Low nigrostriatal reserve for motor parkinsonism in nonhuman primates

Abstract

ObjectiveNigrostriatal reserve refers to the threshold of neuronal injury to dopaminergic cell bodies and their terminal fields required to produce parkinsonian motor deficits. Inferential studies have estimated striatal dopamine reserve to be at least 70%. Knowledge of this threshold is critical for planning interventions to prevent symptom onset or reverse nigrostriatal injury sufficient to restore function in people with Parkinson disease. In this study, we determine the nigrostriatal reserve in a non-human primate model that mimics the motor manifestations of Parkinson disease. MethodsFifteen macaque monkeys received unilateral randomized doses of the selective dopaminergic neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We compared blinded validated ratings of parkinsonism to in vitro measures of striatal dopamine and unbiased stereologic counts of nigral neurons after tyrosine hydroxylase immunostaining. ResultsThe percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2months (r=−0.87, p<0.0001). The parkinsonism score at 2months correlated linearly with the percent residual striatal dopamine (r=−0.77, p=0.016) followed by a flooring effect once nigral cell loss exceeded 50%. A reduction of about 14 to 23% of nigral neuron counts or 14% to 37% of striatal dopamine was sufficient to induce mild parkinsonism. ConclusionsThe nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought.