Presynaptic Dopaminergic Dysfunction in Schiophrenia

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Presynaptic Dopaminergic Dysfunction in
Schiophrenia

• By
• Rahul Kapoor

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• Based on a study performed by Stephen McGowan
  MRCPsych
• Andrew D. LawrenceMRCPsych
• Tim Sales MRCPsych
• Digby Quested MRCPsych
• Paul Grasby MRCPsych
• Performed at Hammersmith Hospital , Imperial
  college , London

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Introduction

• Objective Assessment of presynaptic
  dopaminergic fuction in a group of patients
  suffering from Schizophrenia by means of
  fluorodopa uptake and PET scanning
• Patients 16 male medicated outpatients with DSM
  IV daignosis of schizophrenia and 12 age matched
  patients free of psychiatric and neurologic
  disorders
• Main outcome measure fluorodaopa (FD) uptake
  constant measures and region of interest analysis
• Results and conclusion in the end

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Introduction (contd)

• Dopamine (DA) overactivity hypothesis still
  remains to be fully confirmed or refuted.
• Multiple causes for DA synthesis ? increases
  synthesis, release, receptor number, affinity
  etc.
• Most imaging studies have confirmed the DA
  receptor changes in schizophrenia
• Prefrontal D1 receptors reported to be increased,
  decreased or unchanged in the illness
• Increase in striatal D2 receptors (smaller
  magnitude than in the reported post mortem
  changes)
• Evidence of increased DA release has been shown
  in the recent studies (laurelle et al and Brier
  et al)

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Fluorodopa

• Radioactive analogue of L-dopa (precursor for
  dopamine)
• FD taken up by presynaptic monoaminergic
  neurons where it is metabolized to fluorodopamine
  (enzyme aromatic acid decarboxylase/AADC)
• Flourodopamine is trapped and stored within the
  vesicles in the nerve terminals
• FD uptake can be measured as influx constant (Ki)
  can be used to measure AADC activity and
  vesicular storage capacity
• High values of fluorodopa observed in areas of
  dense DA nerve terminal innervation (e.g.
  striatum)
• Fluorodopa extinsively used in the assessment
  of straiatal dopaminergic neurons specially in
  Parkinsons disease and other movement disorders

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Patients

• 12 right handed healthy individuals as volunteers
  (mean age 38.3 years)
• 20 patients meeting DSM IV criteria for
  schizophrenia (mran age 39.9 years)
• EXCLUSION ? 4 patients were excluded
• 1 patient had
  bilateral perisylvian atrophy on MRI
• in 1 patient,
  there were technical problems with PET
• 2 patients had
  excessive head movement during PET

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Data analysis

• 2 methods used ? i) statistical parametric
  mapping (SPM) ii) Region of interest approach
  (ROI)
• SPM template of FD uptake created using
  combined images of FD and T1 MR images.
• ROI- data analyzed by means of standardized ROIs
  on representative single participant image
  available in T1 MRI

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Results

• SPM analysis increases in FD uptake (Ki) in
  the striatum of patients compared with controls
  increased FD predominantly in ventral striatum
• Using ROIs Ki values in the whole striatum and
  the ventral striatum were increased in patients
  compared to controls (supporting the SPM
  analysis)
• FD uptake in ROI not significantly correlated
  with the presence of positive or negative
  symptoms (scores)
• Structural MRI imaging no volume differences in
  the striatal volumes between the controls and the
  patients (whether assessed as a whole or ventral
  or dorsal separately)

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Conclusion

• The increased Ki (uptake of FD) by the
  schizophrenic patients confirms that presynaptic
  striatal dopamine dysfunction is present,
  predominantly being in the ventral striatum.

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Thank you for your attention