Gray Matter Pathology in MS: Neuroimaging and Clinical Correlations

17 Pages·2015·2.32 MB·English

HindawiPublishingCorporation
MultipleSclerosisInternational
Volume2013,ArticleID627870,16pages
http://dx.doi.org/10.1155/2013/627870
Review Article
Gray Matter Pathology in MS: Neuroimaging and
Clinical Correlations
JustinMorrisHonce
RadiologyDepartment,DivisionofNeuroradiology,UniversityofColoradoDenver,12700E19thAvenueMailStopC278,
Aurora,CO80045,USA
CorrespondenceshouldbeaddressedtoJustinMorrisHonce;[email protected]
Received8April2013;Accepted28May2013
AcademicEditor:AugustoA.Miravalle
Copyright©2013JustinMorrisHonce.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Itisabundantlyclearthatthereisextensivegraymatterpathologyoccurringinmultiplesclerosis.Whileattentiontograymatter
pathologywasinitiallylimitedtostudiesofautopsyspecimensandbiopsies,thedevelopmentofnewMRItechniqueshasallowed
assessmentofgraymatterpathologyinvivo.CurrentMRItechniquesallowthedirectvisualizationofgraymatterdemyelinating
lesions,thequantificationofdiffusedamagetonormalappearinggraymatter,andthedirectmeasurementofgraymatteratrophy.
Graymatterdemyelination(bothfocalanddiffuse)andgraymatteratrophyarefoundintheveryearlieststagesofmultiplesclerosis
andareprogressiveovertime.Accumulationofgraymatterdamagehassubstantialimpactonthelivesofmultiplesclerosispatients;
agrowingbodyoftheliteraturedemonstratescorrelationsbetweengraymatterpathologyandvariousmeasuresofbothclinical
disabilityandcognitiveimpairment.Theeffectofdiseasemodifyingtherapiesontherateaccumulationofgraymatterpathologyin
MShasbeeninvestigated.ThisreviewfocusesontheneuroimagingofgraymatterpathologyinMS,theeffectoftheaccumulation
ofgraymatterpathologyonclinicalandcognitivedisability,andtheeffectofdisease-modifyingagentsonvariousmeasuresofgray
matterdamage.
1.Background Despiteinitialfocusonwhitematterdemyelination,there
has been increasing focus on the gray matter pathology
Multiple sclerosis (MS) is a chronic inflammatory demyeli- occurring in MS. This shift in focus was spurred by new
nating disease of the central nervous system (CNS); focal immunohistochemicaltechniqueswhichmarkedlyincreased
areasofwhitematterdemyelinationhavelongbeenconsid- the visibility of cortical lesions ex vivo [7, 8]. Improved ex
eredthekeyfeatureofMS[1].DespitethisbeliefthatMSis vivodetectionofgraymatterlesionsspurredworktoimprove
primarilyawhitematterdisease,earlypathologicstudieshad the in vivo detection of gray matter pathology with MRI.
reportedfocalareasofcorticaldemyelinationinMSpatients As a result, new MRI imaging modalities are being utilized
[2,3].In1962,BrownellandHughes[4]showedthat,inMS, to provide greater insight into both the spatiotemporal
corticaldemyelinatinglesionsrepresentedupto26%ofthe patternanddistributionofgraymatterpathologyinMS.In
totalnumberofcerebralplaques.Despitetheseearlyindica- vivo evaluation of the impact of gray matter pathology on
tions of the cortical pathology occurring in MS, in general disabilityandcognitionandtheeffectofdisease-modifying
verylittleattentionwaspaidtocorticalpathology.Itislikely therapiesontheaccumulationofgraymatterpathologyare
thatthiswasduetoboththedifficultyinidentifyingcortical now ongoing. While many questions have yet to be fully
lesionsatautopsyviaconventionalhistochemicaltechniques answered,theimportanceofgraymatterpathologyinMSis
and the marked conspicuity of inflammatory lesions in the clear,andithastakenthecenterstageinMS-relatedresearch.
white matter [5]. This focus on white matter demyelination Thisreviewfocusesonimaginggraymatterpathologyin
ratherthancorticalpathologywasinitiallycompoundedwith MSandaddressestherelationshipbetweenmeasuresofgray
theadventofMRI:conventionalMRItechniquesforimaging matterpathologyandtheclinicalandcognitivestatusofMS
MSidentifyamajorityoffocalwhitematterlesionsbutare patients. First, the pathologic classification and theories of
veryinsensitiveforthedetectionofcorticalMSlesions[6]. pathogenesisofgraymatterpathologyarereviewed.Wethen
2 MultipleSclerosisInternational
detail the current imaging techniques utilized for both the autopsyspecimensdemonstrateamarkedlackofinflamma-
detectionofcorticaldemyelinationandquantitationofboth tion:theyarecharacterizedbyageneralabsenceofT-celland
diffusegraymatterdamageandgraymatteratrophy.Finally, B-celllymphocytes,complementdeposition,vascularinflam-
we discuss the clinical impact of gray matter pathology on mation, and blood-brain barrier disruption [7, 23]. This
disability and the effect of disease-modifying therapies on paucityofinflammationstandsinstarkcontrasttothehighly
measuresofgraymatterpathology. inflammatorynatureofWMlesions,whichcontainthirteen
times more lymphocytes and six times more microglia and
2.PathologicDescriptionofGrayMatter macrophagesthancorticallesions[10].Whiletheinflamma-
PathologyinMS torycellcontentwithincorticallesionsatautopsyisquitelow,
most of the inflammatory cells that are present are part of
2.1.ClassificationofCorticalDemyelination. Theinitialclas- theintrinsicCNSimmuneresponse:activatedmicroglia[10].
sificationsystemproposedforcorticaldemyelinatinglesions Whilethereislittleinflammationwithincorticalspecimens
subdivided lesions into seven types: a classification based fromautopsy,biopsiesfrompatientsinearlyMSsuggestadif-
ontherelationshipoflesionstothecerebralcorticalvenous ferentinflammatorypicture,withextensivecorticallympho-
supply[9].Petersonetal.(2001)devisedalesscomplexclassi- cyticinfiltrationseeninthecortexinsomepatients[14,15].
