title: Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.
abstract: Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [(18)F]MK-9470 and [(18)F]JNJ42259152 small-animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in presymptomatic, early symptomatic, and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([(18)F]FDG PET), brain morphology (magnetic resonance imaging) and motor function. Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxelwise. Volumetric microMRI imaging was performed to assess HD pathology. In R6/2 mice, CB1 receptor binding was decreased in comparison with WT in a cluster comprising the bilateral caudate-putamen, globus pallidus, and thalamic nucleus at week 5 (-8.1% ± 2.6%, p = 1.7 × 10(-5)). Longitudinal follow-up showed further progressive decline compared with controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus, and cerebellum (late vs. presymptomatic age: -13.7% ± 3.1% for R6/2 and +1.5% ± 4.0% for WT, p = 1.9 × 10(-5)). In R6/2 mice, PDE10A binding potential also decreased over time to reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1% ± 1.9% for R6/2 and +2.1% ± 2.7% for WT, p = 1.5 × 10(-4)). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, whereas no correlation was found with magnetic resonance imaging-based striatal volume. Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, which may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide evidence of subtle motor deficits at earlier stages than previously described.
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Ooms
authors.affiliation: MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium; Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
authors.forename: Roma
authors.initials: R
authors.lastname: Rietjens
authors.affiliation: KU Leuven Medical Image Computing (ESAT/PSI), Department of Electrical Engineering & Medical Imaging Research Center, University Hospital Leuven, Leuven, Belgium.
authors.forename: Janaki Raman
authors.initials: JR
authors.lastname: Rangarajan
authors.affiliation: Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vunckx
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Valdeolivas
authors.affiliation: KU Leuven Medical Image Computing (ESAT/PSI), Department of Electrical Engineering & Medical Imaging Research Center, University Hospital Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Maes
authors.affiliation: Biomedical NMR Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernandez-Ruiz
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.affiliation: MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium; Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium; Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium. Electronic address: cindy.casteels@med.kuleuven.be.
authors.forename: Cindy
authors.initials: C
authors.lastname: Casteels
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D005947:Glucose / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: C543264:Cnr1 protein, rat; D043884:Receptor, Cannabinoid, CB1; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D005947:Glucose
keywords: Huntington disease; Phosphodiesterase 10A; R6/2 mice; Small-animal PET; Type 1 cannabinoid receptor