title: Metabolic and type 1 cannabinoid receptor imaging of a transgenic rat model in the early phase of Huntington disease.
abstract: Several lines of evidence imply early alterations in metabolic and endocannabinoid neurotransmission in Huntington disease (HD). Using [(18)F]MK-9470 and small animal PET, we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding in vivo in pre-symptomatic and early symptomatic rats of HD (tgHD), in relation to glucose metabolism, morphology and behavioral testing for motor and cognitive function. Twenty-three Sprague-Dawley rats (14 tgHD and 9 wild-types) were investigated between the age of 2 and 11 months. Relative glucose metabolism and parametric CB1 receptor images were anatomically standardized to Paxinos space and analyzed voxel-wise. Volumetric microMRI imaging was performed to assess HD neuropathology. Within the first 10 months, bilateral volumes of caudate-putamen and lateral ventricles did not significantly differ between genotypes. Longitudinal- and genotype evolution showed that relative [(18)F]MK-9470 binding progressively decreased in the caudate-putamen and lateral globus pallidus of tgHD rats (-8.3%, p≤1.1×10(-5) at 5 months vs. -10.9%, p<1.5×10(-5) at 10 months). In addition, relative glucose metabolism increased in the bilateral sensorimotor cortex of 2-month-old tgHD rats (+8.1%, p≤1.5×10(-5)), where it was positively correlated to motor function at that time point. TgHD rats developed cognitive deficits at 6 and 11 months of age. Our findings point to early regional dysfunctions in endocannabinoid signalling, involving the lateral globus pallidus and caudate-putamen. In vivo CB1 receptor measurements using [(18)F]MK-9470 may thus be a useful early biomarker for HD. Our results also provide evidence of subtle motor and cognitive deficits at earlier stages than previously described.
authors: Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Belgium. cindy.casteels@med.kuleuven.be
authors: C
authors: C
authors: Casteels
authors: C
authors: C
authors: Vandeputte
authors: J R
authors: JR
authors: Rangarajan
authors: T
authors: T
authors: Dresselaers
authors: O
authors: O
authors: Riess
authors: G
authors: G
authors: Bormans
authors: F
authors: F
authors: Maes
authors: U
authors: U
authors: Himmelreich
authors: H
authors: H
authors: Nguyen
authors: K
authors: K
authors: Van Laere
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001931:Brain Mapping; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006816:Huntington Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D009048:Motor Skills / Q000502:physiology; D009474:Neurons / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D043884:Receptor, Cannabinoid, CB1; D005947:Glucose