fication system based on the location of lesions within the Althoughtheinflammatoryprofilesofcorticaldemyeli-
layers of the cortex [10]. In this new system, there were natinglesionsshowmarkeddifferencesbetweenautopsyand
three,ratherthanseventypes.Type1“leukocortical”lesions early biopsy, prominent areas of meningeal inflammation
involvethedeeplayersofgraymatterandunderlyingwhite havebeendemonstratedthroughoutthecourseofthedisease.
matter.Type2“intracortical”lesionsaredemyelinatedlesions ThismeningealinflammationispresentbothinearlyRRMS
entirelycontainedwithinthecortex,notreachingthepialor [14], and in SPMS [16, 24–26], and in PPMS [27]. In many
subcorticalwhitemattersurface.Type3lesionsextendfrom instances,meningealinflammationisassociatedwithectopic
the pial surface into the superficial cortical layers. Bo et al. B-celltertiarystructureswhicharereportedtobetopograph-
furtherrefinedthisclassificationsystemwiththeadditionof ically associated with cortical lesions [25, 26]. Meningeal
a fourth type: demyelination of all layers of the cortex but inflammationismostcommonly,butnotalways,associated
nottheunderlyingwhitematter,typicallyinvolvingmultiple with subpial lesions (Type III/IV), and it is theorized that
gyri [7]. Under this classification, both Type 3 and Type 4 myelinotoxicagentsmaydiffusefromthemeningesintothe
lesionsare“subpial.”Examplesofthe4lesiontypesareshown superficial gray matter, possibly contributing to demyelina-
in Figure1. Subpial Type 3 lesions are the most common, tion[25].
accounting for up to 60% of the total number of cortical Giventhesefindings,howthencanoneexplainthediffer-
lesions and 67% of the total lesion area. The leukocortical ences between the scant inflammation found in cortical
Type 1 and intracortical Type 2 lesions are the next most lesions reported on autopsy studies, the marked inflamma-
common. Subpial Type 4 lesions are the least common but tionincorticallesionsinearlyMS,andthemeningealinflam-
coverthelargestsurfacearea[7,8,11]. mation occurring throughout the course of the disease? It
is possible that specimens from autopsy and biopsies are
2.2.Distribution/ExtentofGrayMatterDemyelination. Cor- presentingatleastasomewhatskewedpictureoftheinflam-
ticaldemyelinatinglesionsinvolveapproximately15–30%of matory profiles of MS lesions: lesions requiring biopsy in
the cortical gray matter [7, 12, 13]. Cortical demyelinating earlyMSaremuchmoreinflammatoryandaggressivethan
lesions occur in the early phases of relapsing remitting more typical MS lesions and autopsy specimens come pre-
multiplesclerosis(RRMS)[14];inrarecasesoccurringbefore dominantly from older patients with end-stage disease. It
focal WM lesions have developed [15]. Lesions accumulate may be that there are changing inflammatory profiles at
over time, and in the later stages of secondary progressive differentstagesoflesiondevelopment[28].WorkbyMerkler
andprimaryprogressivemultiplesclerosis(SPMS&PPMS) et al. (2006) has shown that early intense inflammation
theyarelargerandarepresentingreaternumbers[16,17].In within cortical demyelinating lesions in an EAE rat model
fact,insomeextremecasesofSPMS,corticaldemyelinating resolves relatively rapidly [29]. Merkler et al. (2006) and
lesionsmayinvolveupto68%ofthetotalcorticalarea[16]. Albert et al. (2007) have shown that cortical remyelination
Cortical demyelination is clearly widespread, and while isquiteprominentintheearlierstagesofMS[12,29].Bythe
there are relatively little differences in the involvement of timelesionsareanalyzedonautopsy,theinflammationwithin
each brain lobe, in general, the frontal and temporal lobes thesecorticallesionsmayhavewaned.Itremainstobeseen
areaffectedslightlymorethantheparietaloroccipitallobes whetherinflammatoryprofilesareisolatedtospecificpoints
[8, 12]. Within the temporal lobe, the hippocampus can be intimeintheevolutionofMS,oriftheymightoccuracross
heavily involved [18, 19]. Deep gray matter structures such alldiseasestages.
asthecaudate,putamen,globuspallidus,andthalamuscan While cortical demyelination is clearly occurring, there
beaffected[17,20].Graymatterinotherstructurescanalso isalsoevidenceofdamagetotheneuronsthemselves:mul-
be involved, most notably the cerebellum and spinal cord tiple studies show evidence of neuronal atrophy, apoptosis,
[13,21,22]. decreasedneuronaldensities,andreducedsynapticandglial
densities [10, 11, 30]. The close approximation of activated
2.3. Pathogenesis of Gray Matter Pathology: Inflammation, microgliaandastrocytestoneuronsincorticallesions,with
Neurodegeneration,orBoth? Corticallesionsobtainedfrom activatedmicrogliaensheathingneuronalbodiesandneuritic
MultipleSclerosisInternational 3
(a) (b)
(c) (d)
Figure1:Pathologicclassificationofcorticallesions.(a)Type1“Leukocortical”lesionsinvolvethedeeperlayersofgraymatterandunderlying
whitematter.Arrowheaddemonstratestheportionofthelesionextendingintothewhitematter.(b)Type2“Intracortical”lesionsaresmall
lesionscompletelycontainedwithinthecortex,typicallycenteredaroundsmallbloodvessels.(c)Type3“Subpial”lesionsextendfromthe
pialsurfaceintothesuperficialcorticallayers,notreachingthewhitematter.(d)Type4“Subpial”lesionsinvolvealllayersofthegraymatter
butdonotinvolveunderlyingwhitematter.
elements such as axons and dendrites in cortical lesions, the disease, the correlation of this damage with clinical
suggestsaprominentrolefortheintrinsicimmuneresponse disability and cognitive impairment, and assessment of the
and inflammatory cortical demyelination [10]. It has been efficacyofdisease-modifyingtherapiesonmeasuresofgray
suggestedhoweverthatprimaryneurodegenerativeprocesses matterpathology.
