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Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques
Author(s) -
Brown Christopher A.,
Karimi Morvarid K.,
Tian LinLin,
Flores Hugh,
Su Yi,
Tabbal Samer D.,
Loftin Susan K.,
Moerlein Stephen M.,
Perlmutter Joel S.
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23939
Subject(s) - mptp , substantia nigra , positron emission tomography , dopaminergic , striatum , parkinson's disease , binding potential , dopamine , midbrain , medicine , endocrinology , neuroscience , tyrosine hydroxylase , chemistry , nuclear medicine , psychology , central nervous system , disease
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 ( r s = −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. Ann Neurol 2013;74:602–610