title: Validation of nigrostriatal positron emission tomography measures: critical limits.
abstract: OBJECTIVE
  Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.
  
  
  METHODS
  Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells.
  
  
  RESULTS
  Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001).
  
  
  CONCLUSIONS
  Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.
authors: Departments of Neurology, Washington University, St Louis, MO.
authors: Morvarid
authors: M
authors: Karimi
authors: LinLin
authors: L
authors: Tian
authors: Christopher A
authors: CA
authors: Brown
authors: Hubert P
authors: HP
authors: Flores
authors: Susan K
authors: SK
authors: Loftin
authors: Tom O
authors: TO
authors: Videen
authors: Stephen M
authors: SM
authors: Moerlein
authors: Joel S
authors: JS
authors: Perlmutter
mesh_terms: D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000473:pathology*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18; D020267:MPTP Poisoning / Q000000981:diagnostic imaging / Q000473:pathology*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000473:pathology*; D013747:Tetrabenazine / Q000031:analogs & derivatives
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C032811:dihydrotetrabenazine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D013747:Tetrabenazine