mayalsobeoccurringandthattheymaybepartiallyindepen-
dent[11,17,21,31,32].Mitochondrialdysfunction[33–35]and 3.1. Imaging of Gray Matter Demyelination. Conventional
defectsinionchannels[36]havebeenproposedaspossible MRI techniques for imaging MS are very insensitive for
independentmechanismsforprimaryneurodegenerationin detectionoffocalcorticalMSlesions:T2-weightedspinecho
MS. The picture however is not clear. Other studies have (T2-SE) and fluid attenuated inversion recovery (FLAIR)
shown that mitochondrial injury appears to be driven by imaging identify around 2/3rds of pathologically identified
inflammation—specifically inflammation-associated oxida- WM lesions; yet respectively, they miss up to 97% and
tiveburstsinactivatedmicrogliaandmacrophages[37,38].In 95%ofcorticallesions[6].Doubleinversionrecovery(DIR)
keepingwiththis,ahumanpathologystudyhasdemonstrat- improvesontheperformanceofFLAIRandT2-SEimaging,
ed a direct relationship between neuronal injury, axonal detecting 538% more cortical lesions than T2-SE and 152%
injury, and inflammation, arguing that in human MS there morecorticallesionswhencomparedtoFLAIR[40].Exam-
isnotaseparateneurodegenerativeprocess[39]. plesofcorticallesionsonDIRareshowninFigure2.
Despite these gains, DIR is not without its drawbacks.
3.NeuroimagingofGrayMatterPathology As DIR suppresses signal from both WM and CSF, the
resultingimagehasalowsignaltonoiseratio[41].DIRisalso
Advancedneuroimagingtechniquesmakeitpossibletoassess pronetoflowandpulsationartifactsandhasrelativelyslow
the development and progression of gray matter pathology acquisition times [41–44]. These artifacts produce regional
in vivo something impossible using immunohistochemical variations in gray matter signal intensity that can lead to
approaches from autopsy and early biopsies. These in vivo errorsinlesiondetection[45].Whilethesedeficienciescan
MRI approaches have inherent advantages and limitations. be improved by certain multislab [43, 46] and single slab
Despite these limitations, they allow assessment of the [47]3Dacquisitions,theSNRdoesnotsubstantiallyimprove
accumulation of gray matter pathology over the course of [47]. The low SNR, image artifacts, and variations in DIR
4 MultipleSclerosisInternational
Figure2:CorticallesionsinMSonDoubleInversionRecovery.41-year-oldfemalepatientwithRRMS.MultipleaxialDIRimagesdemonstrate
multiplesmallcorticalandleukocorticallesionsscatteredinthesupratentorialbrain(redarrows).
techniquebetween institutionscontributetorelativelylarge thesignofthemagnetization,additivelycombiningnegative
differences in agreement between observers when scoring and positive magnetization, which effectively doubles the
cortical lesions, variation which persists even when using dynamic range of the image and provides superior gray
internationalconsensusguidelines[48]. whitemattercontrast[52].CombinedPSIRandDIRresults
Assuch,DIRstillmissesthemajorityofcorticallesions in a 337% improvement in total number of cortical lesions
[49,50].Seewannetal.,performingpostmortemconfirma- detectedascomparedtoFLAIR[45]:morethandoublethe
tionofcorticaldemyelinatingplaques,showedthat3D-DIR 150% improvement was seen when DIR is used alone [43].
fails to identify 80% of pathologically confirmed cortical Sethietal.comparedPSIRandDIRheadtoheadin60MS
lesions, predominantly the purely cortical lesions (Type II– patientsand30controlsandfoundthatPSIRdetected3times
IV) [50]. In this study, DIR had a prospective sensitivity of more intracortical lesions and 3 times more leukocortical
83% for leukocortical lesions (Type 1) and 7% for subpial and juxtacortical lesions than DIR [52]. The high SNR of
lesions (Type III/IV). Despite the relative insensitivity of T1-3D-FSPGR imaging is also useful in the detection of
DIR for purely intracortical lesions, specificity was much cortical lesions [51], primarily allowing greater anatomic
higher at 90%. Interestingly DIR’s sensitivity is greatest for specificity.Nelsonetal.showedthattheinclusionofT1-3D-
lesionsintheinfratentorialbrain[44].Whyaresomelesions FSPGR imaging improved lesion classification as compared
visible on MRI while others are not? Seewaan et al. have tocombinedDIRPSIR,overturningtheoriginalclassification
shown that cortical lesions that are visible on MRI are not in30of119lesions[53].
histopathologically different from lesions invisible on MRI. The ability to detect cortical lesions improves at higher
They are however significantly larger, thus suggesting that field strengths. Compared to 1.5T, 3T DIR brain imaging
lesion size, rather than underlying pathology, determines if identifies 192% more pure intracortical lesions and 30%
alesionisvisibleornot[49]. more leukocortical lesions [54]. With ultrahigh field MRI
Inordertofurtherimproveonthesensitivityandspeci- (i.e.,≥7T),thereareevenmoresubstantialimprovementsin
ficity of DIR for cortical lesions, other imaging techniques SNR, spatial resolution, and image contrast, which results
have been used in concert with DIR: for example, phase- in increased detection of gray matter lesions [55–57]. The
∗
sensitive inversion recovery (PSIR) [45] and T1-weighted application of specialized 2D T2 -weighted gradient echo
3D FSPGR (T1-3D-FSPGR) imaging [51]. PSIR preserves and3DT1-MPRAGEsequencesinultra-highfieldMRIcan
MultipleSclerosisInternational 5
producehighresolutionanatomicimagesofcorticallesions difficulttovisualizeevenwithadvancedsequences,andthere
[58–60]. Interestingly ultra-high field techniques appear to issignificantvariationbetweenreaders.Graymatteratrophy
beverysensitivetosubpiallesions(TypeIII/IV)[55,59,61], measurementsontheotherhand,aremorereliableandthe
whichareverydifficulttodetectatstandardfieldstrengths. resultsarereproducibleamongresearchinstitutions[117,118].
