178

European Journal of Endocrinology 10.1530/EJE recurrence rate( however, knownforitsaggressive behavior, high tumor, (CP) is a benign pituitary Craniopharyngioma Introduction and inhippocampuswithcognitivedeficitsCP. Conclusions visual . microstructural WMalterationsinhippocampuswereassociated withadeclineingeneralknowledgeandepisodic explaining 19–29%.Patientswhohadsmallerhippocampalvolumeworsegeneralknowledge( recall andrecognition,explaining26–38%ofthevariation,withvisuospatialabilityexecutivefunction, 50% ofthevariation.Alterationsindorsalcingulumwereassociatedwithworseperformanceimmediate,delayed cingulum weresignificantlyassociatedwithworseperformanceinvisualepisodicmemory, explainingapproximately Results volumetry. analyzed usingDTIofuncinatefasciculus,,cingulum,hippocampusandhypothalamusaswellhippocampal Main outcomemeasures 1958–2010 and32controlswithsimilaragegenderdistributions.HLwasfoundin23patients. Participants Setting Design detected withdiffusion tensorimaging(DTI)andcognitioninadultswithchildhood-onsetCP. Objective pathways areaffected isunknown. Context Abstract Lund, Sweden Linköping University, Linköping,Sweden,and Skåne UniversityHospital,Lund,Sweden, of ExperimentalMedicalScience,LundUniversity, Lund,Sweden, 3 1 I M Björkman-Burtscher S Fjalldal cognitive deficitsincraniopharyngioma hippocampal volumesare associatedwith Microstructural whitematteralterationsand Division ofOccupationalandEnvironmentalMedicine, Department ofEndocrinology, SkåneUniversityHospital,Lund,Sweden, https://doi.org/ www.ej Clinical Study Clinical Study e-online.org : Across-sectionalstudywithamedianfollow-uptimeof22(6–49) yearsafteroperation. : Rightuncinatefasciculuswassignificantlyaltered( : TheSouthMedicalRegionofSweden(2.5millioninhabitants). : Patientswithcraniopharyngioma(CP)andhypothalamiclesions(HL)havecognitivedeficits.Whichneural : To determinewhetherthereis a relationshipbetweenmicrostructuralwhitematter(WM)alterations 1 , C Follin 10.1530/EJE : Astructuretofunctionrelationshipissuggestedbetween microstructuralWMalterationsincingulum : Includedwere41patients(24women, -18-0081 1 ) andincreasedmortality( -18-0081 1 , D Svärd : Subjectsperformedcognitivetestsandmagneticresonanceimaging,imageswere 2 , 5 6 , J Lätt 2 , L Rylander 6 S Fjalldalandothers Department ofEndocrinologyandMedicalHealthSciences, 5 , B Ekman 7 Department ofPsychologyandPsychiatry, SkåneUniversityHospital, Published byBioscientifica Ltd. Printed inGreat Britain 4 3 Translational NeuroendocrineResearchUnit,Department © , S Gabery 2 2018Theauthors 6 , , A Johanson 3 , 4 5 Department ofMedicalImagingandPhysiology, ≥ ) and 17 years) surgicallytreatedforchildhood-onsetCPbetween 4 , Å Petersén 2 Department ofDiagnosticRadiology, ClinicalSciences, P

≤ 7 or itstreatment( primarily due to hypothalamic lesion (HL) by the tumor morbidity incardiovascular diseases( and craniopharyngioma Diffusion tensorimagingin

0.01). MicrostructuralWMalterationsinleftventral E M Erfurth 4 , D van Westen 1 6 ). Themorbidityincludes cognitive Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at09/26/202109:56:40PM 2 , P C Sundgren (2018) Endocrinology European Journal of [email protected] Email to EMErfurth should beaddressed Correspondence 178

