Objective: To use phosphodiesterase (PDE)10A ([¹¹C]IMA107) and PDE4 ([¹¹C]Rolipram) positron emission tomography (PET) molecular imaging combined with diffusion tensor imaging (DTI) based probabilistic tractography to explore the expression of  PDE10A and PDE4 in striatal output pathways in healthy controls and patients with Parkinson’s disease (PD).

Background: PDE10A and PDE4 are enzymes hydrolysing cyclic nucleotides that play a critical role in modulating striatal neuron output and movement regulation. Preliminary human PET studies have demonstrated a loss of PDE10A and PDE4 in patients with movement disorders.

Methods: We studied 24 subjects (12 PD) who had [¹¹C]IMA107 and [¹¹C]Rolipram PET, and DTI scans. MIAKAT^TM was used to generate parametric images of [¹¹C]IMA107 nondisplaceable binding (BP_ND) and [¹¹C]Rolipram volume of distribution (V_T) from the dynamic PET data using the simplified reference tissue model and Logan plot, respectively. FMRIB’s diffusion toolbox (FDT) was used to perform probabilistic tractography on each subjects’ diffusion data to functionally parcellate the striatum according to cortico-striatal, direct sensorimotor striatonigral (substantia nigra [SN]/globus pallidus internus [GPi]) and indirect sensorimotor striatopallidal (globus pallidus externus [GPe]) projections.

Results: In healthy controls, [¹¹C]IMA107 BP_ND and [¹¹C]Rolipram V_T were more highly expressed in the indirect sensorimotor striatopallidal projections compared to direct sensorimotor striatonigral projections ([¹¹C]IMA107 BP_ND: 18%, p<0.001; [¹¹C]Rolipram V_T: 6%, p<0.05). PD patients had higher loss of [¹¹C]IMA107 BP_ND in the direct sensorimotor striatonigral projections compared to indirect sensorimotor striatopallidal projections (13%; P<0.01); whereas loss of [¹¹C]Rolipram V_T was similar between the direct striatonigral (24%; P<0.05) and indirect (22% and P<0.05) sensorimotor striatopallidal projections.

Conclusions: Our findings show: (a) Preferential expression of PDE10A and PDE4 in indirect striatal pathways in humans, in line with animal data; (b) Loss of PDE10A is prominent in the direct striatal pathways; whereas loss of PDE4 expression in both direct and indirect striatal pathways in patients with PD; providing new insights in the pathophysiology of PD which may have relevance to the development of targeted treatments.

References: Niccolini F, Haider S, Reis Marques T, Muhlert N, Tziortzi AC, Searle GE, Natesan S, Piccini P, Kapur S, Rabiner EA, Gunn RN, Tabrizi SJ, Politis M. Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease. Brain. 2015;138:3016-29.

Tziortzi AC, Haber SN, Searle GE, Tsoumpas C, Long CJ, Shotbolt P, Douaud G, Jbabdi S, Behrens TE, Rabiner EA, Jenkinson M, Gunn RN. Connectivity-based functional analysis of dopamine release in the striatum using diffusion-weighted MRI and positron emission tomography. Cereb Cortex. 2014 May;24(5):1165-77.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phosphodiesterases-and-striatal-pathways-in-parkinsons-disease/