White Matter Microstructural Integrity in Youth With Type 1 Diabetes.

0.64 MB·English

by  Antenor-Dorsey, Jo Ann V.

ORIGINALARTICLE
White Matter Microstructural Integrity in Youth With
Type 1 Diabetes
Jo Ann V. Antenor-Dorsey,1 Erin Meyer,2 Jerrel Rutlin,1 Dana C. Perantie,1 Neil H. White,4
Ana Maria Arbelaez,4 Joshua S. Shimony,3 and Tamara Hershey1,2,3
severe hypoglycemia and reduced (7) or increased hippo-
Decreasedwhiteandgraymattervolumeshavebeenreportedin
youth with type 1 diabetes mellitus (T1DM), but the effects campal volumes (8). Volume estimates, however, do not
of hyperglycemia on white matter integrity have not been assessthestructuralintegrityofwhitemattertracts.Animal
quantitativelyassessedduringbraindevelopment.Weperformed and some human studies have suggested that hyperglyce-
diffusiontensorimaging,usingtwocomplimentaryapproaches— mia (9,10) and hypoglycemia have been associated with
region-of-interestandvoxelwisetract-basedspatialstatistics—to changes in white matter microstructural integrity peripher-
quantify white matter integrity in a large retrospective study of ally (11), but prior studies in youth with T1DM have not
T1DM youth and control participants. Exposure to chronic hy- specificallyexaminedthemicrostructuralintegrityofwhite
perglycemia,severehyperglycemicepisodes,andseverehypogly-
matter tracts within the brain.
cemia,asdefinedintheDiabetesControlandComplicationsTrial
Diffusion tensor imaging (DTI) can be used to assess
(DCCT),wereestimatedthroughmedicalrecordsreview,HbA
1c white matter microstructural integrity through the mea-
levels,andinterviewofparentsandyouth.Wefoundlowerfrac-
tional anisotropy in the superior parietal lobule and reduced surementofwatermoleculemovement.DTIissensitiveto
mean diffusivity in the thalamus in the T1DM group. A history subtle white matter brain injury in humans (12) and can
of three or more severe hyperglycemic episodes was associated detect changes even when standard T2-weighted images
withreducedanisotropyandincreaseddiffusivityinthesuperior appear normal and the white matter region volumes are
parietal lobule and increased diffusivity in the hippocampus. similar (13). In addition, DTI measures have been directly
These results add microstructural integrity of white matter to validated by means of comparison with immunohisto-
the range of structural brain alterations seen in T1DM youth
chemicalindicatorsofaxonalinjuryinanimalmodels(14).
and suggest vulnerability of the superior parietal lobule, hippo-
In the current study, we examined DTI parameters using
campus, and thalamus to glycemic extremes during brain devel-
complementary region-of-interest (ROI)-based and voxel-
opment. Longitudinal analyses will be necessary to determine
how these alterations change with age or additional glycemic wise tract-based spatial statistics (TBSS) approaches to
exposure.Diabetes 62:581–589, 2013 determine whether abnormalities in white matter micro-
structure are present in youth with T1DM and varying
degrees of hyperglycemia or hypoglycemia exposure.
T
he effects of type 1 diabetes mellitus (T1DM) on
the central nervous system, especially during RESEARCHDESIGNANDMETHODS
braindevelopment,arecontroversialandnotwell Subjects.Youthaged9–22yearswithT1DMandnondiabeticsiblings(healthy
understood. Structural magnetic resonance im- controlsubjects)wererecruitedfromthePediatricDiabetesClinicatWashington
UniversityinSt.LouisandSt.LouisChildren’sHospital.T1DMsubjectswere
aging (MRI) studies have found regional gray and white
allseenbyapediatricendocrinologistatWashingtonUniversity.Onceaclinic
matter volume differences between youth with T1DM and
member determined which patients met our basic inclusion and exclusion
control subjects (1,2), relating some of these findings to criteria(e.g.,age,diagnoses),thefamilieswerereferredtoourresearchteam
previous hypoglycemia or hyperglycemia exposure (3,4). forfurtherdiscussionaboutthestudy.Afterreviewingthestudydemandsand
These data and studies in adults have suggested a prefer- the more detailed exclusion criteria with the families, if interested, parents
ential vulnerability of some brain regions to diabetes and and children were consented and assented and then enrolled in the study.