P 178 5 .2) and =0.028), , :6 , 577–587 6 2 Creative Commons , ). Thecauseis 5 ,

577 –587 via freeaccess European Journal of Endocrinology www.eje-online.org prefrontal cortex( lobe ( connects limbicregionsinthe temporallobetothefrontal and fasciculus isalsoimportant forepisodicmemory ( importance forepisodicmemory connections withthehippocampusandwell-known is animportantWMtractwithmultiplereciprocal ( memory the episodic(contemporary) retrieving sequencesofeventsthatcomposeparticularly were associatedwithworsecognitiveperformance( 23 investigated theHTusingDTIinhumansubjects( the radiationdoseeffectonWM( surgical defectsafterCPoperationappearedtoaccentuate medial prefrontalcortex( retrievalinthe a defectinneuralcorrelatesofmemory functional magneticresonanceimaging(fMRI)showing CP, theconsequencesofHLhavebeeninvestigatedwith attention andexecutivefunction( dysfunction causing deficits inmemory, Thus, HL mightindirectly lead to frontal and medial HT ( shown connectivitybetweenthehippocampusand including thefrontalcortex( several hypothalamus(HT)compartmentstoWMareas DTI inhumanshasshowndirectconnectivitybetween andasuccessivelong-termmemory.short-term memory executive function, a pre-requisite for workingmemory, demyelination oredema( and increasedMDmaybecausedbyforexample, mean diffusivity(MD),whichquantifiesdirectionality, measure molecules isquantifiedbytheDTIsummary is fairlynonspecific.Thedegreeofdirectionalitywater decreased WMintegrity( anisotropy (FA) andlowerFA valuesareassociatedwith abnormalities. WMintegrityismeasuredbyfractional microstructural WMarchitecture ( neural ( assessing themotionofwatermoleculesalongandacross that allows noninvasive, ( receiving increasinglyimportanceincognitiveresearch outcome ( cognitive domains and how HL contributes to a worse shifted towarddatareflectingimpairmentindifferent andprocessingspeed( memory dysfunction with attention deficits, impaired episodic 10 Clinical Study ), butinobesesubjects,HTmicrostructuralalterations ) anddiffusiontensorimaging(DTI)isatechnique The prefrontalcortexisimportantforattentionand The hippocampusisimportantforencodingand 16 28 ) as well directly to the frontal cortex ( ) andthefornixconnects hippocampustothe 7 , 9 ). Thewhitematter(WM)ofthebrainis 11 29 , 12 ). ). DifferentDTImapsshowthe 14 14 in vivo ). FA issensitivetodamagebut ). 19 15 ). Further, pre-existing S Fjalldalandothers study of the by 7 ). Animalstudieshave 13 , 26 20 18 8 ) andcandepictWM ). Lately, focushas , ). Fewstudieshave ). Inchildrenwith 25 27 ). Thecingulum ). Theuncinate 21 24 , 17 ). 22 ). , at SkåneUniversity Hospital. Excluded subjects ( treated forachildhood-onsetCPbetween1958and2010 (population 2.5 million).Thepatients were surgically 64 eligiblesubjectsfromtheSouthernregionofSweden women, and 36 ( median ageatinvestigationof35(range17–56)yearsin Forty-one (24women)patients,aged Patients Methods as wellhippocampalvolumetry. of importanceandalsoDTIintheHThippocampus, childhood-onset CP. We analyzed DTI in neural pathways alterations detectedwithDTIandcognitioninadults there isastructuretofunctionrelationshipbetweenWM modalities areshownin the exceptionoffornix( patients completingtheDTI partoftheMRIanalysiswith criteria forROIplacement.Thisresultedinatotalof32 of HLpreventedtheimagingdatatofulfillquality excluded fromtheDTIanalysesofHTasextent the regionofinterest(ROI).Sixadditionalpatientswere data didnotfulfillthequalitycriteriaforplacement of involving onlythefornixandHTasimaging One furtherpatient was excludedfrom the data analysis causing insufficientresolutionforDTIprocessing; due totechnicalproblems(shunt, Four patientswereexcludedfromtheDTIdataanalyses attributed topostoperativeanatomicalchanges( automated anatomicaldelineationofthehippocampus after manualinspectionrevealedadiscrepancyinthe were excludedfromthehippocampalvolumeanalysis ( included intheinvestigationofcognitivefunction restrictions ( ( presence ofeitherashuntcausingsignificantMRartifacts ( not giveanyreason( according topatients( n neuromuscular disease were eitherassessedtobetooill(meningioma craniopharyngioma Diffusion tensorimagingin n n n

