Parkinson’sDiseaseAnOverviewofConventionalandExperimentalTreatmentsParkinson’sDiseaseAnOverview1BackgroundParkinson’sdiseaseisadisorderthataffectsnervecellsinthepartofthebraincontrollingmusclemovementDiseaseisprogressive–signs/symptomsworsenovertimeEventuallyisdisabling,butprogressesgraduallyBelievedtobecausedbygenetics,environmentalfactorsoracombinationofthetwoBackgroundParkinson’sdisease2Parkinson’sDiseaseStatsFirstdesribedbyJamesParkinsonin1817Affects~1millionintheU.S.Onsettypicallybetween50-60yearsofage,andslowlyprogresseswithageAverageonsetis62.4yearsofageParkinson’sDiseaseStatsFirst3NeurologicalBasis“NeurodegenerativeDisease”:causedbydegeneration(dysfunctionanddeath)ofneuronswithinthebrain(nigrastriatalpathwayofthebasalganglia)NORMALBRAINFUNCTION–BasalGangliaCellsinsubstantianigraproduce/releasedopamineDopaminereleasedbySNneuronslandsonneuronsofotherbraincenters,controllingtheirfiringMaintargetsarecaudatenucleusandputamen(striatum)Thisbasalgangliapathwayisinvolvedinregulationofmovement NeurologicalBasis“Neurodegene4ParkinsonsDisease教學(xué)講解課件5NeurologicalBasisPARKINSON’SBRAINFUNCTION–BasalGangliaCellsofsubstantianigradegenerateThesecellscannolongerproduceadequateamountsofdopamineNeuronsofstriatum,etc.arenolongerwellregulated,thusdonotbehaveinnormalmannerResultsinlossofcontrolofmovements–leadstosymptomscharacteristicofParkinson’sdiseaseNeurologicalBasisPARKINSON’S6ParkinsonsDisease教學(xué)講解課件7CharacteristicSymptomsMOTORtremorbradykinesiarigidity/freezinginplacelackoffacialexpressionposturalinstabilitystooped,shufflinggaitNONMOTORdiminishedsenseofsmelllowvoicevolumefootcrampssleepdisturbancedepressionconstipationdroolingCharacteristicSymptomsMOTORNO8ParkinsonsDisease教學(xué)講解課件9ConventionalTreatments:MedicationLEVODOPA(L-DOPA)precursortodopamine,convertedtodopaminebynervecellsinthebrainTreatmentwithdopaminenotpossible,becausedopaminecan’tcrossblood-brainbarrierGenerallycombinedwithcarbidopa(Sinemet)–helpslevodopagettothebrain+reducessomesideeffectsExtendeduseoftenproducesdyskinesias–uncontrolledmovements(writhing,twitching,shaking)amongotherminorsideeffectsConventionalTreatments:Medic10ConventionalTreatments:MedicationDOPAMINEAGONISTSnotchangedintodopamine,butratheractLIKEdopamineatbrainsynapseswheredopamineisusuallypresent(nigrostriatalpathwaysinParkinson’spatients)UsedbothasadjunctstoL-DopatherapyandinyoungerParkinson’sdiseasepatientsSideeffectssimilartolevodopa,butlesslikelytodevelopinvoluntarymovements,morelikelytocausehallucinationsConventionalTreatments:Medic11ConventionalTreatments:MedicationMAOInhibitors(Selegiline)COMTInhibitorsAnticholinergicsConventionalTreatments:Medic12ConventionalTreatments:SurgeryThalamotomyInvolvesdestructionofsmallamountsoftissueinthethalamus—majorcenterforrelayingmessages/transmittingsensationsCancauseslurredspeechandlackofcoordinationPallidotomyelectriccurrentusedtodestroysmallamountoftissueinthepallidum(globuspallidus)Mayimprovetremors,rigiditybyinterruptingpathwaybetweenglobuspallidusandthalamusConventionalTreatments:Surge13ConventionalTreatments:SurgeryDeepBrainStimulationimplantdevice,pacemaker-likeunittransmitsimpulsestoelectrodesplacedinsubthalamicnucleusProducessameeffectsoflesionsurgeries,butcanbeturnedonandoffConventionalTreatments:Surge14ExperimentalTreatment:SurgeryFetalCellTransplantTherapy