Subjects were excluded for mental retardation, chronic diseases other than
glycemicextremes.Forexample,wehavefoundthatwhite
T1DM(e.g.,includinghypothyroidism),significantneurologichistorynotdue
mattervolumeinthesuperiorparietalregionwasdecreased
to diabetes, diagnosed psychiatric disorder, current use of psychoactive
in youth with T1DM with greater hyperglycemic exposure medications,knownprematurebirth(,36weeks’gestation) withcomplica-
(4), similar to findings in adults (5,6). Furthermore, studies tions, or contraindications to MRI (e.g., metal implants).T1DM participants
of youth with T1DM have reportedan association between wereoninsulintherapyforatleast2yearsbeforestudyentry.Handedness
wasassessedwithamodifiedEdinburghHandednessInventory.Procedures
were approved by the Washington University School of Medicine Human
StudiesCommittee,andallparticipantsandtheirparentsorguardianssigned
Fromthe1DepartmentofPsychiatry,WashingtonUniversitySchoolofMedi- informedconsents.Althoughsomedatafromthiscohorthavebeenpublished
cine, St. Louis, Missouri; the 2Department of Neurology, Washington Uni- previously (4,8,15,16), the white matter microstructural integrity analyses
versity School of Medicine, St. Louis, Missouri; the 3Department of reportedherehavenotbeenpublishedpreviouslyexceptinabstractform.
Radiology,WashingtonUniversitySchoolofMedicine,St.Louis,Missouri; Clinical variables. Detailed information about each diabetic participant’s
andthe4DepartmentofPediatrics,WashingtonUniversitySchoolofMedi- history of severe hypoglycemia, hyperglycemia, and other diabetes compli-
cine,St.Louis,Missouri.
cations was collected by parental and child interview and medical record
Corresponding authors: Tamara Hershey, [email protected], and Jo Ann review.AsdefinedintheDiabetesControlandComplicationsTrial(DCCT)
V.Antenor-Dorsey,[email protected].
Received25May2012andaccepted25July2012. (17), severe hypoglycemia was identified as an event with neurologic dys-
DOI:10.2337/db12-0696 function,includingseizure,lossofconsciousness,and/orinabilitytoarouse
(cid:1)2013bytheAmericanDiabetesAssociation.Readersmayusethisarticleas from sleep, that required assistance of someone other than the patient for
longastheworkisproperlycited,theuseiseducationalandnotforprofit, treatmentandimprovedaftertheadministrationofcarbohydrateorglucagon
and the work is not altered. See http://creativecommons.org/licenses/by injection(18).Severehyperglycemiawasidentifiedaseventsincludingvom-
-nc-nd/3.0/fordetails. iting,ketosisevidentinserumorurine,withorwithoutacidemia,thatrequired
See accompanying commentary, p. 341. assistanceofsomeoneotherthanthepatientfortreatmentandimprovedafter
diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 581
WHITEMATTERINTEGRITYINT1DMYOUTH
administrationofinsulinand/orintravenousfluids(Table1).Thenumberof radialdiffusivity[(l +l)/2],whichindicatestheaveragemagnitudeofwater
2 3
severehypoglycemicandhyperglycemiceventswascategorizedzero(0group), moleculemovementinthetwominoraxes.Diffusionencodingscorruptedby
onetotwo(1–2group),andthreeormore(3+group)episodesbecausethese subjectmotionwereautomaticallyremoved,andaresidualmapwascreated
variableswerenotnormallydistributed.Hyperglycemicexposurehistorywas todeterminethevarianceinthereconstructeddata.Ared-green-bluemapwas
estimatedfromallavailableHbA testresults.HbA testsapproximatedav- alsousedforqualitycontrolofparametricmaps.
