Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy.
OBJECTIVE
Biomarkers are increasingly important to diagnose and test treatments of neurodegenerative diseases such as Parkinson disease (PD). This study compared neuroimaging, neurochemical, and olfactory potential biomarkers to detect central dopamine (DA) deficiency and distinguish PD from multiple system atrophy (MSA).


METHODS
In 77 PD, 57 MSA, and 87 control subjects, radioactivity concentrations in the putamen (PUT), caudate (CAU), occipital cortex (OCC), and substantia nigra (SN) were measured 2h after 6-[18F]fluorodopa injection, septal myocardial radioactivity measured 8min after 6-[18F]fluorodopamine injection, CSF and plasma catechols assayed, or olfaction tested (University of Pennsylvania Smell Identification Test (UPSIT)). Receiver operating characteristic curves were constructed, showing test sensitivities at given specificities.


RESULTS
PUT:OCC, CAU:OCC, and SN:OCC ratios of 6-[18F]fluorodopa-derived radioactivity were similarly low in PD and MSA (p<0.0001, p<0.0001, p=0.003 compared to controls), as were CSF dihydroxyphenylacetic acid (DOPAC) and DOPA concentrations (p<0.0001, each). PUT:SN and PUT:CAU ratios were lower in PD than in MSA (p=0.004; p=0.005). CSF DOPAC correlated positively with PUT:OCC ratios (r=0.61, p<0.0001). Myocardial 6-[18F]fluorodopamine-derived radioactivity distinguished PD from MSA (83% sensitivity at 80% specificity, 100% sensitivity among patients with neurogenic orthostatic hypotension). Only PD patients were anosmic; only MSA patients had normal olfaction (61% sensitivity at 80% specificity).


CONCLUSIONS
PD and MSA feature low PUT:OCC ratios of 6-[18F]fluorodopa-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical approaches but not distinguishing the diseases. PUT:SN and PUT:CAU ratios of 6-[18F]fluorodopa-derived radioactivity, cardiac 6-[18F]fluorodopamine-derived radioactivity, and olfactory testing separate PD from MSA.
Goldstein
David S
DS
Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA. goldsteind@ninds.nih.gov
Holmes
Courtney
C
Bentho
Oladi
O
Sato
Takuya
T
Moak
Jeffrey
J
Sharabi
Yehonatan
Y
Imrich
Richard
R
Conant
Shielah
S
Eldadah
Basil A
BA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D004295:Dihydroxyphenylalanine / Q000134:cerebrospinal fluid; D004298:Dopamine / Q000172:deficiency*; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006346:Heart Septum / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D019578:Multiple System Atrophy / Q000000981:diagnostic imaging* / Q000378:metabolism*; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D012680:Sensitivity and Specificity
D015415:Biomarkers; D019788:Fluorodeoxyglucose F18; D015102:3,4-Dihydroxyphenylacetic Acid; D004295:Dihydroxyphenylalanine; D004298:Dopamine