Putaminal serotonergic innervation flags levodopa-induced dyskinesia risk

By Lucy Piper, Senior medwireNews Reporter

Increased serotonergic fibre innervation relative to dopaminergic fibre availability may be a potential marker of disease progression in Parkinson’s disease (PD) patients and a possible warning of levodopa-induced dyskinesia (LID), indicates an in vivo imaging study.

The researchers found that serotonergic innervation relative to dopamine fibre availability increased in the putamen of 30 patients with the condition in line with clinical PD progression and was highest in 10 of the patients with established dyskinesia.

“[Serotonergic] fibres have the potential to convert [levodopa] into dopamine; thus, in advanced PD where substantial dopaminergic fiber degeneration occurs, these fibers may be a major source of dopamine release in the basal ganglia”, explains the team in Neurology.

This makes blocking the serotonergic fibres as a means of reducing LID unhelpful because it could reduce the antiparkinsonian benefit of levodopa.

But, in a related editorial, Philippe Huot (University of Montreal, Quebec, Canada) and William Hutchison (University of Toronto, Ontario, Canada) say the current findings could “provide a way to determine when dyskinesia will begin at the clinical level”.

The threshold at which dopamine release by serotonin fibres is greater than the dopamine released by the remaining dopaminergic fibres represents a “tipping point” beyond which dyskinesia is likely to be present, below this, as yet to be determined, threshold, dyskinesia will be absent, they comment.

So by monitoring the putaminal ratio of serotonin to dopamine transporters, “it might be possible to begin administering agents that could delay, or even prevent, the emergence of dyskinesia, were such agents to exist and be clinically available”, the editorialists suggest.

Researchers Jee-Young Lee (Seoul National University, South Korea) and colleagues measured the binding potentials of dopamine and serotonin using positron emission tomography scans with the two tracers ¹⁸F-FP-CIT and ¹¹C-DASB, respectively.

¹⁸F-FP-CIT showed significant functional loss of nerve terminals expressing dopamine transporters (DAT) in the caudate, putamen and globus pallidus of the 30 patients, being worse for the 20 patients who had received levodopa treatment, irrespective of dyskinesia status, relative to the 10 patients in the early stages of PD who were treatment naïve.

¹¹C-DASB showed that nerve terminals expressing serotonin transporters (SERT) were significantly decreased in the caudate and putamen in the 10 PD patients who had received levodopa and developed dyskinesia compared with the treated PD patients without dyskinesia and non-treated PD patients.

While both tracer uptakes decreased with PD progression, they showed topographical differences, in that DAT binding loss correlated with severity and duration of PD for both the caudate and putamen, but only for the caudate in the case of SERT binding loss.

The researchers looked at the ratio of serotonin to dopaminergic fibre availability and found that it was highest in the putamen of PD patients with dyskinesia, reaching an average of 0.78. The ratio was lowest for treatment-naïve PD patients and intermediate for treated patients without dyskinesia.

The ratio of serotonin to dopaminergic fibre availability at the putamen correlated positively with Unified Parkinson’s Disease Rating Scale (UPDRS) total scores and duration of PD, while pallidal binding ratio additionally correlated with the UPDRS motor scores but did not differ significantly between patients with and without dyskinesia.

The researchers therefore conclude: “Relative increases in the availability of serotonergic fibers compared with dopaminergic fibers might be a predictor of future risk of dyskinesia and might be a more sensitive marker of disease severity than clinical variables such as disease duration or UPDRS score.”

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