45 1.27 1.80 0.00 −0.13 0.14 0.743 RD 0.36 0.24 0.47 0.37 0.23 0.52 0.00 −0.08 0.18 0.345 In e nalcapsulele FA 0.71 0.47 0.80 0.71 0.49 0.83 0.01 −0.18 0.32 0.814 MD 0.73 0.66 0.87 0.73 0.66 0.84 0.01 −0.06 0.07 0.092 AD 1.46 1.25 1.69 1.48 1.25 1.83 0.03 −0.20 0.45 0.068 RD 0.35 0.26 0.61 0.35 0.25 0.58 0.01 −0.27 0.15 0.566 No e.Annualchangeisde inedasdi e encebe weenmedianDTI aluea 1yea andmedianDTI aluea baseline. DTI: di usion enso  imaging; FA: ac ional aniso opy; MD: mean di usi i y (×10−3 mm2/s); axial di usi i y (×10−3 mm2/s); adial di usi i y (×10−3 mm2/s). ap‐Value o Wilcoxon es ;inbold,p<0.05. | 7 o 10 KOLASA e AL. Mon ag, Giesse , & Sico e, 2011). Mo eo e , a his og am‐based analysis e ealed a co ela ion be ween whole‐b ain di usi i y al‐ e a ions and disabili y p og ession exp essed by he MS Func ional Composi eScaleo e 1yea (Samanne al.,2012).Thesigni icance o ou obse a ion is s eng hened by he ac ha axonal degene ‐ a ion, ep esen edhe ebyinc easedAD,ismainly esponsible o  sus aineddisabili yinMS(Tallan y ee al.,2010).The easonwhy hemos s ableco ela ionbe weenDTIanddisabili yp og ession was obse ed in he CC splenium o ou s udy coho migh be e‐ la ed o hin axons ha a e denses in he splenium and hei p e ‐ e en ialsuscep ibili y oinju yinMS,asalsosugges edbyo he s (Cicca ellie al.,2003).As heCCbodyisa hinana omicals uc u e, he pa ial olume e ec om ce eb ospinal luid may in luence he esul so DTImeasu emen sin he egionweobse ed.ROI‐based me hodology is sensi i e o he change inDTI pa ame e s, a oids pos p ocessing calcula ion e o s, and is sui able o  in es iga ing well‐de inedb ains uc u essuchasCCandIC(Snook,Plewes,& Beaulieu,2007).Good ep oducibili yo DTImeasu emen sinou  p esen andp e iouss udies(B ande e al.,2010;Hakulinene al., 2012;Kolasae al.,2015),alongwi hcohe en  ibe sin hewhi e ma e  ac so  heICand heCC,sugges s ha di usi i yabno ‐ mali ies,asobse edhe e,maybe ela ed owhi ema e pa hology TABLE 4 Rela ionshipo baselineDTIme icswi hdisabili yp og essionmeasu edbyEDSSinc easeo e  he4‐yea  ollow‐up DTI me ics S able g oup n = 24 P og ession g oup n = 22 p‐ValueaOdds a io 95% CIMedian Min Max Median Min Max Co pus callosum genu FA 0.81 0.52 0.88 0.74 0.48 0.88 0.04 0.00 0.00 0.61 MD 0.80 0.62 1.21 0.83 0.67 1.31 0.06 1.05 1.00 1.10 AD 1.70 1.47 2.07 1.76 1.55 2.25 0.36 1.02 0.98 1.06 RD 0.28 0.17 0.80 0.37 0.17 0.84 0.04 1.05 1.00 1.09 Co pus callosum body igh FA 0.67 0.40 0.87 0.52 0.30 0.77 0.01 0.00 0.00 0.24 MD 0.80 0.58 1.07 0.87 0.69 1.08 0.04 1.08 1.00 1.15 AD 1.51 1.07 1.79 1.39 1.18 1.84 0.25 0.98 0.95 1.01 RD 0.46 0.20 0.73 0.62 0.30 0.92 0.01 1.07 1.02 1.12 Co pus callosum body le FA 0.66 0.38 0.85 0.53 0.29 0.82 0.07 0.02 0.00 1.37 MD 0.81 0.67 1.32 0.84 0.70 1.39 0.12 1.03 0.99 1.08 AD 1.50 1.19 2.08 1.42 1.06 2.04 0.53 0.99 0.97 1.02 RD 0.46 0.23 0.93 0.58 0.30 1.14 0.04 1.04 1.00 1.08 Co pus callosum splenium FA 0.82 0.63 0.89 0.76 0.52 0.94 0.04 0.00 0.00 0.76 MD 0.71 0.56 0.95 0.79 0.68 1.28 0.01 1.13 1.03 1.23 AD 1.62 1.23 1.87 1.80 1.50 2.13 0.01 1.08 1.02 1.14 RD 0.25 0.16 0.50 0.35 0.11 0.86 0.02 1.07 1.01 1.14 In e nalcapsule igh FA 0.72 0.62 0.78 0.72 0.62 0.83 0.89 1.01 0.89 1.14 MD 0.72 0.66 0.79 0.75 0.66 0.78 0.14 1.13 0.96 1.33 AD 1.45 1.33 1.61 1.49 1.34 1.73 0.16 1.05 0.98 1.12 RD 0.35 0.29 0.47 0.36 0.24 0.46 0.78 1.02 0.90 1.15 In e nalcapsulele FA 0.71 0.47 0.80 0.71 0.58 0.80 0.49 1.03 0.94 1.13 MD 0.71 0.66 0.87 0.74 0.66 0.80 0.15 1.12 0.96 1.32 AD 1.42 1.25 1.63 1.48 1.30 1.69 0.05 1.07 1.00 1.15 RD 0.35 0.26 0.61 0.36 0.31 0.48 0.86 0.99 0.90 1.09 No e.DTI:di usion enso imaging;FA: ac ionalaniso opy;MD:meandi usi i y(×10−3 mm2/s);axialdi usi i y(×10−3 mm2/s); adialdi usi i y (×10−3 mm2/s);EDSS:ExpandedDisabili yS a usScale. ap‐Value o logis ic eg essionadjus ed o ageanddu a iono symp oms o p edic iono EDSSp og essiono e  he4‐yea  ollow‐up;inbold, p<0.05. 8 o 10 | KOLASA e AL. a he han me hod‐based a iabili y o c ossing ibe s wi hin a oxel(Wheele ‐Kingsho &Ce cignani,2009). The1‐yea longi udinalDTIanalysis e ealedasigni ican change o DTIme icsin heCCbu no in heIC.In hiscoho wi hac‐ i e MS (Lublin e  al., 2014), we obse ed an inc ease ins ead o  heexpec eddec easeo FAin heCC.Thisinc easewasd i enby inc easedADanddec easedRDin heCCgenuand hebodyand dec easedRDin heCCsplenium.Due oasho  adiological ol‐ low‐upwi honly woMRIexamina ions,wecanno  ullyde e mine hesus ainedchangesinDTIpa ame e s.Alongi udinalDTIs udy wi hsho e in e alMRIexamina ionswouldbemo eapp op ia e oe alua e he empo alchangesindi usi i y(Tiane  al.,2012). Mo eo e , wi hou  heal hy con ols in he longi udinal analysis, we canno clea ly assess pa hophysiological p ocesses in ol ed in empo alDTIchangesobse edhe ein heCC.Simila  oou ob‐ se a ion, se ial DTI s udy using ac og aphy showed signi ican  longi udinalchangeinDTIme icsin hesup a en o ialb ainand he CCo  heMScoho wi hdi e en diseasepheno ypes(Ha isone  al.,2011).Howe e ,such empo alDTIe olu ionwasno obse ed ina ecen ROI‐basedMSs udyincludingna alizumab‐ ea edpa‐ ien s(On anedae al.,2017).Inano he s udyinea lyRRMSwi ha 2‐yea  ollow‐up, he a eo changeindi usi i ycha ac e is icsas‐ sessed by a his og am‐based whole‐b ain analysis did no co ela e wi h disabili y p og ession exp essed by an EDSS inc ease, which con i msou  esul s(Rashide al.,2008).Con e sely, heassocia ion be weendi usi i yin he on alNAWManddisabili yasmeasu ed by he MS Func ional Composi e Scale has been ound in p ima y‐ p og essi eMS(Schmie e e al.,2004).Thus,inconsis en  esul s obse ed in p e ious s udies may ela e o echnical di e ences, in insiche e ogenei yo MS(Ba onee al.,2018)andMScoho s, and di e en clinical scales used in disabili y e alua ion in MS. Al oge he , he esul so ou longi udinals udysugges  ha DTI is a sensi i e ool in moni o ing di use abno mali ies esponsible o disabili yaccumula ion,andCCmaybeagood a ge  o DTIanaly‐ sis.Webelie e ha anassessmen o  hep ognos ic alueo DTIin an MS coho wi h a iable clinical cha ac e is ics such as ou s which is ypicallyencoun e edine e ydayp ac icehasp ac ical alue,as sugges ed by o he s (Ha ison e  al., 2011). Mo eo e , changes in RDobse edhe emayplayanimpo an  oleinmoni o ingimmu‐ nomodula o y ea men e ec s because he a enua ion o in lam‐ ma o y demyelina ion is he main a ge o cu en MS he apies. This s a emen is suppo ed by he esul s o he s udy by Fox e al.,whe eDTIabno mali iesindica ing emyelina ionha ebeenob‐ se eda e s a ingna alizumab ea men (Foxe al.,2011). We did no  obse e any associa ions in he IC be ween base‐ line DTI and disabili y p og ession. Mo eo e , no longi udinal changes in DTI me ics we e obse ed in he IC, al hough signi i‐ can  