Download The IDDRC Reporter: Frontiers in Down Syndrome Research

October2016
TheIDDRCReporter:FrontiersinDownSyndromeResearch
DownSyndrome:AnIntroduction
WehavelearnedalotaboutDownsyndromesinceitwasrecognizedbyDr.JohnLangdon
Down150yearsago,whenhepublishedapaperin1866describingpeoplewhosharedvery
similarfacialfeatures.WeknownowthatDownsyndromeisrelativelycommon:about250,000
AmericanshaveDownsyndrome,and1outof700babies(nearly6,000peryear)isbornwith
thecondition.ChildrenwithDownsyndromeoftenhavecognitiveimpairmentsandareatrisk
forarangeofhealthproblems.AbouthalfofallnewbornswithDownsyndromehavea
congenitalheartdefect,whichoccurswhenthebaby’sheartdoesnotformproperly.
Fortunately,withearlyidentificationandtreatment,includingcardiacsurgery,manyinfantsdo
wellwiththiscondition.
WhenDr.Downfirstrecognizedthecondition,hehadnoideawhatreallycausedthis
“syndrome,”suggestingthatitmighthavebeencausedbymaternaltuberculosis.Itwasnot
until1959thatresearchersfoundthelinkbetweenthecognitivedisabilityandachromosomal
difference,afirstinthefieldofgenetics.Typically,peoplearebornwithcellsthatcarry46
chromosomes.However,in1959,FrenchresearchersdiscoveredthatcellsofpeoplewithDown
syndromehave47chromosomesbecausetheycarryanextrachromosome21,or“trisomy21.”
Now,weknowof200to300genesonchromosome21thatmaycontributetothevarious
featuresofthesyndrome.Thisinformationhasprovedvaluableinunderstandingfactors
associatedwithhealthandlearningproblemsinchildrenwiththeconditionandhashelped
advancedevelopmentofspecifictherapies.
ThisnewsletterwillhighlightsomerecentadvancesinDownsyndromeresearchfromthe
EuniceKennedyShriverIntellectualandDevelopmentalDisabilitiesResearchCenters(IDDRCs),a
networksupportedbytheNationalInstituteofChildHealthandHumanDevelopment(NICHD)
attheNationalInstitutesofHealth(NIH).NICHDalsosupportsDS-Connect®:TheDown
syndromeregistry,whichisanonlinehealthregistrytocollectbasicdemographicandhealth
informationaboutpeoplewithDownsyndrome.Approvedscientistsorresearcherscanview
theDS-Connect®de-identifieddataontheProfessionalPortalandusethisinformationto
developresearchprojectsandtorecruitforclinicalstudies,whilestillprotectingtheprivacyof
thosewhotakepartintheregistry.
DevelopmentofLanguageinChildrenwithDownSyndrome
PeoplewithDownsyndromefacemanychallenges,includingdifficultieswithspeechand
communication.Becauseofthesechallenges,manyareinterestedinresearchthatwillimprove
theirdailylives.
Foralongtime,wehaveknownthatchildrenwithDownsyndromestrugglewithdeveloping
speech.Indeed,speechproblemsareoftenmoreseverethanonemightexpect,basedon
cognitivelimitationsalone.CurrentresearchfromtheVocalTractDevelopmentLaboratoryat
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theWaismanCenteroftheUniversityofWisconsinhashelpedexplainthebasisofthese
difficulties.HeadedbyDr.HouriVorperian,theresearchteamusesacombinationofimaging,
soundtechnologies,andcomputermodelingtounderstandthebasisofspeechdevelopment
andproductioninpeoplewithandwithoutDownsyndrome.Bycarefullyimagingthevocal
tract,theteamfoundthatpeoplewithDownsyndromehaveanormal-sizedtongueinsidea
smallmouthandjaw,whichmaylimitthespaceavailableforfront-to-backtonguemovements
andaffectalistener’sabilitytounderstandaperson’sspeech.Toovercomethisissue,future
studieswillfocusondesigninginterventionsthatmightincludeacombinationofbehavioral
training,mouthpieceappliances(orthodontia),andsurgery.