While manual segmentation by trained expert readers
3.2.QuantificationofDiffuseInjuryinNormalAppearingGray is the gold standard for quantification of atrophy, the diffi-
Matter(NAGM). Whilefocalcorticaldemyelinationoccurs culty and time-consuming nature of manual segmentation
inMSandisdetectablewithDIRandotheradvancedsequen- precludes its use on large numbers of patients. As such,
ces,diffusedemyelinationisalsooccurringinNAGM.Both computer-assisted techniques are used. In general, these
conventionalandmoreadvancedtechniquesfailtoidentify techniquescanbedividedintothosethatsegment thebrain
abnormalities in the NAGM, even though this tissue may into its constituent parts and those which use registration
be histopathologically abnormal. Various quantitative MRI andthenimagesubtractiontodirectlyquantifybrainvolume
techniques have been utilized to assess for diffuse demyeli- changes between two time points [119]. Two of the most
nationinNAGM.Ofthem,magnetizationtransferimaging commonlyusedregistration-basedtechniquesarethebrain
(MTI) and diffusion tensor imaging (DTI) have been the boundaryshiftintegral(BBSI)[120]andthestructuralimage
moststudied. evaluation using normalization of atrophy (SIENA) [121].
MTImeasuresthecapacityofprotonsboundtomacro- These registration techniques measure total brain volume
molecules in brain parenchyma to exchange magnetization changes;theydonotspecificallymeasuregraymattervolume,
with free water [101]. The efficiency of this exchange is ratheracombinationofgreyandwhitematteratrophy.Seg-
reflectedinthemagnetizationtransferratio(MTR).Reduc- mentationtechniquesontheotherhandallowquantification
tionsintheMTRprovideameasureoftheextentofdamage oftotalorregionalgraymatter,corticalgraymatter,anddeep
tothemicrostructureofbraintissueandhasbeencorrelated greymattervolumes.Threeofthemostcommonlyreported
with the degree of demyelination and axonal loss in MS techniques are (1) voxel-based morphometry (VBM) using
patients[102].ReducedMTRinNAGMispresentinallMS thestatisticalparametricmapping(SPM)softwaresuite[122],
clinical phenotypes [103–106] but is greatest in SPMS and (2)SIENAxaspartoftheFSLsoftwarelibrary[118],and(3)
PPMS [107]. Similar to neocortical gray matter, decreased Freesurfer[123].Therearealargenumberofothersoftware
MTR has been identified in deep gray matter structures, packages available, commercial, open source, and custom
particularlythethalami[74,108]. softwareusedbyspecificinstitutions.
DTIenablesthemeasurementoftherandomdiffusional Whilethesesoftwarepackagescanperformtheiranalysis
motionofprotonsinwater,providingmetricssuchasmean onavarietyacquiredsequences,isotropic,highresolutionT1
diffusivity and fractional anisotropy [109] which correlate weighted 3D volumetric acquisitions are best able to detect
with demyelination and axonal loss. While typically DTI the small changes in atrophy which occur over time [124].
has been used to assess damage to normal appearing white This atrophy is usually measured as changes in volumes of
matter, DTI can detect damage to myelin in the NAGM. graymatterstructures.Volumescanbeexpressedasabsolute
In all stages of MS, longitudinal studies have demonstrated volumes,butduetobaselinevariationsinheadsize,normal-
increased mean diffusivity values in the NAGM over time izationisnecessarytocomparepatients.Normalizationcan
[70, 110, 111]. As is true for MTR, thalamic damage can be beattainedviaanumberofdifferentprocesses:themostcom-
assessed,withstudiesshowinghighermeandiffusivityinthe monbeingnormalizationtointracranialvolume(asisdone
normalappearingthalamusofpatientswithMSascompared fortheBPF,GMF,andWMF),skullsize,orbytransformation
tocontrols[77]. to standard space. Cortical thickness can also be measured
both with VBM [122] and Freesurfer [123]; VBM assesses
3.3.ImagingofGrayMatterAtrophy. Brainatrophyinmulti- corticalthicknesschangesbetweengroupsofpatientswhile
plesclerosispatientsbeginsatdiseaseonsetinCIS,progress- Freesurfermeasuresthicknessineachindividual.Withcorti-
ing throughout the course of the disease with the greatest calthicknessmeasurements,aswithvolumemeasurements,
accumulation of atrophy in long standing SPMS [112–115]. eitherglobalorregionalchangescanbeassessed.
Atrophy can be quite prominent, as is demonstrated in Measures of gray matter volume and cortical thickness
Figure3.Whilebothgraymatterandwhitemattertissuesare dependheavilyontheappropriateclassificationofgrayand
beinglost,itisthegraymatteratrophywhichappearstopre- white matter, but in general the available software is not
dominate:Fisheretal.demonstratedprogressivelyincreased specifically designed to account for the similarity of signal
ratesofgraymatteratrophyinthevariousstagesofMSbut intensitiesofwhitematterlesionsonT1-weightedimagesto
no change in rate of white matter atrophy over time [83]. that of normal gray matter. As such, this leads to errors in
Similar findings were demonstrated by Fisniku et al. [84]. gray matter tissue classification [122, 125–127]. This tissue
Indeed,graymatterandwhitematteratrophymaybepartially misclassificationoccurswithalltypesofwhitematterlesions
independent [114, 116] suggesting a role for both inflam- butcanbeespeciallyproblematicinpatientswithsubstantial
matorygraymatterdemyelination,retrogradeneuronalloss subcortical disease. Lesion in-painting, where white matter
from white matter injury, and possibly neurodegenerative lesionsareprospectivelymaskedbeforetissuesegmentation,
processesintheevolutionofgraymatteratrophyovertime. significantly improves gray matter segmentation [128, 129]
Measurementofgraymatteratrophyhasseveraladvan- andshouldbeimplementedinfuturestudiestoensurerelia-
tagesoverdetectionofcorticallesions.Graymatterlesionsare bilityofvolumemeasurements.
6 MultipleSclerosisInternational
(a) (b)
Figure3:AtrophyinmultiplesclerosisasmeasuredusingFreesurfer(http://surfer.nmr.mgh.harvard.edu/).(a)Corticalandsubcorticalseg-
mentationinahealthycontrolpatient.(b)Corticalandsubcorticalsegmentationinanage-matchedpatientwithlongstandingRRMS.Note
theprominentsubcortical,whitematter,andneocorticalatrophyinMScomparedtohealthycontrol.