1c 1c
eragebloodglucosecontrolovertheprevious2–3months.Theamountoftime Imaginganalysisapproach.WeanalyzedFA,meandiffusivity,axialdiffusivity,
representedbytheHbA tests(HbA coverage)wascalculatedbymultiplying andradialdiffusivitymeasuresusingtwocomplementarymethods1):ROI-based
1c 1c
thenumberoftestsby3monthsanddividingbydurationofdiabetesinmonths approachand2)voxelwiseanalysisusingTBSS.TheROImethodhasseveral
(4). Participants with HbA coverage for ,30% of their duration of di- advantagesovervoxelwiseanalyses:itminimizestheriskoftype1error,avoids
1c
abetes (n = 10) were excluded from hyperglycemia analyses. Less-than- themanystatisticalassumptionsovervoxelwiseanalyses,andallowsfortai-
completecoveragewasduetoclinicalappointments.3monthsapart,transfers loringROIstoavoidpartialvolumeeffects,thusreducingtheeffectofimperfect
fromotherclinics,oruseoftotalglycatedhemoglobintestsinsteadofHbA . registrationprocedures(12).However,voxelwiseanalysesconsiderallofthe
1c
To account for duration of exposure to hyperglycemia, a hyperglycemia imagingspacewithoutregardforarbitraryorunreliableboundariesandwithout
exposurescorewascalculated.BecauseachildwithanaverageHbA of8% aprioriassumptions.Weusedbothapproachesheretoprovideacomprehen-
1c
anddurationofdiabetesfor10yearshashadmoreexposuretohyperglycemia siveviewofthewhitemattermicrostructuralabnormalitiesinT1DMyouth.
thanachildwiththesameaverageHbA for2years,ascorethatweighted ROImethod:Regionswereselectedbasedonawell-establishedDTIatlas(19)
1c
durationandHbA equallywascalculatedbyaddingeachpatient’szscoreof andwerecheckedbyaneuroradiologistwithexpertiseinDTI.Wethencom-
1c
medianHbA tothezscoreofdurationofdiabetes.Thismethodofcalcu- paredtheplacementoftheregionsoneachsubject’sred-green-bluemap,T1,and
1c
lation results in a near-normal distribution ofscores, with higher scores in- T2imagessimultaneously.ROIswereshiftedbyafewvoxelsasnecessarybya
dicatingmoreoverallexposuretohyperglycemiaandlowerscores,less.Thus, trainedtechniciantobetterconformtoeachindividual’snativeanatomy.Final-
eachchild’shyperglycemiaexposurescorecanbeinterpretedrelativetothis ized regions were then applied to each subject’s fractional anisotropy, mean
sampleonly.BloodglucoseatthetimeoftheMRIscanwasalsorecordedand diffusivity,axialdiffusivity,andradialdiffusivityparametricmapsandsampled
hadtobeabove70mg/dLbeforebeginningscanning. usingAnalyze8.0 software (20).Ratershaveestablishedinterratercorrelation
Image acquisition. Structural images were acquired for each subject on coefficientsabove0.90forfractionaldiffusivityandmeandiffusivityvaluesforall
a Siemens Sonata 1.5 Tesla imaging system witha standard Siemens 30-cm ROIs.Tominimizefalse-positives,wefocusedonaselectnumberofregions:2
circularlypolarizedradiofrequencyheadcoil.Threetofiveimages,consisting aprioriregions(superiorparietallobuleandhippocampus)and10exploratory
of128contiguous1.25-mmsagittalslices,wereacquiredforeachsubjectusing regions(cerebellum,opticradiation,posteriorlimboftheinternalcapsule,cor-
magnetization-preparedrapidgradientecho(repetitiontime=1,900ms,echo puscallosum(splenium,bodyandgenu),centrumsemiovale,thalamus,putamen,
time=3.93ms,flipangle=15°,matrix=2563256pixels,voxelresolution= andpons),andaveragedvaluesfromleftandrighthomologousregions(Fig.1).
13131.25mm,time=7:07min).Subjectswithmovementorotherartifact TBSS.Asacomplementaryapproach,weusedTBBS(21)voxelwiseanalysesto
were excluded from further analyses. Images with suspected anatomic ab- confirmourROIfindingsandtoexplorewhitemattereffectsinotherlocations
normalitieswerereferredtoaneuroradiologistforreview.Threesubjectsin without regard for strict anatomical boundaries. Diffusion weighted images
theT1DMgroup wereexcludedforconfirmedbrainabnormalities:onehad were internally motion-corrected using nine-parameter affine (rigid body +
apinealcyst,onehadanarterialmalformationinthemedulla,andtheother scanneraxisstretch)registrationusingsoftwaredevelopedin-house.Then,BET
hadhippocampaldysplasiathatwassevereenoughtopreventthescanfrom (FMRIBBrainExtractionTool)wasusedtocomputeabrainmaskfromeach
aligningwellwiththebrainatlasusedforourstructuralanalyses. individual’s motion-corrected, aligned, and averaged DWI data set, and FDT
Diffusion-weightedimageswerecollectedtomeasurewhitemattermicro- (FMRIBdiffusiontoolbox)wasusedtocomputefractionalanisotropymaps.