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1; 1, European Journal of Endocrinology male; S,surgery;SR,stereotacticradiosurgery; T, levothyroxine; y, years. ADH, antidiuretichormone;C,cortisone; CRT, cranialradiotherapy;F, female;G,gonadalsteroids;GH,growthhormone; In,installationofyttrium;M, based onclinicaljudgment. patients had3operations(2hypothalamic lesion). group basedonoperationrecords. *Hypothalamic lesionaccordingtothe neurosurgeon’s retrospective assignmentofpatientstothenon-hypothalamiclesionandhypothalamic lesion

Without HTlesion( With HTlesion( Gender lesion andwithout. Table 1 based oneachpatient’s operationrecords:intra-sellar neurosurgeon gradedthetumorlocationretrospectively 42 operation was21( women and9( ( received cranialradiotherapy(CRT),mediandose50 35 Clinical Study M M M M M M M F F F F F F F F F F F F M M M M M M M M F F F F F F F F F M F F F ) yearsinmen.Atthetimeofthisstudy, thesame – 55 ) Gy. Ageatfirstoperationwas12(

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– 23 withfollowingexceptions:WAIS blockdesign Recognition Delayed recall Immediate recall Recognition Delayed recall Immediate recall 40 ) mginwomenand20(

(see sectionon 50 Neuropsychological testscoresof23 13 –250) – 21 ) pmol/L(referencerange12–22 μ g and150( ≥ 0.5) alongwithnormalorminor supplementary data supplementary 100 10 S Fjalldalandothers – –200) 30 ) mginmen.None 11 n

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pmol/L). 10th–90th percentiles 30–60 32–36 17–50 46–105 22–41 19–39 17–39 50–88 19–33 20–23 10–15 31–65 18–40 5–12 6–27 6–29 2–15 neuropsychological assessment( All 41CPpatientsand32controlsunderwent Cognitive tests consent. (DNR 2011/769). All participants gave writteninformed day ineachpatient. The presentinvestigationswereperformedduringasingle Study design ( another wasexcludedfromDTIinvolvinghypothalamus control subject terminated MRI due to claustrophobia and population registeraspreviouslydescribed( controls wererandomlyselectedfromacomputerized participated inourpreviousstudies( measuring executive function. Rey Auditory Verbalmeasuring executive function. Rey Auditory test ofworkingmemory, thesubtestdigitspanbackward ( representing semanticmemory Adult IntelligenceScale)isatestofverbalknowledge by twopsychologists.WAIS (Wechsler vocabulary craniopharyngioma Diffusion tensorimagingin n

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16 as7patients 30 P ). One 0.001 0.042 0.025 0.033 0.061 0.012 0.021 0.054 0.004 -value ns ns ns ns ns ns ns ns 580 via freeaccess European Journal of Endocrinology USA). DTIvolumeswereregisteredtoMNI152standard (MATLAB 2013a,TheMathWorks Inc.,Natick, MA, in-house developedsoftware,implementedinMatlab parameter maps for MD and FA were calculated using were correctedusingElastiX( flip angle9).Motionandeddycurrent-inducedartifacts acquired (1 measurements, axialT1-weightedMPRAGEimageswere EPI (TR/TE8100/103 of 2.3 In all52contiguousaxialsliceswithaspatialresolution distributed over6,20and64directions,respectively. acquired using acquired with receiver coil.DTIdataconsistedofthreevolumes Erlangen, Germany)usinga20-channelhead/neck scanner (MAGNETOMSkyra,Siemenshealthcare, Imaging sequenceswereacquiredona3-Tesla MRI and MD Data acquisition,post-processinganddefinitionof FA Neuroimaging protocols making test. with WAIS codingandWAIS blocktestalong withTrail function, attention and processing speed were measured subtest fromtheReyComplexFigureTest. Executive were testedwithWAIS BlockDesignTest andthecopy Rey ComplexFigureTest ( wastestedinasimilarmannerwithvisual memory delayed recall(30 including immediate (1–2 verbal memory Learning Test (RAVLT) wasusedtoevaluateepisodic Clinical Study × 2.3 mm isotropicresolution,TE3 × 2.3mm b -values of250,500,1000and2750 b =0s/mm min) andrecognition( 3 wereacquiredusingasingle-shot ms/ms) sequence.Forvolumetric 2 , followedby96volumes 31 32 ). Visuospatial abilities S Fjalldalandothers ). Foreachsubject,DTI ms, TR1900 31 ). Episodic min) and s/mm ms, 2

