Brain. 2015 Jul 21. pii: awv214. [Epub ahead of print]
Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.
Niccolini F1, Haider S2, Reis Marques T3, Muhlert N4, Tziortzi AC5, Searle GE5, Natesan S3, Piccini P6, Kapur S3, Rabiner EA7, Gunn RN8, Tabrizi SJ2, Politis M9.
11 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.
23 Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
34 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
45 School of Psychology and Cardiff University Brain Research Imaging Centre, Cardiff University, UK 6 School of Psychological Sciences, University of Manchester, Manchester, UK.
57 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
62 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
77 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.
82 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK 7 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
91 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.
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. |
