PET Molecular Imaging Research of Levodopa-Induced Dyskinesias in Parkinson's Disease

Abstract

Purpose of review: To review the current status of positron emission tomography (PET) molecular imaging research of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD).

Recent findings: Recent PET studies have provided robust evidence that LIDs in PD are associated with elevated and fluctuating striatal dopamine synaptic levels, which is a consequence of the imbalance between dopaminergic and serotonergic terminals, with the latter playing a key role in mishandling presynaptic dopamine release. Long-term exposure to levodopa is no longer believed to solely induce LIDs, as studies have highlighted that PD patients who go on to develop LIDs exhibit elevated putaminal dopamine release before the initiation of levodopa treatment, suggesting the involvement of other mechanisms, including altered neuronal firing and abnormal levels of phosphodiesterase 10A. Dopaminergic, serotonergic, glutamatergic, adenosinergic and opioid systems and phosphodiesterase 10A levels have been shown to be implicated in the development of LIDs in PD. However, no system may be considered sufficient on its own for the development of LIDs, and the mechanisms underlying LIDs in PD may have a multisystem origin. In line with this notion, future studies should use multimodal PET molecular imaging in the same individuals to shed further light on the different mechanisms underlying the development of LIDs in PD.

Keywords: Dyskinesias; Molecular imaging; Parkinson’s disease; Positron emission tomography.

Fig. 1

The pathways involved in the development of levodopa-induced dyskinesia (LID). a In Parkinson’s disease patients with stable response to levodopa, dopamine transporter (DAT) takes up dopamine and it is stored in the presynaptic vesicles, via vesicular monoamine transporter 2 (VMAT2). As a consequence, dopamine levels remain relatively stable in the synaptic cleft, even after levodopa supplementation. Dopamine levels are maintained within a normal range as serotonergic terminals do not release dopamine excessively after levodopa supplementation, and DAT and noradrenaline transporter (NET) continue to take it up. At the postsynaptic level, the concentrations of dopaminergic, glutamatergic, adenosinergic, opioid and cannabinoid type 1 receptors are within the normal range. However, there is a decline in the concentration of phosphodiesterase 10A (PDE10A), which is an intracellular modulator of these receptors. b Parkinson’s disease patients with LIDs lack the capacity to store dopamine, as a result of reduced VMAT2 levels, and fail to take up dopamine, due to the loss of DAT. This is associated with increased dopamine levels in the synaptic cleft. Excessive and inappropriate release of dopamine from serotonergic terminals contributes to the sharp increase of dopamine concentration after levodopa supplementation. At the postsynaptic level, the concentrations of glutamatergic and adenosinergic receptors are increased and those of opioid receptors are reduced. The concentrations of D₁, D₂ and cannabinoid type 1 receptors are within the normal range. Compared with Parkinson’s disease patients with stable response to levodopa, there is a further decline of PDE10A concentration, which also correlates with the severity of dyskinesias. A2A-R adenosine A_2A receptor, CB1-R cannabinoid receptor type 1, D1-R dopamine receptor D₁, D2-R dopamine receptor D₂, D3-R dopamine receptor D₃, 5HT1A-R serotonin receptor 1A, NMDA-R N-methyl-d-aspartate receptor, opioid-R opioid receptor, SERT serotonin transporter