DTBZ-PET correlates of levodopa responses in asymmetric Parkinson ' s disease

Levodopa effectively improves motor symptoms of Parkinson's disease. However, the bene®cial effects of levodopa often erode over time with the emergence of response ̄uctuations. Although these response changes have been recognized from the early levodopa era, their mechanisms remain poorly understood. We investigated the role of dopamine (DA) terminal loss in the development of motor ̄uctuations by employing PET with [11C](6)dihydrotetrabenazine ([11C]DTBZ) as an in vivo marker for DA nerve terminals. Levodopa response was characterized by analysing the time±response curve to a single dose of levodopa with a ®nger-tapping test. PET scans were performed in 11 patients with asymmetric Parkinson's disease (age: 61.12 6 7.97 years; duration of Parkinson's disease: 10.55 6 4.53 years; mean 6 SD). Each patient performed ®nger-tapping tests for up to 5 h after taking a therapeutic dose of levodopa. Results showed signi®cantly lower [11C]DTBZ binding potential (BP; Bmax/Kd) and baseline tapping rates on the more affected putamen and corresponding body side, respectively, than on the other (P = 0.003 for the former, P = 0.013 for the latter). Among the variables describing the time±response curve, the duration and early decay time were signi®cantly shorter on the more affected side (P = 0.051 and P = 0.021, respectively). Latency to the onset and latency to 50% Emax (the magnitude of the levodopa response) were signi®cantly longer on the more-affected side (P = 0.013 and P = 0.004, respectively). Emax was not signi®cantly different between the two sides. The asymmetry (difference from the more affected to less affected side) of [11C]DTBZ BP in the putamen showed a highly signi®cant correlation with the corresponding asymmetry of the estimated EC50 (levodopa concentration producing 50% of the maximal response; P = 0.022; r = ±0.727), a marginally signi®cant correlation with that of latency to the onset (P = 0.065; r = ±0.583) and no signi®cant correlation with that of the magnitude, duration or early decay time. This pattern of changes in levodopa response from the less affected to more affected side was similar to that from stable to ̄uctuating responders except for the latency to onset. These ®ndings suggest a pathogenetic role for DA terminal loss in the development of motor ̄uctuations. However, the absence of a signi®cant correlation between the early decay of levodopa response and DA terminal density suggests that DA terminal loss alone cannot account for the development of motor ̄uctuations. Therefore, our study suggests that both levodopa treatment and DA terminal loss contribute to the pathogenesis of motor ̄uctuations.