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

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 (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 non-displaceable binding (BPND) 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 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 (11)C-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 (11)C-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 (11)C-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.

955. Striatal Phosphodiesterase 10A and Medial Prefrontal Cortical Thickness in Patients with Schizophrenia: A PET and MRI Study

“…Similarly, neither previous studies of patients with schizophrenia (RN Gunn, personal communication) 16 or Parkinson's disease, nor experimental animal models have established a correlation between age and PDE10A availability. 13,35 Another limitation was the difference in coffee and smoking habits between the two The difference between groups was significant at Po0.001 as revealed with a Mann-Whitney U-test (Levene's test revealed no significant difference in variance, Fo 1).…”

“…[8][9][10][11][12] Moreover, patients with other striatal disorders, such as Parkinson's and Huntington's disease, have lower availability of striatal PDE10A early in the disease course. 13,14 Although PDE10A inhibition has shown promise as a novel target of the treatment of schizophrenia, 15 recently the first positron emission tomography (PET) study of PDE10A expression in patients with schizophrenia found no difference compared to healthy controls using the [ 11 C]IMA107 ligand. 16 However, the sample size was small and did not include treatment-resistant patients treated with diazepines such as clozapine.…”

Imaging in Parkinson's Disease

“…Among PDEs family, PDE10A is expressed almost exclusively in the striatum (Coskran et al, 2006;Lakics, Karran, & Boess, 2010), where it modulates cAMP/PKA/DARPP-32 signaling cascade thus having a key role in the regulation of striatal output and in promoting neuronal survival (Girault, 2012;Nishi et al, 2008). Using [ 11 C]IMA107 PET, our group has recently investigated PDE10A expression in 24 levodopa-treated moderate to advanced PD patients (Niccolini, Foltynie, et al, 2015;Niccolini, Haider, et al, 2015). PD patients showed lower [ 11 C]IMA107 binding in the caudate, putamen, and pallidum compared to healthy controls.…”

“…PD patients showed lower [ 11 C]IMA107 binding in the caudate, putamen, and pallidum compared to healthy controls. Longer PD duration and higher UPDRS-III motor scores correlated with lower [ 11 C]IMA107 binding in the caudate, putamen, and pallidum (Niccolini, Foltynie, et al, 2015;Niccolini, Haider, et al, 2015). Higher Unified Dyskinesia Rating Scale (UDysRS) scores in those PD patients with levodopa-induced dyskinesias correlated with lower [ 11 C]IMA107 binding in the caudate and putamen.…”

“…Positive evidence on the role of PDE10A in movement disorders comes from recent genetic studies on PDE10A gene mutations (Diggle et al, 2016;Mencacci et al, 2016). Patients with homozygous (Diggle et al, 2016) and heterozygous (Mencacci et al, 2016) PDE10A mutation present with benign childhood-onset chorea that may be followed by adult-onset levodopa-responsive parkinsonism (Mencacci et al, 2016 (Pagano, Niccolini, Fusar-Poli, et al, 2017;Pagano, Niccolini, & Politis, 2016a, 2016b spanning from far-onset premanifest stages (Niccolini, Foltynie, et al, 2015;Niccolini, Haider, et al, 2015) to early manifest (Russell et al, 2014(Russell et al, , 2016 and advanced (Ahmad et al, 2014) manifest HDGECs. Thus, PDE10A activity is critical for the control of movements and for neuronal survival and could serve as a novel therapeutic target for manipulation with pharmacotherapy in the neuropathological salient circuits, which promote neuronal survival and control of movements.…”