神经病理学.ppt

Schizophrenia Whatcausesschizophrenia NeuropathologyStructuralandfunctionalchangesNeurochemicalalterationsTreatments Schizophrenia EmilKraepelin DementiaPraecox 1896 Blueler Schizophrenia Onset adolescenceoryoungadulthoodDSM IVreview Positivesymptoms delusions hallucinations disorganizedspeechorbehavior Negativesymptoms catatonia affectiveflattening withdrawal oravolition Social occupationaldisturbance6 months AssociatedFeatures CognitiveDisturbancesMemorySensoryfilteringAttentionEmotionrecognitionEye trackingInterpersonalDysfunction Subtypes CatatonicParanoidDisorganizedUnlikelytobearelatedtoasinglephysiopathology Neuropathology NeurodevelopmentalhypothesisNeurodegenerativehypothesisDopaminehypothessisGlutamatergichypothesis Thesearenotexclusive Whatcausesschizophrenia Heritable Shastry 2002 EnvironmentalfactorsEpidemiologicalstudiesBirthcomplicationsMaternalstressSeasonalityeffectViralepidemicsLatitudeeffectRhincompatibility NeuropathologyStructuralalterations Behavioralsymptomsindicativeofbraindamage unusualratesofblinking poorcontrolofeyemovements unusualfacialexpressions Enlargedventricles WeinbergerAndreason Ventricularenlargementinmonozygotictwinwithschizophrenia Barondes 1993 Hippocampalvolumelossandenlargedventricles VanHeronetal 2005 NeuropathologyStructuralalterations cont Alterationsinnumerousareas includingfrontallobes medialtemporallobes lateraltemporallobes parietallobe basalganglia corpuscallosum thalamusandeventhecerebellumWhitematterdeficitsEvidenceofdisorganizedneuronsandfailuresofmigrationAltereddensityanddisorganizationofneuronsfoundinthewhitematterbelowlayerVIinthecortexDisorganizedpyramidalcellsinthehippocampus Altereddevelopmentofhippocampalpyramidalneurons NeurodevelopmentalHypothesis Homemoviesfromfamilieswithschizophrenicchilddisplayedabnormalbehavior Walkeretal 1994 1996 ChildrenwholaterbecomeschizophrenicexhibitpoorsocialadjustmentandschoolperformanceDevelopmentaldelaysPremorbidpsychopathology anxiety depression conductdisorders ADHD Kim Cohenetal 2003 Physicalabnormalities Schiffman etal 2002 Ratesofconcordancearehigherinmonochorionictwinscompareddichorionictwins 60 vs 11 Davis etal 1995 Butwhyaresymptomsnotobserveduntiladolescence SomethingmusttriggerthedegenerativeprocessattheperiodofadolescenceLossanddisorganizationofneuronsbecome unmasked withpruningandsynapticreorganization Rapidlossofbrainvolumeduringadolescenceinschizophrenics Thompsonetal 2001 Thompsonetal 2001 Twinstudy lossofdlPFCandtemporalcorticaltissue Cannonetal2002 Hypofrontality ReducedactivationofthedorsolateralprefrontalcortexcontributestonegativesymptomsandcognitivedeficitsFunctionalimagingstudiesreportreducedactivationEvidenceofexecutivefunctioningdeficits Reducedactivationofthedorsolateralprefrontalcortexduringacontextprocessing attentiontaskinfirstepisode drugna veschizophrenics MacDonaldetal 2005 poorlyinnervated poorneuronalmigration inadequatesynapseselection Couldaltereddevelopmentberelatedtoglutamatergicdysfunction Underactivationofsystemsaltersmigration synapticorganizationandcellsurvival Overactivationofsystemscanleadtoalteredsynapticconnectivityandcelldeath NeurodegenerativeHypothesis Couldthepsychoticsymptomsthemselvesbeproducingadditionalexcitotoxicity NeurochemicalAlterations DopamineHypothesis OriginalFormulationOveractivityofsubcorticalD2receptorscontributestopositivesymptomsClassicalantipsychoticswereDAD2antagonistsDAagonistsinducepsychotogeniceffects c DOPAMINEPATHWAYS mesolimbicpathway mesolimbicoveractivity positivesymptomsofpsychosis pureD2blocker Re formulationofdopaminehypothesis ImagingstudiesindicatelossoftissueinthefrontallobesaswellasreducedactivationDeficitinactivationofD1receptorsintheprefrontalcortexcontributestonegativesymptomsandcognitivedeficits meso corticalpathway Amphetamine induceddopaminereleaseisenhancedinschizophrenics Laruelleetal2003 Amphetamine induceddopaminereleaseproducespositivesymptoms Laruelleetal 1996 Increaseddopaminereleaseinmedication na veschizophrenicpatients