帕金森病【D】PPT课件.ppt

Parkinson sDisease ZhangluM D Ph D DepartmentofNeurology Outline PartA SummaryofParkinson sdiseasePartB MolecularbiologyofParkinson sdisease PARTA SummaryofParkinson sdisease1 History2 Epidemiology3 Riskfactors4 Clinicalfeatures5 Neuropathology6 Functionalneuroanatomy7 Neurochemistry8 Therapy9 Diagnosis10 Summary HistoryofParkinson sdisease PD Firstdescribedin1817byanEnglishphysician JamesParkinson in AnEssayontheShakingPalsy ThefamousFrenchneurologist Charcot furtherdescribedthesyndromeinthelate1800s History JamesParkinson 1755 1824 whilebestrememberedforthediseasestatenamedafterhimbyCharcot wasamanofmanytalentsandinterests Publishingonchemistry paleontologyandotherdiversetopics hewas earlyinhiscareer asocialactivistchampioningtherightsofthedisenfranchisedandpoor HiseffortsinthisareawereenoughtoresultinhisarrestandappearancebeforeThePrivyCouncilinLondononatleastoneoccasion Incollaborationwithhisson whowasasurgeon healsoofferedthefirstdescription intheEnglishlanguage ofarupturedappendix ANESSAYONTHESHAKINGPALSYCHAPTERIDEFINITION HISTORY ILLUSTRATIVECASESSHAKINGPALSY ParalysisAgitans MonographbyJamesParkinson1817 JamesParkinson HistoryofParkinson sDisease Hissmallbutfamouspublication EssayontheShakingPalsy appearedin1817 7yearsbeforehisdeathin1824 Theclinicaldescriptionof6patientswasaremarkablemasterpiecetestifyingtohisprodigiouspowersofobservationformostofthe6wereneveractuallyexaminedbyParkinsonhimself rather theyweresimplyobservedwalkingonthestreetsofLondon EpidemiologyofPDThemostcommonmovementdisorderaffecting1 2 ofthegeneralpopulationovertheageof65years ThesecondmostcommonneurodegenerativedisorderafterAlzheimer sdisease AD IncidenceofPD Age Incidence 100000 PrevalenceofPD Age Prevalence 100000 EpidemiologyofPD MaybelessprevalentinChinaandotherAsiancountries andinAfrican Americans Prevalenceratesinmenareslightlyhigherthaninwomen reasonunknown thougharoleforestrogenhasbeendebated RiskfactorsofPDAge themostimportantriskfactorPositivefamilyhistoryMalegenderEnvironmentalexposure Herbicideandpesticideexposure metals manganese iron wellwater farming ruralresidence woodpulpmills andsteelalloyindustriesRaceLifeexperiences trauma emotionalstress personalitytraitssuchasshynessanddepressiveness Aninversecorrelationbetweencigarettesmokingandcaffeineintakeincase controlstudies EtiologyofParkinson sDisease Degenerationofthesubstantianigra withLewybodies Parkinson sdisease PARK 1 a Synuclein PARK 2 Parkin mitochondrialdysfuction oxidativestress geneticsusceptibiliesDebrisoquinhydroxylase PARK 5 UbiquitinCterminalhydrolaseL1 Toxins MPTP Rotenone Neuroinflammation Infection PARK 4 3xa Synuclein PARK 7 DJ1 Parkinson sDisease Thebasalganglia throughtheactionofdopamine areresponsibleforplanningandcontrollingautomaticmovementsofthebody suchaspointingwithafinger pullingonasock writingorwalking Ifthebasalgangliaarenotworkingproperly asinParkinson sdiseasepatients allaspectsofmovementareimpaired resultinginthecharacteristicfeaturesofthedisease slownessofmovement stiffnessandeffortrequiredtomovealimband often tremor ClinicalfeaturesofPD Threecardinalsymptoms restingtremor bradykinesia generalizedslownessofmovements musclerigidity ClinicalfeaturesofPDRestingtremor Mostcommonfirstsymptom usuallyasymmetricandmostevidentinonehandwiththearmatrest Bradykinesia Difficultywithdailyactivitiessuchaswriting shaving usingaknifeandfork andopeningbuttons decreasedblinking maskedfacies slowedchewingandswallowing Rigidity Muscletoneincreasedinbothflexorandextensormusclesprovidingaconstantresistancetopassivemovementsofthejoints stoopedposture anteroflexedhead andflexedkneesandelbows AdditionalclinicalfeaturesofPDPosturalinstability Duetolossofposturalreflexes Dysfunctionoftheautonomicnervoussystem Impairedgastrointestinalmotility bladderdysfunction sialorrhea excessiveheadandnecksweating andorthostatichypotension Depression Mildtomoderatedepressionin50 ofpatients Cognitiveimpairment Mildcognitivedeclineincludingimpairedvisual spatialperceptionandattention slownessinexecutionofmotortasks andimpairedconcentrationinmostpatients atleast1 3becomedementedduringthecourseofthedisease ClinicalStage Parkinson sDisease NeuropathologyofPDEosinophilic roundintracytoplasmicinclusionscalledlewybodiesandLewyneurites Firstdescribedin1912byaGermanneuropathologist FriedrichLewy Inclusionsparticularlynumerousinthesubstantianigraparscompacta Lewybodies NeuropathologyofPD Whatfeaturehaveyouobserved Asymmetriclesions NeuropathologyofPD LewybodiesNotlimitedtosubstantianigraonly alsofoundinthelocuscoeruleus motornucleusofthevagusnerve thehypothalamus thenucleusbasalisofMeynert