structuralintegrity.Wecollectedthreesetsofinterleaveddiffusion-weighted Tocreateatargettemplateforregistration,asubsetwaschosenfromthe
images(2-mmslicethickness,12directionsatbvaluesof800,1000and1200 entiresubjectpooltoprovideanevendistributionofmalesandfemalesand
s/mm2andab=0,transverseacquisition;repetitiontime=4500,echotime= ages.Fractionalanisotropyimagesinthetargetgroupwerethennonlinearly
80,voxelresolution=23232mm,time=1:26318=25:48min). alignedto1-31-31-mmspaceandtoeachother.Thetargetimagewasthe
Imageprocessing.Thediffusion-weightedimageswereregisteredtotheT2 image that required theleast amount ofwarping for all other fractional an-
(b=0),whichwasregisteredtothebestmagnetization-preparedrapidgradient isotropy images to align to it. All fractional anisotropy images in the entire
echo,whichinturnwasregisteredtoanin-houseatlas.Parametricmapswere subjectpoolwerethennonlinearlyalignedtoeachotherin1-31-31-mm
generatedformeandiffusivity(whichindicatestheaveragemagnitudeofwater spaceandtothetargetimage.Thetargetimagewasaffine-alignedintoMNI152
moleculemovementinthethreeaxes),fractionalanisotropy(whichindicates standardspace,andeveryfractionalanisotropyimagewasthentransformed
thedirectionalityofwatermoleculemovement),andeigenvalues(l,l,and into1-31-31-mmMNI152space.Ameanfractionalanisotropyimagewas
1 2
l).Alsorecordedwerethemeasuresofaxialdiffusivity(l),whichindicates calculated and used to produce the mean fractional anisotropy skeleton to
3 1
the magnitude of water molecule movement along the principal axis, and representthecenterofwhitemattertracts.Fractionalanisotropyimageswere
projectedontothemeanfractionalanisotropyskeletonandthresholdedsetat
fractional anisotropy = 0.2 for voxelwise analyses. Mean diffusivity, axial
TABLE1 diffusivity,andradialdiffusivityimageswerealsocalculated.
Symptoms reportedduringseverehyperglycemicepisodes Statisticalanalyses.ForallROIanalyses,weperformedunivariateanalyses
ofeachregionwithgroup(T1DMvs.control)orsubgroup(severehypergly-
Symptoms Of63severehyperglycemicepisodesreported cemia or severe hypoglycemia subgroups) as the independent variable and
covaryingageandsex.Thehyperglycemiaexposurescorewascorrelatedwith
(%) DTImeasuresforeachregion.ThecriteriaforsignificancewasP,0.05forour
Ketonuria 86 twoaprioriregionsandP,0.005(Bonferronicorrection,0.05/10regions)for
Vomiting 70 our exploratory regions within analyses for each DTI parameter (fractional
Tired 41 anisotropy,meandiffusivity,axialdiffusivity,andradialdiffusivity).Regions
Weakness 38 thatsurvivedmultiplecomparisonscorrectionswereexaminedfordifferences
betweengroupswithposthoccomparisons.
Drowsiness 30
Forvoxelwiseanalyses,DTIparameterimageswereanalyzedusingRan-
Dizziness 27
domize(FSL,FMRIB,Oxford,U.K.),apermutation-basedmultiplecomparisons
Irritable 27
corrected statistical approach (22). Age and sex were covaried in analyses
Sweating 27 comparinggroups,asdescribedfortheROIanalyses.Eachanalysisusedthe
Headaches 24 software-specificmultiplecomparisoncorrectionprocedures.
Confused 22
Pallor 21
Other* ,20 RESULTS
T1DM versus control subjects
*Troublemovingbody,slurredspeech,poorconcentration,stomach Demographicandclinicaldata.Thestudyincluded73
pain,aggressive,tearful,trembling,discoordinated,dehydrated,hun-
T1DM youth and 30 healthy control subjects. T1DM and
gry, disoriented, flu, strange thoughts, thirsty, unresponsive, loss of
control groups were similar in all demographic measures,
consciousness,problemsbreathing,clammy,hyperventilation,lossof
appetite, muscle ache, nausea, blurred vision, cold, lethargic, slug- with the exception that there were proportionally more
gish,stubborn,stumbling. right-handed youth in the control than in the T1DM group
582 DIABETES,VOL.62,FEBRUARY2013 diabetes.diabetesjournals.org
J.A.V.ANTENOR-DORSEYANDASSOCIATES
FIG.1.ROIsdefinedonaT2(left)andfractionalanisotropy(right)image.CC,corpuscallosum;PLIC,posteriorlimboftheinternalcapsule.(A
high-qualitycolorrepresentationofthisfigureisavailableintheonlineissue.)
