title: Plasma biomarkers of decreased vesicular storage distinguish Parkinson disease with orthostatic hypotension from the parkinsonian form of multiple system atrophy.
abstract: BACKGROUND
  Parkinson disease with orthostatic hypotension (PD + OH) and the parkinsonian form of multiple system atrophy (MSA-P) can be difficult to distinguish clinically. Recent studies indicate that PD entails a vesicular storage defect in catecholaminergic neurons. Although cardiac sympathetic neuroimaging by (18)F-dopamine positron emission tomography can identify decreased vesicular storage, this testing is not generally available. We assessed whether plasma biomarkers of a vesicular storage defect can separate PD + OH from MSA-P.
  
  
  METHODS
  We conceptualized that after F-dopamine injection, augmented production of F-dihydroxyphenylacetic acid (F-DOPAC) indicates decreased vesicular storage, and we therefore predicted that arterial plasma F-DOPAC would be elevated in PD + OH but not in MSA-P. We measured arterial plasma F-DOPAC after (18)F-dopamine administration (infused i.v. over 3 min) in patients with PD + OH (N = 12) or MSA-P (N = 21) and in healthy control subjects (N = 26). Peak F-DOPAC:dihydroxyphenylglycol (DHPG) was also calculated to adjust for effects of denervation on F-DOPAC production.
  
  
  RESULTS
  Plasma F-DOPAC accumulated rapidly after initiation of (18)F-dopamine infusion. Peak F-DOPAC (5-10 min) in PD + OH averaged three times that in MSA-P (P < 0.0001). Among MSA-P patients, none had peak F-DOPAC > 300 nCi-kg/cc-mCi, in contrast with 7 of 12 PD + OH patients (χ(2) = 16.6, P < 0.0001). DHPG was lower in PD + OH (3.83 ± 0.36 nmol/L) than in MSA-P (5.20 ± 0.29 nmol/L, P = 0.007). All MSA-P patients had peak F-DOPAC:DHPG < 60, in contrast with 9 of 12 PD + OH patients (χ(2) = 17.5, P < 0.0001). Adjustment of peak F-DOPAC for DHPG increased test sensitivity from 58 to 81% at similar high specificity.
  
  
  CONCLUSIONS
  After F-dopamine injection, plasma F-DOPAC and F-DOPAC:DHPG distinguish PD + OH from MSA-P.
authors: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS, NIH), 10 Center Drive MSC-1620, Building 10 Room 5N220, Bethesda, MD, 20892-1620, USA, goldsteind@ninds.nih.gov.
authors: David S
authors: DS
authors: Goldstein
authors: Irwin J
authors: IJ
authors: Kopin
authors: Yehonatan
authors: Y
authors: Sharabi
authors: Courtney
authors: C
authors: Holmes
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015897:Comorbidity; D003430:Cross-Sectional Studies; D003937:Diagnosis, Differential; D004298:Dopamine / Q000494:pharmacology; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007024:Hypotension, Orthostatic / Q000097:blood* / Q000175:diagnosis*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000097:blood* / Q000175:diagnosis*; D010300:Parkinson Disease / Q000097:blood* / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology
chemical_list: D015415:Biomarkers; D005462:Fluorine Radioisotopes; D015102:3,4-Dihydroxyphenylacetic Acid; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine
references: Clin Auton Res. 1996 Apr;6(2):125-6
references: 8726100
references: J Chromatogr B Biomed Appl. 1994 Mar 4;653(2):131-8
references: 8205240
references: Parkinsonism Relat Disord. 2008 Dec;14 (8):600-7
references: 18325818
references: Ann Intern Med. 2000 Sep 5;133(5):338-47
references: 10979878
references: J Am Coll Cardiol. 1993 Dec;22(7):1961-71
references: 8245356
references: Clin Auton Res. 2000 Oct;10(5):285-91
references: 11198484
references: Clin Exp Hypertens. 1997 Jan-Feb;19(1-2):155-61
references: 9028643
references: J Hypertens. 1991 May;9(5):417-23
references: 1649861
references: N Engl J Med. 1977 Feb 10;296(6):293-7
references: 831126
references: J Pharmacol Exp Ther. 2003 Jun;305(3):800-11
references: 12649306
references: J Neurochem. 2013 Sep;126(5):591-603
references: 23786406
references: J Clin Invest. 2011 Aug;121(8):3320-30
references: 21785221
references: Parkinsonism Relat Disord. 2012 Jun;18(5):494-500
references: 22321865
references: Neurology. 2003 Apr 22;60(8):1327-32
references: 12707437