standard spaceandwarpedbackutilizingthewarp- Boolean operations. All ROIs were defined in MNI152 region for eachtract and to segment the tract based on fasciculus ( cingulum, the fornix and the right and left uncinate right andleftdorsalcingulum,theventral generated the investigatedwhitematter structures: the based onconstrainedsphericaldeconvolutionand wasperformedusingdeterministictracking Tractography alterations willresultinlowerFA andhigherMD( 1 The resolutionoftheresultingparametermapswas ( FMRIB SoftwareLibrary); registration algorithmofFLIRTandFNIRT(partthe space andtoT1-weightedMPRAGEvolumesusingthe through thecorpuscallosumonaxialslices,respectively. to theanteriorpillars,caudalcrusforniciand the splenium,respectively, andthree‘NOT’ROIsrostral the anteriorpillarsandaroundcrusforniciinferiorto two ‘AND’ROIsaroundthebodyoffornixcaudalto across onemid-sagittalslice.The inferior tothesplenium,respectively, andone‘NOT’ROI two ‘AND’ROIsaroundthetractrostraltoponsand slice. The respectively, andone‘NOT’ROIacrossmid-sagittal around the tract superior to the genu and splenium, The generated usingoneseedROIcoveringtheentiretract. fields generatedbyFNIRTtonativespace.Alltractswere craniopharyngioma Diffusion tensorimagingin × 1 When alldiffusion is parallel FA isnear 1. Thus, WM dorsal cingulum × 1mm ventral (hippocampal)cingulum i. 1 Fig. 3 . ). ROIswereusedtodefinetheseed representative subject. on amid-sagittalFA mapina and (D)uncinatefasciculussuperimposed cingulum, (B)ventral (C)fornix, segmented tractographyof(A) dorsal anterior-posterior; blue,superior-inferior) color-coded (red,right-left;green, Graphical renderingsofdirectionally Figure 1 was defined using two ‘AND’ ROIs Downloaded fromBioscientifica.com at09/26/202109:56:40PM 33 ) andElastiX,respectively. fornix 178 wasdefinedusing wasdefinedusing www.eje-online.org :6 12 581 ). via freeaccess European Journal of Endocrinology www.eje-online.org max). Dataonneuropsychologicaltestingispresented as Patients’ characteristicsarepresentedasmedian(min– Statistics edu/ 5.1.0), freelyavailableat images, using the FreeSurfersoftware package (version The volumetricanalysiswasperformedontheT1-MPRAGE Volumetry ofhippocampus subsequent analyses. co-registered DTIparametermapsandusedinthe to calculate the mean DTIparametervaluefromthe described inGabery according tothesameHTdelineationprotocolas on T1-weightedvolumesintherightandleftHT and lefthippocampus.AROIwasmanuallydefined the meandiffusionparametervaluesfromright on co-registereddiffusionparametermapstoextract and used as ROIs for delineation of the ( hippocampus onT1-weightedvolumesinnativespace FreeSurfer wasusedtoautomaticallysegment DTI ofhippocampusandHT analysis. estimates foreachWMtractwereusedinthesubsequent in theintendedanatomicalregion.Theaverageparameter tract werevisuallyinspectedandadjustedifnotlocated was total number ofstreamlines generated for each WM tract slices, andacrossonemid-sagittalslice,respectively. Ifthe front ofthepons,throughcorpuscallosumonaxial pons, respectively, andthree‘NOT’ROIscaudaltothe where itbendsintothetemporallobeventraltoupper around thetractrostraltogenuand The 34 Clinical Study ). These segmentations were visually inspected < uncinate fasciculus ) ( 100, theROIsutilizedfordefinitionofspecific Fig. 2 ). t al et was defined using two ‘AND’ ROIs http://surfer.nmr.mgh.harvard. . ( 35 ). TheseROIswereused S Fjalldalandothers analysis. presented. We usedSPSS,version22.0,forthestatistical statistically significant (defined as scatter plotsaswellresidualanalyses.Onlythe regressions were reasonably fulfilled, we investigated ( explained bythevariablesincludedinmodels models, wepresentedtheproportionofvariance intracranial volume(ICV).Fromthelinearregression estimates wereconfoundedbyageatinvestigationand regressions wereperformedtoinvestigatewhetherthe reasonable, scatterplotswereinvestigated.Linear To ensurethattheassumptionoflinearitywas were assessedusingPearson’s correlationcoefficient( Whitney patients andcontrolswere compared usingMann– median and10th–90thpercentiles. Differencesbetween controls. speed wassignificantlydifferentbetweenpatientsand the Trail Makingsubtest1,3and 5measuringmotor recall. In executive function and processing speed, was found, on delayedin episodic visual memory patients andcontrols.Further, asignificantdifference delayed recallandrecognition,wasfoundbetween a significantdifferenceinverbalmemory, including between patientsandcontrols.Inepisodicmemory, significant differencewasfoundinsemanticmemory control group( and thecontrols( cognitive tests between the wholepatient group ( No significantdifferenceswererecordedinanyofthe and controls Cognitive comparisonbetweenCPpatients Results craniopharyngioma Diffusion tensorimagingin r 2 ). To ensurethatmodelassumptionsforthelinear Patients with HL ( U test.Amongthepatientsbivariatecorrelations n