(x2=17.95,P,0.001;Table2).NoneoftheT1DMpatients limboftheinternalcapsule,externalcapsule,andcerebral
had a history of retinopathy or neuropathy. peduncle, compared with controls (Fig. 2A). There were
ROI analyses. Fractional anisotropy was lower (F = nodifferencesinfractionalanisotropy,meandiffusivity,or
1,99
7.59, P = 0.007) and radial diffusivity was higher (F = radialdiffusivityparametricmapsbetweenthetwogroups.
1,99
7.45,P=0.008)intheT1DMgroupcomparedwithcontrol Hyperglycemia categories
subjects in the superior parietal lobule region. No differ- Demographic and clinical data. Subjects in the three
ences were seen between groups in the hippocampus hyperglycemiacategories(0,1–2,3+)weresimilarinallof
(fractionalanisotropy,mean,radial,andaxialdiffusivities; thedemographicandclinicalmeasurescollected,withthe
Table 3). For exploratory regions, the T1DM group had exception that there were significantly fewer Caucasians
lower mean (F = 10.36, P = 0.002) and lower radial in the 3+ group (x2 = 9.79, P = 0.008; Table 2).
1,99
diffusivity (F = 9.37, P = 0.003) in the thalamus and ROI analyses. The superior parietal lobule had de-
1,99
lower axial diffusivity in the cerebellum (F = 9.08, creased fractional anisotropy (F = 2.88, P = 0.005) and
1,99 5,97
P = 0.003) compared with control subjects (Table 3). increased radial diffusivity (F = 2.99, P = 0.009) with
5,97
TBSS.TheT1DMgrouphadloweraxialdiffusivityacross increased hyperglycemic episodes. The 3+ hyper patients
multiple regions, including the superior parietal lobule, had the lowest fractional anisotropy (3+ hyper less than
corpus callosum (genu, body, and splenium), posterior control subjects, P = 0.009) and the highest radial
diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 583
WHITEMATTERINTEGRITYINT1DMYOUTH
TABLE2
Demographicandclinicalvariables
AmongT1DMgroup(n= 73)
Severehyperepisodes Severehypoepisodes
Control T1DM
subjects subjects None 1–2 3+ None 1–2 3+
N=30 N=73 n=41 n=21 n=11 n=27 n=30 n=16
Age,years(SD) 15.9(3.4) 16.8(2.9) 16.9(2.8) 16.2(3.3) 17.4(2.5) 16.6(3.0) 16.7(2.7) 17.1(3.4)
Sex,n
(%female) 15(50) 29(40) 17(41) 8 (38) 4(36) 8 (30) 14(47) 7 (44)
Race,n
(%Caucasian)† 27(90) 65(90) 37(90) 21(100) 7(64)† 25(93) 27(90) 13(81)
Handedness,
n(%righthanded)** 29(97) 63(86)** 35(85) 20(95) 8(73) 23(85) 26(87) 14(88)
Parental
education,
years(SD) 15.4(1.9) 15.2(2.1) 15.3(2.3) 15.2(1.6) 14.7(1.7) 14.4(1.9) 15.7(2.0) 15.3(2.1)
T1DMduration,
years(SD)§ NA 9.5(2.9) 9.1(2.6) 9.9(3.5) 9.9(3.1) 7.9(2.2)§ 10.2(3.0) 10.6(2.9)
AgeofT1DM
onset,years(SD)‡ NA 7.2(3.1) 7.8(3.4) 6.1(2.6) 7.5(2.6) 8.5(3.2)‡ 6.5(2.9) 6.5(3.0)
HbA ,median(SD)* NA 8.3(1.0) 8.2(0.8) 8.2(1.0) 9.1(1.4) 8.3(1.0) 8.1(0.7) 9 (1.3)*
1c
WeightedHbA ,
1c
mean(SD)# NA 20.04(1.3) 20.26(1.2) 20.04(1.4) 0.87(1.3) 20.63(1.08) 20.02(1.14) 0.91(1.64)#
Blood glucoseat
time ofscan,
meanmg/dL(SD) NA 193.44(91.8) 207.1(89.6) 173.5(96.8) 180(90.0) 193.9(89.1) 173(83.1) 233.5(104.9)
