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. INTERPRETATION: 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.
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. INTERPRETATION: 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: Alan L Whone; Ray L Watts; A Jon Stoessl; Margaret Davis; Sven Reske; Claude Nahmias; Anthony E Lang; Olivier Rascol; Maria J Ribeiro; Philippe Remy; Werner H Poewe; Robert A Hauser; David J Brooks Journal: Ann Neurol Date: 2003-07 Impact factor: 10.422
Authors: Nicolaas I Bohnen; Vikas Kotagal; Martijn L T M Müller; Robert A Koeppe; Peter J H Scott; Roger L Albin; Kirk A Frey; Myria Petrou Journal: Parkinsonism Relat Disord Date: 2014-10-15 Impact factor: 4.891
Authors: Laura L Dugan; LinLin Tian; Kevin L Quick; Josh I Hardt; Morvarid Karimi; Chris Brown; Susan Loftin; Hugh Flores; Stephen M Moerlein; John Polich; Samer D Tabbal; Jonathan W Mink; Joel S Perlmutter Journal: Ann Neurol Date: 2014-07-22 Impact factor: 10.422
Authors: Jonathan Snider; Martijn L T M Müller; Vikas Kotagal; Robert A Koeppe; Peter J H Scott; Kirk A Frey; Roger L Albin; Nicolaas I Bohnen Journal: Parkinsonism Relat Disord Date: 2015-08-28 Impact factor: 4.891
Authors: Susan R Criswell; Mark N Warden; Susan Searles Nielsen; Joel S Perlmutter; Stephen M Moerlein; Lianne Sheppard; Jason Lenox-Krug; Harvey Checkoway; Brad A Racette Journal: Neurology Date: 2018-08-10 Impact factor: 11.800
Authors: Oliver D Howes; Matthew Williams; Kemal Ibrahim; Garret Leung; Alice Egerton; Philip K McGuire; Federico Turkheimer Journal: Brain Date: 2013-10-03 Impact factor: 13.501