Objective: To investigate in vivo whether loss of PDE10A expression in Parkinson’s disease (PD) is an early phenomenon in early untreated PD patients using positron emission tomography  (PET) molecular imaging with [¹¹C]IMA107, a highly selective PDE10A radioligand.

Background: The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinson’s disease are still only partially understood. PDE10A is a basal ganglia expressed dual substrate enzyme, which regulates cAMP and cGMP signalling cascades, thus having a key role in the regulation of dopaminergic signalling in striatal pathways, and in promoting neuronal survival.

Methods: We studied a cohort of 16 early untreated PD patients compared to a group of 16 healthy controls. Subjects undertook one [¹¹C]IMA107 PET and one 3-T MRI scan. Image processing and kinetic modelling was carried out using MIAKAT^TM.  Parametric images of [¹¹C]-IMA107 binding potential relative to nondisplaceable binding (BP_ND) were generated from the dynamic [¹¹C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue.

Results: Region of interest analysis showed lower mean [¹¹C]IMA107 BP_ND in the caudate (38%, P<0.001) and putamen (14%, P<0.001) in PD patients compared to healthy controls, which was confirmed with voxel-based analysis. At structural MRI, PD patients showed no volumetric changes in caudate or putamen but loss of structural connectivity (loss of mean diffusivity in caudate=9%,P=0.005 and putamen=7%, P=0.037). Loss of PDE10A showed no lateralization. Higher Unified Parkinson’s Disease Rating Scale part-III motor scores correlated with lower [¹¹C]-IMA107 BP_ND in the caudate (r=-0.676; P=0.006) and putamen (r=-532; P=0.041).

Conclusions: Our findings demonstrate that loss of PDE10A expression is an early phenomenon in the course of PD over and above structural connectivity changes and is associated with the severity of motor symptoms, independently of levodopa treatment. These data demonstrate that the previous reductions reported in PD are not due to the effects of medication.

References: Niccolini F, Foltynie T, Reis Marques T, Muhlert N, Tziortzi AC, Searle GE, Natesan S, Kapur S, Rabiner EA, Gunn RN, Piccini P, Politis M. Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson’s disease. Brain. 2015 Oct;138(Pt 10):3003-15

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MDS Abstracts - https://www.mdsabstracts.org/abstract/altered-pde10a-expression-detectable-early-in-untreated-parkinsons-disease-patients/