Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2015-07-21
Date Acceptance
2015-05-28
Citation
Brain, 2015, 138 (Pt 10), pp.3016-3029
ISSN
0006-8950
Publisher
Oxford University Press
Start Page
3016
End Page
3029
Journal / Book Title
Brain
Volume
138
Issue
Pt 10
Copyright Statement
© The Author (2015). This is a pre-copyedited, author-produced PDF of an article accepted for publication in Brain following peer review. The version of record 'Altered PDE10A expression detectable early before symptomatic onset in Huntington’s disease'
Flavia Niccolini, Salman Haider, Tiago Reis Marques, Nils Muhlert, Andri C. Tziortzi, Graham E. Searle, Sridhar Natesan, Paola Piccini, Shitij Kapur, Eugenii A. Rabiner, Roger N. Gunn, Sarah J. Tabrizi, Marios Politis is available online at: https://dx.doi.org/10.1093/brain/awv214
Flavia Niccolini, Salman Haider, Tiago Reis Marques, Nils Muhlert, Andri C. Tziortzi, Graham E. Searle, Sridhar Natesan, Paola Piccini, Shitij Kapur, Eugenii A. Rabiner, Roger N. Gunn, Sarah J. Tabrizi, Marios Politis is available online at: https://dx.doi.org/10.1093/brain/awv214
Identifier
PII: awv214
Subjects
MRI
PDE10A
PET
premanifest Huntington’s disease gene carriers
Publication Status
Published