神经病理学医学知识培训培训课件

1、神经病理学医学知识培训神经病理学医学知识培训神经病理学医学知识培训2神经病理学医学知识培训2SchizophreniaEmil Kraepelin “Dementia Praecox (1896)Blueler “Schizophrenia”Onset: adolescence or young adulthoodDSM-IV review:Positive symptoms (delusions, hallucinations, disorganized speech or behavior)Negative symptoms (catatonia, affective flattening

2、, withdrawal, or avolition)Social-occupational disturbance6+ months神经病理学医学知识培训3SchizophreniaEmil Kraepelin “DAssociated FeaturesCognitive DisturbancesMemorySensory filteringAttentionEmotion recognitionEye-trackingInterpersonal Dysfunction神经病理学医学知识培训4Associated FeaturesCognitive SubtypesCatatonicPara

3、noidDisorganizedUnlikely to be a related to a single physiopathology神经病理学医学知识培训5SubtypesCatatonic神经病理学医学知识培训5NeuropathologyNeurodevelopmental hypothesisNeurodegenerative hypothesisDopamine hypothessisGlutamatergic hypothesis *These are not exclusive神经病理学医学知识培训6NeuropathologyNeurodevelopmentWhat caus

4、es schizophrenia?Heritable (Shastry, 2002)Environmental factorsEpidemiological studiesBirth complicationsMaternal stressSeasonality effectViral epidemicsLatitude effectRh incompatibility神经病理学医学知识培训7What causes schizophrenia?HeriNeuropathologyStructural alterationsBehavioral symptoms indicative of br

5、ain damage (unusual rates of blinking, poor control of eye movements, unusual facial expressions)Enlarged ventricles (Weinberger & Wyatt, 1982; Andreason)神经病理学医学知识培训8NeuropathologyStructural alteVentricular enlargement in monozygotic twin with schizophreniaBarondes, 1993神经病理学医学知识培训9Ventricular enlar

6、gement in monHippocampal volume loss and enlarged ventriclesVan Heron et al., 2005神经病理学医学知识培训10Hippocampal volume loss and enNeuropathologyStructural alterations (cont)Alterations in numerous areas, including frontal lobes, medial temporal lobes, lateral temporal lobes, parietal lobe, basal ganglia,

7、 corpus callosum, thalamus and even the cerebellumWhite matter deficitsEvidence of disorganized neurons and failures of migrationAltered density and disorganization of neurons found in the white matter below layer VI in the cortexDisorganized pyramidal cells in the hippocampus神经病理学医学知识培训11Neuropatho

8、logyStructural alteAltered development of hippocampal pyramidal neurons神经病理学医学知识培训12Altered development of hippoca神经病理学医学知识培训13神经病理学医学知识培训13Neurodevelopmental HypothesisHome movies from families with schizophrenic child displayed abnormal behavior (Walker et al, 1994; 1996)Children who later become

9、schizophrenic exhibit poor social adjustment and school performanceDevelopmental delaysPremorbid psychopathology (anxiety, depression, conduct disorders, ADHD) (Kim-Cohen et al, 2003)Physical abnormalities (Schiffman, et al. 2002)Rates of concordance are higher in monochorionic twins compared dichor

10、ionic twins (60% vs. 11%) (Davis, et al, 1995)神经病理学医学知识培训14Neurodevelopmental HypothesisHBut why are symptoms not observed until adolescence?Something must trigger the degenerative process at the period of adolescenceLoss and disorganization of neurons become unmasked with pruning and synaptic reorg

11、anization神经病理学医学知识培训15But why are symptoms not obserRapid loss of brain volume during adolescence in schizophrenicsThompson et al, 2001神经病理学医学知识培训16Rapid loss of brain volume durThompson et al, 2001神经病理学医学知识培训17Thompson et al, 2001神经病理学医学知识培神经病理学医学知识培训18神经病理学医学知识培训18Twin studyloss of dlPFC and tempo

12、ral cortical tissueCannon et al 2002神经病理学医学知识培训19Twin studyloss of dlPFC and tHypofrontalityReduced activation of the dorsolateral prefrontal cortex contributes to negative symptoms and cognitive deficitsFunctional imaging studies report reduced activationEvidence of executive functioning deficits神经

13、病理学医学知识培训20HypofrontalityReduced activatiReduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug nave schizophrenicsMacDonald et al., 2005神经病理学医学知识培训21Reduced activation of the dorspoorly innervatedtoxic or genetic insultdysfunctionde

14、athpoor neuronal migrationinadequate synapse selection神经病理学医学知识培训22poorly innervatedtoxic or geneCould altered development be related to glutamatergic dysfunction?-Underactivation of systems alters migration, synaptic organization and cell survival-Overactivation of systems can lead to altered synap

