An integrative model of Parkinson’s disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression

Véronneau‐Veilleux, Florence; Robaey, Philippe; Ursino, Mauro; Nekka, Fahima

doi:10.1007/s10928-020-09723-y

Cited by 14 publications

(8 citation statements)

References 77 publications

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“…A neurocomputational model of the basal ganglia was combined with a PK model of levodopa to study finger tapping frequencies, an item in Movement Disorder Society-UPDRS. 196 The higher sensitivity of D2 receptors over D1 receptors to reduce disease symptoms was highlighted.…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…DBS eliminated low‐frequency high‐amplitude pathological oscillations and replaced them with high‐frequency low‐amplitude activity. A neurocomputational model of the basal ganglia was combined with a PK model of levodopa to study finger tapping frequencies, an item in Movement Disorder Society‐UPDRS 196 . The higher sensitivity of D2 receptors over D1 receptors to reduce disease symptoms was highlighted.…”

Section: Qsp Models Of Neurodegenerative Disease: Models and Applicat...mentioning

confidence: 99%

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Hallmarks of neurodegenerative disease: A systems pharmacology perspective

Bloomingdale

Karelina

Ramakrishnan

et al. 2022

CPT Pharmacom & Syst Pharma

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Age‐related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease‐modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

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Section: Parkinson's Diseasementioning

confidence: 99%

Section: Qsp Models Of Neurodegenerative Disease: Models and Applicat...mentioning

confidence: 99%

Hallmarks of neurodegenerative disease: A systems pharmacology perspective

Bloomingdale

Karelina

Ramakrishnan

et al. 2022

CPT Pharmacom & Syst Pharma

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“…Dopamine synthesis and metabolism has been modeled in several studies (Table 1), addressing different regulatory aspects and pathological mechanisms. The majority of models have used the Michaelis-Menten type of kinetics with the exceptions of the modeling studies from the Voit lab (which uses the power law formalism) [196,197] and notably the hybrid modeling approach by Nekka and coworkers [198]. The latter combines a two-compartment model of L-DOPA pharmacokinetics, a simplified model of extracellular dopamine and a neurocomputational model of the basal ganglia.…”

Section: Systems Modeling Of Da Synthesis and Metabolismmentioning

confidence: 99%

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

Nygaard

Szigetvari

Grindheim

et al. 2021

JPM

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Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.

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“…In the present study, we used a mechanistic model of the basal ganglia dopaminergic system that we previously developed to help rationally improve pharmacological interventions in Parkinson's disease (Véronneau-Veilleux et al, 2020 ). The model is a combination of a neurocomputational model of the basal ganglia (Baston and Ursino, 2015 ; Baston et al, 2016 ) and a model of dopamine dynamics (Dreyer, 2014 ) that includes dopamine release and reuptake by DAT.…”

Section: Introductionmentioning

confidence: 99%

A mechanistic model of ADHD as resulting from dopamine phasic/tonic imbalance during reinforcement learning

Véronneau‐Veilleux

Robaey

Ursino

et al. 2022

Front. Comput. Neurosci.

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Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Although the involvement of dopamine in this disorder seems to be established, the nature of dopaminergic dysfunction remains controversial. The purpose of this study was to test whether the key response characteristics of ADHD could be simulated by a mechanistic model that combines a decrease in tonic dopaminergic activity with an increase in phasic responses in cortical-striatal loops during learning reinforcement. To this end, we combined a dynamic model of dopamine with a neurocomputational model of the basal ganglia with multiple action channels. We also included a dynamic model of tonic and phasic dopamine release and control, and a learning procedure driven by tonic and phasic dopamine levels. In the model, the dopamine imbalance is the result of impaired presynaptic regulation of dopamine at the terminal level. Using this model, virtual individuals from a dopamine imbalance group and a control group were trained to associate four stimuli with four actions with fully informative reinforcement feedback. In a second phase, they were tested without feedback. Subjects in the dopamine imbalance group showed poorer performance with more variable reaction times due to the presence of fast and very slow responses, difficulty in choosing between stimuli even when they were of high intensity, and greater sensitivity to noise. Learning history was also significantly more variable in the dopamine imbalance group, explaining 75% of the variability in reaction time using quadratic regression. The response profile of the virtual subjects varied as a function of the learning history variability index to produce increasingly severe impairment, beginning with an increase in response variability alone, then accumulating a decrease in performance and finally a learning deficit. Although ADHD is certainly a heterogeneous disorder, these results suggest that typical features of ADHD can be explained by a phasic/tonic imbalance in dopaminergic activity alone.

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An integrative model of Parkinson’s disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression

Cited by 14 publications

References 77 publications

Hallmarks of neurodegenerative disease: A systems pharmacology perspective

Hallmarks of neurodegenerative disease: A systems pharmacology perspective

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

A mechanistic model of ADHD as resulting from dopamine phasic/tonic imbalance during reinforcement learning

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