Objective: Using positron emission tomography (PET) with [¹¹C]IMA107, we investigated the in vivo expression of PDE10A in extra-striatal regions in a cohort of 12 early premanifest HD gene carriers.

Background: Huntington’s disease (HD) is a monogenic, progressive and fatal 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. Altered PDE10A levels has previous been reported within basal ganglia regions in far and near onset premanifest and manifest HD gene carriers.

Methods: Image processing and kinetic modelling was carried out using MIAKAT^TM. Parametric images of [¹¹C]IMA107 non-displaceable binding potential (BP_ND) were generated from the dynamic [¹¹C]IMA107 scans using implementation of the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification for extra-striatal [¹¹C]IMA107 BP_ND at 0.30 in healthy control data.

Results: The occipital pole, occipital fusiform gyrus, insular cortex, frontal operculum cortex and posterior cingulate gyrus met this criterion, were designated as extra-striatal regions-of-interest (ROIs), and subsequent analyses were carried out. MRI based volumetric analysis showed no atrophy in extra-striatal ROIs. We found significant differences in mean extra-striatal ROIs [¹¹C]IMA107 BP_ND between the HD gene carriers and the healthy controls (P=0.037). HD gene carriers had significantly lower mean ¹¹C]IMA107 BP_ND within the insular cortex (P=0.025; -25%) and occipital fusiform gyrus (P=0.010; -42%) compared to healthy controls.

Conclusions: 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 regulating cognitive and limbic function.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/loss-of-extra-striatal-phosphodiesterase-10a-expression-in-early-premanifest-huntingtons-disease-gene-carriers/