A Rapid Non Invasive L-DOPA-13C Breath Test for Optimally Suppressing Extracerebral AADC Enzyme Activity - Toward Individualizing Carbidopa Therapy in Parkinson's Disease

Background: Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability. Objective: Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment. Methods: A single center, randomized, double-blind study was carried out recruiting 5 Parkinson's disease (PD) patients already on LD/CD and 1 treatment naive PD patient using stable isotope labeled LD-1-C-13 as a substrate for a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-C-13 at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite (CO2)-C-13 in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-C-13 and homovanillic acid (HVA) were measured for 4 hours. Results: HVA in plasma and (CO2)-C-13 in breath are metabolic products of LD. We found a significant positive correlation of (CO2)-C-13 DOB AUC(0-240) with serum HVA AUC(0-240) following the oral dose of LD-1-C-13 for all 5 doses of CD (r(2) = 0.9378). With increasing inhibition of AADC enzyme activity with CD, we observed an increase in the plasma concentration of LD. We found an inverse correlation of the (CO2)-C-13 DOB AUC with serum LD-C-13 AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from (CO2)-C-13 generation in breath. Conclusions: The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker (CO2)-C-13 in breath, a first step in personalizing CD doses for PD patients.