Predictive modeling of putamen dopamine in Parkinson's disease: relevance to prognosis, treatment, and prevention.
Predictive modeling of putamen dopamine in Parkinson's disease: relevance to prognosis, treatment, and prevention.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Bethesda, US · Author affiliation
Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States.Location evidence
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Original abstract
Depletion of putamen dopamine (DA) characterizes Parkinson's disease (PD) and precedes the onset of motor symptoms by years. Increasing evidence implicates impaired vesicular sequestration and attenuated detoxification of the toxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL) in disease pathogenesis. We applied a mechanistic kinetic model to examine how perturbations in dopamine handling from DOPAL-induced autotoxicity affect the timing and trajectory of symptomatic PD. Using an icon-based application we constructed a model of intraneuronal dopamine synthesis, vesicular storage, leakage, metabolism, aldehyde detoxification, delayed toxicity, and α-synuclein modification. Model behavior was evaluated by internal consistency and concordance with empirical cellular, animal, imaging, and postmortem neurochemical data. We examined predicted effects of genetic variants, acquired factors (e.g., stress, environmental exposures), and treatments on vesicular dopamine content across the lifespan. Without imposing a predefined disease curve, the model generated a triphasic trajectory of vesicular dopamine loss-homeostasis, dyshomeostasis, and symptomatic decline-from delayed DOPAL-mediated toxicity, with progressive impairment of vesicular sequestration and other intraneuronal processes. The model predicted that genetic decreases in vesicular uptake or aldehyde detoxification and increases in dopamine biosynthesis would shorten the time to the onset of symptomatic disease, whereas monoamine oxidase inhibition, levodopa, and antioxidant treatment applied early and in combination would be protective. Preclinical, multitarget interventions would delay or prevent crossing a symptomatic threshold within the modeled lifespan. Systems modeling across the lifespan predicts a triphasic decline in putamen dopamine stores in PD. The timing and combination of interventions may be decisive for delaying or preventing symptomatic disease.NEW & NOTEWORTHY We used kinetic modeling to predict the temporal course of putamen dopamine depletion across the lifespan in Parkinson's disease and predict effects of autotoxicity, genetics, environmental exposures, and possible treatments on the timing of the onset of symptomatic disease.