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Understanding Huntington's Disease: Causes, Symptoms, and Treatment Options

This overview provides information on Huntington's Disease, including the degeneration of the caudate nucleus and putamen, uncontrollable movements, progressive cognitive and emotional changes, and the lack of a cure. It also discusses Alzheimer's Disease, Multiple Sclerosis, and Schizophrenia, along with their respective causes and treatment options.

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Understanding Huntington's Disease: Causes, Symptoms, and Treatment Options

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  1. Overview • Huntington’s Disease • Degeneration of caudate nucleus and putamen • Uncontrollable movements, jerky limb movements • Progressive, cognitive and emotional changes • Gene that codes the huntingtinprotein (htt) (chromosome 4) • No cure • Death (10-15 years) • Alzheimer’s Disease • Amyloid Plaque • Neurofibrillary Tangle • APP gene – chromosome 21 • Protective value of intellectual activity • Cholingericagonists (acetylcholinesteraseinhibitors) • NMDA receptor antagonist (memantine) • Multiple Sclerosis • Autoimmune disorder, attacks myelin • Interferon β • Glaterimer acetate (copaxone)

  2. Schizophrenia and the Affective Disorders Chapter 16

  3. Schizophrenia • Description • Schizophrenia is a serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors.

  4. Schizophrenia • “Splitting of psychic functions” • Refers to the breakdown of integration of emotion, thought, and action • Affects 1% of the population • A diverse disorder – multiple types exist with varied profiles Scientific American (2008)

  5. See Table 16.1 Schizophrenia Symptoms • Negative and Cognitive symptoms are closely related, may involve dysfunction in similar brain areas • Negative and Cognitive symptoms are not specific to schizophrenia

  6. Diagnosis • The recurrence of only 2 symptoms for one month • 1 symptom is necessary if the person exhibits delusions that are particularly bizarre or hallucinations that include 1 voice providing a running commentary or 2 voices conversing

  7. Schizophrenia • Biological Basis • Classification - according to onset • acute • chronic – gradual onset, progressive deterioration • ~ 1/3 of those diagnosed will show progressive deterioration & become chronic schizophrenics

  8. Behavioural Genetics Heritability: statistic which gives an estimate of the total variance in a trait that is attributable to genetic variation in a group • Maximum value of the estimate is 1.0 (which is equivalent to 100%) • Important: Because a trait is heritable, does NOT mean it cannot be altered by the environment Example: • Height is a heritable trait • Table manners is not

  9. Schizophrenia: Heritability • Heritability • Schizophrenia is a heritable trait • Not likely to be a single gene (dominant or recessive) • Several genes or susceptibility hypothesis Schizophrenia.com

  10. Schizophrenia: Heritability Fig. 16.1 • Susceptibility hypothesis (genetic propensity, not necessarily expressed) • Risk for Sz is 17% in children with a Sz parent but ALSO in children of unaffected MZ parents – risk is being passed on in genes. Lack of expression of Sz in normal MZ co-twins tells us that environment is important to Sz.

  11. Schizophrenia: Heritability • Also linked: paternal age • Children of older fathers • Copying error in DNA replication (spermocytes); high amount of replication (divides everyone 16 days after puberty) • Genes identified: • No single gene • DISC1: Disrupted in schizophrenia • Neuronal migration • Neurogenesis • Function of PSD in excitatory neurons, function of mitochondria • EPIGENETICS: • Mechanisms that control the expression of genes (environmental control e.g. toxins)

  12. http://www.youtube.com/watch?v=kp1bZEUgqVI

  13. Antipsychotic Drugs • Much of our understanding of schizophrenia is a consequence of the drugs that are able to treat it • Chlorpromazine • Henri Laborit: drug reduced anxiety and shock • Developed to treat neuroses and psychoses (not always effective) • Calms many agitated schizophrenics • Block DA receptors

  14. Dopamine Theory of Schizophrenia • 1960 – link between dopamine and Parkinson’s disease established • Antipsychotic drug side effects suggests role for dopamine – drugs work by decreasing dopamine levels; positive symptoms of schizophrenia are associated with dopamine overactivity • Reserpine depletes brain of dopamine and other monoamines by making vesicles leaky • Amphetamine, cocaine and L-dopa are dopamine agonists and produce psychosis

  15. PROJECTIONS DOPAMINE & POSITIVE SYMPTOMS POSITIVE SYMPTOMS Mesolimbic Dopamine VTA-amygdala Drugs that agonize DA release (cocaine, etc.) can also cause positive symptoms of schizophrenia Major CNS dopaminergic systems include: Nigrostriatal System (role in movement) Mesolimbic System (role in reinforcement/reward) Mesocortical System (role in short-term memory, planning, and problem solving)

  16. Dopamine Theory of Schizophrenia • Laruelle et al (1996) • Intravenous injection of amphetamine in control and patients with schizophrenia • Amphetamine caused more release of DA in striatum of schizophrenics • See Figure 16.2 DA Release

  17. Dopamine Theory of Schizophrenia • Greater amount of DA release was also correlated with positive symptoms • See Figure 16.2

  18. Dopamine Receptors

  19. Potency of Binding to DA Rs Results Snyder & colleagues demonstrated: • Potency of a particular drug in binding to DA Rs in vitro was positively correlated with its clinical effectiveness

  20. All DA receptors are metabotropic • This division is based on whether or not receptor activation stimulates formation of the 2nd messenger, cyclic AMP. • Activation of D1-like Rs stimulates cAMP • Activation of D2-like Rs inhibits cAMP