= n nmr.mgh.harvard.edu/ obtained fromFreeSurfer( Hippocampus regionoutlined in white, the threeorthogonalplanes,with An exampleofatypicalMPRAGE imagein Figure 2 =32). 32) inthefollowingtests( Downloaded fromBioscientifica.com at09/26/202109:56:40PM n

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European Journal of Endocrinology and recognition (MD: recall (MD: P correlated withadeclineinimmediaterecall(FA: (MD: the varianceofReycomplexfigure,immediaterecall dorsal cingulum(right), age and ICV explained 29% of (MD: (Reycomplexfigure)forimmediaterecall visual memory was significantlyassociatedwithadecreaseinepisodic patients, anincreaseinMDofrightdorsalcingulum After adjustmentforageatinvestigationandICVamong cognitive function Associations betweenDTImeasures and comparing patientsandcontrols( the HT( significant differenceswerefoundinDTIparameters controls ( FA valuesinrightuncinatefasciculuscomparedto patients andcontrols( hippocampus, cingulumorfornixwhencomparing differences werefoundinDTIparameterstheHT( ( only inrightuncinatefasciculuscomparedtocontrols Patients ( and controls Comparison ofDTImeasures inCPpatients memory (WAISmemory (FA: vocabulary) associated significantlywith adecreaseinsemantic P ( forimmediate recall a reducedepisodicvisualmemory MD ofleftventralcingulumassociatedsignificantlywith recognition ( ( (Reycomplexfigure)for immediaterecall memory associated significantlywithreducedepisodicvisual digit spanbackward)(MD: decline inexecutivefunctionandprocessingspeed(WAIS r decline invisuospatialabilities(WAIS blockdesign)(FA: decrease inFA inrightdorsalcingulumcorrelatedwitha 2 n r r

< = 2 2 =0.29, Clinical Study 1 ( =31) =0.48, =0.27, .0) ( 0.001) 0.003). Comparableresultswerefoundfordelayed An increaseinMDoftherightventralcingulum Patients withHL( A decreaseinFA oftherightuncinatefasciculus r r 2 2 =0.29,

= P P n n 0.29). Thismeansthatthemodelincluding n P

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= P ) andrecognition( 0.02). AlsoadecreaseinFA ofthistract .0 and =0.005 P

= P i. 3A Fig. 0.01, respectively).Nosignificant Supplementary Table 2Supplementary .2 n FA: and =0.02 n P r

2

= = =0.32, 15) hadhigherMDandlower 0.01). Further, an increasein r 2 =0.19, ), delayed recall ( P r .1, epciey. No respectively). =0.011, 2 S Fjalldalandothers P =0.19, Supplementary Table 2Supplementary