4.GrayMatterPathologyandDiagnosisofMS coefficient of variation between gray matter lesion counts
withDIRwasquitelarge(42%),evenwhenusingconsensus
Neuroimagingstudieshaveclearlydemonstratedthatcortical guidelines [48]. The reliability of measures of gray matter
lesions occur in all phenotypes of multiple sclerosis [42], volumesaresubstantiallybetter,withcoefficientsofvariation
occurringnotjustinthelatestagesofdisease,butearlyonas in gray matter volumes of 1% or less [133]. While it is clear
well.Infactcorticallesionshavebeenvisualizedbeforewhite that the addition of measures of gray matter pathology to
matter lesions have developed [15, 130], as well as in both diagnosticcriteriaforMSislikelytoimproveaccuracy,itis
radiologicallyisolatedsyndrome[131]andclinicallyisolated asofyetestablishedwhatspecificMRImeasuresofthegray
syndrome[42].Similartocorticaldemyelination,graymatter andwhitematterdiseaseareoptimaltopredictconversionto
atrophyisdetectableveryearlyinthediseaseandaccelerates MSinpatientswithRISorCIS.
overtime[87,90,114].
Ifbothcorticalatrophyanddemyelinationareoccurring 5.EffectofGrayMatterLesionson
beforeadiagnosisofclinicallydefiniteMScanbemade,how
DisabilityandCognition
thencanmeasuresofcorticallesionsandcorticalatrophybe
bestappliedtomakeanearlyandaccuratediagnosisofMS?
Graymatterlesionburdenhasbeencorrelatedwithclinical
Filippi et al. have shown that the addition of DIR to detect
disability in all phenotypes of MS (Table1). Calabrese et al.
corticallesionsmakessmallbutsignificantimprovementto
have demonstrated that increased numbers of intracortical
the accuracy of conventional MRI diagnostic criteria (81%
lesions accumulate in later stages of the disease, with 36%
accuracy versus 75–78% accuracy with traditional criteria)
of CIS, 64% of RRMS, and 73% of SPMS patients having
[132].Thepresenceofgraymatterlesionsmaybepredictive
detectablecorticallesions[42].Inthisstudy,thenumberof
ofconversiontoMS:Filippietal.,showedthatapatientwith
clinicallyisolatedsyndromewith≥1intracorticallesionhad intracortical lesions was moderately correlated with higher
Expanded Disability Status Scale Scores (EDSS) (𝑟 = 0.48,
anoddsratioof15.3forconversiontoclinicallydefiniteMS
𝑃 = 0.001)[42].Mikeetal.haveshownsimilarcorrelation
[132].Aswithcorticallesions,graymatteratrophymeasures
between lesion number and EDSS (𝑟 = 0.472, 𝑃 ≤ 0.05)
appear to be predictive: Calabrese et al., demonstrated that
comparedtoCISpatientsmeetingcriteriafordissemination [66]andothershaveshownsuchacorrelationbetweenlesion
inspace,patientswithCISandatrophyofeitherthesuperior numberandphysicaldisabilityinPPMS[134].
frontal gyrus, thalamus, or cerebellum had double the risk Accumulations of greater numbers of lesions are not
of conversion to clinically definite MS [90]. It should be the whole picture, as both lesion volume and the rate of
noted, however, that the predictive power of gray matter accumulation of cortical lesions appear to play a role [66].
atrophy may be less than gray matter lesions [90]. While In a 3-year longitudinal study, Calabrese et al. found that
the presence of gray matter lesions may be more predictive corticallesionvolumewasthebestindependentpredictorof
of conversion to MS than atrophy, one must keep in mind worsening EDSS scores (𝑟 = 0.55 in RRMS and 𝑟 = 0.43
the reliability of measures of both these types of pathology. in SPMS (𝑃 ≤ 0.001)); cortical lesion volume and cortical
As mentioned previously, Geurts et al. showed that the lesion numbers increased over time faster in patients with
MultipleSclerosisInternational 7
Table1:Neuroimagingstudiesevaluatingtherelationshipbetweencorticallesions,clinicaldisabilityandcognitiveimpairment.
Study Method Numberofpatients Relevantfindings
Corticallesionsoccuringreaternumbersin
116CIS,163RRMS,
Crosssectional SPMSthaninCISorRRMS.
Calabreseetal.2007[42] 101SPMS
1.5T;DIR Corticallesionnumbersarecorrelatedwith
40HC
EDSS.
BenignMSpatientshavelowernumbersof
corticallesionsandlowercorticallesion
1yrlongitudinal 48BenignMS
Calabreseetal.2009[62] volumesascomparedtoearlyRRMS,anddo
1.5T;DIR 96RRMS
notaccumulateastatisticallysignificant
numberofnewlesionsover1year.
CorticallesionsincreasesignificantlyinMS
patientsovertimeandareassociatedwith
3yrlongitudinal 9RRMS,4SPMS
Roosendaaletal.2009[63] worseperformanceonneuropsychological
1.5T;DIR 7HC
measures.
CorticallesionsaremostfrequentinSPMS.
Corticallesionvolumeandnumbercorrelate
withmost,butnotall,ofthecognitivetestsof
Crosssectional
Calabreseetal.2009[64] 70RRMS Rao’sbriefrepeatablebattery.
1.5T;DIR
Corticallesionvolumeisanindependent
predictorofthecognitiveimpairmentindex.
Baselinecorticallesionvolumebestpredicted
3yrlongitudinal
Calabreseetal.2010[65] 76RRMS,31SPMS disabilityprogression(asmeasuredbyEDSS)
1.5T;DIR
overthefollow-upperiod.
Corticallesionnumberandvolume
independentlypredictedEDSS.
Corticallesionnumberandvolume
Crosssectional
independentlypredictedperformance
Mikeetal.2011[66] 3T;3DFLAIR& 20RRMS,6SPMS
measuredbytheSymbolDigitModalityTest.
3DIRSPGR
Onlycorticallesionnumberpredicted
performancemeasuredbytheCalifornia
VerbalLearnTest.
Leukocorticallesionnumbersare
independentlycorrelatedwithcognitive
39MS impairment,whilepurelyintracorticallesions
Crosssectional
Nelsonetal.2011[67] (Subtypesnot arenotindependentcontributors.
3T;DIR/PSIR
specified) Thesizeofcorticallesions,notthetissue
specificlocation,maybetterexplainthe
correlationwithcognitiveimpairment.
