Neurodegenerative Disease Parkinson’s Disease
Continuous Dopaminergic Stimulation in Parkinson’s Disease – What Have We Learned from Positron-emission Tomography?
David J Brooks1 and Nicola Pavese2
1. Hartnett Professor of Neurology, and Head, Centre for Neuroscience, Department of Medicine, Imperial College London; 2. Senior Investigator Scientist, Medical Research Council – Neurology PET Group, and Honorary Senior Lecturer, Imperial College London
Abstract
The hypothesis that pulsatile stimulation of striatal dopamine receptors in Parkinson’s disease (PD) induces molecular and physiological changes in basal ganglia neurons and may contribute to the development of motor complications has led to the design of therapeutic strategies that provide more continuous dopaminergic stimulation. Newer agents and drug-delivery systems, such as slow-release preparations, catechol- O-methyltransferase and monoamine oxidase inhibitor agents, apomorphine and Duodopa™ infusions, represent a significant step towards less pulsatile dopaminergic administration. However, their efficacy in providing steady brain levels of dopaminergic stimulation in the short and longer term has not yet been proved in patients. This article briefly reviews and discusses the findings of published positron-emission tomography (PET) studies that support or oppose the value of continuous dopaminergic stimulation in PD. The potential future value of PET for proof of mechanism in this area is also debated.
Keywords Parkinson’s disease (PD), positron emission tomography (PET), dopamine release, levodopa, continuous dopaminergic stimulation
Disclosure: David J Brooks and Nicola Pavese have received consultancy fees from GE Healthcare. Received: 10 May 2010 Accepted: 11 June 2010 Citation: European Neurological Review, 2010;5(1):22–5 Correspondence: David J Brooks, Cyclotron Building, Hammersmith Hospital, DuCane Road, London, W12 0NN, UK. E:
david.brooks@
csc.mrc.ac.uk
Oral levodopa remains the most effective symptomatic drug for Parkinson’s disease (PD); however, its long-term use is limited by the emergence of motor fluctuations and involuntary movements, particularly in young-onset patients. A growing number of pre- clinical and clinical studies suggest that non-physiological pulsatile stimulation of striatal dopamine (DA) receptors induced by the use of short-acting oral levodopa preparations, which produce swinging levels of synaptic DA, may contribute to the onset of motor fluctuations and dyskinesias. By contrast, more continuous and less pulsatile forms of dopaminergic stimulation delivered by longer- acting oral DA agonists result in a more stable clinical response and delay the development of motor complications, while steady infusions of apomorphine and levodopa can abolish motor fluctuations and dyskinesias.1–3
Based on these observations, new
levodopa formulations and alternative routes of administration for both levodopa and DA agonists have been introduced in the treatment of PD during the last decade, including slow-release preparations, addition of a catechol-O-methyltransferase (COMT) (entacapone or tolcapone) or monoamine oxidase B (MAOB) inhibitor (rasagaline), intravenous and enteral (duodenal) infusions of levodopa and transdermal administration and subcutaneous infusion of DA-receptor agonists. All of these strategies aim to optimise the clinical response by achieving stable and prolonged levels of synaptic DA. However, whether these strategies truly provide continuous dopaminergic stimulation has not yet been ascertained.
Positron-emission tomography (PET) is a neuroimaging technique that tags short-lived positron-emitting radioisotopes to chemical compounds of biological interest to produce 3D images of
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functional processes and drug-receptor occupancy in the body. In patients with PD, PET has been extensively used to investigate the function of brain dopaminergic nerve terminals, providing useful information on the density of functioning nerve terminals in the striatum and DA storage capacity, the availability of post-synaptic dopaminergic receptors and changes in synaptic DA levels following behavioural and pharmacological challenges. This article will briefly review and discuss the findings of published PET studies that support or oppose the value of continuous dopaminergic stimulation in PD.
Dopamine-replacement Treatment and Pre-synaptic Dopaminergic Function The COMT inhibitors entacapone and tolcapone increase levodopa bioavailability in the plasma and increase its transport into the brain by blocking the peripheral 3-O-methylation of levodopa. Like levodopa, 3- O-methyldopa (3-OMD) is transported into the brain by the large neutral aminoacid (LNAA) carrier, but it is not decarboxylated. The effect of COMT inhibitors on striatal levodopa kinetics has been extensively investigated with 18F-dopamine PET in both PD patients and healthy controls.4–8
Striatal 18F-dopa uptake, as measured by the
influx constant Ki, reflects four sequential processes: transport by LNAA through the blood–brain barrier, uptake into dopaminergic
neurons, metabolism to 18F-dopamine by aromatic amino acid decarboxylase (AADC) and vesicular storage of 18F-dopamine (see Figure 1). As 18F-dopa and non-fluorinated levodopa follow the same metabolic pathway, peripheral COMT inhibition boosts 18F-dopa bioavailability to the brain and increases its striatal uptake and subsequent metabolism in PD patients.
© TOUCH BRIEFINGS 2010
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