Journal article Open Access

Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.

Ooms, Maarten; Rietjens, Roma; Rangarajan, Janaki Raman; Vunckx, Kathleen; Valdeolivas, Sara; Maes, Frederik; Himmelreich, Uwe; Fernandez-Ruiz, Javier; Bormans, Guy; Van Laere, Koen; Casteels, Cindy


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    <subfield code="a"> Huntington disease</subfield>
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    <subfield code="u">MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium and Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Belgium</subfield>
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    <subfield code="u">Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain</subfield>
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    <subfield code="a">Fernandez-Ruiz, Javier</subfield>
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    <subfield code="u">Laboratory for Radiopharmacy, KU Leuven, Belgium and MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium</subfield>
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    <subfield code="a">Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.</subfield>
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    <subfield code="a">&lt;p&gt;Purpose: Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase&amp;nbsp;10A (PDE10A) signaling in Huntington disease (HD). Using [18F]MK-9470 and [18F]JNJ42259152&amp;nbsp;small-animal PET, we investigated for the first time cerebral changes in type 1 cannabinoid (CB1)&amp;nbsp;receptor binding and PDE10A levels in vivo in pre-, early- and late symptomatic HD (R6/2) mice, in&amp;nbsp;relation to glucose metabolism ([18F]FDG PET), brain morphology (MRI) and motor function.&amp;nbsp;&lt;/p&gt;

&lt;p&gt;Methods:&amp;nbsp;Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4&amp;nbsp;and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to&amp;nbsp;Paxinos space and analyzed voxel-wise. Volumetric microMRI imaging was performed to assess HD&amp;nbsp;pathology.&amp;nbsp;&lt;/p&gt;

&lt;p&gt;Results: In R6/2 mice, CB1 receptor binding was decreased in comparison to WT in a&amp;nbsp;cluster comprising the bilateral caudate-putamen, globus pallidus and thalamic nucleus at week 5 (-8.1&amp;plusmn;2.6%; p=1.7.10-5). Longitudinal follow-up showed further progressive decline compared to controls&amp;nbsp;in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior&amp;nbsp;colliculus, thalamic nucleus and cerebellum (late vs. presymptomatic age: -13.7&amp;plusmn;3.1% for R6/2 and&amp;nbsp;+1.5&amp;plusmn;4.0% for WT; p=1.9.10-5). In R6/2 mice, PDE10A binding potential also decreased over time, to&amp;nbsp;reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1&amp;plusmn;1.9% for&amp;nbsp;R6/2 and +2.1&amp;plusmn;2.7% for WT; p=1.5.10-4). The observed changes in CB1 receptor and PDE10A binding&amp;nbsp;were correlated to anomalies exhibited by R6/2 animals in motor function, while no correlation was&amp;nbsp;found with MRI-based striatal volume.&amp;nbsp;&lt;/p&gt;

&lt;p&gt;Conclusion: Our findings point to early regional dysfunctions in&amp;nbsp;endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus,&amp;nbsp;that may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo&amp;nbsp;CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide&amp;nbsp;evidence of subtle motor deficits at earlier stages than previously described.&lt;/p&gt;</subfield>
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    <subfield code="a">10.1016/j.neurobiolaging.2014.06.010</subfield>
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