= r 0.01). Further, also a P 2 r =0.29, 2 =0.01). =0.43, r 2 P =0.34, 0.02) ( =0.02) P P ). .1 and =0.01) =0.001). P r r Fig. 3C =0.004) 2 2 n =0.38, =0.51, =25), ). ). Figure 3 coefficient ( volume among34CPpatients.Pearson’s correlation test ofGeneralknowledgeinrelationtototalhippocampal fasciculus). Pearson’s correlationcoefficient ( relation toDTI(FA; fractionalanisotropyintherightuncinate 32 CPpatients.(C)Cognitivetestofgeneralknowledgein DTI intheleftventralcingulum(MD;meandiffusivity) among Immediate recall(A)andDelayed(B)inassociationto Episodic visualmemory(ReyComplexFigureTest) with variable explainedlessthan 5%ofthevariance. by ICV, explaining34%ofthevariance,whilegroup population (patientsandcontrols) waslargelyexplained The variation of hippocampal volumes in the study mm 4478 (3570–5650)mm compared tocontrols( ( After adjustmentforageandICV, theCPpatients among patients hippocampal volumesandcognitivefunction patients andcontrols and associationsbetween Comparison ofhippocampalvolumesbetweenall cognitive testswererecordedamongthecontrols. no associationsbetweentheaboveDTImeasuresand craniopharyngioma Diffusion tensorimagingin CD A n Episodic visual memory (Rey complex figure)

General knowledge raw score = 34) hadsmallerleftandrighthippocampal volumes No associations were found involving the fornix and 3 vs4579(3821–5927)mm DT DTI - I–Left ventralcing Ri r Immediate recall ght uncinatefascicul ). ul um MD us FA r =–0.69 P <0. P =0. r =0.46 n 3 ( Downloaded fromBioscientifica.com at09/26/202109:56:40PM

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r =–0.7 P <0. 583 3 ) 02 3 00 3 vs via freeaccess 2 1 European Journal of Endocrinology www.eje-online.org could explainworsegeneral knowledge, wearguethatthis tend tohavealowerlevelof education( the controls.We have previouslyshownthatCPpatients knowledge. Importantly, no association was found among reduced FA inthistractwasassociatedwithworsegeneral important forgeneralknowledge( in therightuncinatefasciculus,atractknowntobe WM alterations(bothreducedFA andincreasedMD) performance ingeneralknowledge. have asmallerhippocampalvolumeassociatedwithlower function andprocessingspeed.Inaddition,thepatients in episodicvisualmemory, visuospatialability, executive cingulum (increasedMD)wasassociatedwithadecline knowledge. Further, demyelination or edema of the was associatedwithlowerperformanceingeneral the rightuncinatefasciculus,andlossofWMintegrity and loss of WM integrity (reduced FA) was recorded in Compared tocontrols,demyelination(increasedMD) alterations detectedwithDTIinseveralneuralpathways. deficits thatareassociatedwithmicrostructuralWM late complicationsafterCPtreatmentinvolvecognitive In thepresentstudy, weshowforthefirsttimethat Discussion associations werefoundamongthecontrols. (MD: (Reycomplexfigure)fordelayedrecall visual memory r (WAISreduced semantic memory (MD: vocabulary) FA ofthelefthippocampus associated significantly with r reduced visuospatialabilities(WAIS blockdesign)(FA: right hippocampuswassignificantlyassociatedwith After adjustment for age ( cognitive functionamongpatients Associations betweenDTIinthehippocampusand found amongthecontrols. ( continuedtobesignificant and semanticmemory age, theassociationbetweentotalhippocampalvolume and ( (WAIS (( vocabulary) were significantlycorrelatedwithsemanticmemory right and left side as well as total hippocampal volume, 2 2 r 2 =0.19, =0.12, Clinical Study =0.12, Our resultsshowthatCPpatientshavemicrostructural Among CPpatient( r r =0.39, 2 =0.13, P P P .1 n FA: and =0.01

= .2) ( =0.026) 0.04). AnincreaseinMDandadecrease P

= P .3 n FA: and =0.03 0.023), respectively).Afteradjustmentfor r i. 3D Fig. =0.38, r n 2 n =0.26, 4 hpoapl volumes, hippocampal =34)

