Abstract
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Objectives Huntington’s disease (HD) is a progressive neurodegenerative autosomal dominant movement disorder. PDE-10A is an enzyme highly expressed in the striatal medium spiny neurons, where it regulates both cAMP and cGMP signalling cascades, mediating the striatal outputs and having a central role in the control of movement. The objective of this study was to evaluate the in vivo availability of PDE-10A in the brain of early premanifest HD gene carriers, using [11C]-IMA-107 positron emission tomography (PET).
Methods We have quantified the availability of PDE10 in the brains of 7 premanifest HD gene carriers (4 males; CAG range: 40-44; mean disease-burden score = 265). The mean predicted symptom onset for the group was 24 years. PET images were anatomically coregistered and resliced to the corresponding volumetric T1-weighted MRI using the Mutual Information Registration algorithm in SPM8. Regions-of-interest (ROIs) were delineated manually using ANALYZE 11.Regional [11C]-IMA-107 BPND were generated using a simplified reference tissue model (SRTM) with the cerebellum as the reference region.
Results Premanifest HD gene carriers had significantly lower mean [11C]-IMA-107 BPND than healthy volunteers in the caudate (27.7%; p = 0.003), putamen (23.7%; p = 0.004) and globus pallidus (15.4%; p = 0.004). In the substantia nigra the HD patients BPND was higher than that of healthy volunteers (18.5%; p>0.05).
Conclusions Our findings suggest that PDE-10A is dysregulated in HD gene carriers, decades before the appearance of clinical symptoms. [11C]-IMA-107 PET may provide a valuable tool to understand the pathophysiology of HD, and monitor both disease progression and the response to treatment.
Research Support NIHR Biomedical Research Centre