Foranyinfant,acquiringlanguageisacomplexprocessthatinvolvesinteractionsbetween
parentandchild.ResearcherssupportedbytheIDDRCattheUniversityofKansasMedical
Centerhaveusedasoftwareprogramtoanalyzevocalinteractionsbetweeninfantsand
childrenwithDownsyndromeandtheirparents.Bytalkingtotheinfant,anadultdemonstrates
sounds,whichtheinfantrepeats,resultinginapositivereactionfromtheadult.These
interactionsformamutuallyreinforcingrelationshipthatsupportsspeechlearning.Headedby
Dr.StevenWarren,theKansasteamhadtwogoalsforunderstandingthisrelationship:(1)
measuringthe“languageenvironment”ofachildwithDownsyndrome,comparedtothatof
typicallydevelopinginfants,and(2)understandingwhetherthisenvironmentchangesasthe
infantsgrowintotoddlers.Theresearchersfoundthatparentsoftypicallydevelopinginfants
tendedtousemorewordsthanparentsofinfantswithDownsyndrome.Asaresult,children
withDownsyndromemadesignificantlyfewervocalizations,eventhoughtoddlerswithDown
syndromedemonstratedmorevocalizationsthaninfantswithDownsyndrome.Thesedatamay
helplanguagespecialistsandparentsbetterunderstandthelanguagedelaysinchildrenwith
Downsyndrome,eveninearlyinfancy,andprovideopportunitiesforintervention.
IDDRC-supportedinvestigatorsalsoaredevelopingstrategiestoimprovespeechdevelopment
inpeoplewithDownsyndrome.AcollaborationbetweentheUniversityofKansasandthe
VanderbiltUniversityKennedyCenterforResearchonHumanDevelopmentfoundthatchildren
withDownsyndromewhoundergodaily,insteadofweekly,speechtherapysessionshave
largerspokenvocabularies.Thesedailytherapieshelpedincrease“canonicalsyllabic
communication,”orduplicatedsyllables(suchas"babababa"),andimprovethechildren’s
understandingoflanguage.LedbyDrs.PaulYoder(Vanderbilt)andStevenWarren(Kansas),
thisstudywasthefirsttoexplainwhyincreasingthefrequencyofspeechtherapycanimprove
speechacquisitioninchildrenwithDownsyndrome.
BrainDevelopmentinPeoplewithDownSyndrome
Inadditiontospeechandcommunication,peoplewithDownsyndromealsomayhave
numerousmedicalproblems,themostchallengingofwhichareassociatedwithbehaviorand
mentalabilities.TheIDDRCshavelongsupportedresearchfocusedonthesefeatures.
AprimeexamplecomesfromtheIDDRCattheKennedyKriegerInstituteandJohnsHopkins
University,whereDr.RogerReeveshaspioneeredthedevelopmentofmousemodelsof
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trisomy21.Dr.Reevesandhisco-investigatorshavefoundthat,similartohumanswithDown
syndrome,micewithtrisomy21demonstratedefectsinlearningandmemory.Astudyoftheir
brainsrevealedanabnormallysmallcerebellumwhencomparedtomicewithouttrisomy21.
Theresearchershypothesizethatagenecalled“sonichedgehog,”whichiscriticaltonormal
braindevelopment,mightbedeficientinpeoplewithtrisomy21.Whenthemiceweregivena
drugthatenhancedtheactivityofthesonichedgehoggene,theydevelopedanormal-sizedand
-shapedcerebellum.Theircognitiveperformancealsowasindistinguishablefrommicewithout
trisomy21.Remarkably,thedrugwasgivenonlyonce,whentheanimalswerenewborns.
Althoughtheirworkestablishestheexcitingpossibilityofusingmedicationsthataffectgene
action,thesonichedgehoggeneisinvolvedinmanykeyprocesses,andresearchersmusttest
thesafetyandeffectivenessofthisdrugbeforeitcanbeusedinhumantrials.Dr.Reevesand
hiscolleaguesarecontinuingthislineofresearch.
