Neurology. 2026 Jul 28;107(2):e218226. doi: 10.1212/WNL.0000000000218226. Epub 2026 Jul 1.
ABSTRACT
BACKGROUND AND OBJECTIVES: Putamen dopamine depletion characterizes Parkinson disease (PD). Intraneuronal processes determining dopamine stores have not been systematically examined. This study explored relative contributions of dopamine synthesis, storage, and metabolism to control-PD differences.
METHODS: We updated an intramural tabulation from 2002 to 2024 of postmortem putamen tissue contents of reactants, including the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), from patients with PD and controls. Based on computational models applying first-order kinetics and equilibrium equations, we then compared estimated rates of dopamine synthesis through tyrosine hydroxylase (TH), L-aromatic-amino-acid decarboxylase, vesicular active uptake and passive leakage, exocytotic release and reuptake, and other intraneuronal processes. Results from the modeling were compared with those from in vivo 18F-DOPA PET.
RESULTS: Postmortem data were analyzed from 13 patients with PD (median age 77 years, range 73-85 years) and 20 controls (median age 77 years, range 35-91 years). There was approximately a 98% decrease in putamen tissue dopamine in PD, and the concentration ratio of DOPAL/dopamine (DA) was approximately 9 times that of control. Applying the simplest kinetic model, vesicular sequestration was estimated to be decreased by 98.5% (0.073 vs 4.91 nmol/minute). Approximately 3-fold greater in vivo “washout” of putamen 18F-DOPA-derived radioactivity compared with controls also indicated attenuated vesicular storage in PD. According to the complete model, control-PD differences in intraneuronal reaction rates were in descending order of vesicular uptake ≈ vesicular leakage > exocytotic release ≈ neuronal reuptake > L-aromatic-amino-acid decarboxylase activity ≈ TH activity > other reactions.
DISCUSSION: Convergent quantitative evidence points to a substantial vesicular storage defect in residual dopaminergic terminals in PD. This finding challenges the sufficiency of nigrostriatal dopaminergic denervation alone to account for the biochemical phenotype of PD and highlights vesicular dopamine handling as a critical determinant of putamen dopamine deficiency. The reaction rate estimates were drawn from published point values rather than fitted to an experimental data set, and so conventional goodness-of-fit regression statistics were not conducted. Because of the assumption of steady-state conditions for calculating reaction rates based on equilibrium equations, the model does not address the dynamics of disease pathogenesis over years but does provide a platform for further extension to disease progression.
BRIEF SUMMARY: We estimated rates of reactions involved with the synthesis, storage, release, reuptake, and metabolism of dopamine in the putamen in PD and found that the main intraneuronal functional abnormality separating PD from controls was attenuated vesicular sequestration, implicating decreased vesicular uptake through the vesicular monoamine transporter and increased vesicular leakiness as key determinants of putamen dopamine deficiency in PD.
PMID:42385115 | DOI:10.1212/WNL.0000000000218226
