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
2015 Brain  
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
more » ... sing positron emission tomography molecular imaging with 11 C-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 11 C-IMA107 binding potential relative to nondisplaceable binding (BP ND ) were generated from the dynamic 11 C-IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue. Corresponding region of interest analysis showed lower mean 11 C-IMA107 BP ND in the caudate (P 5 0.001), putamen (P 5 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 11 C-IMA107 BP ND in the caudate (r = À0.65; P = 0.005), putamen (r = À0.51; P = 0.025), and globus pallidus (r = À0.47; P = 0.030). Higher Unified Parkinson's Disease Rating Scale part-III motor scores correlated with lower 11 C-IMA107 BP ND in the caudate (r = À0.54; P = 0.011), putamen (r = À0.48; P = 0.022), and globus pallidus (r = À0.70; P 5 0.001). Higher Unified Dyskinesia Rating Scale scores in those Parkinson's disease with levodopa-induced dyskinesias (n = 12), correlated with lower 11 C-IMA107 BP ND in the caudate (r = À0.73; P = 0.031) and putamen (r = À0.74; 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. Abbreviations: BP ND = non-displaceable binding potential; LIDs = levodopa-induced dyskinesias; UDysRS = Unified Dyskinesia Rating Scale; UPDRS = Unified Parkinson's Disease Rating Scale 3004 | BRAIN 2015: 138; 3003-3015 F. Niccolini et al. by guest on October 6, 2016 http://brain.oxfordjournals.org/ Downloaded from PDE10A loss in Parkinson's disease BRAIN 2015: 138; 3003-3015 | 3005 by guest on October 6, 2016 http://brain.oxfordjournals.org/ Downloaded from PDE10A loss in Parkinson's disease BRAIN 2015: 138; 3003-3015 | 3007 by guest on October 6, 2016 http://brain.oxfordjournals.org/ Downloaded from *P-values are Bonferroni corrected but are not corrected for disease duration. Statistical significance was lost after using disease duration as a covariate in the analysis. Significant P-values and per cent changes are highlighted in bold. 3010 | BRAIN 2015: 138; 3003-3015 F. Niccolini et al. by guest on October 6, 2016 http://brain.oxfordjournals.org/ Downloaded from *P-values are FWE corrected except for globus pallidus where P-values are uncorrected. PDE10A loss in Parkinson's disease BRAIN 2015: 138; 3003-3015 | 3011 by guest on October 6, 2016 http://brain.oxfordjournals.org/ Downloaded from Figure 3 Correlations between loss of PDE10A and progression and severity of Parkinson's disease. (A) Longer disease duration correlated with lower 11 C-IMA107 BP ND in caudate (r = À0.65; P = 0.005), putamen (r = À0.51; P = 0.025) and globus pallidus (r = À0.47; P = 0.03). (B) Higher UPDRS-III scores correlated with lower 11 C-IMA107 BP ND ratio in caudate (r = À0.54; P = 0.011), putamen (r = À0.48; P = 0.022) and globus pallidus (r = À0.70; P 5 0.001). (C) Higher bradykinesia subscore was correlated with lower 11 C-IMA107 BP ND in caudate (r = À0.58; P = 0.007), putamen (r = À0.53; P = 0.010) and globus pallidus (r = À0.69; P 5 0.001). (D) Higher rigidity subscore was correlated with lower 11 C-IMA107 BP ND in caudate (r = À0.51; P = 0.022), putamen (r = À0.48; P = 0.022) and globus pallidus (r = À0.67; P 5 0.001).
doi:10.1093/brain/awv219 pmid:26210536 fatcat:mrw3zyqshvhonbgayisalvyws4