Presynaptic Dopaminergic Dysfunction in Schiophrenia

1. PresynapticDopaminergic Dysfunction in Schiophrenia By Rahul Kapoor

2. 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

3. 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

4. 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)

5. 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 Parkinson’s disease and other movement disorders

6. 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

7. 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

8. 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)

9. 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.

10. Thank you for your attention