  21. Anti-Schizophrenic Drugs 2 Classes Butyrophenones Phenothiazines Chlorpromazine Haloperidol (Haldol) Spiroperidol Bind to D2 Receptors only Binds to D1 & D2 Receptors

  22. Revised DA Theory of Schizophrenia • Schizophrenia is caused by hyperactivity at D2 Rs, rather than DA Rs in general • Based on 2 findings: • Selective binding of butyrophenones to D2 Rs • Butyrophenones greater potency in the clinic

  23. Brain Imaging • Measure DA Rs in brains of recently diagnosed schizophrenics not previously exposed to neuroleptics • Radioactive ligand of the D2 R was injected iv & its concentration measured in the corpus striatum • Two Results • Brains of schizophrenics have an abnormally high # of D2 Rs • Higher level of occupancy of those Rs by DA • Suggest both pre & postsynaptic abnormalities • Too much release & too many receptors (modest)

  24. Side-Effects of Long-Term Anti-Schizophrenic Drugs • Similarly to long-term use of Parkinson’s drug treatments, there can be side-effects with long-term use of anti-psychotic drugs. • TardiveDyskinesia • Tardus – slow • Dyskinesia- faulty movement • Late-developing • TD: unable to stop moving • Supersensitivity: possible that DA receptors become hypersensitive if they are blocked for long periods of time • D2 receptors in caudate and putamen

  25. Problems with the D2 Theory • Schizophrenia associated with brain damage • Little damage to dopamine circuitry • Damage not explained by dopamine theory • It takes several weeks of neuroleptic therapy to alleviate schizophrenic symptoms • Conventional neuroleptics (D2 blockers) mainly effective for positive symptoms • Negative and cognitive symptoms might be caused by brain damage • May be best to think of schizophrenia as multiple disorders with multiple causes

  26. Schizophrenia as a Neurological Disorder • Predisposing factors (genetic, environmental, or both) give rise to: • Abnormalities in both DA transmission and PFC • Abnormalities in DA transmission that cause abnormalities in PFC • Abnormalities in PFC cause abnormalities in DA transmission

  27. Schizophrenia: Brain Abnormalities • Evidence of brain damage • Negative and cognitive symptoms • Loss of brain tissue • Lateral ventricles more than twice as large in schizophrenic patients than control subjects

  28. Possible Causes of Brain Abnormalities • Epidemiological Studies • Season of birth • Viral epidemics • Population density • Prenatal malnutrition • Maternal stress

  29. Possible Causes of Brain Abnormalities • Season of birth (seasonality) • Late winter and early spring (northern hemisphere) • Reverse in southern hemisphere • Possible link: viruses • Effect seen in cities, not in countryside See Figure 16.5

  30. Possible Causes of Brain Abnormalities • Vitamin D deficiency • Dealberto (2007) • Northern Europe: 3-fold increase in schizophrenia in immigrants (equatorial regions) • Thiamine deficiency • Two-fold increase in incidence of schizophrenia in offspring of women pregnant during severe food shortage in WWII (Germany and Netherlands) • Maternal/paternal substance abuse – smoking • Complications during childbirth • Mother: Diabetes of mother, bleeding, preclampsia (high blood pressure, protein in urine) • Other: oxygen or blood flow deprivation

  31. Evidence for Abnormal Brain Development • Home movies from families with schizophrenic child • Compared to normal siblings, schizophrenic child displayed more negative affect and more abnormal movements • 265 Danish children (11-13 years) were videotaped eating lunch • Children who later developed schizophrenia displayed less sociability and deficient psychomotor functioning • Hypothesis – although schizophrenia is not seen in childhood, the early brain development of children who become schizophrenic is not normal

  32. Age of Onset • See Figure 16.8 • Symptoms rarely begin before late adolescence or early adulthood • Progression: • Negative symptoms  cognitive symptoms  positive symptoms

  33. Abnormal Brain Development • Brain damage is sudden (during young adulthood) • Thompson et al. (2001) • Adolescence with early onset schizophrenia • MRI • Normals: • Loss of 0.5-1.0% • Schizophrenic patients: • 2-3% • See Figure 16.9 • Loss: • Parietal to temporal lobe • Somatosensory and motor • Prefrontal cortex

  34. Abnormal Brain Development • Hypofrontality and Negative and Cognitive Symptoms • Decreased activity of the prefrontal cortex (dlPFC); believed to be responsible for the negative symptoms of schizophrenia. • Above fig: Task required increased concentration and attention • Possibly caused by decreased DA activity in prefrontal regions • See Figure 16.10

  35. NMDA , Dopamine and Hypofrontality • PCP and ketamine can cause positive, negative and cognitive-like symptoms • NMDA receptor antagonists; decrease DA and metabolic activity in frontal cortex

  36. Role of D2 Receptors in Development of Schizophrenia • Abnormalities in the striatal DA system may be the cause of schizophrenia • Virus inserted into striatum that increased D2 recpetors • Caused the development of behavioral deficits characteristic of schizophrenia • Abnormal activity of dlPFC

  37. Treatment with Partial DA Receptor Agonists • Atypical drugs are able to reduce ALL symptoms • Increase DA activity in PFC • Reduce DA activity in the NA • Aripoprazole: Atypical • Partial DA agonist • High affinity for receptor but less than ligand • Can act like an antagonist • Nucleus accumbens • Can act like an agonist • Prefrontal cortex

  38. http://www.youtube.com/watch?v=USxHsSWCaJA

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