15、tic connectivity and cell death神经病理学医学知识培训23Could altered development be SPECTRUM OF EXCITATION BY GLUTAMATEExcess excitation- Mania- PanicExcitotoxicity- Damage to neuronsExcitotoxicity- Slow neuro- degenerationExcitotoxicity- Catastrophic neurodegenerationNormal excitationNeurodegenerative Hypothe

16、sis神经病理学医学知识培训24SPECTRUM OF EXCITATION BY GLUTCould the psychotic symptoms themselves be producing additional excitotoxicity?神经病理学医学知识培训25Could the psychotic symptoms tNeurochemical Alterations神经病理学医学知识培训26Neurochemical Alterations神经病理学Dopamine HypothesisOriginal FormulationOveractivity of subcortic

17、al D2 receptors contributes to positive symptomsClassical antipsychotics were DA D2 antagonistsDA agonists induce psychotogenic effects神经病理学医学知识培训27Dopamine HypothesisOriginal FohypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS神经病理学医学知识培训28hypothalamusdcNucleus

18、 accumbenmesolimbic pathway神经病理学医学知识培训29mesolimbic pathway神经病理学医学知识培训2mesolimbic overactivity = positive symptoms of psychosis神经病理学医学知识培训30mesolimbic overactivity = posipure D2 blocker11-2Stahl S M, Essential Psychopharmacology (2000)神经病理学医学知识培训31pure D2 blocker11-2Stahl S M, Re-formulation of dopam

19、ine hypothesisImaging studies indicate loss of tissue in the frontal lobes as well as reduced activationDeficit in activation of D1 receptors in the prefrontal cortex contributes to negative symptoms and cognitive deficits神经病理学医学知识培训32Re-formulation of dopamine hypmeso-cortical pathway神经病理学医学知识培训33m

20、eso-cortical pathway神经病理学医学知识Amphetamine-induced dopamine release is enhanced in schizophrenicsLaruelle et al 2003神经病理学医学知识培训34Amphetamine-induced dopamine rAmphetamine-induced dopamine release produces positive symptomsLaruelle et al, 1996神经病理学医学知识培训35Amphetamine-induced dopamine rIncreased dopamin

21、e release in medication-nave schizophrenic patientsHietala, et al. 1995神经病理学医学知识培训36Increased dopamine release in D2 receptors?Mixed dataSome find no differencesOthers find moderate increases (Kestler et al., 2001)What about D3 and D4 receptors?神经病理学医学知识培训37D2 receptors?Mixed data神经病理学医学What about t

22、he mesocortical DA system?One postmortem study indicated a decrease in DA innervation of the dorsolateral prefrontal cortex (Akil, et al 1999)Two PET studies had mixed findings, but the ligands used for D1 receptors were not selective (Okubo et al 1997; Karlsson et al 2002)More recently, there is ev

23、idence of an upregulation of D1 receptors in the DLPFC神经病理学医学知识培训38What about the mesocortical DAIncreased D1 receptor availability in schizophrenics suggests underactivationAbi-Dargham et al, J Neurosci, 2002神经病理学医学知识培训39Increased D1 receptor availabiIncreases in D1 receptor availability in the DLP

24、FC are correlated with working memory deficitsAbi-Dargham et al, J Neurosci, 2002神经病理学医学知识培训40Increases in D1 receptor availReduction in dendritic spines in dopaminergic neurons in the dorsolateral prefrontal cortexLewis et al, 2003神经病理学医学知识培训41Reduction in dendritic spines Glutamate HypothesisDefic

25、iencies in glutamatergic neurotransmissionDysregulation of DA systems may be secondary to a deficit in the function of the glutamatergic NMDA receptor神经病理学医学知识培训42Glutamate HypothesisDeficienciGlutamate HypothesisNoncompetitve NMDA receptor antagonists (like PCP and ketamine) induce both positive an

26、d negative symptomsUnmedicated schizophrenic patients are more sensitive to the effects of NMDA receptor antagonistsAdjunctive treatment with NMDA agonists might provide a modest improvement in symptoms神经病理学医学知识培训43Glutamate HypothesisNoncompetiEvidence from human studiesAlterations in CSF glutamate

27、 levels, altered glutamate metabolism and altered NMDA receptor subunit gene expression (Keshavan, 1999)Direct evidence is still lacking and a coherent picture has not yet emergedLack of adequate radioligands to visualize the GLU system in the living brain is a major impediment神经病理学医学知识培训44Evidence

28、from human studiesAltGlutamate-Dopamine InteractionsLaruelle et al, 2003神经病理学医学知识培训45Glutamate-Dopamine InteractionChronic PCP treatment reduces dorsolateral prefrontal cortex dopamine and leads to negative symptomsHuman studiesAnimal studies神经病理学医学知识培训46Chronic PCP treatment reduces Jentsch and Rot

