title: Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.
abstract: There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.
authors.affiliation: 1 Neurodegeneration Imaging Group, Department of 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 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: 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: 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
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 7 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: 3 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: 1 Neurodegeneration Imaging Group, Department of 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: D000293:Adolescent; D000328:Adult; D001931:Brain Mapping; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011810:Quinoxalines / Q000493:pharmacokinetics; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020079:Terminal Repeat Sequences / Q000235:genetics; D055815:Young Adult
chemical_list: C086055:HTT protein, human; D006574:Heterocyclic Compounds, 2-Ring; D000071058:Huntingtin Protein; C000588665:IMA107; D009419:Nerve Tissue Proteins; D011810:Quinoxalines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: MRI; PDE10A; PET; premanifest Huntington’s disease gene carriers