Objective: To assess phosphodiesterase 10A (PDE10A) expression in vivo, using [¹¹C]IMA107 PET in patients with PDE10A and adenylate cyclase 5 (ADYC5) mutations.

Background: Cyclic adenosine monophosphate (cAMP) is an essential second messenger regulating multiple intracellular signalling pathways. In the striatal medium spiny neurons, cAMP activity is determined from the balance between its synthesis by ADYC5 and its degradation by PDE10A. Functional dysregulation of striatal cAMP signalling due to de novo or familial mutations in these two genes causes chorea and other hyperkinetic movement disorders.

Methods: We studied two unrelated patients with de novo heterozygous p.Phe300Leu PDE10A mutation (Patient 1, 61F; Patient 2, 23F); one patient with heterozygous p.Ile625Phe PDE10A mutation inherited from her asymptomatic father (Patient 3, 26F); and one patient with familial heterozygous p.R418W ADYC5 mutation (Patient 4, 38M). Patients 1 and 2 presented in childhood with progressive chorea and Patient 1 developed levodopa-responsive parkinsonism in the fifth decade. Patient 3 presented with childhood onset of paroxysmal kinesigenic dyskinesias. Patient 4 presented with childhood onset of progressive chorea and dystonia. All patients underwent one [¹¹C]IMA107 PET scan and one MRI scan. Parametric images of [¹¹C]IMA107 binding potential relative to nondisplaceable binding (BP_ND) were generated from the dynamic [¹¹C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue.

Results: Patients 1 and 2 showed >70% decreases in [¹¹C]IMA107 BP_ND in the striatum (−72% in caudate and −78% in the putamen) and 65% loss of [¹¹C]IMA107 BP_ND in pallidum compared to a group of healthy controls. Patient 3 showed >20% decreases in [¹¹C]IMA107 BP_ND in the striatum (−21% in caudate and −31% in the putamen) and 9% loss of [¹¹C]IMA107 BP_ND in pallidum; and Patient 4 showed >10% decreases in [¹¹C]IMA107 BP_ND in the striatum (−8% in caudate and −11% in the putamen) and 9% loss of [¹¹C]IMA107 BP_ND in pallidum compared to a group of healthy controls.

Conclusions: PDE10A expression is decreased in patients with PDE10A and ADYC5 mutations and pharmacological modulation of PDE10A could help restoring restore physiological levels of cAMP, and therefore alleviate symptoms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/loss-of-pde10a-expression-in-patients-with-pde10a-and-adyc5-mutations/