= ). Nosuchassociationswere P 32), a decrease in FA of the .2) ( =0.025), r 2 =0.12, S Fjalldalandothers P .0) n episodic and =0.002) 28 P r 7 =0.38, .4. o such No =0.04). ). Inaddition, ). Althoughthat P =0.027) was associated with a decline in episodic visual memory was associatedwithadeclineinepisodicvisualmemory disease whereearlydegenerationintheventralcingulum patients withmildcognitiveimpairmentandAlzheimer or edema( seemed tobeparticularlyaffectedwithdemyelination and 51%ofthevariation.Thus,leftventralcingulum recall ( visual memory, forimmediaterecall( left ventralcingulum(increasedMD)andworseepisodic ( medial temporallobeimportantforepisodicmemory associated withaseverityindepressivesymptoms( in theuncinatefasciculus(reducedFA), whichwas Cushing syndrome,DTIhasshownreducedWMintegrity treatment-related WMalterations.Also,inpatientswith until theearlythirties( is amongfewneuralpathways,whichcontinuetomature may beaconsequensofthedisease,asuncinatefasciculus but among patients the variation in ICV explains 34% of CP patientshadlowerrightand lefthippocampalvolumes ( decreases insizewithincreasing age,eveninhealthyadults cardiovascular riskfactors( to beindependentofconcomitanthypercortisolism and data werepredominantfordemyelinationandseemed connections withthecingulum.Özyurt cortex islinkedtothehippocampusviaitsabundant situated abovethecingulum,andposteriorcingulate andincludesthecingulatecortex in episodicmemory cortical thickness( on cognitivefunctionhavefocusedbrainvolumesand endocrinology ( find anassociationtoaspecificWMtract. previously shown in CPs ( Worse performance in executive function has been deficits in visuospatial ability and executive function. (increasedMDandreducedFA)memory togetherwith between rightventralcingulumwithworseepisodicvisual ( FA) anddemyelination/edema(increase in MD)( recorded with both a decrease WM integrity (decrease in syndrome widespreadWMinvolvementonDTIwas ( episodic memory ,theyrecordedapositiveassociationwith growth. Byanalyzinggraymattervolumeintheposterior gray andwhitematteroutsidetheareaofCPtumor thatHLimpacts introduced resultssupportingthetheory craniopharyngioma Diffusion tensorimagingin 38 43 27 ) andthestrongestassociationwasfoundbetween ). Thus,weadjustnotonlyfor agebutalsoforICV. The ). We also recorded highly significant associations The ventralcingulumishighlyconnectedtothe It iswellknownthatthe hippocampalvolume There arescarce datainvolving DTIinthefieldof i. 3B Fig. 14 ). Thisisinlinewithapriorstudyamong ) andrecognition,explainingbetween43 18 18 , 23 18 , 39 , ). AmongpatientswithCushing 39 36 Downloaded fromBioscientifica.com at09/26/202109:56:40PM , 40 , ), makingitvulnerabletoearly 7 41 40 , ). Graymatterareaisinvolved 9 ). , ), but for the first time, we 41 , 42 178 ), andrecentstudies i. 3A Fig. :6 t al et ), delayed 41 ). Their . ( 37 584 ). 18 via freeaccess ) European Journal of Endocrinology the studypopulationis small. Nevertheless,witha tumor and/or treatment. Due to the rarity of the disease, and theneuraltracts( as theconnectivity between several HTcompartments with therecordedcognitive deficits,but,alsoindirectly, could bethedirectcauseofWMalterationsassociated The HTdamagecausedbythetumororitstreatment might tosomepointhaveanimpactonthepresentresult. hormonereplacement, and toHL.Alsothenecessary radiotherapy wascloselyrelatedtoextensivere-operations pathogenesis behindtheWMalterations,ase.g.cranial not allowforanyassumptionsregardingcausalitynorthe specific neuralpathway. Further, thestudydesigndoes function to asingle impossible torelateacertainmemory function dependsoncomplexneuralnetworks,andit is cognitive function( patients, withintactHT, hasamuchbetterprognosisand results areinlinewiththefactthatthissubgroupofCP DTI measuresbetweenpatientsandcontrols( HT arepublishedelsewhere,showingnodifferencesin to