Bystudyingmousemodels,researcherscanbetterunderstandabnormalpatternsofbrain
developmentandtesttherapiesthatmayimprovecognitiveperformance.Foralongtime,
researchershaveknownthatcognitiveandsensorimotortherapycanhelpthedevelopmentof
childrenwithDownsyndrome.AttheChildren’sNationalMedicalCenter,theIDDRChas
sponsoredresearchbyDrs.TarikHaydarandVittorioGallothatexploresthebiologicalbasisfor
thisphenomenon.Theseinvestigatorsexaminedbraingrowthinthemousemodelandfound
thatwhenyoungmice(18daysold)wereexposedtoanenrichedenvironmentandaprogram
ofregularphysicalexercise,theyhadamarkedincreaseinnervecells(calledneurons)anda
significantexpansionofconnectionsbetweenthosecells.Indeed,insomebrainareas,these
beneficialchangesweresodramatictheyalmostrestoredthenormalgrowthrateofthe
mouse’sbrain.
TheIDDRCattheWaismanCenterattheUniversityofWisconsinalsohasmadeadvancesin
betterunderstandingtheconsequencesoftrisomy21onbraindevelopment.Intheirstudies,
Drs.AnitaBhattacharyyaandSu-ChunZhanghavesampledskincellsfrompeoplewithtrisomy
21andtransformedthesecellsintoneuronstoexaminehumannervefunction.Whilenerve
cellsnormallycommunicateextensivelythroughconnectionscalledsynapses,theWaisman
researchersfoundthatneuronswithanextracopyofchromosome21weremuch“quieter”
andfailedtoestablishthenormalcommunicationnetworksessentialformentalfunctions,such
asmemoryandabstractthought.Thisimpairmentmaybethefailuretodevelopaspecific
nervecellcalledaninterneuron.Inaddition,theBhattacharyyagroupnotedthattheneurons
experiencedconsiderable“oxidativestress,”aformoftoxicitythatcandamagecells.The
relationshipbetweenoxidativestressanddiseaseisimportantinmedicalresearch,and
evidencesuggeststhattreatmentwithanti-oxidants,suchasvitaminCorE,canprotectcells
fromthisinjury.Thislineofresearchisvaluable,notonlyforunderstandingabnormalbrain
developmentinDownsyndrome,butalsothecognitivedeclinethatolderadultsoften
experience.
ThePossibilityofPharmacologicInterventiontoImproveCognition
October2016
WhileitisnotfullyclearwhyneuralpathwaysleadtocognitivedeficitsinpeoplewithDown
syndrome,someevidencepointstoexcessiveactivityofspecializedneurons,calledGABA-ergic
neurons,thatslowdownthecommunicationamongotherneurons.Theseinhibitoryneurons
canpreventtheformationofcomplexneuralnetworksresponsibleforlearningandmemory.
Aninternational,multi-siteclinicaltrial,supportedbytheIDDRCsatBostonChildren’sHospital
andtheWaismanCenter,testedtheeffectivenessofadrugintendedtodecreasetheactivityof
GABA-ergicneuronstoimprovelearningandmemory.Althoughtheresultsindicatedthatthe
drugissafetogivetochildren(age6-17yearsold),thedrugdidnotimprovethechildren’s
cognitiveperformance.Otherdrugsthatdecreasetheactivityofinhibitoryneuronsmayprove
moreeffective.
AttheUniversityofCaliforniaDavisMINDInstitute,IDDRCdirectorDr.LeonardAbbedutoleads
aresearchconsortiumthatisdevelopingstandardizedtestsofexpressivelanguage(using
wordsandlanguage).Suchtestswillprovideawaytomeasureresponsestopharmacologicand
behavioralinterventionsinpeoplewithintellectualdisabilities,suchasDownsyndrome.Data
collectionwilloccurat7sites,includingtheIDDRCsatUCDavis,theUniversityofWisconsinMadison,andtheUniversityofWashington.Inarelatedproject,Dr.DavidHesslandother
investigatorsattheMINDInstituteareworkingwithcolleaguesattheUniversityofDenverand
RushUniversitytoadaptasetofcomputerizedtestsofoverallcognitivefunctionspecificallyfor
thosewithDownsyndrome.Thegoaloftheseprojectsistovalidatethereliabilityofthesetests
foruseacrossthepediatricandearlyadultyears.“Theseprojectsarebenefittingfromthe
servicesofourIDDRC.Moreover,theIDDRCwillsupporttheuseofthesemeasuresbyother
investigatorswithintheIDDRCnetworkoncetheyarevalidated,”Dr.Abbedutonoted.