Corticallesionnumberandvolumesarelarger
32RRMSwith inpatientswithepilepsythanthosewithout.
3yrlongitudinal
Calabreseetal.2012[68] epilepsy,60RRMS RRMSpatientswithepilepsyaccumulate
1.5T;DIR
withoutepilepsy lesionsatafasterratethannonepileptic
patientsover3years.
Highercorticallesionloadscorrelatewith
higherEDSS.
157RRMS,35
Patientswithclinicalprogressionhavethe
5yrlongitudinal PediatricMS,45
Calabreseetal.2012[69] highestrateofcorticallesionaccumulation.
1.5T;DIR BenignMS,44
Corticallesionvolumesareindependent
PPMS,31SPMS
predictorsofdisabilityprogressionand
cognitiveimpairment.
disabilityprogressionthanthosewhowerestable[65].Ina5- RRMSwithsimilardisabilityscores[62,135].Inthesestudies,
yearlongitudinalstudyofMSpatientscorticallesionvolume thebestpredictorsofbenigndiseaseweresmallervolumesof
wasanindependentcontributortoEDSS,andpatientswith corticallesionsandslowerrateofincreaseovertime.
clinical progression accumulated cortical lesions the fastest Using a variety of cognitive tests such as the Paced
[69].ConverselyinstudiesofbenignMS(EDSS<3,15years Auditory Serial Addition Test (PASAT), the Symbol Digit
fromclinicalonset),Calabreseetal.showedthatpatientswith Modality Test (SDMT), and Rao’s Brief Repeatable Bat-
benignMShadfewercorticallesions,smallerlesionvolumes, tery (RBRB), cortical lesions have also been shown to be
andsloweraccumulationofcorticallesionsthanpatientswith associated with cognitive impairment (Table1). Attention
8 MultipleSclerosisInternational
deficitsandslowingofinformationprocessingspeedarethe While gray matter atrophy in MS is a global and wide-
most commonly observed impairments. Various aspects of spread phenomenon, it appears that the location of atro-
executive function are frequently affected [136]. As is true phy (i.e., what specific brain region is affected) may be
withphysicaldisability,increasesinbothlesionnumber[63, as important as global changes in gray matter volumes.
69]andlesionvolume[64,66,67,69,137]arecorrelatedwith Calabreseetal.havedemonstratedthatcorticalthinningin
cognitiveimpairment. the precentral gyrus is strongly and significantly correlated
withmotorFunctionalSystemScoresinRRMS(𝑟 = −0.626,
6.EffectofDiffuseInjurytoNAGMon 𝑃<0.001)[114].Corticalgraymatterthinningintheparietal
andprecentralgyriissignificantlycorrelatedwithdisability
DisabilityandCognition
progression as measured by MSFC and EDSS, respectively
[79].Usingvariouscognitivetests,localizedcorticalatrophy
StudiesofMTRreductioninNAGMshowclearcorrelation
in the prefrontal, parietal, temporal and insular regions
with progression of clinical disability and cognitive impair-
has been associated with deficits in attention, information
ment(Table2).Fisnikuetal.,assessing69patients20years
processing speed and verbal memory [81, 92]. Regional
after they originally presented with CIS, demonstrated that
atrophyplaysarolenotjustincerebralcortex,butalsointhe
reducedpeakheightMTRofgraymatterwasboththebest
cerebellumanddeepgraymatterstructures.Andersonetal.
independentpredictorofdisabilityasmeasuredbyEDSSand
have demonstrated that cerebellar gray matter volumes are
the only independent predictor of cognitive impairment as
significantly smaller in patients with cerebellar dysfunction
measured by the MSFC [76]. Agosta et al. have shown that
thaninthosewithnormalcerebellarfunction[140].Thedeep
reduction of MTR peak height in gray matter is an inde-
gray matter volumes (basal ganglia and especially the tha-
pendentpredictorofaccumulationofdisabilityover8years
lami)arecorrelatedwithdisabilityandcognitiveimpairment:
[72].InbenignMS,Amatoetal.foundcorrelationsbetween
particularlysignificantaredeficitsininformationprocessing
reduced cortical MTR and measures of cognition [75]. speed[82,94],butfatigue[89]andEDSSscores[86,90]are
RegionalratherthandiffusechangesinMTRinNAGMmay also correlated. When gray matter atrophy and other MRI
also be important. Khaleeli et al., studying 46 patients with parameters such as T2 lesion volume, T1 lesion volumes,
PPMS,demonstratedthatEDSScorrelatedwithlowerMTR andwhitematteratrophy,aremeasured,graymatteratrophy
intherightprimarymotorcortex,andpoorerperformance is the strongest correlate of cognitive and clinical disability.
onPASATcorrelatedwithMTRintherightinferiorparietal Examples of the studies showing correlation between gray
andinferioroccipitalcortices[74].Therewerenocorrelations matteratrophyanddisabilityareshowninTable3.
inotherregions.SimilarcorrelationsbetweenPASATperfor-
manceandregionalMTRreductionsintheparietallobe(left 8.EffectofDisease-ModifyingTherapieson
BA40)havealsobeendemonstratedinRRMS[71]. GrayMatterPathology
Similar to MTR, alterations in mean diffusivity in the
NAGMofMSpatientsarecorrelatedwithclinicaldisability Although the interrater variability in cortical lesion counts
onDIRimaginglimitsitsutilityforlargemulticenterclinical
and cognitive impairment. Rovaris et al. have shown that
trials, single center data where imaging techniques and
average gray matter mean diffusivity is correlated with the
raters are standardized appear to demonstrate that disease-
degree of cognitive impairment as measured by the SDMT
modifying therapies (DMT) slow the development of cor-
[70].InPPMS,averagegraymattermeandiffusivitywasan
tical lesions in MS (Table4). Calabrese et al., in a 2-year
independent predictor of subsequent clinical deterioration
randomizedstudydemonstratedthatbothinterferonbeta-1a
over 5 years as measured by changes in EDSS scores [73].
(IFN-beta-1-a)andglatirameracetate(GA)therapyresulted
Elevatedgraymattermeandiffusivitychangesinthethalami
in significantly decreased new cortical lesion development
correlate with both PASAT performance (𝑟 = −0.42, 𝑃 =
(at1year74%ofuntreatedpatientshadnewcorticallesions
0.034)andtheEDSS(𝑟=0.47,𝑃=0.021)[77].
versus 45% of treated patients) [99]. The effect was greatest
for high dose, high frequency subcutaneous IFN beta-1a.
