title: Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers.
abstract: Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [(11)C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [(11)C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [(11)C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [(11)C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [(11)C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.
authors.affiliation: Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Wilson
authors.affiliation: Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Flavia
authors.initials: F
authors.lastname: Niccolini
authors.affiliation: Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
authors.forename: Salman
authors.initials: S
authors.lastname: Haider
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Tiago Reis
authors.initials: TR
authors.lastname: Marques
authors.affiliation: Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pagano
authors.affiliation: Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Coello
authors.affiliation: 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: 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: Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK; 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: Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK; Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.affiliation: Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK. Electronic address: marios.politis@kcl.ac.uk.
authors.forename: Marios
authors.initials: M
authors.lastname: Politis
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics; D006801:Humans; D006816:Huntington Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011810:Quinoxalines / Q000493:pharmacokinetics
chemical_list: D002250:Carbon Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring; C000588665:IMA107; D011810:Quinoxalines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Insula; MRI; Occipital fusiform gyrus; PDE10A; PET; Premanifest Huntington's disease