Objective: The objective of this study was to examine the loss of Phosphodiesterase 10A enzyme (PDE10A) across a broad spectrum of Huntington’s disease (HD) stages.

Background: PDE10A is enriched in striatal medium spiny neurons and is involved in signal processing within the cortico-striato-thalamic circuit.  PDE10A in the striatum is decreased in HD gene expansion carriers (HDGECs) and has the potential to serve as a disease or pharmacodynamic marker.

Methods: Forty-five HDGECs (10 early pre-manifest (disease burden ≤250), 7F, 39±7y; 15 late pre-manifest (disease burden ≥275), 9F, 39±7y; 15 stage I, 4F, 50±10y; and 5 stage II 3F, 56±15y) and 45 age- and sex-matched healthy controls (HCs; 23F, 44±11y) were examined with PET using the radioligand ¹⁸F-MNI-659 (PDE10A). Partial volume effect correction was applied to PET data using 3T MR images. The outcome measure was the binding potential (BP_ND) estimated with the 2 tissue compartment model using the cerebellum as reference region. Differences in ¹⁸F-MNI-659 BP_ND values in the caudate, putamen and globus pallidus between HDGECs and HCs were assessed using independent sample t-tests. Differences in PDE10A availabilities between HD stages in each region were assessed using multivariate ANOVA. Associations between BP_ND values and disease burden scores were examined using linear regression.

Results: 89 participants (44 HDGECs/45 HCs) were included in this per protocol analysis.  Very strong evidence in support of a difference in BP_ND values between HDGECs and HCs was observed in each region of interest (p_s < 0.0001). BP_ND values were lower in HDGECs relative to HCs. In HDGECs, strong evidence in support of a main effect of both HD stage (p < 0.0001) and region (p < 0.0001) was observed for BP_ND values. Statistically significant but weaker evidence was observed for an interaction between stage and region (p < 0.0296).  An effect of disease burden on BP_ND was observed in each brain region (p < 0.0001).

Conclusions: ¹⁸F-MNI-659 BP_ND values are lower in HDGECs relative to HCs in the caudate, putamen, and globus pallidus; BP_ND values differ between HD stages with lower values typically observed as disease stage severity increases; BP_ND values are associated with disease burden score.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/imaging-of-phosphodiesterase-10-a-pde10a-enzyme-levels-in-the-living-human-brain-of-huntingtons-disease-gene-expansion-carriers-and-healthy-controls-with-positron-emission-tomography/