神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)培訓(xùn)課件

1、神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)2神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)2SchizophreniaEmil Kraepelin “Dementia Praecox (1896)Blueler “Schizophrenia”O(jiān)nset: 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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)3SchizophreniaEmil Kraepelin “DAssociated FeaturesCognitive DisturbancesMemorySensory filteringAttentionEmotion recognitionEye-trackingInterpersonal Dysfunction神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)4Associated FeaturesCognitive SubtypesCatatonicPara

3、noidDisorganizedUnlikely to be a related to a single physiopathology神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)5SubtypesCatatonic神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)5NeuropathologyNeurodevelopmental hypothesisNeurodegenerative hypothesisDopamine hypothessisGlutamatergic hypothesis *These are not exclusive神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)6NeuropathologyNeurodevelopmentWhat caus

4、es schizophrenia?Heritable (Shastry, 2002)Environmental factorsEpidemiological studiesBirth complicationsMaternal stressSeasonality effectViral epidemicsLatitude effectRh incompatibility神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)8NeuropathologyStructural alteVentricular enlargement in monozygotic twin with schizophreniaBarondes, 1993神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)9Ventricular enlar

6、gement in monHippocampal volume loss and enlarged ventriclesVan Heron et al., 2005神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)11Neuropatho

8、logyStructural alteAltered development of hippocampal pyramidal neurons神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)12Altered development of hippoca神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)13神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)15But why are symptoms not obserRapid loss of brain volume during adolescence in schizophrenicsThompson et al, 2001神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)16Rapid loss of brain volume durThompson et al, 2001神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)17Thompson et al, 2001神經(jīng)病理學(xué)醫(yī)學(xué)知識培神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)18神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)18Twin studyloss of dlPFC and tempo

12、ral cortical tissueCannon et al 2002神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)

13、病理學(xué)醫(yī)學(xué)知識培訓(xùn)20HypofrontalityReduced activatiReduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug nave schizophrenicsMacDonald et al., 2005神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)21Reduced activation of the dorspoorly innervatedtoxic or genetic insultdysfunctionde

14、athpoor neuronal migrationinadequate synapse selection神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)23Could altered development be SPECTRUM OF EXCITATION BY GLUTAMATEExcess excitation- Mania- PanicExcitotoxicity- Damage to neuronsExcitotoxicity- Slow neuro- degenerationExcitotoxicity- Catastrophic neurodegenerationNormal excitationNeurodegenerative Hypothe

16、sis神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)24SPECTRUM OF EXCITATION BY GLUTCould the psychotic symptoms themselves be producing additional excitotoxicity?神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)25Could the psychotic symptoms tNeurochemical Alterations神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)26Neurochemical Alterations神經(jīng)病理學(xué)Dopamine HypothesisOriginal FormulationOveractivity of subcortic

17、al D2 receptors contributes to positive symptomsClassical antipsychotics were DA D2 antagonistsDA agonists induce psychotogenic effects神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)27Dopamine HypothesisOriginal FohypothalamusdcNucleus accumbensTegmentumbSubstantia nigraBasal GangliaaDOPAMINE PATHWAYS神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)28hypothalamusdcNucleus

18、 accumbenmesolimbic pathway神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)29mesolimbic pathway神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)2mesolimbic overactivity = positive symptoms of psychosis神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)30mesolimbic overactivity = posipure D2 blocker11-2Stahl S M, Essential Psychopharmacology (2000)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)32Re-formulation of dopamine hypmeso-cortical pathway神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)33m

20、eso-cortical pathway神經(jīng)病理學(xué)醫(yī)學(xué)知識Amphetamine-induced dopamine release is enhanced in schizophrenicsLaruelle et al 2003神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)34Amphetamine-induced dopamine rAmphetamine-induced dopamine release produces positive symptomsLaruelle et al, 1996神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)35Amphetamine-induced dopamine rIncreased dopamin

21、e release in medication-nave schizophrenic patientsHietala, et al. 1995神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)36Increased dopamine release in D2 receptors?Mixed dataSome find no differencesOthers find moderate increases (Kestler et al., 2001)What about D3 and D4 receptors?神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)37D2 receptors?Mixed data神經(jīng)病理學(xué)醫(yī)學(xué)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)38What about the mesocortical DAIncreased D1 receptor availability in schizophrenics suggests underactivationAbi-Dargham et al, J Neurosci, 2002神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)40Increases in D1 receptor availReduction in dendritic spines in dopaminergic neurons in the dorsolateral prefrontal cortexLewis et al, 2003神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)44Evidence