**P,0.001,#P=0.03significantlydifferentamongT1DMsubjects;†P=0.008;‡P=0.037;§P=0.002;*P=0.04.
diffusivity (3+ hyper greater than controls, P = 0.013). We were found among the different groups in the DTI mea-
also found that increased hyperglycemic episodes were sures of the hippocampus. In addition, none of the ex-
associated with higher mean (F = 2.64, P = 0.034) and ploratory regions were statistically significantly different
5,97
higher radial diffusivity (F = 3.02, P = 0.034) in the hip- among the hypoglycemic categories.
5,97
pocampus, with the 3+ hyper patients having the highest TBSS. One-way ANOVA identified significantly different
mean (3+ greater than 1–2 hyper, P = 0.043) and highest axial diffusivity values along multiple white matter tracts,
radialdiffusivity(3+greaterthan1–2hyper,P=0.052).None including the superior posterior limb of the internal cap-
oftheexploratoryregionswerestatisticallydifferentamong sule,externalcapsule,andcerebralpeduncle,betweenthe
the three hyperglycemic categories and the control group. different hypoglycemic groups, but none of the pairwise
TBSS. One-way ANOVA identified significantly different comparisonsreachedsignificance(Fig.2C).Therewereno
axial diffusivity values along multiple white matter tracts, differences in fractional anisotropy, mean diffusivity, or
including the posterior limb of the internal capsule, exter- radial diffusivity parametric maps among the hypoglyce-
nal capsule, and cerebral peduncle, between the different mic groups and control subjects.
hyperglycemic groups; however, none of the pairwise Hyperglycemia score. Our ROI-based DTI measures
comparisons reached our predesignated statistical signifi- showed that none of the regions exhibited a statistically
cance (Fig. 2B). There were no differences in fractional significantcorrelationbetweentheirfractionalanisotropy,
anisotropy,meandiffusivity,orradialdiffusivityparametric or mean, radial, and axial diffusivity values and the hy-
maps among the hyperglycemic groups and controls. perglycemia exposure score. Similarly, using the TBSS
Hypoglycemia categories approach,wedidnotfindasignificantcorrelationbetween
Demographic and clinical data. Subjects in the three hyperglycemia exposure score and the fractional anisot-
hypoglycemia categories were similar in all demographic ropyormean,radial,andaxialdiffusivityparametricmaps.
measures collected. In clinical measures, youth in the
different hypoglycemic groups differed in age of onset DISCUSSION
(F = 3.46, P = 0.037), median HbA (F = 3.4, P = In this study, we detected differences in white and gray
2,72 1c 2,63
0.04),anddurationofdisease(F =6.82,P=0.002),with mattermicrostructurebetweenyouthwithT1DMandtheir
2,71
the3+hypogrouphavinghighermedianHbA (3+higher nondiabeticsiblingsusingROIandvoxel-basedanalysesof
1c
than 1–2 hypo group, P = 0.037), and those who experi- diffusiontensorimages.ThesefindingssuggestthatDTIis
enced a severe hypoglycemic episode having longer du- a sensitive method for detecting brain abnormalities in
rationofdisease(0shorterthan1–2hypogroup,P=0.007; T1DM, even in structures without apparent volumetric
0 shorter than 3+ hypo group, P = 0.007; Table 2). changes on conventional MRI.
