Low nigrostriatal reserve for motor parkinsonism in nonhuman primates

Abstract

Objective Nigrostriatal 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. Methods Fifteen 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. Results The percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2 months (r = −0.87, p <0.0001). The parkinsonism score at 2 months 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. Conclusions The nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought.

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

“…Two postmortem studies using more rigorous quantitative methods, such as using a tessellation method [17] and dissector-based neuromorphometry [27], found that about 30% of nigral neuronal loss appeared sufficient to cause motor symptoms in PD [2]. However, recent research suggests that the first symptoms of Parkinson's disease may manifest after just a 20% decrease in the number of dopaminergic neurons SNc, which has been shown in animal models where a reduction of about 14 to 23% of nigral neuron count or 14% to 37% of striatal dopamine was sufficient to induce mild parkinsonism [43].…”

Neuroimaging of Parkinson's disease: Expanding views

“…Some investigations have indicated that motor symptoms appear when there has been loss of approximately 30% of substantia nigra dopamine neurons or 50 to 70% of nigrostriatal dopaminergic axonal terminals in the striatum, although other studies have suggested that motor symptoms may appear with more preservation of dopamine neurons and striatal dopamine terminals than previously understood (Burke & O’Malley, 2013; Tabbal et al, 2012). Further, although Braak staging has drawn attention to α-synuclein inclusions in the substantia nigra and, therefore, degeneration of neuron cell bodies (soma) in the substantia nigra, it is possible that degeneration of neuron axon terminals in the striatum may progress more rapidly than degeneration of nigral cell bodies.…”

Neuroimaging biomarkers for Parkinson disease: Facts and fantasy

“…8 A reduction of between 14 – 24% of nigral TH neurons or 14 – 34% of striatal dopamine could cause parkinsonian motor manifestations. These values are similar to those reported (about 38% reduction) in low resolution SPECT studies of striatal uptake of a DAT radiotracer in the “normal” side in a group of eight hemiparkinsonian patients 27 and recall that striatal DAT measures strongly correlate with striatal dopamine.…”