Hietala etal 1995 D2receptors MixeddataSomefindnodifferencesOthersfindmoderateincreases Kestleretal 2001 WhataboutD3andD4receptors WhataboutthemesocorticalDAsystem OnepostmortemstudyindicatedadecreaseinDAinnervationofthedorsolateralprefrontalcortex Akil etal1999 TwoPETstudieshadmixedfindings buttheligandsusedforD1receptorswerenotselective Okuboetal1997 Karlssonetal2002 Morerecently thereisevidenceofanupregulationofD1receptorsintheDLPFC IncreasedD1receptoravailabilityinschizophrenicssuggestsunderactivation Abi Darghametal JNeurosci 2002 IncreasesinD1receptoravailabilityintheDLPFCarecorrelatedwithworkingmemorydeficits Abi Darghametal JNeurosci 2002 Reductionindendriticspinesindopaminergicneuronsinthedorsolateralprefrontalcortex Lewisetal 2003 GlutamateHypothesis DeficienciesinglutamatergicneurotransmissionDysregulationofDAsystemsmaybesecondarytoadeficitinthefunctionoftheglutamatergicNMDAreceptor GlutamateHypothesis NoncompetitveNMDAreceptorantagonists likePCPandketamine inducebothpositiveandnegativesymptomsUnmedicatedschizophrenicpatientsaremoresensitivetotheeffectsofNMDAreceptorantagonistsAdjunctivetreatmentwithNMDAagonistsmightprovideamodestimprovementinsymptoms Evidencefromhumanstudies AlterationsinCSFglutamatelevels alteredglutamatemetabolismandalteredNMDAreceptorsubunitgeneexpression Keshavan 1999 DirectevidenceisstilllackingandacoherentpicturehasnotyetemergedLackofadequateradioligandstovisualizetheGLUsysteminthelivingbrainisamajorimpediment Glutamate DopamineInteractions Laruelleetal 2003 ChronicPCPtreatmentreducesdorsolateralprefrontalcortexdopamineandleadstonegativesymptoms HumanstudiesAnimalstudies JentschandRoth 1999 ChronicPCPleadstobehavioraldeficitsconsistentwithdorsolateralprefrontalcortexdysfunction Jentschetal Science 1997 ChronicPCPreducescorticaldopamine Jentschetal Science 1997 Effectsarereversedwithclozapine Jentschetal Science 1997 NMDAreceptorantagonismenhancesamphetamine inducedsubcorticalDArelease Kegellesetal2000 Reducedprefrontalcortexactivationinschizophrenics Meyeretal 2002 ReduceddlPFCactivationwasnegativelycorrelatedwithstriataldopaminerelease Meyeretal 2002 SubcorticalDopamine GlutamateInteractions GABAalterations GlutamateorGABA Putitalltogether Neurodevelopmentalbraindamage leadstodysfunctioninareasliketheprefrontalcortex whichleadstoincreasedDAinthemesolimbicareas Whataboutthetemporallobedamage Hippocampusandamygdalacontrolagatethatinfluencestheeffectsoftheprefrontalcortexonn accumbensneuronalfiringThisgatemodulatesreactionsofthen accumbensgiventhecontext Hippocampusmaymodulateprefrontalactivationofn accumbens Grace 2000 Grace 2000 HowdoesexaggerationsofmesolimbicDAactivityleadtopositivesymptoms Couldaltereddopamineinthenucleusaccumbensalterthesalienceattributedtointernalandexternalstimuli Kapurreading Treatments ConventionalneurolepticsChlorpromazineHaloperidolLoxapinePimozideThieoridazinethirothixene pureD2blocker TypicalantipsychoticsareD2receptorantagonists Blockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup regulate Thisup regulationmayleadtotardivedyskinesia Conventionalantipsychoticshaveothersitesofaction MuscariniccholinergicblockadeSideeffectsofconstipationandblurredvisionReducethelikelihoodofextrapyramidalsymptoms Problemswithconventionalantipsychotics Becauseofsideeffects manypatientsdiscontinuetreatments relapse gobackontreatmentrepeatedlyNeurolepticmalignantsyndrome Atypicalantipsychoticdrugs Serotonin dopamineantagonistsClozapineRisperidoneOlanzapineQuetiapineZiprasidone 5HT DAInteractions serotoninneuron dopamineneuron Substantianigra Raphe dopamine 5HT2Areceptor serotonin 5HT2Areceptor serotoninneuron dopamineneuron Substantianigra Raphe dopamine 5HT2Areceptor serotonin 5HT2Areceptor serotoninneuron dopamineneuron Substantianigra Raphe 5HT2Areceptor DAneuron 5HTneuron postsynapticneuron dopamine D2receptor 5HT2Areceptor Nigrostriatalpathway serotonin Nigrostriatalpathway nodopaminerelease SDA D2receptor Nigrostriatalpathway 5HT2Areceptor Nigrostriatalpathwa