A Rapid Non Invasive L-DOPA-13C Breath Test for Optimally Suppressing Extracerebral AADC Enzyme Activity - Toward Individualizing Carbidopa Therapy in Parkinson's Disease
Affiliations: Cambridge Isotope Laboratories Inc., Andover, MA, USA | VA Boston Healthcare System, Boston, MA, USA | Department of Neurology, Boston University School of Medicine, Boston, MA, USA | Physical Sciences Inc., Andover, MA, USA
Note: [] Correspondence to: Anil Modak, PhD, Cambridge Isotope Laboratories Inc., Andover, MA 01830, USA. E-mail: anilm@isotope.com
Abstract: 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 naïve PD patient using stable isotope labeled LD-1-13C as a substrate for a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-13C at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite 13CO2 in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-13C and homovanillic acid (HVA) were measured for 4 hours. Results: HVA in plasma and 13CO2 in breath are metabolic products of LD. We found a significant positive correlation of 13CO2 DOB AUC0-240 with serum HVA AUC0-240 following the oral dose of LD-1-13C for all 5 doses of CD (r2 = 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 13CO2 DOB AUC with serum LD-13C AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from 13CO2 generation in breath. Conclusions: The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker 13CO2 in breath, a first step in personalizing CD doses for PD patients.
Keywords: Parkinson's disease, personalized therapy, dopa decarboxylase, L-DOPA-$^{13}$C breath test
