Neurodegenerative Disease Parkinson’s Disease Figure 2: Schematic Representation of the 11C-raclopride Displacement Paradigm Scan 1: Baseline Scan 2: Levodopa administration
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D2 receptors DA Endogenous dopamine 11C-raclopride
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D2 receptors DA Levodopa-induced dopamineL
Changes in 11C-raclopride binding between baseline and post-treatment states (in this case administration of oral levodopa/carbidopa) represent a change in synaptic dopamine levels, reflecting the release of dopamine induced by levodopa administration.
Figure 3: 11C-raclopride Positron-emission Tomography Images from a Parkinson’s Disease Patient
with and without peak-dose dyskinesias.24 Each patient received three
11C-raclopride PET scans. The first one was performed at baseline with the patient ‘off’ medication and the others at one hour and four hours after levodopa. PD patients with dyskinesias had larger increases in synaptic DA levels than patients with stable response to levodopa one hour after administration, whereas there were no between-group differences at four hours. This finding suggests that peak-dose dyskinesias are associated with enhanced pulses of DA release induced by levodopa administration. In line with this interpretation, our group has recently reported that large putaminal 11C-raclopride binding changes induced by Sinemet® 275 were directly associated with higher dyskinesias scores during the scan session.25
T39 Baseline T39 Levodopa challenge
Images taken at baseline and after oral administration of standard levodopa/ carbidopa (250/25).
Effect of Dopamine-replacement Treatment on
Striatal Dopamine Release 11C-raclopride PET can also be used to assess fluctuations in synaptic concentrations of DA following pharmacological or behavioural challenges (see Figure 2). Rises in synaptic DA levels translate into
decreases in DA D2-receptor availability, which can be detected as reductions in 11C-raclopride binding.11
It has been estimated that a
10% reduction in 11C-raclopride binding reflects a five-fold increase in synaptic DA levels.21
This paradigm has recently been employed to
assess the changes in synaptic DA levels after administration of a single dose of exogenous levodopa in PD patients (see Figure 3). Results from these studies have shown that striatal reductions in 11C- raclopride binding after a levodopa challenge become greater as motor disability increases and the disease progresses.22–25
Changes in
11C-raclopride binding after oral administration of standard levodopa/carbidopa (250/25) were assessed in a group of PD patients
24
The increased synaptic DA levels that result from levodopa administration in dyskinetic and in more advanced PD patients probably reflect the reduced DA storage capacity of the severely affected putamen. However, another explanation could be the reduction of DA transporters (DAT) available to clear the transmitter. In line with this theory, Sossi and colleagues26
found a significant
negative correlation between changes in synaptic DA concentration and binding of the DAT marker 11C-methylphenidate. Greater reductions in 11C-raclopride, indicative of lower changes in synaptic DA concentration and lower DA turnover, were observed to be associated with lower 11C-methylphenidate binding. This finding suggests that DAT may play an important functional role in maintaining synaptic DA levels when pulsatile levodopa is administered. Therefore, decreases in DAT availability/function may result in greater oscillations in synaptic DA levels, contributing to the development of motor complications as the disease progresses.
Although previous studies indicate that 11C-raclopride PET represents an useful tool to investigate turnover of levodopa-induced synaptic DA in PD, this paradigm has not been applied to assess the efficacy of approaches to continuous levodopa delivery. Our group is currently testing the hypothesis that enteral (duodenal) infusions of levodopa
EUROPEAN NEUROLOGICAL REVIEW
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