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 2 h after 6-[¹⁸F]fluorodopa injection, septal myocardial radioactivity measured 8 min 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.