Flavia Niccolini1, Niccolo E Mencacci2,3, Tayyabah Yousaf1, Eugenii A Rabiner4,5, Vincenzo Salpietro2, Gennaro Pagano1, Bettina Balint6, Stephanie Efthymiou2, Henry Houlden2, Roger N Gunn4,7, Nicholas Wood2, Kailash P Bhatia6, Marios Politis1. 1. Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 2. Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK. 3. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 4. Imanova Ltd, Centre for Imaging Sciences, Hammersmith Hospital, London, UK. 5. Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK. 6. Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK. 7. Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Abstract
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.
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.
Authors: Gonzalo S Tejeda; Ellanor L Whiteley; Tarek Z Deeb; Roland W Bürli; Stephen J Moss; Eamonn Sheridan; Nicholas J Brandon; George S Baillie Journal: Proc Natl Acad Sci U S A Date: 2019-12-23 Impact factor: 11.205
Authors: Dong-Hui Chen; Caitlin S Latimer; Min Spencer; Prasanthi Karna; Luis F Gonzalez-Cuyar; Marie Y Davis; C Dirk Keene; Thomas D Bird; Wendy H Raskind Journal: Mov Disord Clin Pract Date: 2019-12-14
Authors: Diane Doummar; Christel Dentel; Romane Lyautey; Julia Metreau; Boris Keren; Nathalie Drouot; Ludivine Malherbe; Viviane Bouilleret; Jérémie Courraud; Maria Paola Valenti-Hirsch; Lorella Minotti; Blandine Dozieres-Puyravel; Séverine Bär; Julia Scholly; Elise Schaefer; Caroline Nava; Thomas Wirth; Hala Nasser; Marie de Salins; Anne de Saint Martin; Marie Thérèse Abi Warde; Philippe Kahane; Edouard Hirsch; Mathieu Anheim; Sylvie Friant; Jamel Chelly; Cyril Mignot; Gabrielle Rudolf Journal: Eur J Hum Genet Date: 2020-05-28 Impact factor: 4.246