7.EffectofGrayMatterAtrophyon
Natalizumab also appears to slow the rate of cortical lesion
DisabilityandCognition development: Rinaldi et al. demonstrated that after 1 year
of therapy only 14% of treated patients had developed at
Gray matter atrophy is significantly correlated with both
least one new cortical lesion [141]. At two years, 20% of
physical and cognitive disability in MS patients [64, 80– natalizumabpatientshadanewcorticallesioncomparedwith
95, 138, 139]. These correlations are found at all stages of 74% of untreated patients [100]. The effect of natalizumab
disease and have the strongest correlation in SPMS. While on new cortical lesion development was stronger than that
correlationsarestrongestinlatestagesofthedisease,cortical of other first line immunomodulatoryagents (IMAs) (IFN-
atrophy appears relevant even before clinical symptoms are beta-1a or GA) with on average 0.2 new cortical lesions in
evident: Amato et al. have shown that in asymptomatic natalizumab treated patients and 1.3 new cortical lesions in
patients with radiologically isolated syndrome, 27.6% of thegrouptreatedwithotherIMAs[100].
patientshavesignsofcognitiveimpairmentsimilartothoseof Theimprovedreliabilityofgraymatteratrophymeasure-
RRMSandlownormalizedcorticalvolumeswereassociated mentsandstandardizationofproceduresacrossinstitutions
withahighernumberoffailedcognitivetests[93]. hasallowedevaluationoftheeffectofDMTsonmeasuresof
MultipleSclerosisInternational 9
Table2:NeuroimagingstudiesassessingtherelationshipbetweenmarkersofdiffusedamageinNAGMandclinicaldisabilityandcognitive
impairment.
Study Method Numberofpatients Relevantfindings
Averagegraymattermeandiffusivitycorrelateswith
Crosssectional
Rovarisetal.2002[70] 34RRMS cognitiveimpairmentmeasuredbytheSymbolDigit
1.5T;DTI
ModalityTest(SDMT).
DecreasedMTRintheparietallobe(BA40)
Crosssectional 18CIS
Ranjevaetal.2005[71] correlateswithpoorerperformanceonPaced
1.5T;MTR 18HC
AuditorySerialAdditionTest(PASAT).
73MS LowergraymatterMTR-peakheightatbaselineisan
8-yearlongitudinal (34RRMS,19SPMS) independentpredictorofaccumulationofdisability
Agostaetal.2006[72]
1.5T;MTR 20CIS over8yearsasmeasuredbytheExpandedDisability
16HC StatusScale(EDSS).
Averagegraymattermeandiffusivitywasan
5-yearlongitudinal
Rovarisetal.2006[73] 55PPMS independentpredictorofclinicaldeteriorationas
1.5T;DTI
measuredbyEDSS.
LowerMTRintherightprimarymotorcortex
correlatedwithdisabilityasmeasuredbyEDSS.
Crosssectional 46PPMS
Khaleelietal.2007[74] LowerMTRintherightparietalandoccipital
1.5T;MTR 23HC
corticescorrelatedwithpoorerperformanceon
PASAT.
Crosssectional 47BenignMS ReducedcorticalMTRcorrelatedwithavarietyof
Amatoetal.2008[75]
1.5T;MTR 24HC measuresofcognitiveimpairment.
ReducedgraymatterpeakheightMTRisthebest
41MS
independentpredictorofdisabilityasmeasuredby
Crosssectional (31RRMS,10SPMS)
Fisnikuetal.2009[76] EDSS,andonlyindependentpredictorofcognitive
1.5T;MTR 28CIS
impairmentasmeasuredbytheMultipleSclerosis
19HC
FunctionalComposite(MSFC).
24MS
Crosssectional Elevatedmeandiffusivitywithinthethalamus
Tovar-Molletal.2009[77] (13RRMS,11SPMS)
3T;DTI correlatedwithperformanceonPASATandEDSS.
24HC
GraymatterMTRdecreaseissignificantlyassociated
Crosssectional 88CIS
Crespyetal.2011[78] withworseEDDSscores.
1.5T;MTR 44HC (𝑅2=0.135,𝑃=0.002).
graymatteratrophy.Tiberioetal.showednoeffectongray While these studies indicate that DMTs slow rate of
matteratrophyat1yearforpatientstreatedwithIFN-b[142]; accumulationofgraymatterlesionsandgraymatteratrophy
however,morerecentstudieshaveshownpositiveeffectsof in MS, the nonrandomized nature of the bulk of these
therapy. Zivadinov et al., in a nonrandomized open label studiessomewhatlimitstheirimpact.Currently,nodisease-
study,demonstratedthatintramuscularIFN-beta-1-asignifi- modifying therapy available for treating MS patients have
cantlyslowedtheprogressionofwholebrainandgraymatter completelystoppedtheevolutionfromRRMStotheprogres-
atrophy compared with untreated patients (−1.3% BPF in sive phase of the disease. However, highly active therapies,
treatedpatientsversus−2.5%BPFinuntreatedpatients)[96]. suchasnatalizumab,mayhaveagreaterimpactontheaccu-
mulation of gray matter damage than first line agents [100,
Nakamura et al. [97] have shown similar results. Calabrese
142]. Randomized studies investigating the effects of longer
et al. [99] did not show differences in the rate of decrease
termtreatmentwithhighlyactivetherapy(>2years)willpro-
ingraymatterfractionbetweentherapeuticgroups;however,
videfurtherinsightintotheirabilitytoalterthecourseofMS.
