ABSTRACT Childrenwithsicklecelldisease(SCD)experiencewidespreadcognitivedeficitsalongwithnumerousother medicalconsequencesincludingstroke,acutechestsyndrome,pulmonaryhypertension,chronickidney disease,andprematuredeath.Althoughitisclearthatmoleculechangeswithinthesickledcellgreatly reducestheoxygen-carryingcapacityoftheblood,ourunderstandingofSCDpathophysiologyis inadequate.Therefore,thespecificmechanismsbywhichcognitivedeficitsoccurarenotyetfully understood.Currently,therearenobiologicalinterventionsaimedatimprovingcognitioninchildrenwith SCD.Thereare,however,biologicalinterventionsthatimprovehealthanddiseaseoutcomesinSCD.Blood transfusionisaninterventionthatisanessentialandlife-savingcomponentofclinicalcareinSCDandis themajorfocusofpreventingincidenceandrecurrenceofcerebralvascularaccidentssuchasstrokeand silentinfarct.Bloodtransfusionincreasesoxygencarryingcapacity,replacesrigid,sickle-shapedredblood cellswithnormalcells,andrestoresbloodflow.Anotherbiologicalinterventionishydroxyureatherapy, whichisacommonlyuseddiseasemodifyingtreatmentforSCDthatincreasesoverallbloodflowthroughits abilitytoboostlevelsoffetalhemoglobin.Becausebloodtransfusionandhydroxyureatherapyincreasethe availabilityofoxygenrichbloodinthebody,includingthemetabolicallyactivebrain,thisprojectproposes thatthebloodtransfusionandhydroxyureatherapyareinterventionsthroughwhichimprovementsin cognitioncouldbeachievedforchildrenwithSCD.Intheproposedproject,wewillfirsttestcognitionina cohortofchildrenwithSCDattwotimepoints,afterabloodtransfusionand4?6weekslaterbeforetheir nexttransfusion.Thismethodologywillallowustodetermineifcognitionworsensthefartherawaychildren arefromtheoxygenimprovingtransfusion.Resultswillbecomparedtoacohortofchildrenreceiving hydroxyureatherapy(hydroxyureagroup)andtoagroupofchildrennotreceivingtransfusionor hydroxyurea(controlgroup).WewillrelatefindingstobloodbiomarkersofSCD.Giventhataftertransfusion (highoxygendelivery)thereisarecentincreasedavailabilityofoxygenrichbloodtothebrain,we hypothesizethatthetransfusiongroupwillhaveimprovedcognitioncomparedtothehydroxyureagroup andcontrolgroup.Wefurtherhypothesizethatbecausehydroxyureaimprovesbloodflow,thehydroxyurea groupwillhaveimprovedcognitioncomparedtothecontrolgroup.Thefindingswillhaveimportant implicationsforfunctionalandacademicoutcomesforchildrenwithSCDandwillprovideinformationthat couldinfluencethedevelopmentoffuturetreatmentoptionstailoredtothespecificcognitiveandclinical needsofthispopulationstrugglingwithSCD.
NIH ExPorter
NIH ExPorter