Assessing Dopamine Function by PET in the MPTP-Primate Model of Parkinson's Disease

Doudet, Doris J. (1), Chan Grace L.Y. (2), Ruth Thomas J. (2), Holden James E. (3)

(1) Department of Medicine/Neurology, University of British Columbia, Vancouver, Canada

(2) UBC/TRIUMF PET Program, University of British Columbia, Vancouver, Canada

(3) Department of Medical Physics, University of Wisconsin, Madison, USA

Contact: Dr. Doris J. Doudet

Rm M36, Purdy Pavilion

2211 Wesbrook Mall, UBC,

Vancouver, V6T 2B5

Canada

email: ddoudet@interchange.ubc.ca

Phone: (604) 822 7163

Abstract:

We study the status of the striatal dopamine (DA) system in Parkinson's disease and its well-characterized MPTP primate model by PETusing specific tracers of pre and postsynaptic function. To characterize the presynaptic function, we use the fluoro-L-Dopa uptake rate constant Ki and, from the acquisition of long (3-4hrs) scans, we determine an index of effective DA turnover, which has allowed us to demonstrate "in vivo" an increase in DA turnover in symptomatic monkeys but also in animals with a subclinical lesion (i.e. asymptomatic but with a decreased Ki). Studies of the binding potential (BP) of DA D1 and D2 receptors in PD yield conflicting results. Our own studies in monkeys reveal a 15% decrease in the BP of SCH23390, the DA D1 receptor tracer, in all lesioned animals, symptomatic or asymptomatic. Alternatively, the BP of raclopride, the D2 receptor tracer, is decreased (14%) in asymptomatic animals but increased (30%) in symptomatic monkeys with early, short-term lesions, while unchanged compared to age matched normal controls in symptomatic animals with long-term lesions. The BP combines information on the density and affinity of the receptor and correlates to Bmax/Kd. It is usually obtained from a single, high specific activity scan. Thus, when a change in BP is observed, it cannot be determined if the change is due to a change in density, affinity or both, or if a lack of change in BP is due to a lack of effect of the disease or a lack of discrimination of the method. Thus, to study independently the density and affinity of the receptors, we recently developed a simplified version of the Scatchard analysis described by Farde et al. in order to 1) facilitate the interpretation of the conflicting single scan data in our animals and 2) evaluate its potential for human routine clinical studies of PD.