Long-TermOutcomesforPeoplewithDownsyndrome:TheProblemofDementia
Overthepast20to30years,researchershavefocusedonthelong-termoutcomesofpeople
withDownsyndrome.Advancesinmanagingcongenitalheartdiseaseandothercomplications
havedramaticallyincreasedlifeexpectancy.In1960,apersonwithDownsyndromewas
expectedtoliveanaverageofonly10years.By2007,themajorityofchildrenwithDown
syndromeweresurvivingintoadulthood.Expertsnotethatlifeexpectancyiscontinuingto
increase,andmanypeoplewithDownsyndromearenowlivingpastmiddleageandbecoming
seniorcitizens.
Theincreaseinlifeexpectancyhaspromptedafocusonlong-termcharacteristicsofpeople
withDownsyndrome,oneofthemostworrisomebeingAlzheimer’sdisease.Bythetimethey
reach35to40yearsofage,almostallpeoplewithDownsyndromewilllikelydevelopbrain
changesassociatedwithAlzheimer’sdisease,knownasamyloidplaques.However,dementia
rarelyoccursuntiltheyareconsiderablyolder,andthosechangesdonotoccurineveryperson
withDownsyndrome.Nevertheless,theriskfordementiaishighforadultswithDown
syndrome,whichhaspromptedasearchforbloodorbrainimagingmarkers(called
“biomarkers”)thatwillhelpdetectcognitivedeclineearlyandeventuallyleadtotherapiesthat
preventorreducememoryloss.
October2016
OneexampleofthissearchforbiomarkerscomesfromtheIDDRCatVanderbilt.Drs.Alexandra
KeysandElisabethDykenshaveexaminedevent-relatedpotential(ERP)markersofvisual
memoryinbothyounger(19-25yearsold)andolder(35-40yearsold)adultswithDown
syndrome.Theresearchersmeasuredthesubjects’responsetounfamiliarscenesofcitiesor
natureandfoundchangesintheelectricalsignalsthatcorrespondedwiththesubjects’learning
differences.Thisstudyunderscorestheusefulnessofelectricalbrainsignalsasearlymarkersof
cognitivedeclineinDownsyndrome.Dr.Dykenscommentedthattheirfindingsholdpromise
notonlyforagingindividualswithDownsyndrome,butalsoforothergroupsthathave
difficultyprovidingabehavioralorverbalresponse.
TwootherIDDRCsareplayingmajorrolesinlarge,multi-siteprojectstoidentifybiomarkersof
Alzheimer’sdiseaseinadultswithDownsyndrome.Theresearchteamsbehindtheseprojects
haveseverallong-termgoals,whichincludediscoveringwhyadultswithDownsyndromeare
morelikelytodevelopAlzheimer’sdisease,determiningwhichfactorsaffectwhowilldevelop
dementia,recognizingearlyclinicalsymptoms,andlearninghowtosupportclinicaltrialsaimed
atslowingorpreventingdementiaprogression.
TheIDDRCattheWaismanCenteroftheUniversityofWisconsinissupportingtheresearchof
Drs.BradleyChristianandSiganHartley,whoareusingMRI(magneticresonanceimaging)and
PET(positronemissiontomography)tostudyearlysignsofAlzheimer’sdiseaseinthebrainsof
adultswithDownsyndrome.TheirresearchhasshownthatadultswithDownsyndromeoften
haveamyloidplaques,orproteindepositsinthebrain,despiteshowingnosignsofdementia.