di e ences ela ed o DTI be ween heal hy con ols and he MS g oup we e al eady obse ed. This esul indica es ha di u‐ si i yabno mali iesmayal eadyexis in heIC,bu  heyp og ess a di e en  a es,andimagedisabili yp og essiondis inc ly hanin heCC(Gee al.,2004).Ou  indingissuppo edbys udieswhe e no co ela ion be ween DTI indices in he co icospinal ac  and disabili yp og essionexp essedbyanEDSSinc easehasbeenob‐ se ed(F i z,Kelle ,Calab esi,&Zackowski,2017;Line al.,2007). Con e sely,suchco ela ionbe weenDTIpa ame e sandEDSShas been p e iously epo ed in c oss‐sec ional s udies (Daams e  al., 2015;To a ‐Molle al.,2015). Ou esul s co obo a e he obse ed lack o clea ‐cu asso‐ cia ionbe ween heT1/T2 b ainlesionload,b ain a ophy,and disabili yp og essionexp essedbyEDSSchangeino he  ollow‐ ups udies o o e 2yea sin elapsingMS(Enzinge e al.,2011; Tibe ioe al.,2005).Al hough olume icmeasu emen sdidno  clea lyco ela ewi hdisabili yp og essioninou s udy, heFLAIR lesion olume and BPF showed some e ec and modi ied he co ‐ ela ion be ween DTI and disabili y p og ession. In con as  o ou  esul s,associa ionbe weensho ‐ e mphysicalwo sening, T2b ainlesionload(Gau hie e al.,2007;Moodiee al.,2012), andb aina ophyhasbeen epo edelsewhe e(Minnebooe al., 2008;Samanne al.,2012).Thesedisco dan  esul ssugges  ha  he ocal b ain lesion load and b ain a ophy may ha e addi ional impac on disabili y accumula ion in elapsing‐onse MS. The lack o signi ican co ela ion he e may be limi ed by a small numbe o casesin hes udycoho ,whe ediseaseac i i yanddisabil‐ i y p og ession we e a iable. O he limi a ions in ou in e ences may esul  om he ai lyg ossna u eo  o alEDSSinasi ua ion whe e he e is a need o e alua e sub le changes in mo o unc‐ ions du ing a sho obse a ion pe iod. Inconclusion,ou  esul samongo he ssugges  ha di usi i y abno mali iesexis  in elapsing‐onse MS pa ien s;howe e , hei  dynamic change o e ime is di e en wi h espec o ana omical loca ion. Addi ionally, di usi i y me ics in he no mal‐appea ing CC may be associa ed wi h disabili y accumula ion in elapsing‐onse MS and sugges he c ucial ole o he CC in moni o ing disease p o‐ g ession.Gi eni shighsensi i i yinde ec ingdi useb ainabno ‐ mali ies,DTIindicesmayse easapo en ialbioma ke o disease p og ession;howe e ,me hods anda diza ionisneeded.Mo eo e , s abili yandsensi i i y ounde lyingpa hologyo DTIme icsha e obecon i medinlongi udinals udies(Wa jese al.,2015).Acom‐ bina ion o di usion measu es wi h o he indings om con en ional MRImayp o idecomplemen a yin o ma ionondi e en  ypeso  pa hological damage in MS. ACKNOWLEDGMENTS The au ho s hank Mika Helminen, MSc, o  s a is ical assis ance, Minna Raunio, MD, o  neu ological examina ion o  he pa ien s, Maija Rossi, MSc, DSc, o  olume ic measu emen s, and Pabi a Basnya ,MSc, o helpinp epa a iono  he igu es.Thiss udywas unded by Compe i i e Resea ch Funding o  Tampe e Uni e si y Hospi al, he Finnish Cul u al Founda ion, and he Finnish B ain Founda ion. CONFLICT OF INTEREST We decla e ha we ha e no con lic o in e es . | 9 o 10 KOLASA e AL. ORCID Ma cin Kolasa h ps://o cid.o g/0000‐0003‐3782‐4938 Ma ja‐Liisa Sumelah i h ps://o cid.o g/0000‐0001‐6581‐0483 REFERENCES Alexande , A. L., Lee, J. E., Laza , M., & Field, A. S. (2007). Di usion enso imaging o he b ain. 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