1. Other markers of dopamine function in CSF and serum of RLS Karin Stiasny-Kolster Department of Neurology Philipps University Marburg Germany

2. Dopaminergic and serotonergic metabolism Diseases with impaired dopaminergic metabolism: PD: HVA , 3-OMD  L-DOPA treated PD: HVA , 3-OMD  Dopa-responsive dystonia: HVA , 5-HIAA , BH4 , neopterin  MAO/COMT TH 5-Hydroxytryptophan (5-HTP) Serotonin 5-HIAA Tyrosine L-Dopa Dopamine Nor- epinephrine 3-ortho- methyldopa (3-OMD) Phenylalanine Homovanillic acid (HVA) Tryptophan GTP Neopterins Tetrahydrobiopterin cofactor biosynthesis BH 4 AADC BH 2

4. Earley et al. Mov Disord 2001 Measurements at 10 a.m. -PLM > 15/h, off medication (2 weeks), dopaminergic response -16 RLS patients and 14 controls (64.2 vs. 51.4 years) -HVA, 5-HIAA, BH4, Neopterin CSF studies in RLS (I)

5. Earley et al. Mov Disord 2001 Measurements at 10 a.m. -PLM > 15/h, off medication (2 weeks), dopaminergic response -16 RLS patients and 14 controls (64.2 vs. 51.4 years) -HVA, 5-HIAA, BH4, Neopterin CSF studies in RLS (I) -No significant differences in: HVA, 5-HIAA, BH4 Neopterin increased (p=0.01)

6. Explanation for normal dopaminergic metabolites -Dopaminergic abnormalities are somewhere else, e.g. lie in dopamine receptor dysfunction and is not reflected in HVA changes -Absence of changes in HVA during the morning when patients are asymptomatic does not exclude changes in the evening when patients are symptomatic Earley et al. Mov Disord 2001

7. Measurements between 6 p.m. and 8 p.m. 22 patients with idiopathic moderate to severe RLS -Patients were untreated -IRLS score 26.5 (18– 35) points -15 female; age 58.6 ± 13 (26 – 81) years -RLS since 14.1 ± 13.1 (1- 40) years 11 controls -7 female, 57.9 ± 14.1 (36 – 80) years Stiasny-Kolster et al. Mov Disord 2004 CSF studies in RLS (II)

8. Dopaminergic and serotonergic metabolism in RLS Normal CSF metabolites (evening): - HVA - 3-OMD - L-DOPA - 5-HTP - 5-HIAA Normal blood metabolites (evening): - Serotonin (blood) - AADC activity (plasma) Stiasny-Kolster et al. Mov Disord 2004 5-Hydroxytryptophan (5-HTP) Serotonin 5-HIAA Tyrosine L-Dopa Dopamine Nor- epinephrine 3-ortho- methyldopa (3-OMD) Phenylalanine Homovanillic acid (HVA) Tryptophan GTP Neopterins Tetrahydrobiopterin cofactor biosynthesis BH 4 AADC BH 2 Dopaminergic metabolites Serotonergic metabolites MAO/COMT TH

9. Stiasny-Kolster et al. Mov Disord 2004

11. Measurements at 10 p.m. -PLM > 20/h, off medication, dopaminergic response -30 RLS patients and 22 controls (balanced for gender and age) Earley et al. Sleep Medicine 2006 CSF studies in RLS (III)

12. Measurements at 10 p.m. -PLM > 20/h, off medication, dopaminergic response -30 RLS patients and 22 controls (balanced for gender and age) -No significant differences in: HVA, 5-HIAA, neopterin, BH4, HVA:5-HIAA No differences between EO- and LO-RLS -Higher concentrations for 3-OMD compared to controls (p= 0.006) Earley et al. Sleep Medicine 2006 CSF studies in RLS (III)

13. Measurements at 10 p.m. -PLM > 20/h, off medication, dopaminergic response -30 RLS patients and 22 controls (balanced for gender and age) -No significant differences in: HVA, 5-HIAA, neopterin, BH4, HVA:5-HIAA No differences between EO- and LO-RLS -Higher concentrations for 3-OMD compared to controls (p= 0.006) -Higher concentrrations for 3-OMD compared to controls (p = 0.0001) in the a.m. measurements but not reported in Earley et al. Mov Disord 2001 Earley et al. Sleep Medicine 2006 CSF studies in RLS (III)

14. Comparison of 10 a.m. (2001) and 10 p.m. (2006) variables (HVA, 5-HIAA, BH4, neopterin, 3-OMD) Small circadian changes in the controls Larger circadian differences in RLS patients in the opposite direction Various subanalyses - high vs. lpw 3-OMD group, cut-off 10 nmol/l - correlation with ferritin Earley et al. Sleep Medicine 2006 CSF studies in RLS (III)

15. Explanation for increased 3-OMD: -increased TH, decreased AADC or increased COMT Earley et al. Sleep Medicine 2006

16. 3OMD Increased in RLS Two Separate Studies 32 RLS, 22 controls 0 10 20 30 40 50 60 70 80.811.21.41.61.822.2 DX RLS Cntrl 30MD (nmol/l) 10:00 PM CSF samples 17 RLS, 14 controls 0 10 20 30 40 50 60 70 80.811.21.41.61.822.2 DX RLS Cntrl 30MD (nmol/l) 10:00 AM CSF samples + (Allen et al, Sleep Med. 2008)

17. Stiasny-Kolster et al. Mov Disord 2004