Thispre-dementiamarkerappearsseveraldecadesearlierinpeoplewithDownsyndromethan
itdoesinthegeneralpopulation.Anewprojectwillinvolveapproximately200adultswith
Downsyndromeandthosewithouttheconditionandwillcharacterizetheprogressionof
Alzheimer’sdiseasebystudyingasetofclinical,cognitive,neuroimaging,genetic,and
biochemicalmarkers.Thisprojectisaninternational,multi-centereffortthatincludes
investigatorsattheUniversityofPittsburgh,theBannerInstituteinArizona,andCambridge
UniversityintheUnitedKingdom.
Usingmanyofthesamemethods,theIDDRCattheKennedyKriegerInstituteandJohns
HopkinsUniversityissupportingasecondmulti-sitecollaborationinvolvingColumbia
University,NewYorkState;theUniversityofCalifornia,Irvine;MassachusettsGeneralHospital;
andtheUniversityofNorthTexasHealthScienceCenter.Drs.WayneSilverman(KennedyKrieger/Hopkins),NicoleSchupf(Columbia),andIraLott(U.C.Irvine)aretheleadinvestigators,
andtheirteamsplantofollowanadditionalgroupofapproximately200to300olderadults
withDownsyndrometodocumenttheircognitiveabilitiesastheyage.
AnIDDRC-supportedcollaborationbetweeninvestigationsattheChildren’sHospitalof
Philadelphia,theUniversityofPennsylvania(CHOP/Penn),andtheChildren’sNationalMedical
Center(CNMC)seekstounderstandwhethertheonsetofdementiainpeoplewithDown
syndromeisrelatedtotheiroverallmetabolicstatus.AschildrenwithDownsyndromeage,
theyaccumulatemorebodyfatthanthosewithoutDownsyndrome.Thisformofbodyfatis
closelylinkedtoheartdiseaseandcouldbeariskforobesity-relatedconditionssuchas
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diabetesandheartandvasculardisease.LedbyDrs.AndreaKellyandBabetteZemel
(CHOP/Penn)andDr.SheelaMagge(CNMC),theteamisinvestigatingtherelationshipbetween
bodycompositionandcognitiveabilitiesbycollectinginformationsuchasmeasuresofbone
density,bloodlipids(fats)andhormones,glucosetolerance,andcardiacfunction.Their
preliminaryfindingssuggestthatchildrenandadolescentswithDownsyndromedohavealipid
profileassociatedwithatherosclerosis(narrowandhardenedarteries),eventhoughtheyhave
lessbodyfat.Theresearchersseektounderstandthebiologicbasisforthiscontradictionand
willexplorewhetheroneormoregenesonchromosome21mightcauseapotentially
dangerouslipidprofileinbloodorifpeoplewithDownsyndromehaveadefectintheir
mitochondria,cellcomponentsthatregulatehowenergyismadeandused.
Conclusion
CollaborationsamongtheIDDRCNetworkhavesignificantlyadvancedourunderstandingof
Downsyndrome.IDDRC-supportedresearchhasallowedustoprogressfromDr.Down’s
relativelysimple,19thCenturydescriptionofphysicalfindingstoarichunderstandingofDown
syndrome’simpactonbraindevelopment,acquisitionoflanguage,andtheagingprocess.The
collaborativeeffortsofthe15IDDRCsandtheirresearchpartnershavehelpedustoappreciate
howDownsyndromemanifestsitselfacrossculturesandindifferentenvironments.Most
importantly,thisinformationpromisestohelpimprovedevelopmentaloutcomesandprovide
familiesandcommunitieswiththetoolstheyneedtosupportpeoplewithtrisomy21.
Dr.Downlikelywouldbeastoundedtolearnhowmuchhasbeendiscoveredinthe150years
sincehefirstdescribedthissyndrome.Heundoubtedlywouldendorsethepropositionthat
onlyadditionalinvestigationwillyieldtheknowledgenecessarytopreventandevenreverse
theconsequencesofbeingbornwithanextracopyofchromosome21.