Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3 receptors and sub-cortical volumes in the human basal ganglia: A PET study with 18F-MNI-659 and 11C-raclopride with correction for partial volume effect

Abstract

Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D_2/3 receptors (D_2/3 R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D_2/3 R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D_2/3 R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand ¹⁸F-MNI-659 and D_2/3 R radioligand ¹¹C-raclopride were used. The outcome measure was the binding potential (BP_ND) estimated with the two-tissue compartment model (¹⁸F-MNI-659) and the simplified reference tissue model (¹¹C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D_2/3 R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D_2/3 R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D_2/3 R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BP_ND the female group.