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E31 Positron Emission Tomography Imaging Of Phosphodiesterase 10 A Enzyme And Dopamine D2 Receptor In Huntington´s Disease Gene Expansion Carriers
  1. P Fazio1,
  2. C Fitzer-Attas2,
  3. L Mrzljak2,
  4. S Martinsson1,
  5. GB Landwehrmeyer2,
  6. J Bronzova3,
  7. N Al-Tawil4,
  8. C Halldin1,
  9. C Sampaio2,
  10. A Varrone1
  1. 1Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatry Research, Stockholm, Sweden
  2. 2CHDI Foundation, Princeton, NJ, USA
  3. 3European Huntington´s Disease Network (EHDN), on Behalf of EHDN Recruiting Sites
  4. 4Karolinska Trial Alliance, Karolinska University Hospital, Huddinge, Sweden

Abstract

Background Degeneration of striatal medium-spiny neurons is a pathological feature of Huntington´s disease (HD). D2 receptor imaging with positron emission tomography (PET) is a marker of neuronal integrity in HD. Phosphodiesterase 10A (PDE10A) enzyme is highly enriched in the striatal medium-spiny neurons and is a target of interest for drug development in HD.

Aims The aim of this study was to quantify the PDE10A enzyme and D2 receptor availability in HD gene expansion carriers (HDGECs) with PET.

Methods Five stage 1 HDGECs (4M/1F, 54 ± 9y), 10 pre-manifest HDGECs (6M/4F, 42 ± 8y; disease burden score ≥275) and 15 age- and gender-matched controls (10M/5F, 46 ± 11y) were studied. PET measurements with [11C]raclopride (D2 receptors) and [18F]MNI-659 (PDE10A) were performed using the high-resolution research tomograph. 3T magnetic resonance imaging was performed for striatal volume measures and region-of-interest delineation using FreeSurfer. PET outcome measures were the binding potential (BPND) estimated with simplified reference tissue model for [11C]raclopride and calculated with Logan graphical analysis (VT/VND-1=BPND) for [18F]MNI-659. Data were expressed as percent of the age-related control values.

Results Striatal volumes, D2 receptor and PDE10A availability were 62 ± 5%, 62 ± 12%, and 21 ± 33% of control values (p < 0.05) in stage 1 HDGECs, and 80 ± 18%, 72 ± 12% and 53 ± 22% of control values (p < 0.05, except for n.accumbens´ volume) in pre-manifest HDGECs.

Conclusion [18F]MNI-659 BPND showed larger between-subject variability than [11C]raclopride BPND. Differences of PET outcome measures between HDGECs and controls were larger than differences of striatal volumes. PDE10A enzyme (direct and indirect pathway) availability was more affected than D2 receptor (indirect pathway) availability. [18F]MNI-659 PET might serve as suitable molecular imaging marker of PDE10A for therapeutical trials in HD.

KeyWords
  • HDGEcs
  • Molecular Imaging
  • PDE10A enzyme
  • D2 receptors

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