帕金森病-过去、现在和未来-20140826

Parkinson’sDiseasePast,Present,andFuture范益2014.08南京医科大学1234TheHistoryofParkinson’sDiseaseNeuropathologyofParkinson’sDiseaseGeneticsofParkinson’sDiseasePathophysiologyofParkinson’sDisease5TreatmentofParkinson’sDiseaseIndex2TheHistoryofParkinson’sDisease3History1000BCAncientIndianAncientChina1817JamesParkinson18724History1872Jean-MartinCharcottheNapoleonoftheneurosesCharcotwasthefirsttosuggesttheuseoftheterm“Parkinson’sdisease”SigismundSchlomoFreud18875History1872Jean-MartinCharcot1887MyographiccurvesSegmentABindicates“atrest,”andBCindicatesincreasingoscillationsduringvoluntarymovementCharcot’simportantcontributiontothestudyofParkinson’sdiseasewashisdifferentiationofthisdisorderfromothertremorousdisorders,specificallymultiplesclerosis18986History1872Jean-MartinCharcot1887Belladonnaalkaloids——thefirstwell-establishedtreatmentofParkinson’sdiseaseBelladonnaalkaloids18987History1872Jean-MartinCharcot1887Vibratorytherapy18988History1872EdouardBrissaud18871898alludedtomidbraininvolvementinParkinson’sdisease1909VictorHorsleyRobertHenryClarkeEarlysurgicalinterventions19109History1910GeorgeBarger？JamesEwensDopamine1911CasimirFunkL-dopa1912FriedrichHeinrichLewyLewybody1950s10HistoryJ.G.Greenfield1953？FrancesD.Bosanquet1954Parkinsoniandisordersincludesdrug-inducedandtoxin-inducedcases1958Dopamine'sfunctionasaneurotransmitterArvidCarlssonDopaminelocalizationwithinthebrain,specificallyinthestriatumReserpine-modelusedasthefirstmodelofParkinsonism1961OlehHornykiewicz•thediscoverythatParkinson'sDiseasewasduetodopaminedeficiencyinthebrain•ThedevelopmentofL-dopaasatherapyforthedisorder.11the2000NobelPrizeHistory1961OlehHornykiewicz•ThediscoverythatParkinson'sDiseasewasduetodopaminedeficiencyinthebrain•ThedevelopmentofL-dopaasatherapyforthedisorder.Moremoderndiscoveriesofdopamineagonistsandenzymeinhibitorsthatenhancethebioavailabilityofdopamine1979MPTP•The“goldstandard”modeltostudyParkinson’sdiseaseinpreclinicalstudiesofnewtreatmentsforParkinson’sdisease1997alpha-synucleinDeepbrainstimulation1967L-dopaenteredclinicalpractice12History19970100020003000400050006000ThepapersofParkinson’sdiseaseinPubMed13History199714NeuropathologyofParkinson’sDisease15NeuropathologyJ.G.Greenfield？FrancesD.Bosanquet16NeuropathologyMovementdisorderThelossofthedopaminergicneuronsinthesubstantianigra17NeuropathologyJean-MartinCharcotNon-motorsymptomsinPDNeuropsychiatricSleepAutonomic18NeuropathologyPremotorSymptomsofPDChenH,et.al.ResearchonthePremotorSymptomsofParkinson'sDisease:ClinicalandEtiologicalImplications.EnvironHealthPerspect.2013;121:1245-1252.19NeuropathologyPremotorSymptomsofPDChenH,et.al.ResearchonthePremotorSymptomsofParkinson'sDisease:ClinicalandEtiologicalImplications.EnvironHealthPerspect.2013;121:1245-1252.20NeuropathologyLewybodiesandα-synucleinopathiesFriedrichHeinrichLewyLewybodiesLewyneuritesα-synucleinubiquitinCrystallinAlphaBNeurofilament21NeuropathologyBraakstagingBraak,H.,etal.,StagingofbrainpathologyrelatedtosporadicParkinson'sdisease.NeurobiolAging,2003.24(2):p.197-211..22Neuropathologyα-synucleinopathiesMcCannH,StevensCH,CartwrightH,HallidayGM.α-Synucleinopathyphenotypes.Parkinsonism&RelatedDisorders.2014;20,Supplement1:S62-S67.23Neuropathologyα-synucleinopathies&ADMcCannH,StevensCH,CartwrightH,HallidayGM.α-Synucleinopathyphenotypes.Parkinsonism&RelatedDisorders.2014;20,Supplement1:S62-S67.24Neuropathologyα-synucleinopathiesJennerP,et.al..Parkinson'sdisease-thedebateontheclinicalphenomenology,aetiology,pathologyandpathogenesis.JParkinsonsDis.2013;3:1-11..25GeneticsofParkinson’sDisease26GeneticsFamilialandsporadicPD27GeneticsTimelineofgeneticsinPDandMSAα-synucleinHouldenH,SingletonAB.ThegeneticsandneuropathologyofParkinson'sdisease.ActaNeuropathol.2012;124:325-33828GeneticsConfirmedgenesimplicatedinmonogenicparkinsonismsBonifatiV.GeneticsofParkinson'sdisease–stateoftheart,2013.Parkinsonism&RelatedDisorders.2014;20,Supplement1:S23-S28.29GeneticsThecurrentresearchstrategiesforfindinggenesBonifatiV.GeneticsofParkinson'sdisease–stateoftheart,2013.Parkinsonism&RelatedDisorders.2014;20,Supplement1:S23-S28.30GeneticsConfirmedgenesimplicatedinparkinsonismsOzansoyM,BasakAN.ThecentralthemeofParkinson'sdisease:alpha-synuclein.MolNeurobiol.2013;47:460-465.31GeneticsConfirmedgenesimplicatedinparkinsonismsNallsMA,etal.(2014)Large-scalemeta-analysisofgenome-wideassociationdataidentifiessixnewrisklociforParkinson'sdisease.Naturegenetics.32GeneticsGenieticfactorofPD33PathophysiologyofParkinson’sDisease34PathophysiologyThecauseofPD35AnimalmodelsofPD:Neurotoxinsinjectedlocally6-HydroxydopamineistheclassicPDmodelPathophysiology36AnimalmodelsofPD:neurotoxinsinjectedsystemicallyMPTPisthegoldstandardmodelPathophysiology37OCT-3OCT-3:organiccationtransporter3.AnimalmodelsofPD:NeurotoxinsinjectedsystemicallyMPTPisthegoldstandardmodeladisadvantageofsystemicdeliveryisthepossibilityofcausingtoxicityinotherpartsofthenervoussystemorotherorgansleadingtoageneralillnessand/orachangeinbehaviorthatmaybedifficulttointerpret.Pathophysiology38Pathophysiology39Ani