lowstatisticalpower. DataonCPpatientswithintact quality. Thus,ournonsignificantresultscouldbedue resulting inonly8patientswithHLandsufficient DTI of patientsincludedfortheoverallDTIanalyses( inthenumber which alsowasreflectedinareduction lower performanceincognition. hippocampus, thereweremanypotentialreasonsfora delayed recall.Thus,basedonthepresentalterationsin for in generalknowledgeandepisodicvisualmemory edema, whichwasassociatedwithworseperformance altered bybothlossofWMintegrityanddemyelination/ reduced visuospatialability, andthelefthippocampuswas in therighthippocampus,whichwasassociatedwith We recordedalterationsinWMintegrity(decreaseFA) confounder butwasmorepartofachaindiseaseevents. asa only forageasweassumedthatICVdidnotserve Regarding DTI measures in the hippocampus, we adjusted ( suffered from impairedepisodic visual memory syndrome withreducedhippocampalvolumewho with astudyinvolvinggroupofpatientsCushing and inepisodicvisualmemory. Thelatterisinaccordance associated withlowerperformanceingeneralknowledge volumes. Thereducedhippocampalvolumeswere volume ratherthananisolatedeffectonhippocampal treatment effectmaybeageneralizeddecreaseinbrain which maybetreatmentrelated.Inotherwords,the tend to have asmaller ICV, including the hippocampus, the variation in total hippocampal volume. Thus, patients Clinical Study Our studyhasanumberoflimitations.Cognitive This is the first studypresenting DTI inCPwith HL, 7 ). 15 ) hasbeendisrupteddueto the S Fjalldalandothers 23 ). These n =15), 39 ). WM integrity and demyelination, associated with lower CP patientshaveasmallerhippocampus,butalsoreduced edema, toadeclineinvisualepisodicmemory. Further, with bothlossofWMintegrityanddemyelination/ were found between WM alterations in the cingulum, cognitive dysfunction in CP. The strongest associations established between WM alterations detected with DTI and For thefirsttime,astructuretofunctionrelationshipis Conclusion cingulum aredefined( the heterogeneityinastohowdifferentsegmentsof important tokeepinmindwhencomparingstudiesis as itismostrelevant for episodicmemory. Anotherfactor compare ourresultstoDTImeasuresinAlzheimerdisease CP, in this area of Sweden. We chose to during 52 years adult population of childhood-onset eligible surviving background populationof2.5million,weincludedthe References approved thefinalversion. extensively revisedthepaperwithinputfromallauthors.Allauthors helped tointerpretthedata.SBFdraftedoriginalpaperandEME the dataanalysis.DSandVWanalyzedtractography. Allauthors All authorshelpedtoconceptualizethestudy. SBF, EME,LRconducted Author contributionstatement and theMedicalFaculty, LundUniversity, Sweden. This workwassupportedbytheSwedishChildren’s CancerFoundation, Funding perceived asprejudicingtheimpartialityofthisstudy. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest EJE-18-0081. This is linked to the online version of the paper at Supplementary data patients withHTdamage. for optimizing postoperative outcome and care among CP increased awareness of cognitive dysfunction is essential performance ingeneralknowledge.Newknowledgeand craniopharyngioma Diffusion tensorimagingin 1 Müller HL,Gebhardt U,Teske C, Faldum A,Zwiener I,Warmuth- Journal ofEndocrinology Journal KRANIOPHARYNGEOM 2000after3-yearfollow-up. 2011European resultsofthemultinationalprospectivetrial craniopharyngioma: Post-operative hypothalamiclesions andobesityinchildhood Metz M, Pietsch T, Pohl F, Sörensen N,Calaminus G 2011 44 Downloaded fromBioscientifica.com at09/26/202109:56:40PM ). 165 17–24. 178 https://doi.org/10.1530/ www.eje-online.org :6 et al . 585 via freeaccess European Journal of Endocrinology www.eje-online.org

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Revised versionreceived16March2018 Received 30January2018 Accepted 28March2018

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