title: Monoaminergic PET imaging and histopathological correlation in unilateral and bilateral 6-hydroxydopamine lesioned rat models of Parkinson's disease: a longitudinal in-vivo study.
abstract: Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate that (11)C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat.
authors: Movement Disorders Laboratory, Neurosciences Area, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; MicroPET Research Unit, CIMA, University of Navarra, Pamplona, Spain.
authors: Francisco
authors: F
authors: Molinet-Dronda
authors: Movement Disorders Laboratory, Neurosciences Area, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Belén
authors: B
authors: Gago
authors: Movement Disorders Laboratory, Neurosciences Area, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Ana
authors: A
authors: Quiroga-Varela
authors: Movement Disorders Laboratory, Neurosciences Area, CIMA, University of Navarra, Pamplona, Spain; Department of Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Carlos
authors: C
authors: Juri
authors: MicroPET Research Unit, CIMA, University of Navarra, Pamplona, Spain; Department of Nuclear Medicine, Clínica Universidad de Navarra, Pamplona, Spain.
authors: María
authors: M
authors: Collantes
authors: Brain Mapping Unit, Multidisciplinary Institute, Complutense University of Madrid, Madrid, Spain.
authors: Mercedes
authors: M
authors: Delgado
authors: Department of Nuclear Medicine, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Elena
authors: E
authors: Prieto
authors: MicroPET Research Unit, CIMA, University of Navarra, Pamplona, Spain.
authors: Margarita
authors: M
authors: Ecay
authors: Movement Disorders Laboratory, Neurosciences Area, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Elena
authors: E
authors: Iglesias
authors: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; INGENIO, IRCE, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Concepció
authors: C
authors: Marín
authors: MicroPET Research Unit, CIMA, University of Navarra, Pamplona, Spain; Department of Nuclear Medicine, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Iván
authors: I
authors: Peñuelas
authors: Movement Disorders Laboratory, Neurosciences Area, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: jobeso.hmcinac@hospitalesdemadrid.com.
authors: José A
authors: JA
authors: Obeso
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000209:etiology*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: D018663:Adrenergic Agents; D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; C032811:dihydrotetrabenazine; D016627:Oxidopamine; D001058:Apomorphine; D013747:Tetrabenazine
keywords: 6-Hydroxydopamine; Dopaminergic marker; Nigro-striatal depletion; Parkinson's disease; Positron emission tomography; Rat models; [(11)C]-dihydrotetrabenazine ((11)C-DTBZ)