title: Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies.
abstract: There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder. Whether low CSF DOPAC is associated specifically with parkinsonism has been unclear. In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DA). Theoretically, oxidative stress or decreased activity of aldehyde dehydrogenase (ALDH) in the residual nigrostriatal dopaminergic neurons would increase CSF Cys-DA levels with respect to DOPAC levels. PD, parkinsonian multiple system atrophy (MSA-P), and pure autonomic failure (PAF) are synucleinopathies; however, PAF does not entail parkinsonism. We examined whether an elevated Cys-DA/DOPAC ratio provides a specific biomarker of parkinsonism in synucleinopathy patients.
  
  
  
  CSF catechols were assayed in PD (n = 24), MSA-P (n = 32), PAF (n = 18), and control subjects (n = 32).
  
  
  
  Compared to controls, CSF DOPAC was decreased in PD and MSA-P (p < 0.0001 each). In both diseases Cys-DA/DOPAC ratios averaged more than twice control (0.14 ± 0.02 and 0.13 ± 0.02 vs. 0.05 ± 0.01, p < 0.0001 each), whereas in PAF the mean Cys-DA/DOPAC ratio was normal (0.05 ± 0.01).
  
  
  
  CSF Cys-DA/DOPAC ratios are substantially increased in PD and MSA-P and are normal in PAF. Thus, in synucleinopathies an elevated CSF Cys-DA/DOPAC ratio seems to provide a specific biomarker of parkinsonism.
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA. Electronic address: goldsteind@ninds.nih.gov.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sullivan
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA.
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA.
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kopin
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1620, USA; Hypertension Unit, Sheba Medical Center, Tel Hashomer Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid*; D000368:Aged; D000818:Animals; D002396:Catechols / Q000134:cerebrospinal fluid; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000494:pharmacology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging; D016716:PC12 Cells / Q000187:drug effects; D010300:Parkinson Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging; D011699:Putamen / Q000000981:diagnostic imaging; D051381:Rats
chemical_list: D002396:Catechols; D019788:Fluorodeoxyglucose F18; D015102:3,4-Dihydroxyphenylacetic Acid; D004295:Dihydroxyphenylalanine; C047408:5-S-cysteinyldopamine; D004298:Dopamine
keywords: Aldehyde dehydrogenase; Multiple system atrophy; Parkinson disease