Bendfeldt et al. [98] demonstrated slowing of atrophy, with
progressionofregionalgraymatteratrophydifferingbetween
9.Conclusions
patients treated with different IMAs [98]. Most recently
Rinaldietal.hasshownslowingofcorticalatrophy/thinning As is clear from pathologic studies and neuroimaging, gray
withbothIFN-bandGA(3.7%globalcorticalthicknessloss matter pathology is of critical importance in multiple scle-
in treated patients versus 4.6% in untreated patients over rosis.Despitetheadvancesthathavebeenmade,itremains
2 years) [100]. As with cortical lesions, natalizumab has a unclear as to what are the underlying causes of gray matter
strongereffectontheslowingofcorticalatrophythanother pathology, and what the exact relationship is between gray
IMAs: natalizumab had the lowest rate of atrophy at 1.7% matter demyelination and measures of diffuse gray matter
corticalthicknesslossover2years.Thisthinningwasnotsta- damage and atrophy. Some have suggested that primary
tisticallydifferentwhencomparedtohealthycontrols[100]. neurodegenerative process occurring in MS may be at least
10 MultipleSclerosisInternational
Table3:Neuroimagingstudiesevaluatingtherelationshipbetweengraymatteratrophy,clinicaldisability,andcognitiveimpairment.
Study Method NumberofPatients RelevantFindings
1yrlongitudinal Corticalthicknessdecreased3.13%±2.88%/yearin
Chenetal.2004[79] 1.5T;cortical 24RRMS,6SPMS patientswithprogressivedisability.Instablepatients
thickness 0.06±2.31%/yearchangeincorticalthickness.
Crosssectional 427RRMS,140SPMS GMFisthemostsignificantMRIvariablein
Tedeschietal.2005[80]
1.0T;GMF 104HC determiningfinaldisabilityasmeasuredbyEDSS.
Patientswithlowcognitiveperformanceshowed
Crosssectional 19RRMS
Morgenetal.2006[81] moreextensivecorticalvolumelossthanHCinthe
1.5T;NGMV 19HC
frontal,temporal,andparietallobes.
Cognitiveperformanceinalldomainswascorrelated
Houtchensetal.2007[82] Crosssectional 26RRMS,5SPMS withthalamicvolumeinMSgroup(𝑟=0.506–0.724,
1.5T;NTV 𝑃<0.005)andEDSS(𝑟=−0.316,𝑃=0.005).
7CIS,36RRMS,27 GMFcorrelatedwithboththeMSFCandEDSS.
4yrlongitudinal
Fisheretal.2008[83] SPMS IncreasingcontributionofGMatrophytowhole
1.5T;GMF
17HC brainatrophyasMSadvances.
29CIS,33RRMS,11
Crosssectional GMF,notwhitemattervolume,correlatedwith
Fisnikuetal.2008[84] SPMS
1.5T;GMF clinicaldisabilityasmeasuredbyEDSSandMSFC.
25HC
5yrlongitudinal 181EarlyRRMS NGMVandagewerethebestpredictorsof
Horakovaetal.2009[85]
1.5T;NGMV 27HC progressionofEDSS.
20CIS,34RRMS,19
8yrlongitudinal Baselinethalamicatrophysignificantlycorrelates
Roccaetal.2010[86] SPMS
1.5T;NTV withdeteriorationinEDSSscore.
13HC
RightcerebellaratrophycorrelatedwithEDSSscores
Crosssectional 62CIS
Audoinetal.2010[87] butnocorrelationbetweenregionalatrophyand
1.5T;regionalGMV 37HC
cognitivestatus.
Crosssectional Awidespreadpatternofcorticalthinningisthebest
100RRMS
Calabreseetal.2010[88] 1.5T;Cortical predictorofcognitiveimpairmentasmeasuredby
42HC
thickness theRao’sBriefRepeatableBattery
Crosssectional Significantatrophyofstriatum,thalamus,superior
152RRMS
Calabreseetal.2010[89] 1.5T;Cortical frontalgyrus,andinferiorparietalgyrusinfatigued
42HC
thickness,DGMV patientscomparedtononfatiguedpatients
4yrlongitudinal CISwithatrophyofthesuperiorfrontalgyrus,
105CIS
Calabreseetal.2011[90] 1.5T;Cortical thalamus,and/orcerebellumdoubledtheriskof
42HC
thickness conversiontoMS.
95CIS,657RRMS, NGMVwasthestrongestpredictorofdisabilityand
Crosssectional
Roosendaaletal.2011[91] 125SPMS, cognitiveimpairmentasmeasuredbyEDSSand
1.5T;NGMV
50PPMS PASAT.
Crosssectional Significantassociationsfoundbetweenscoresonthe
Nocentinietal.2012[92] 1.5T;GMF,regional 13RRMS,5SPMS SDMTandLDCR-CVLTwithregionalGMatrophy
GMV inprefrontal,parietal,temporal,andinsularcortex
Crosssectional 29RIS,26RRMS InRIS,lowerNCVcorrelatedwithworsecognitive
Amatoetal.2012[93]
1.5T;NCV 21HC performance.
BothNCVanddeepgraymattervolumesare
Crosssectional significantlycorrelatedwithcognitiveimpairment.
Batistaetal.2012[94] 59RRMS,27SPMS
3.0T;NCV,NDGMV ThalamicatrophyplayssignificantroleinIPS
slowing.
2yrlongitudinal SignificantcorticalatrophyoccursinearlyRRMS
Zivadinovetal.2013[95] 136RRMS
1.5T;NCV over2yearsandisassociateddisabilityprogression.
Label:IPS:informationprocessingspeed.GMF:graymatterfraction.GMV:graymattervolume.MSFC:multiplesclerosisfunctionalcomposite.NCV:
normalizedcorticalvolume.NDGMV:normalizeddeepgraymattervolume.NGMV:normalizedgraymattervolume.NTV:normalizedthalamicvolume.
RIS:radiologicallyisolatedsyndrome.SDMT:symboldigitmodalitytest.LDCR-CVLT:longdelayedcuedrecall-CaliforniaVerbalLearningTest.
partiallyindependentinflammation,whileotherstudieshave will be vitally important; however, if inflammation drives
shown a direct relationship between neuronal and axonal subsequentneurodegeneration,anti-inflammatorytherapies
injuryandinflammation.Thespecificsoftheseinteractions wouldbethebestchoiceforpatients.
need to be fully investigated as this has significant implica- Theimprovedexvivodetectionofgraymatterpathology
tionsfortherapeuticdesign.Ifindependentneurodegenera- inMShasspurredresearchwhichhassubstantiallyimproved
tiveprocessesareoccurringinMS,neuroprotectivetherapies the detection of gray matter damage in vivo with MRI. It