ROIanalyses.Wefoundthatthesuperiorparietallobule Previousworkfromourlaboratoryandothershasfound
exhibitedincreasedfractionalanisotropy(F =2.97,P= that greater hyperglycemic exposure within the T1DM
5,97
0.045) with increased hypoglycemic episodes, but none of group was associated with reduced white and gray matter
the pairwise comparisons were significant. No differences volume in the superior parietal lobule, particularly the
584 DIABETES,VOL.62,FEBRUARY2013 diabetes.diabetesjournals.org
J.A.V.ANTENOR-DORSEYANDASSOCIATES
D A TT
ataareprese PonsCerebellumPutamenThalamussemiovaleCentrumradiationOpticBodyGenuSpleniumcallosumCorpuscapsuleinternalthelimbofPosteriorregionsExploratoryHippocampulobuleparietalSuperiorregionspriori 1DMversusABLE3
n s n
ted 00000 0 000 0 00 ond
asmeanSD.*0.01,*6P, .3990.040.4070.0566.2300.040.2190.0366.1140.020.1120.0266.2720.010.2790.0266.3970.040.3820.0366 .5160.040.5060.0466 .5900.060.5920.0766.7150.050.7120.0466.7910.030.7870.0466 .5900.020.5850.0366 .1490.020.1530.0366.4650.050.4350.05*66 subjectssubjectsControlT1DM (dimensionless)Fractionalanisotropy iabeticsiblingcontrolyou
*P (C th
0.00, 0.180.310.100.440.42 0.25 0.030.070.11 0.20 0.160.60 ohens’sizeEffect
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33222 4 653 1 62 md
0.65760.68360.70560.73660.6916 0.7626 0.77260.69460.6536 0.6676 0.88360.7476 subjeT1D m/s)iffusivity
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0.0360.0460.0260.0260.036 0.046 0.0860.0660.036 0.026 0.0560.046 jectsntrol (mRadial
0.499060.607060.667060.627060.54706 0.52206 0.478060.346060.26606 0.41706 0.812060.56206 subjecT1DM m/s)diffusivity
.0.0.0.0.0 .0 .1.0.0 .0 .0.0 ts
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diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 585
WHITEMATTERINTEGRITYINT1DMYOUTH
FIG.2.A:TBSSresultscomparingaxialdiffusivitymapsbetweenT1DMandcontrolsubjects,whichwerereducedinT1DMyouthcomparedwith
controlsubjects.B:Differentseverehyperglycemiccategoriesandcontrolsubjects.One-wayANOVAwassignificant,butnoneofthepairwise
comparisons reached significance. C: Severe hypoglycemic categories and control subjects. One-way ANOVA was significant, but none of the
pairwisecomparisonsreachedsignificance.Green,TBSSskeleton;red,P=0.05;orange,P=0.02.(Ahigh-qualitydigitalrepresentationofthis
figureisavailableintheonlineissue.)
precuneus/cuneus cortical region (4–6). In the current dependent cascade such as hyperglycemia-induced oxida-
study, we consistently observed that T1DM had altered tive stress (25,27). Alternatively, the DTI changes reported
DTI parameters in this region compared with controls, here could also be due to other glycolysis-independent
even after controlling for age and sex. Furthermore, DTI biologicalfactorsthatarealteredconcurrentlywithsevere
measureswereparticularlyalteredintheT1DMsubjectsin hyperglycemic episodes.
the 3+ hyper group, which suggests that this brain region The pattern of DTI alterations can provide clues to the
maybeanareaofpreferentialsensitivitytohyperglycemia underlying neuropathology in the brain. Animal studies
inT1DM.Hyperglycemiacouldaffectwhiteorgraymatter suggest that the combination of decreased fractional an-
integrity in the brain through several mechanisms, in- isotropy, increased radial diffusivity, and decreased axial
cludingmitochondrialsuperoxideproduction(23).Animal diffusivity is indicative of acute axonal injury along white
studies have found that hyperglycemia causes alterations matter tracts (14,28). In contrast, increased radial diffu-
in mitochondrial dynamics and function (24), which leads sivity, without an accompanying decrease in fractional
to accumulation of reactive oxygen species, oxidative anisotropy, is consistent with demyelinated white matter
stress, and impaired axonal transport in central nervous tracts (28). Thus, the pattern of differences in DTI
system axons, which can then result in axonal de- parameters detected in the superior parietal lobule in
generation (25). This mechanism could provide some ra- particular, and across the brain using TBSS, is suggestive
tionale why the superior parietal lobule, which is located of axonal injury as opposed to demyelination of axons.