thecerebralcortex theolfactorybulbandtheautonomicnervoussystem Confinedlargelytoneurons glialcellsonlyrarelyaffected Lewybodies FunctionalneuroanatomyofPDSubstantianigra Themajororiginofthedopaminergicinnervationofthestriatum Partofextrapyramidalsystemwhichprocessesinformationcomingfromthecortextothestriatum returningitbacktothecortexthroughthethalamus Onemajorfunctionofthestriatumistheregulationofpostureandmuscletonus Substantianigraandtheextrapyramidalsystem 2020 1 7 31 NeurochemistryofPDLate1950s Dopamine DA presentinmammalianbrain andthelevelshighestwithinthestriatum 1960 EhringerandHornykiewicz ThelevelsofDAseverelyreducedinthestriatumofPDpatients PDsymptomsbecomemanifestwhenabout50 60 oftheDA containingneuronsinthesubstantianigraand70 80 ofstriatalDAarelost Dopaminepathwaysinhumanbrain Dopaminesynthesis TherapyofPD levodopaLate1950s L dihydroxyphenylalanine L DOPA levodopa aprecursorofDAthatcrossestheblood brainbarrier couldrestorebrainDAlevelsandmotorfunctionsinanimalstreatedwithcatecholaminedepletingdrug reserpine FirsttreatmentattemptsinPDpatientswithlevodoparesultedindramaticbutshort termimprovements tookyearsbeforeitbecomeanestablishedandsuccesfulltreatment Stilltoday levodopacornerstoneofPDtreatment virtuallyallthepatientsbenefit SINEMET CARBIDOPA LEVODOPA DESCRIPTIONSINEMET Carbidopa Levodopa isacombinationofcarbidopaandlevodopaforthetreatmentofParkinson sdiseaseandsyndrome http www learningcommons umn edu neuro mod6 carb html TherapyofPD limitationsoflevodopaEfficacytendstodecreaseasthediseaseprogresses Chronictreatmentassociatedwithadverseevents motorfluctuations dyskinesiasandneuropsychiatricproblems InhibitionofperipheralCOMTbyentacaponeincreasestheamountofL DOPAanddopamineinthebrainandimprovesthealleviationofPDsymptoms TherapyofPD limitationsoflevodopaDoesnotpreventthecontinuousdegenerationofnervecellsinthesubtantianigra thetreatmentbeingthereforesymptomatic TherapyofPD OthertreatmentsDAreceptoragonists bromocriptine pergolide pramipexole ropinirole cabergoline AmantadineAnticholinergics TreatmentofParkinson sDisease MonoamineOxidaseInhibitors MAOI s Asshownabove monoamineoxidaseisanenzymethatcatalyzesthedestructionofprimaryamines suchasdopamine norepinephrine seritonin andsecondaryamines ThetypeBisoformofMAO MAO B isprimarilyresponsibleformetabolismofdopamine MetabolismofDopamineviaMonoamineOxidase MAO InhibitorofMAO B Selegiline l deprenyl Eldepryl orAnipryl veterinary isadrugusedforthetreatmentofearly stageParkinson sdiseaseandseniledementia InnormalclinicaldosesitisaselectiveirreversibleMAO Binhibitor InlatestageParkinson sDisease Selegilineisusuallyaddedtolevodopatoprolongandenhanceitseffect MetabolismofDopamineviaCatachol O MethylTransferase COMT InhibitorsofCOMT Entacapone Tolcapone InhibitorsofCOMT EntacaponeismarketedbyNovartisasComtanintheUSStalevoisacombinationofLevodopa Carbidopa andEntacapone SummaryoftheTreatmentofParkinson sDisease Endorphin Endorphins ormorecorrectlyEndomorphines areendogenousopioidbiochemicalcompounds Theyarepeptidesproducedbythepituitaryglandandthehypothalamusinvertebrates andtheyresembletheopiatesintheirabilitiestoproduceanalgesiaandasenseofwell being Inotherwords theymightworkas naturalpainkillers Usingdrugsmayincreasetheeffectsoftheendorphins Serotonin AlthoughtheCNScontainslessthan2 ofthetotalserotonininthebody serotoninplaysaveryimportantroleinarangeofbrainfunctions Itissynthesizedfromtheaminoacidtryptophan Withinthebrain serotoninislocalisedmainlyinnervepathwaysemergingfromtheraphenuclei agroupofnucleiatthecentreofthereticularformationintheMidbrain ponsandmedulla Theseserotonergicpathwaysspreadextensivelythroughoutthebrainstem thecerebralcortexandthespinalcord Inadditiontomoodcontrol serotoninhasbeenlinkedwithawidevarietyoffunctions includingtheregulationofsleep painperception bodytemperature bloodpressureandhormonalactivity Outsidethebrain serotoninexertsanumberofimportanteffects particularlyinvolvingthegastrointestinalandcardiovascularsystems Serotonin Inthecentralnervoussystem serotoninisbelievedtoplayanimportantroleintheregulationofbodytemperature mood sleep vomiting sexuality andappetite Lowlevelsofserotoninhavebeenassociatedwithseveraldisorders namelyclinicaldepression obsessive compulsivedisorder OCD migraine irritablebowelsyndrome tinnitus fibromyalgia bipolardisorder andanxietydisorders Ifneuronsofthebrainstemthatmakeserotonin serotonergicneurons areabnormal thereisariskofsuddeninfantdeathsyndrome SIDS inaninfant Serotonin UnderstandingSerotonin Serotonergicactionisterminatedprimarilyviauptakeof5 HTfromthesynapse Thisisthroughthespecificmonoaminet