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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.

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  • Authors+Show Affiliations

    ,

    Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Belgium. cindy.casteels@med.kuleuven.be

    , , , , , , , ,

    Source

    Experimental neurology 229:2 2011 Jun pg 440-9

    MeSH

    Analysis of Variance
    Animals
    Brain
    Brain Mapping
    Disease Models, Animal
    Exploratory Behavior
    Glucose
    Huntington Disease
    Image Processing, Computer-Assisted
    Male
    Maze Learning
    Memory
    Motor Skills
    Neurons
    Positron-Emission Tomography
    Rats
    Rats, Sprague-Dawley
    Rats, Transgenic
    Receptor, Cannabinoid, CB1
    Statistics, Nonparametric

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    21459091

    Citation

    * When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Metabolic and type 1 cannabinoid receptor imaging of a transgenic rat model in the early phase of Huntington disease. AU - Casteels,C, AU - Vandeputte,C, AU - Rangarajan,J R, AU - Dresselaers,T, AU - Riess,O, AU - Bormans,G, AU - Maes,F, AU - Himmelreich,U, AU - Nguyen,H, AU - Van Laere,K, Y1 - 2011/03/31/ PY - 2011/01/17/received PY - 2011/03/11/revised PY - 2011/03/21/accepted PY - 2011/4/5/entrez PY - 2011/4/5/pubmed PY - 2011/8/6/medline SP - 440 EP - 9 JF - Experimental neurology JO - Exp. Neurol. VL - 229 IS - 2 N2 - 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. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/21459091/abstract/Metabolic_and_Type_1_cannabinoid_receptor_imaging_of_a_transgenic_rat_model_in_the_early_phase_of_Huntington_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(11)00098-7 DB - PRIME DP - Unbound Medicine ER -