within the precuneus/cuneus cortical region, appears par- Although DTI traditionally is used to characterize white
ticularly vulnerable to hyperglycemia. The precuneus/ matter, DTI can also be used to examine mean diffusivity
cuneus region is known to have the highest levels of gly- in gray matter regions, including the thalamus, putamen,
colysis in the brain in resting state conditions (26). A high and globus pallidus (29). Our a priori ROI for gray matter
rate of glycolytic activity due to systemic hyperglycemia was the hippocampus, due to the extensive literature
could possibly make brain tissue more vulnerable to linking hyperglycemia and hypoglycemia exposure to
damage or dysfunction by augmenting a metabolism- changesinthisregion(30–34).WefoundthatT1DMyouth
586 DIABETES,VOL.62,FEBRUARY2013 diabetes.diabetesjournals.org
J.A.V.ANTENOR-DORSEYANDASSOCIATES
exhibited increased mean and radial diffusivity in the identify the external capsule as an exploratory region but
hippocampus that was associated with hyperglycemic ex- saw differences in the axial diffusivity of this white matter
posure. Our earlier work demonstrated that greater ex- tract using TBSS. We also note that the average effect
posure to severe hypoglycemia, but not hyperglycemia, sizes of the fractional anisotropy, mean, and radial dif-
was associated with larger hippocampal volumes in fusivity values obtained using our ROI-based approach
T1DM youth. These seemingly disparate results empha- are smaller compared with the average effect size of the
size that DTI and volumetric analyses examine comple- axialdiffusivitymeasures(Table3).Thismayaccountfor
mentary,butdifferent,characteristicsofbrainstructure, our ability to find significant differences between our
yet both point to significant alterations in the hippo- studygroupsintheaxialdiffusivityparametricmapsonly
campus in diabetes. using TBSS (Table 4).
Among our exploratory regions, we found reduced dif- Our results differ from the DTI findings in adults with
fusivity in the thalamus of T1DM youth. This finding is T1DM. Although T1DM adults had lower fractional an-
notable because the thalamus has also been associated isotropy than control subjects in the posterior corona
with T1DM and glycemic exposure in other imaging and radiata and the optic radiation (40) that correlated with
neuropathological studies of adults (35–37) and youth (1). hyperglycemic exposure (41), these results were not con-
Specifically, diabetic ketoacidosis has been reported to firmed in our cohort of youth with T1DM. These differ-
acutely affect the diffusivity of the thalamus in a pediatric ences could be due to the longer disease duration and/or
population (38,39). Our findings suggest that the thalamus greater degree of exposure to hyperglycemia in T1DM
may exhibit long-term consequences associated with adults compared with our youth cohort and underscores
multiplediabeticketoacidosisepisodes.Differencesinthe thenecessityofconductingseparateneuroimagingstudies
diffusivityofthesegraymatterregionscouldreflectdirect during development. We also cannot rule out that the DTI
pathologic damage or secondary degeneration due to the differencesreportedherewerepresentbeforeexposureto
disruption of white matter tracts linking these structures glycemic extremes or diabetes. Retrospective report of
to other areas (29). severe glycemic experiences has been found to be fairly
Our study is strengthened by a relatively large sample reliable (42), but prospective measures are likely to be
size and complementary DTI analyses strategies with good more accurate, especially over long periods of time (43).
control of type I error. There is some overlap between our Analysis of the prospective follow-up data from our study
ROI-based and TBSS findings (Table 4), such as identifica- population is ongoing and should be able to determine if
tion of the superior parietal lobule as a preferentially af- further exposure to hyperglycemia accentuates the DTI
fected region in T1DM youth. Some ROIs, such as the differences reported here. Finally, the current study can-
thalamus, cannot be investigated using TBSS due to its notdiscernwhetherseverehyperglycemiaitself,orfactors
limitation to white matter tracts. However, we did not that occur concurrently with severe hyperglycemic
TABLE4
Summaryofanalysisandresults
Contrasts Analysis FA MD RD AD
T1DMvs.NC ROI Superiorparietal Thalamus(NC. Superiorparietal Cerebellum
lobule(NC. T1DM) lobule(NC , (NC.T1DM)
T1DM) P50.002 T1DM) P50.003
P50.007 P50.008
Thalamus(NC.
T1DM)
P50.003
TBSS NS NS NS Multiplesignificant
regions(NC.
T1DM)
Severehyperglycemia ROI Superiorparietal Hippocampus Superiorparietal NS
categories lobule(NC.31) (1–2,31) lobule(NC ,31)
P50.005 P50.034 P50.009
Hippocampus
(1–2,31)
P50.034
TBSS NS NS NS Multiplesignificant
regions(NC.
T1DM)
Severehypoglycemia ROI Superiorparietal NS NS NS
categories lobule(1–2 ,31)
P50.045
TBSS NS NS NS Multiplesignificant
regions(NC.
T1DM)
Hyperglycemia ROI NS NS NS NS
exposurescore TBSS NS NS NS NS
AD,axialdiffusivity;FA,fractionalanisotropy;MD,meandiffusivity;NC,normalcontrolsubjects;RD,radialdiffusivity.
diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 587
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