stemcellsobtainedviaabortedfetus,growninculture,transplantedintoParkinson’spatientatnigrostriatalpathwayNewcellsestablishconnectionsand“replace”cellsoriginallylost,thesecellsfunctionnormallyandevenproducedopamineAutologous“Self”Transplantanalagoustofetalcelltransplant,exceptthatprecursornervecellsaretakenfrompatientandcoaxedtoproducedopamine,thenimplantedbackintooriginalpatientReducesthreatofautoimmuneresponseandreduced“controversialbaggage”associatedwithFCTtherapyExperimentalTreatment:Surger15ExperimentalTreatment:SurgeryRetinalPigmentedEpithelialCellTransplantDopamine-producingcellstakenfrompigmentedretinalepitheliumMechanismoftransplantanalagoustofetalcelltransplanttherapyIflossofcontactfromsubstrate,thesecellsdieConsequently,lowerriskofaberrantintegration—possiblecauseofdyskinesiasseeninsomeFCTpatientsExperimentalTreatment:Surger16SourcesAminoff,M.(2003).ParkinsonPrimer:OverviewofParkinson’sDisease.Retrieved November16,2005,from /site/pp.asp?c=9dJFJLPNB&b=71354.Thissourceprovidedmewiththemostofthebackgroundinformationnecessaryinexplainingthefoundationofthedisease.Thissourcewasespeciallyhelpfulindeterminingthecharacteristicsymptomsofthedisorderaswellasstatistics.Freed,C.R.,Green,P.E.,Breeze,R.E.,Tsai,W.,DuMouchel,W.,Kao,R.,Dillon,S.,et al. (1994).TransplantationofEmbryonicDopamineNeuronsforSevere Parkinson’s Disease.NewEnglandJournalofMedicine,344,(7),710-719.Thissourceplayedalargepartinwritingtheactualpaper.Inthisarticlewasinformationonthebackgroundofstemcells,implicationsinstemcellresearch,andmostbeneficial,theactualexperimentalprocedureitself.Lieberman,A.(2004).WhatisParkinson’sDisease?RetrievedNovember14,2005, from/WhatIsParkinsons.html.Thissourcedidn’thelpmuchbackgroundinformationonthedisease,butdidhelpinprovidingancomprehendableversionofthesubstantianigraanditsroleindevelopmentofParkinson’sdisease.Alsobeneficialwerethefiguresassociatedwiththissource.SourcesAminoff,M.(2003).P17Parkinson’sDiseaseAnOverviewofConventionalandExperimentalTreatmentsParkinson’sDiseaseAnOverview18BackgroundParkinson’sdiseaseisadisorderthataffectsnervecellsinthepartofthebraincontrollingmusclemovementDiseaseisprogressive–signs/symptomsworsenovertimeEventuallyisdisabling,butprogressesgraduallyBelievedtobecausedbygenetics,environmentalfactorsoracombinationofthetwoBackgroundParkinson’sdisease19Parkinson’sDiseaseStatsFirstdesribedbyJamesParkinsonin1817Affects~1millionintheU.S.Onsettypicallybetween50-60yearsofage,andslowlyprogresseswithageAverageonsetis62.4yearsofageParkinson’sDiseaseStatsFirst20NeurologicalBasis“NeurodegenerativeDisease”:causedbydegeneration(dysfunctionanddeath)ofneuronswithinthebrain(nigrastriatalpathwayofthebasalganglia)NORMALBRAINFUNCTION–BasalGangliaCellsinsubstantianigraproduce/releasedopamineDopaminereleasedbySNneuronslandsonneuronsofotherbraincenters,controllingtheirfiringMaintargetsarecaudatenucleusandputamen(striatum)Thisbasalgangliapathwayisinvolvedinregulationofmovement