Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson's disease

Flavia Niccolini, Thomas Foltynie, Tiago Reis Marques, Nils Muhlert, Andri C. Tziortzi, Graham E. Searle, Sridhar Natesan, Shitij Kapur, Eugenii A. Rabiner, Roger N. Gunn, Paola Piccini, Marios Politis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

Abstract

The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinson's disease are still only partially understood. Phosphodiesterase 10A (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. This study aimed to assess in vivo the availability of PDE10A in patients with Parkinson's disease using positron emission tomography molecular imaging with 11C-IMA107, a highly selective PDE10A radioligand. We studied 24 patients with levodopa-treated, moderate to advanced Parkinson's disease. Their positron emission tomography imaging data were compared to those from a group of 12 healthy controls. Parametric images of 11C-IMA107 binding potential relative to non-displaceable binding (BPND) were generated from the dynamic 11C-IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue. Corresponding region of interest analysis showed lower mean 11C-IMA107 BPND in the caudate (P < 0.001), putamen (P < 0.001) and globus pallidus (P = 0.025) in patients with Parkinson's disease compared to healthy controls, which was confirmed with voxel-based analysis. Longer Parkinson's duration correlated with lower 11C-IMA107 BPND in the caudate (r = -0.65; P = 0.005), putamen (r = -0.51; P = 0.025), and globus pallidus (r = -0.47; P = 0.030). Higher Unified Parkinson's Disease Rating Scale part-III motor scores correlated with lower 11C-IMA107 BPND in the caudate (r = -0.54; P = 0.011), putamen (r = -0.48; P = 0.022), and globus pallidus (r = -0.70; P < 0.001). Higher Unified Dyskinesia Rating Scale scores in those Parkinson's disease with levodopa-induced dyskinesias (n = 12), correlated with lower 11C-IMA107 BPND in the caudate (r = -0.73; P = 0.031) and putamen (r = -0.74; P = 0.031). Our findings demonstrate striatal and pallidal loss of PDE10A expression, which is associated with Parkinson's duration and severity of motor symptoms and complications. PDE10A is an enzyme that could be targeted with novel pharmacotherapy, and this may help improve dopaminergic signalling and striatal output, and therefore alleviate symptoms and complications of Parkinson's disease.

Original languageEnglish
Pages (from-to)3003-3015
Number of pages13
JournalBrain : a journal of neurology
Volume138
Issue number10
Early online date25 Jul 2015
DOIs
Publication statusPublished - 1 Oct 2015

Keywords

  • LIDs
  • motor
  • Parkinson's disease
  • PDE10A
  • PET

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