PET demonstrates reduced dopamine transporter expression in PD with dyskinesias

Abstract

Objective: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications.

Methods: Thirty-six patients with PD with motor fluctuations were assessed with PET using [¹¹C]-d-threo-methylphenidate (MP) and [¹¹C]-(±) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data.

Results: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 ± 0.36, dyskinesia 1.39 ± 0.28; mean ± SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 ± 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 ± 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity.

Conclusions: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias.

BP = binding potential; COMTi = catechol-O-methyl transferase inhibitors; CR = controlled release; DA = dopamine; DAT = DA transporter; DTBZ = [¹¹C]-(±) dihydrotetrabenazine; DVR = distribution volume; MF = motor fluctuation; MP = [¹¹C]-d-threo-methylphenidate; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.