神经病理学ppt课件

Schizophrenia lWhat causes schizophrenia? lNeuropathology Structural and functional changes Neurochemical alterations lTreatments Schizophrenia lEmil Kraepelin “Dementia Praecox (1896) lBlueler “Schizophrenia” lOnset: adolescence or young adulthood lDSM-IV review: Positive symptoms (delusions, hallucinations, disorganized speech or behavior) Negative symptoms (catatonia, affective flattening, withdrawal, or avolition) Social-occupational disturbance 6+ months Associated Features lCognitive Disturbances Memory Sensory filtering Attention Emotion recognition Eye-tracking lInterpersonal Dysfunction Subtypes lCatatonic lParanoid lDisorganized lUnlikely to be a related to a single physiopathology Neuropathology lNeurodevelopmental hypothesis lNeurodegenerative hypothesis lDopamine hypothessis lGlutamatergic hypothesis *These are not exclusive What causes schizophrenia? lHeritable (Shastry, 2002) lEnvironmental factors Epidemiological studies lBirth complications lMaternal stress lSeasonality effect lViral epidemics lLatitude effect lRh incompatibility Neuropathology Structural alterations lBehavioral symptoms indicative of brain damage (unusual rates of blinking, poor control of eye movements, unusual facial expressions) lEnlarged ventricles (Weinberger Andreason) Ventricular enlargement in monozygotic twin with schizophrenia Barondes, 1993 Hippocampal volume loss and enlarged ventricles Van Heron et al., 2005 Neuropathology Structural alterations (cont) lAlterations in numerous areas, including frontal lobes, medial temporal lobes, lateral temporal lobes, parietal lobe, basal ganglia, corpus callosum, thalamus and even the cerebellum lWhite matter deficits lEvidence of disorganized neurons and failures of migration Altered density and disorganization of neurons found in the white matter below layer VI in the cortex Disorganized pyramidal cells in the hippocampus Altered development of hippocampal pyramidal neurons Neurodevelopmental Hypothesis lHome movies from families with schizophrenic child displayed abnormal behavior (Walker et al, 1994; 1996) lChildren who later become schizophrenic exhibit poor social adjustment and school performance lDevelopmental delays lPremorbid psychopathology (anxiety, depression, conduct disorders, ADHD) (Kim-Cohen et al, 2003) lPhysical abnormalities (Schiffman, et al. 2002) lRates of concordance are higher in monochorionic twins compared dichorionic twins (60% vs. 11%) (Davis, et al, 1995) But why are symptoms not observed until adolescence? lSomething must trigger the degenerative process at the period of adolescence lLoss and disorganization of neurons become unmasked with pruning and synaptic reorganization Rapid loss of brain volume during adolescence in schizophrenics Thompson et al, 2001 Thompson et al, 2001 Twin studyloss of dlPFC and temporal cortical tissue Cannon et al 2002 Hypofrontality lReduced activation of the dorsolateral prefrontal cortex contributes to negative symptoms and cognitive deficits Functional imaging studies report reduced activation Evidence of executive functioning deficits Reduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug nave schizophrenics MacDonald et al., 2005 poorly innervated toxic or genetic insult dysfunction death poor neuronal migration inadequate synapse selection Could altered development be related to glutamatergic dysfunction? -Underactivation of systems alters migration, synaptic organization and cell survival -Overactivation of systems can lead to altered synaptic connectivity and cell death SPECTRUM OF EXCITATION BY GLUTAMATE Excess excitation - Mania - Panic Excitotoxicity - Damage to neurons Excitotoxicity - Slow neuro- degeneration Excitotoxicity - Catastrophic neurodegeneration Normal excitation Neurodegenerative Hypothesis Could the psychotic symptoms themselves be producing additional excitotoxicity? Neurochemical Alterations Dopamine Hypothesis lOriginal Formulation Overactivity of subcortical D2 receptors contributes to positive symptoms lClassical antipsychotics were DA D2 antagonists lDA agonists induce psychotogenic effects hypothalamus d c Nucleus accumbens Tegmentum b Substantia nigra Basal Ganglia a DOPAMINE PATHWAYS mesolimbic pathway mesolimbic overactivity = positive symptoms of psychosis pure D2 blocker 11-2 Stahl S M, Essential Psychopharmacology (2000) Re-formulation of dopamine hypothesis lImaging studies indicate loss of tissue in the frontal lobes as well as reduced activation lDeficit in activation of D1 receptors in the prefrontal cortex contributes to negative symptoms and cognitive deficits meso-cortical pathway Amphetamine-induced dopamine release is enhanced in schizophrenics Laruelle et al 2003 Amphetamine-induced dopamine release produces positive symptoms Laruelle et al, 1996 Increased dopamine release in medication-nave schizophrenic patients Hietala, et al. 1995 D2 