title: 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.
authors.affiliation: 1 Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Flavia
authors.initials: F
authors.lastname: Niccolini
authors.affiliation: 3 Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Foltynie
authors.affiliation: 4 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Tiago
authors.initials: T
authors.lastname: Reis Marques
authors.affiliation: 5 School of Psychology and Cardiff University Brain Research Imaging Centre, Cardiff University, UK 6 School of Psychological Sciences, University of Manchester, Manchester, UK.
authors.forename: Nils
authors.initials: N
authors.lastname: Muhlert
authors.affiliation: 7 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: Andri C
authors.initials: AC
authors.lastname: Tziortzi
authors.affiliation: 7 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Searle
authors.affiliation: 4 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Natesan
authors.affiliation: 4 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.affiliation: 7 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK 8 Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.affiliation: 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
authors.affiliation: 1 Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK marios.politis@kcl.ac.uk.
authors.forename: Marios
authors.initials: M
authors.lastname: Politis
mesh_terms: D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D001931:Brain Mapping; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D015999:Multivariate Analysis; D010300:Parkinson Disease / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011810:Quinoxalines / Q000493:pharmacokinetics; D012720:Severity of Illness Index; D013223:Statistics as Topic
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; C000588665:IMA107; D011810:Quinoxalines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: LIDs; PDE10A; PET; Parkinson’s disease; motor