Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease

Abstract

We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified using perfusion MRI. Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant k _e was estimated from simulated response data plus Gaussian noise. Predicted time - effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated k _e from noisy input data was recovered with good accuracy. These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in all brain regions with a robust imaging response to exogenous levodopa.

Keywords: ASL; drug discovery and development; hysteresis; levodopa; phMRI; pharmacodynamics; pharmacokinetic-pharmacodynamic modeling; pharmacological biomarkers.