Continuous Dopaminergic Stimulation in Parkinson’s Disease
Several PET studies have been performed to measure the effect of peripheral COMT inhibitor entacapone on striatal uptake of 18F- dopa.4–7
corrected for levels of 18F-3-OMD, the striatal Ki value primarily reflects the rate constant for dopa decarboxylation. Alternatively, if
an occipital cortex reference input function is used, the 18F reference signal reflects occipital levels of both 18F-dopa and 18F-3-OMD in
equilibrium with plasma. The striatal Ki then reflects the product of the rate constant for dopa decarboxylation and the striatal volume of distribution (VD) of 18F-dopa.
Sawle and colleagues4 performed 18F-dopa PET in four early
parkinsonian patients and six age-matched normal controls both before and after taking entecapone 400mg. Using a plasma input
function, they found no change in striatal Ki after entacapone, implying that this agent does not influence dopa decarboxylation. However, they found a 45% increase in the striatal 18F-dopa influx
constant Ki after entacapone when computed with an occipital reference input function. As the effect of entacapone was to increase the fraction of unmetabolised 18F-dopa in plasma from 22 to 56%
90 minutes after injection, this 45% increase in Ki represents a corresponding increase in striatal 18F-dopa VD. In a similar study in PD patients,5
Post-synaptic neuron
18 F-dopamine 18 F-dopa Aromatic amino acid decarboxylase
Figure 1: Scheme Showing the Metabolic Pathway of 18F-dopa
Striatal Ki values can be computed by graphical analysis in two main ways. If a plasma input reference function is used,
18 F-dopa
Pre-synaptic DA neuron
D2
receptors
Studies in untreated PD patients have reported 10–20% increases in entacapone enhanced the striatal
18F-dopa Ki (computed with an occipital reference input function) by 53.5% compared with placebo. However, changes in striatal 18F- dopa uptake induced by entacapone are smaller in patients with advanced PD. This probably reflects a more severe loss of dopaminergic terminals, leading to impaired DA storage capacity in these patients.6,7
From these studies it can be concluded that
entacapone has little effect on 18F-dopa decarboxylation in the striatum and that its main pharmacological effect is related to reduced peripheral 3-O-methylation and increased availability of plasma 18F-dopa to the brain.
Unlike entacapone, which is purely a peripheral COMT inhibitor, tolcapone is a mixed peripheral and central COMT inhibitor.9,10
The
effect of tolcapone on COMT activity has been investigated in 12 PD patients with 18F-dopa PET.8
The study design comprised two PET
scans on two separate days. Each patient received levodopa/ carbidopa (100/125mg) with either tolcapone (200mg) or placebo one hour before an 18F-dopa injection and was scanned for 240 minutes
after tracer injection. 18F-dopa Ki values were computed using a graphical approach with a plasma input function corrected for the
presence of 18F-3-OMD. Mean putaminal 18F-dopa Ki values for the first 30–90 minutes, reflecting central AADC activity, were not
modified by tolcapone pretreatment in PD. Mean putamen Ki values calculated 180–240 minutes after tracer injection, which reflect dopa metabolism by both central AADC and COMT, fell with placebo but were unchanged with tolcapone, implying that this agent was successfully blocking central COMT.
Effect of Dopamine-replacement Treatment on
Post-synaptic Dopamine Function 11C-raclopride, a reversibly binding DA D2/D3 receptor ligand, is often used to assess post-synaptic dopaminergic receptor availability with
PET. Its uptake is influenced by the synaptic level of DA, which competes for the same receptors, so 11C-raclopride PET can potentially be used to monitor dopaminergic transmission.11
EUROPEAN NEUROLOGICAL REVIEW
scanned 10 untreated PD patients with 11C-raclopride PET who were subsequently treated with either Sinemet® (300mg of levodopa daily) or Sinemet® CR (400mg of levodopa controlled- release daily) for six months and then crossed over to the other levodopa preparation for a further six months. At baseline, these workers found striatal 11C-raclopride binding to be increased in the untreated PD patients. When the patients were re-scanned after six months of levodopa treatment, there were no significant differences in striatal 11C-raclopride binding in either group from baseline. After the second six-month period of levodopa treatment, again no differences in 11C-raclopride binding were seen compared with baseline or between type of levodopa preparation. Clinically, both groups received similar symptomatic benefit following treatment, and none developed motor fluctuations. These workers concluded that
Uitti et al.19
striatal DA D2 normalisation via downregulation in PD following levodopa exposure must take longer than 12 months.
Striatal DA D1 receptor availability can be assessed with 11C-SCH23390 PET and is preserved in untreated PD patients, but reduced by 20% in patients chronically exposed to levodopa.14,20
To summarise, exposure to oral levodopa appears to have only mild
effects on the total availability of DA D1 and D2 receptors in PD patients. Having said that, current PET studies with antagonist tracers are unable to separate signal from high and low agonist affinity- receptor conformations and it is possible that the relative sub-populations are altered. Additionally, they do not exclude that downstream neurotransmitter changes can be induced depending on the kinetics of DA-receptor stimulation.
23
putaminal 11C-raclopride binding, suggesting increased DA D2 receptor availability is present.12–14
This increase could simply reflect
lower synaptic DA levels competing for DA D2 sites or, conversely, could represent compensatory receptor upregulation to loss of
nigrostriatal input. In PD patients treated long-term with levodopa, putaminal 11C-raclopride binding returns to the normal range as synaptic DA levels are restored and adaptive upregulation reverses.14–18
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