帕金森病【PD】PPT课件

ParkinsonsDisease,ZhangluM.D.Ph.D.DepartmentofNeurology,Outline:,PartA:SummaryofParkinsonsdiseasePartB:MolecularbiologyofParkinsonsdisease,PARTA:SummaryofParkinsonsdisease1.History2.Epidemiology3.Riskfactors4.Clinicalfeatures5.Neuropathology6.Functionalneuroanatomy7.Neurochemistry8.Therapy9.Diagnosis10.Summary,HistoryofParkinsonsdisease(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,HistoryofParkinsonsDisease,Hissmallbutfamouspublication,EssayontheShakingPalsy,appearedin1817,7yearsbeforehisdeathin1824.,Theclinicaldescriptionof6patientswasaremarkablemasterpiecetestifyingtohisprodigiouspowersofobservationformostofthe6wereneveractuallyexaminedbyParkinsonhimself;rather,theyweresimplyobservedwalkingonthestreetsofLondon.,EpidemiologyofPDThemostcommonmovementdisorderaffecting1-2%ofthegeneralpopulationovertheageof65years.ThesecondmostcommonneurodegenerativedisorderafterAlzheimersdisease(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.,EtiologyofParkinsonsDisease,Degenerationofthesubstantianigra(withLewybodies?),Parkinsonsdisease,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),ParkinsonsDisease,Thebasalganglia,throughtheactionofdopamine,areresponsibleforplanningandcontrollingautomaticmovementsofthebody,suchaspointingwithafinger,pullingonasock,writingorwalking.Ifthebasalgangliaarenotworkingproperly,asinParkinsonsdiseasepatients,allaspectsofmovementareimpaired,resultinginthecharacteristicfeaturesofthediseaseslownessofmovement,stiffnessandeffortrequiredtomovealimband,often,tremor.,ClinicalfeaturesofPD,Threecardinalsymptoms:restingtremorbradykinesia(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,ParkinsonsDisease,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,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)isacombinationofcarbidopaandlevodopaforthetreatmentofParkinsonsdiseaseandsyndrome.,/neuro/mod6/carb.html,TherapyofPD:limitationsoflevodopaEfficacytendstodecreaseasthediseaseprogresses.Chronictreatmentassociatedwithadverseevents(motorfluctuations,dyskinesiasandneuropsychiatricproblems).,InhibitionofperipheralCOMTbyentacaponeincreasestheamountofL-DOPAanddopamineinthebrainandimprovesthealleviationofPDsymptoms.,TherapyofPD:limitationsoflevodopaDoesnotpreventthecontinuousdegenerationofnervecellsinthesubtantianigra,thetreatmentbeingthereforesymptomatic.,TherapyofPD:OthertreatmentsDAreceptoragonists(bromocriptine,pergolide,pramipexole,ropinirole,cabergoline)AmantadineAnticholinergics,TreatmentofParkinsonsDisease:MonoamineOxidaseInhibitors(MAOIs),Asshownabove,monoamineoxidaseisanenzymethatcatalyzesthedestructionofprimaryamines(suchasdopamine,norepinephrine,seritonin)andsecondaryamines.ThetypeBisoformofMAO(MAO-B)isprimarilyresponsibleformetabolismofdopamine.,MetabolismofDopamineviaMonoamineOxidase(MAO),InhibitorofMAO-B,Selegiline(l-deprenyl,EldeprylorAniprylveterinary)isadrugusedforthetreatmentofearly-stageParkinsonsdiseaseandseniledementia.InnormalclinicaldosesitisaselectiveirreversibleMAO-Binhibitor.,InlatestageParkinsonsDisease,Selegilineisusuallyaddedtolevodopatoprolongandenhanceitseffect,MetabolismofDopamineviaCatachol-O-MethylTransferase(COMT),InhibitorsofCOMT,Entacapone,Tolcapone,InhibitorsofCOMT,EntacaponeismarketedbyNovartisasComtanintheUSStalevoisacombinationofLevodopa,Carbidopa,andEntacapone,SummaryoftheTreatmentofParkinsonsDisease,Endorphin,Endorphins(ormorecorrectlyEndomorphines)areendogenousopioidbiochemicalcompounds.Theyarepeptidesproducedbythepituitaryglandandthehypothalamusinvertebrates,andtheyresembletheopiatesintheirabilitiestoproduceanalgesiaandasenseofwell-being.Inotherwords,theymightworkasnaturalpainkillers.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.Ifneuronsofthebrainstemthatmakeserotoninserotonergicneuronsareabnormal,thereisariskofsuddeninfantdeathsyndrome(SIDS)inaninfant.,Serotonin,UnderstandingSerotonin,Serotonergicactionisterminatedprimarilyviauptakeof5-HTfromthesynapse.Thisisthroughthespecific