title: Increased DAT binding in the early stage of the dopaminergic lesion: a longitudinal [11C]PE2I binding study in the MPTP-monkey.
abstract: The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BP(ND) during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanisms. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France. Electronic address: julien.vezoli@esi-frankfurt.de.
authors.forename: Julien
authors.initials: J
authors.lastname: Vezoli
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France; Primastem (LifeStemCells), Bron, France.
authors.forename: Kwamivi
authors.initials: K
authors.lastname: Dzahini
authors.affiliation: CERMEP imagerie du vivant, Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Costes
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France.
authors.forename: Charles R E
authors.initials: CR
authors.lastname: Wilson
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fifel
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Cooper
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France.
authors.forename: Henry
authors.initials: H
authors.lastname: Kennedy
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, Bron, France; Université de Lyon, Université Lyon1, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Procyk
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005260:Female; D008137:Longitudinal Studies; D020267:MPTP Poisoning / Q000000981:diagnostic imaging / Q000378:metabolism*; D008252:Macaca fascicularis; D009662:Nortropanes / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography
chemical_list: D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes
keywords: DAT; Dopamine innervation; MPTP; Non-motor symptoms; PET; Premotor compensation