receptors? lMixed data lSome find no differences lOthers find moderate increases (Kestler et al., 2001) lWhat about D3 and D4 receptors? What about the mesocortical DA system? lOne postmortem study indicated a decrease in DA innervation of the dorsolateral prefrontal cortex (Akil, et al 1999) lTwo PET studies had mixed findings, but the ligands used for D1 receptors were not selective (Okubo et al 1997; Karlsson et al 2002) lMore recently, there is evidence of an upregulation of D1 receptors in the DLPFC Increased D1 receptor availability in schizophrenics suggests underactivation Abi-Dargham et al, J Neurosci, 2002 Increases in D1 receptor availability in the DLPFC are correlated with working memory deficits Abi-Dargham et al, J Neurosci, 2002 Reduction in dendritic spines in dopaminergic neurons in the dorsolateral prefrontal cortex Lewis et al, 2003 Glutamate Hypothesis lDeficiencies in glutamatergic neurotransmission lDysregulation of DA systems may be secondary to a deficit in the function of the glutamatergic NMDA receptor Glutamate Hypothesis lNoncompetitve NMDA receptor antagonists (like PCP and ketamine) induce both positive and negative symptoms lUnmedicated schizophrenic patients are more sensitive to the effects of NMDA receptor antagonists lAdjunctive treatment with NMDA agonists might provide a modest improvement in symptoms Evidence from human studies lAlterations in CSF glutamate levels, altered glutamate metabolism and altered NMDA receptor subunit gene expression (Keshavan, 1999) lDirect evidence is still lacking and a coherent picture has not yet emerged lLack of adequate radioligands to visualize the GLU system in the living brain is a major impediment Glutamate-Dopamine Interactions Laruelle et al, 2003 Chronic PCP treatment reduces dorsolateral prefrontal cortex dopamine and leads to negative symptoms lHuman studies lAnimal studies Jentsch and Roth, 1999 Chronic PCP leads to behavioral deficits consistent with dorsolateral prefrontal cortex dysfunction Jentsch et al, Science, 1997 Chronic PCP reduces cortical dopamine Jentsch et al, Science, 1997 Effects are reversed with clozapine Jentsch et al, Science, 1997 NMDA receptor antagonism enhances amphetamine-induced subcortical DA release Kegelles et al 2000 Reduced prefrontal cortex activation in schizophrenics Meyer et al., 2002 Reduced dlPFC activation was negatively correlated with striatal dopamine release Meyer et al., 2002 Subcortical Dopamine-Glutamate Interactions GABA alterations Glutamate or GABA? Put it all together lNeurodevelopmental brain damage, leads to dysfunction in areas like the prefrontal cortex, which leads to increased DA in the mesolimbic areas What about the temporal lobe damage? lHippocampus and amygdala control a gate that influences the effects of the prefrontal cortex on n. accumbens neuronal firing lThis gate modulates reactions of the n. accumbens given the context Hippocampus may modulate prefrontal activation of n. accumbens Grace, 2000 Grace, 2000 How does exaggerations of mesolimbic DA activity lead to positive symptoms? Could altered dopamine in the nucleus accumbens alter the salience attributed to internal and external stimuli? Kapur reading Treatments lConventional neuroleptics Chlorpromazine Haloperidol Loxapine Pimozide Thieoridazine thirothixene pure D2 blocker Typical antipsychotics are D2 receptor antagonists Blockade of receptors in the nigrostriatal dopamine pathway causes them to up- regulate This up-regulation may lead to tardive dyskinesia Conventional antipsychotics have other sites of action lMuscarinic cholinergic blockade Side effects of constipation and blurred vision Reduce the likelihood of extrapyramidal symptoms Problems with conventional antipsychotics lBecause of side effects, many patients discontinue treatments, relapse, go back on treatment repeatedly lNeuroleptic malignant syndrome Atypical antipsychotic drugs lSerotonin-dopamine antagonists Clozapine Risperidone Olanzapine Quetiapine Ziprasidone 5HT-DA Interactions Substantia nigra raphe nucleus brake brake serotonin neuron dopamine neuron Substantia nigra Raphe dopamine 5HT2A receptor serotonin 5HT2A receptor serotonin neuron dopamine neuron Substantia nigra Raphe dopamine 5HT2A receptor serotonin 5HT2A receptor 11-19 Stahl S M, Essential Psychopharmacology (2000) serotonin neuron dopamine neuron Substantia nigra Raphe 5HT2A receptor 11-20 Stahl S M, Essential Psychopharmacology (2000) DA neuron 5HT neuron postsynaptic neuron dopamine D2 receptor 5HT2A receptor Nigrostriatal pathway serotonin Nigrostriatal pathway no dopamine release 11-22 Stahl S M, Essential Psychopharmacology (2000) SDA D2 receptor 11-23 Stahl S M, Essential Psychopharmacology (2000) Nigrostriatal pathway 5HT2A receptor Nigrostriatal pathway 11-24 Stahl S M, Essential Psychopharmacology (2000) conventional antipsychotic caudate nucleus serotonin-dopamine