title: Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques.
abstract: OBJECTIVE
  Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates.
  
  
  METHODS
  Presynaptic PET tracers 6-[(18)F]-fluorodopa (FD), [(11)C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [(11)C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration.
  
  
  RESULTS
  We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R(2) = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = -0.77, -0.71, respectively, p < 0.001), but FD uptake did not.
  
  
  CONCLUSIONS
  Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function.
authors.affiliation: Department of Neurology, Washington University of Medicine, St Louis, MO.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Brown
authors.forename: Morvarid K
authors.initials: MK
authors.lastname: Karimi
authors.forename: LinLin
authors.initials: L
authors.lastname: Tian
authors.forename: Hugh
authors.initials: H
authors.lastname: Flores
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.forename: Samer D
authors.initials: SD
authors.lastname: Tabbal
authors.forename: Susan K
authors.initials: SK
authors.lastname: Loftin
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Moerlein
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
mesh_terms: D000818:Animals; D002247:Carbon Isotopes; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18; D020267:MPTP Poisoning / Q000000981:diagnostic imaging / Q000473:pathology*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008636:Mesencephalon / Q000473:pathology*; D009474:Neurons / Q000502:physiology*; D049268:Positron-Emission Tomography; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000473:pathology*; D013747:Tetrabenazine / Q000031:analogs & derivatives
chemical_list: D002247:Carbon Isotopes; D019788:Fluorodeoxyglucose F18; C032811:dihydrotetrabenazine; D013747:Tetrabenazine