29、h, 1999神经病理学医学知识培训47Jentsch and Roth, 1999神经病理学医学知Chronic PCP leads to behavioral deficits consistent with dorsolateral prefrontal cortex dysfunctionJentsch et al, Science, 1997神经病理学医学知识培训48Chronic PCP leads to behavioraChronic PCP reduces cortical dopamineJentsch et al, Science, 1997神经病理学医学知识培训49Ch

30、ronic PCP reduces cortical dEffects are reversed with clozapine Jentsch et al, Science, 1997神经病理学医学知识培训50Effects are reversed with clozNMDA receptor antagonism enhances amphetamine-induced subcortical DA releaseKegelles et al 2000神经病理学医学知识培训51NMDA receptor antagonism enhanReduced prefrontal cortex a

31、ctivation in schizophrenicsMeyer et al., 2002神经病理学医学知识培训52Reduced prefrontal cortex actiReduced dlPFC activation was negatively correlated with striatal dopamine releaseMeyer et al., 2002神经病理学医学知识培训53Reduced dlPFC activation was nSubcortical Dopamine-Glutamate Interactions神经病理学医学知识培训54Subcortical Do

32、pamine-GlutamateGABA alterationsGlutamate or GABA?神经病理学医学知识培训55GABA alterationsGlutamate or GPut it all togetherNeurodevelopmental brain damage, leads to dysfunction in areas like the prefrontal cortex, which leads to increased DA in the mesolimbic areas神经病理学医学知识培训56Put it all togetherNeurodeveloWha

33、t about the temporal lobe damage?Hippocampus and amygdala control a gate that influences the effects of the prefrontal cortex on n. accumbens neuronal firingThis gate modulates reactions of the n. accumbens given the context神经病理学医学知识培训57What about the temporal lobe dHippocampus may modulate prefront

34、al activation of n. accumbensGrace, 2000神经病理学医学知识培训58Hippocampus may modulate prefrGrace, 2000神经病理学医学知识培训59Grace, 2000神经病理学医学知识培训59How does exaggerations of mesolimbic DA activity lead to positive symptoms? Could altered dopamine in the nucleus accumbens alter the salience attributed to internal and

35、 external stimuli?Kapur reading神经病理学医学知识培训60How does exaggerations of meso神经病理学医学知识培训61神经病理学医学知识培训61TreatmentsConventional neurolepticsChlorpromazineHaloperidolLoxapinePimozideThieoridazinethirothixene神经病理学医学知识培训62TreatmentsConventional neurolepure D2 blocker神经病理学医学知识培训63pure D2 blocker神经病理学医学知识培训63

36、Typical antipsychotics are D2 receptor antagonists神经病理学医学知识培训64Typical antipsychotics are D2 神经病理学医学知识培训65 神经病理学Blockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulateThis up-regulation may lead to tardive dyskinesia神经病理学医学知识培训66Blockade of receptors in the nConvention

37、al antipsychotics have other sites of actionMuscarinic cholinergic blockadeSide effects of constipation and blurred visionReduce the likelihood of extrapyramidal symptoms神经病理学医学知识培训67Conventional antipsychotics haProblems with conventional antipsychoticsBecause of side effects, many patients discont

38、inue treatments, relapse, go back on treatment repeatedlyNeuroleptic malignant syndrome神经病理学医学知识培训68Problems with conventional antAtypical antipsychotic drugsSerotonin-dopamine antagonistsClozapineRisperidoneOlanzapineQuetiapineZiprasidone神经病理学医学知识培训69Atypical antipsychotic drugsSe5HT-DA Interaction

39、sSubstantia nigraraphe nucleusbrakebrake神经病理学医学知识培训705HT-DA InteractionsSubstantia serotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor神经病理学医学知识培训71serotonin neurondopamine neuroserotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorser

40、otonin5HT2A receptor11-19Stahl S M, Essential Psychopharmacology (2000)神经病理学医学知识培训72serotonin neurondopamine neuroserotonin neurondopamine neuronSubstantia nigraRaphe5HT2A receptor11-20Stahl S M, Essential Psychopharmacology (2000)神经病理学医学知识培训73serotonin neurondopamine neuro神经病理学医学知识培训培训课件serotoninNi

41、grostriatal pathwayno dopamine release11-22Stahl S M, Essential Psychopharmacology (2000)神经病理学医学知识培训75serotoninNigrostriatal pathwaySDAD2 receptor11-23Stahl S M, Essential Psychopharmacology (2000)Nigrostriatal pathway神经病理学医学知识培训76SDAD2 receptor11-23Stahl S M, 5HT2A receptorNigrostriatal pathway11-2

42、4Stahl S M, Essential Psychopharmacology (2000)神经病理学医学知识培训775HT2A receptorNigrostriatal paconventional antipsychoticcaudate nucleus神经病理学医学知识培训78conventional antipsychoticcaudserotonin-dopamine antagonistcaudate nucleus神经病理学医学知识培训79serotonin-dopamine antagonistcmesocortical pathwayprimary dopamine deficiency