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Background: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity., Objectives: To assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden., Methods: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa-treated, 24 moderate-advanced l-dopa-treated patients with PD, and 22 healthy controls). All participants underwent [ 11 C]IMA107 PET, [ 11 C]PE2I PET, and 3-Tesla MRI scan., Results: Early de novo PD patients showed loss of [ 11 C]IMA107 and of [ 11 C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa-treated PD patients showed additional loss of [ 11 C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [ 11 C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [ 11 C]IMA107 correlated with lower [ 11 C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [ 11 C]IMA107 in the caudate (rho = -0.72; P < 0.001) and putamen (rho = -0.48; P < 0.01), and with lower [ 11 C]PE2I only in the putamen (rho = -0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [ 11 C]IMA107 in the caudate (rho = -0.42; P < 0.05) and putamen (rho = -0.41; P < 0.05), and with lower [ 11 C]PE2I only in the putamen (rho = -0.69; P < 0.001)., Conclusion: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A)., Objective: We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations., Methods: We studied 6 subjects with PDE10A and ADCY5 mutations using [ 11 C]IMA107 PET, [ 123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively., Results: We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices., Conclusions: Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)