28、from human studiesAltGlutamate-Dopamine InteractionsLaruelle et al, 2003神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)45Glutamate-Dopamine InteractionChronic PCP treatment reduces dorsolateral prefrontal cortex dopamine and leads to negative symptomsHuman studiesAnimal studies神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)46Chronic PCP treatment reduces Jentsch and Rot

29、h, 1999神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)47Jentsch and Roth, 1999神經(jīng)病理學(xué)醫(yī)學(xué)知Chronic PCP leads to behavioral deficits consistent with dorsolateral prefrontal cortex dysfunctionJentsch et al, Science, 1997神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)48Chronic PCP leads to behavioraChronic PCP reduces cortical dopamineJentsch et al, Science, 1997神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)49Ch

30、ronic PCP reduces cortical dEffects are reversed with clozapine Jentsch et al, Science, 1997神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)50Effects are reversed with clozNMDA receptor antagonism enhances amphetamine-induced subcortical DA releaseKegelles et al 2000神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)51NMDA receptor antagonism enhanReduced prefrontal cortex a

31、ctivation in schizophrenicsMeyer et al., 2002神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)52Reduced prefrontal cortex actiReduced dlPFC activation was negatively correlated with striatal dopamine releaseMeyer et al., 2002神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)53Reduced dlPFC activation was nSubcortical Dopamine-Glutamate Interactions神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)54Subcortical Do

32、pamine-GlutamateGABA alterationsGlutamate or GABA?神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)57What about the temporal lobe dHippocampus may modulate prefront

34、al activation of n. accumbensGrace, 2000神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)58Hippocampus may modulate prefrGrace, 2000神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)59Grace, 2000神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)60How does exaggerations of meso神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)61神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)61TreatmentsConventional neurolepticsChlorpromazineHaloperidolLoxapinePimozideThieoridazinethirothixene神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)62TreatmentsConventional neurolepure D2 blocker神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)63pure D2 blocker神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)63

36、Typical antipsychotics are D2 receptor antagonists神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)64Typical antipsychotics are D2 神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)65 神經(jīng)病理學(xué)Blockade of receptors in the nigrostriatal dopamine pathway causes them to up-regulateThis up-regulation may lead to tardive dyskinesia神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)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神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)67Conventional antipsychotics haProblems with conventional antipsychoticsBecause of side effects, many patients discont

38、inue treatments, relapse, go back on treatment repeatedlyNeuroleptic malignant syndrome神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)68Problems with conventional antAtypical antipsychotic drugsSerotonin-dopamine antagonistsClozapineRisperidoneOlanzapineQuetiapineZiprasidone神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)69Atypical antipsychotic drugsSe5HT-DA Interaction

39、sSubstantia nigraraphe nucleusbrakebrake神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)705HT-DA InteractionsSubstantia serotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorserotonin5HT2A receptor神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)71serotonin neurondopamine neuroserotonin neurondopamine neuronSubstantia nigraRaphedopamine5HT2A receptorser

40、otonin5HT2A receptor11-19Stahl S M, Essential Psychopharmacology (2000)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)72serotonin neurondopamine neuroserotonin neurondopamine neuronSubstantia nigraRaphe5HT2A receptor11-20Stahl S M, Essential Psychopharmacology (2000)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)73serotonin neurondopamine neuro神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)培訓(xùn)課件serotoninNi

41、grostriatal pathwayno dopamine release11-22Stahl S M, Essential Psychopharmacology (2000)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)75serotoninNigrostriatal pathwaySDAD2 receptor11-23Stahl S M, Essential Psychopharmacology (2000)Nigrostriatal pathway神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)76SDAD2 receptor11-23Stahl S M, 5HT2A receptorNigrostriatal pathway11-2

42、4Stahl S M, Essential Psychopharmacology (2000)神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)775HT2A receptorNigrostriatal paconventional antipsychoticcaudate nucleus神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)78conventional antipsychoticcaudserotonin-dopamine antagonistcaudate nucleus神經(jīng)病理學(xué)醫(yī)學(xué)知識培訓(xùn)79serotonin-dopamine antagonistcmesocortical pathwayprimary dopamine deficiency