Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease
We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent dec...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2020.00370/full |
| _version_ | 1818542379903221760 |
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| author | Kevin J. Black Kevin J. Black Haley K. Acevedo Jonathan M. Koller |
| author_facet | Kevin J. Black Kevin J. Black Haley K. Acevedo Jonathan M. Koller |
| author_sort | Kevin J. Black |
| collection | DOAJ |
| description | We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified using perfusion MRI. Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant ke was estimated from simulated response data plus Gaussian noise. Predicted time – effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated ke from noisy input data was recovered with good accuracy. These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in all brain regions with a robust imaging response to exogenous levodopa. |
| first_indexed | 2024-12-11T22:21:18Z |
| format | Article |
| id | doaj.art-131dfc30b654484395b3a1380f9018ce |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-11T22:21:18Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-131dfc30b654484395b3a1380f9018ce2022-12-22T00:48:26ZengFrontiers Media S.A.Frontiers in Neurology1664-22952020-05-011110.3389/fneur.2020.00370536178Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson DiseaseKevin J. Black0Kevin J. Black1Haley K. Acevedo2Jonathan M. Koller3Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United StatesDepartments of Neurology, Radiology and Neuroscience, Washington University in St. Louis, St. Louis, MO, United StatesDepartment of Psychiatry, Washington University in St. Louis, St. Louis, MO, United StatesDepartment of Psychiatry, Washington University in St. Louis, St. Louis, MO, United StatesWe propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified using perfusion MRI. Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant ke was estimated from simulated response data plus Gaussian noise. Predicted time – effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated ke from noisy input data was recovered with good accuracy. These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in all brain regions with a robust imaging response to exogenous levodopa.https://www.frontiersin.org/article/10.3389/fneur.2020.00370/fullphMRIdrug discovery and developmentpharmacological biomarkerslevodopapharmacodynamicshysteresis |
| spellingShingle | Kevin J. Black Kevin J. Black Haley K. Acevedo Jonathan M. Koller Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease Frontiers in Neurology phMRI drug discovery and development pharmacological biomarkers levodopa pharmacodynamics hysteresis |
| title | Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease |
| title_full | Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease |
| title_fullStr | Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease |
| title_full_unstemmed | Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease |
| title_short | Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease |
| title_sort | dopamine buffering capacity imaging a pharmacodynamic fmri method for staging parkinson disease |
| topic | phMRI drug discovery and development pharmacological biomarkers levodopa pharmacodynamics hysteresis |
| url | https://www.frontiersin.org/article/10.3389/fneur.2020.00370/full |
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