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Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease.

ABSTRACT: 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 k e 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 k e 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.

SUBMITTER: Black KJ

PROVIDER: S-EPMC7232584 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease.

Black Kevin J KJ Acevedo Haley K HK Koller Jonathan M JM

Frontiers in neurology 20200506

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 n ...[more]

PMID: 32477245

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Project description:MRI has been used to develop biomarkers for movement disorders such as Parkinson disease (PD) and other neurodegenerative disorders with parkinsonism such as progressive supranuclear palsy and multiple system atrophy. One of these imaging biomarkers is neuromelanin (NM), whose integrity can be assessed from its contrast and volume. NM is found mainly in certain brain stem structures, namely, the substantia nigra pars compacta (SNpc), the ventral tegmental area, and the locus coeruleus. Another major biomarker is brain iron, which often increases in concert with NM degeneration. These biomarkers have the potential to improve diagnostic certainty in differentiating between PD and other neurodegenerative disorders similar to PD, as well as provide a better understanding of pathophysiology. Mapping NM in vivo has clinical importance for gauging the premotor phase of PD when there is a greater than 50% loss of dopaminergic SNpc melanized neurons. As a metal ion chelator, NM can absorb iron. When NM is released from neurons, it deposits iron into the intracellular tissues of the SNpc; the result is iron that can be imaged and measured using quantitative susceptibility mapping. An increase of iron also leads to the disappearance of the nigrosome-1 sign, another neuroimage biomarker for PD. Therefore, mapping NM and iron changes in the SNpc are a practical means for improving early diagnosis of PD and in monitoring disease progression. In this review, we discuss the functions and location of NM, how NM-MRI is performed, the automatic mapping of NM and iron content, how NM-related imaging biomarkers can be used to enhance PD diagnosis and differentiate it from other neurodegenerative disorders, and potential advances in NM imaging methods. With major advances currently evolving for rapid imaging and artificial intelligence, NM-related biomarkers are likely to have increasingly important roles for enhancing diagnostic capabilities in PD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Project description:To apply a recently developed native-space (or native-surface) method to compare resting functional magnetic resonance (MR) imaging correlations (functional connectivity) measured in patients with Parkinson-related dementia (PRD) to those measured in cognitively unimpaired, age-matched control subjects with or without Parkinson disease (PD).The study was approved by the institutional review board and complied with HIPAA regulations. Participants included cognitively unimpaired elderly individuals (n = 19), cognitively unimpaired patients with PD (n = 19), and patients with PRD (n = 18). Resting functional MR data were assessed by calculating correlation coefficients between blood oxygen level-dependent time series of a seed region and of other regions of interest selected a priori. Two seeds were used: a medial parietal region that contributes to the default network affected in Alzheimer disease and the caudate, which is affected by loss of dopaminergic inputs in PD. Correlation analyses were performed in the native space of individual subjects to avoid confounds from transformation to an average brain. Two-sample t tests were applied to data from each native-surface region of interest, and vertex-wise comparisons were made by using two-sample t tests at each vertex on the group surface; statistical results were corrected for multiple comparisons. Cortical thickness and striatal volumes were also compared across groups for the regions of interest.Corticostriatal functional correlations were decreased in PRD patients relative to elderly control subjects in bilateral prefrontal regions; largest difference was observed in the right caudal middle frontal region (r = 0.48 in PRD patients and 0.81 in elderly control subjects, uncorrected P = .001). Conversely, there was no significant difference across groups in the strength of default-network correlations. There was also no significant difference across groups in cortical thickness or striatal volume.PRD was associated with selective disruption of corticostriatal resting functional MR imaging correlations, which suggests that resting functional MR imaging analyzed in subject-native space may be a useful biomarker in this disease. Additionally, at least in the present cohort, this technique was more sensitive to PRD changes than was quantitative structural MR imaging.

Dataset Information

Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease.

Publications

Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease.

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