NeurologicalBasis“Neurodegene21ParkinsonsDisease教學(xué)講解課件22NeurologicalBasisPARKINSON’SBRAINFUNCTION–BasalGangliaCellsofsubstantianigradegenerateThesecellscannolongerproduceadequateamountsofdopamineNeuronsofstriatum,etc.arenolongerwellregulated,thusdonotbehaveinnormalmannerResultsinlossofcontrolofmovements–leadstosymptomscharacteristicofParkinson’sdiseaseNeurologicalBasisPARKINSON’S23ParkinsonsDisease教學(xué)講解課件24CharacteristicSymptomsMOTORtremorbradykinesiarigidity/freezinginplacelackoffacialexpressionposturalinstabilitystooped,shufflinggaitNONMOTORdiminishedsenseofsmelllowvoicevolumefootcrampssleepdisturbancedepressionconstipationdroolingCharacteristicSymptomsMOTORNO25ParkinsonsDisease教學(xué)講解課件26ConventionalTreatments:MedicationLEVODOPA(L-DOPA)precursortodopamine,convertedtodopaminebynervecellsinthebrainTreatmentwithdopaminenotpossible,becausedopaminecan’tcrossblood-brainbarrierGenerallycombinedwithcarbidopa(Sinemet)–helpslevodopagettothebrain+reducessomesideeffectsExtendeduseoftenproducesdyskinesias–uncontrolledmovements(writhing,twitching,shaking)amongotherminorsideeffectsConventionalTreatments:Medic27ConventionalTreatments:MedicationDOPAMINEAGONISTSnotchangedintodopamine,butratheractLIKEdopamineatbrainsynapseswheredopamineisusuallypresent(nigrostriatalpathwaysinParkinson’spatients)UsedbothasadjunctstoL-DopatherapyandinyoungerParkinson’sdiseasepatientsSideeffectssimilartolevodopa,butlesslikelytodevelopinvoluntarymovements,morelikelytocausehallucinationsConventionalTreatments:Medic28ConventionalTreatments:MedicationMAOInhibitors(Selegiline)COMTInhibitorsAnticholinergicsConventionalTreatments:Medic29ConventionalTreatments:SurgeryThalamotomyInvolvesdestructionofsmallamountsoftissueinthethalamus—majorcenterforrelayingmessages/transmittingsensationsCancauseslurredspeechandlackofcoordinationPallidotomyelectriccurrentusedtodestroysmallamountoftissueinthepallidum(globuspallidus)Mayimprovetremors,rigiditybyinterruptingpathwaybetweenglobuspallidusandthalamusConventionalTreatments:Surge30ConventionalTreatments:SurgeryDeepBrainStimulationimplantdevice,pacemaker-likeunittransmitsimpulsestoelectrodesplacedinsubthalamicnucleusProducessameeffectsoflesionsurgeries,butcanbeturnedonandoffConventionalTreatments:Surge31ExperimentalTreatment:SurgeryFetalCellTransplantTherapy

stemcellsobtainedviaabortedfetus,growninculture,transplantedintoParkinson’spatientatnigrostriatalpathwayNewcellsestablishconnectionsand“replace”cellsoriginallylost,thesecellsfunctionnormallyandevenproducedopamineAutologous“Self”Transplantanalagoustofetalcelltransplant,exceptthatprecursornervecellsaretakenfrompatientandcoaxedtoproducedopamine,thenimplantedbackintooriginalpatientReducesthreatofautoimmuneresponseandreduced“controversialbaggage”associatedwithFCTtherapyExperimentalTreatment:Surger32ExperimentalTreatment:SurgeryRetinalPigmentedEpithelialCellTransplantDopamine-producingcellstakenfrompigmentedretinalepitheliumMechanismoftransplantanalagoustofetalcelltransplanttherapyIflossofcontactfromsubstrate,thesecellsdieConsequently,lowerriskofaberrantintegration—possiblecauseofdyskinesiasseeninsomeFCTpatientsExperimentalTreatment:Surger33SourcesAminoff,M.(2003).ParkinsonPrimer:Overviewof