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A Window upon the Brain Analysis of CSF Neurotransmitters Cofactors and Vitamins

A Window upon the Brain Analysis of CSF Neurotransmitters Cofactors and Vitamins. John Earl Australasian Neurochemistry Laboratory Clinical Biochemistry Department The Children’s Hospital at Westmead Sydney, NSW, Australia . AACB ASM Perth 27 th October 2010

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A Window upon the Brain Analysis of CSF Neurotransmitters Cofactors and Vitamins

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  1. A Window upon the Brain Analysis of CSF Neurotransmitters Cofactors and Vitamins John Earl Australasian Neurochemistry Laboratory Clinical Biochemistry Department The Children’s Hospital at Westmead Sydney, NSW, Australia AACB ASM Perth 27th October 2010 NSW/ACT AACB 17th May 2011

  2. CSF Neurotransmittersby HPLC Measurement Australasian Neurochemistry Laboratory Clinical Biochemistry Department The Children’s Hospital at Westmead Sydney, NSW, Australia • Catecholamines • Tyrosine pathway metabolites • Tryptophan pathway metabolites • Dopamine metabolites • Serotonin metabolites • Pteridines • 5-methyltetrahydrofolate • Histamine & metabolites • Amino Acids • Kynurenine pathway • B6 Vitamers Trace level analysis of unstable compounds Protect from light, Store frozen -40oC

  3. Neurochemistry Laboratory Sample Collection Cerebrospinal Fluid (CSF) Collected in 5 tubes with various preservatives 0.5ml CSF added to each tube Immediately frozen. Transport on dry ice Instructions / Details on Internet http://www.cs.nsw.gov.au/csls/handbook/FactSheetView.asp?Number=45 Spot Urine (frozen)

  4. Amperometric Detector Coulometric Detector Array

  5. Single Detector Array Detector

  6. Tyrosine Hydroxylase Deficiency L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline Deficiency of brain dopamine and noradrenaline. Responds to L-DOPA therapy

  7. Pteridines Xanthopterin Neopterin Monapterin Biopterin 7-Biopterin

  8. Central Inflammatory Disease Normal Brain Pterin Profile High levels of xanthopterin neopterin, monapterin CNS Inflammatory Disease

  9. CNS Inflammatory Disease CSF Neopterin Monapterin (<30nM) (<4nM) Aicardi Goutieres disease 231 29 HIE 319 28 ADEM 102 21 Rasmussen’s encephalitis 136 21 Cat scratch encephalitis 146 17 Rotavirus encephalitis 134 9 Batten disease 79 10 Acute cerebellar ataxia 87 14 Sydenham’s chorea 49 5 Development regression/ ataxia 58 9 Demyelinating disease 59 5 CSF Neopterin in Paediatric Neurology. A marker of active CNS inflammation Dale Cr, Brilot F, Fagan E, Earl J Develop Med Child Neurol 2009; 51(4): 317-323

  10. Almost miraculous (awakenings) but transient response to L-DOPA in a group of patients with Encephalitis Lethargica

  11. Progression of Encephalitis Lethargica Ref Ranges: Neopterin 4 – 30nM Biopterin 25 – 40nM

  12. Progression of Encephalitis Lethargica Ref Ranges: HVA > 0.34 5-HIAA > 0.10

  13. Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Russell C. Dale, Andrew J. Church, Robert A. H. Surtees, Andrew J. Lees, Jane E. Adcock, Brian Harding, Brian G. R. Neville and Gavin Giovannoni Brain (2004), 127, 21±33 Autoimmune process targeting the NMDA receptor.

  14. Infantile Spasms Normal CSF HVA, 5-HIAA and pterins 56% Low HVA, 5-HIAA, Biopterin 44% * Raised CSF Neopterin 1% 10 years - 65 cases for Neurotransmitter testing * Increasing evidence for Brain structural abnormalities including defective ARX Homeobox gene

  15. B6 Vitamers (pyridoxal phosphate) Pyridoxic acid Pyridoxal Pyridoxine Pyridoxamine

  16. Pyridoxal 5-Phosphate L-DOPA 5-HTP Glutamate Aromatic Amino Acid Glutamate Decarboxylase Decarboxylase (P5P) (P5P) Dopamine Serotonin GABA

  17. Neonatal Seizures ? PNPO Newborn boy developed seizures at 3 weeks (atypical). No response to pyridoxine Good response after pyridoxal phosphate. MRI: White matter high intensity signals Provisional Diagnosis: Pyridox(am)ine Oxidase Deficiency – PNPO

  18. Neonatal Seizures ? PNPO CSF B6 Vitamers PNPO PNPO Seizure Seizure Unknown * P5P P5P P5P Px P5P Pyridoxal 2570 720 6096 1403 1694 Pyridoxine 3470 996 9109 4841 28 Pyridoxamine 1910 622 74 26 nd Pyridoxic Acid 120 12 1543 66 145 Pyridoxic AL 1170 36 1056 489 470 * Diagnosis: Unlikely to be PNPODeficiency

  19. Neonatal Seizures ? PNPO CSF Neurotransmitter Analysis Male: 32 days of age. Neopterin 101.6 * ( < 30nmol/L) Monapterin 15.5 ( < 8 nmol/L) HVA 520 (540 – 1142 nmol/L) 5-HIAA 400 (380 – 1030 nmol/L) 5-MTHF 178.8 (60 -180 nmol/L) * Provisional Diagnosis: CNS Inflammatory Disease

  20. Neonatal Seizures CNS Inflammatory Disease Masking Therapeutic Trials with Pyridoxine & Pyridoxal Phosphate -> Late Onset neonatal seizures -> MRI: White Matter Hyperintensities

  21. CSF 5-Methyl-tetrahydrofolate

  22. A Window upon the Brain Metabolic Diseases Deficiency Diseases Inflammatory Diseases Neurodegenerative Diseases Structural diseases

  23. Improvement in detection and identification of Brain Diseases by cerebrospinal fluid analysis. Improve monitoring and treatment of Brain Diseases Towards evidence based Neurology and Neuropharmacology “Chemical Imaging of the Brain” - Identify chemical markers which arise from different brain regions. A window upon the Brain

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