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Original Investigation |

Correlation of Parkinson Disease Severity and 18F-DTBZ Positron Emission Tomography

Ing-Tsung Hsiao, PhD1,2,3; Yi-Hsin Weng, MD4,5,6; Chia-Ju Hsieh, MSc1,2; Wey-Yil Lin, MD4,5; Shiaw-Pyng Wey, PhD1,2,3; Mei-Ping Kung, PhD1,2,7; Tzu-Chen Yen, MD, PhD2,3; Chin-Song Lu, MD2,4,5; Kun-Ju Lin, MD, PhD1,2,3
[+] Author Affiliations
1Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
2Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
3Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
4Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
5Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
6School of Medicine, Chang Gung University, Taoyuan, Taiwan
7Department of Radiology, University of Pennsylvania, Philadelphia
JAMA Neurol. 2014;71(6):758-766. doi:10.1001/jamaneurol.2014.290.
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Importance  Currently, diagnosis of Parkinson disease is mainly based on clinical criteria characterized by motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability. Reliable in vivo biomarkers to monitor disease severity and reflect the underlying dopaminergic degeneration are important for future disease-modifying therapy in Parkinson disease.

Objectives  To use [18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-DTBZ; [18F]AV-133) positron emission tomography (PET) to explore the characteristics of vesicular monoamine transporter type 2 imaging in patients with Parkinson disease (PD) with different severity levels as well as to investigate its capability in monitoring clinical severity.

Design, Setting, and Participants  Regional uptakes for 18F-DTBZ PET of different disease stages were measured. Seventeen healthy control participants and 53 patients in 3 groups of mild, moderate, and advanced stages of PD were recruited for 18F-DTBZ PET scans from the Movement Disorders Clinic in the Chang Gung Memorial Hospital, Taiwan.

Main Outcomes and Measures  The severity of disease in patients with PD was quantified by modified Hoehn-Yahr Scale, Unified Parkinson Disease Rating Scale total scores and subscores of posture instability and gait disturbance, tremor, akinesia, and rigidity while not taking medication. Both voxelwise- and volume of interest–based image analyses were performed. The specific uptake ratio (SUR) of each volume of interest and voxel was calculated as (target uptake − reference uptake) / reference uptake using the occipital reference region from magnetic resonance imaging–based spatially normalized 18F-DTBZ images for each participant. Average SUR images were displayed as 2-dimensional and 3-dimensional to illustrate the image patterns in each group. The nonparametric Kruskal-Wallis test on regional SUR was used for group comparison between healthy control participants and patients with PD at different stages. Quantitative parameters were correlated with severity of disease and disease duration by Spearman correlation. Voxelwise analysis for evaluating dopaminergic neuron decline of different PD stages was performed by SPM5.

Results  The 2-dimensional and 3-dimensional 18F-DTBZ PET images demonstrated that the reduction of vesicular monoamine transporter type 2 availability was obviously correlated with the severity of disease in patients with PD. The mean reductions of vesicular monoamine transporter type 2 density for the caudate, putamen, and substantia nigra were 21.50%, 58.20%, and 21.10% for mild PD; 60.75%, 79.49%, and 39.87% for moderate PD; and 63.94%, 83.20%, and 44.00% for advanced PD, respectively. The SURs of bilateral striatal regions exhibited significantly exponential correlations to stage; disease duration; Unified Parkinson Disease Rating Scale motor score; posture instability and gait disturbance; and akinesia, rigidity, and tremor scores.

Conclusions and Relevance  In PD, 18F-DTBZ PET is a potential imaging biomarker for measuring dopaminergic degeneration in vivo and monitoring the severity of disease.

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Figure 1.
Averaged 2-Dimensional and 3-Dimensional [18F]9-fluoropropyl-(+)-Dihydrotetrabenazine Specific Uptake Ratio Images of Normal Participants and Patients With Parkinson Disease (PD) of Varying Severity

Averaged [18F]9-fluoropropyl-(+)-dihydrotetrabenazine specific uptake ratio 2-dimensional images of healthy control participants (A) and patients with mild PD (C), moderate PD (E), and advanced PD (G). Symmetric and bilateral vesicular monoamine transporter type 2 (VMAT2) binding in dopamine innervation is illustrated in healthy control participants. Asymmetric pattern of nigrostriatal VMAT2 uptake loss is visible in mild PD, while less obvious in moderate PD, and asymmetry almost disappears, but with severe VMAT2 binding decline, in advanced PD. Posterior-to-anterior 3-dimensional views of VMAT2 binding images of dopamine innervation are illustrated for healthy control participants (B), mild PD (D), moderate PD (F), and advanced PD (H). The frame wire in 3-dimensional images indicates the complete volumes of interest of the caudate nuclei, putamen, substantia nigra, and midbrain.

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Figure 2.
Bilateral Posterior Putamen [18F]9-fluoropropyl-(+)-dihydrotetrabenazine Specific Uptake Ratio vs Modified Hoehn-Yahr Stage, Disease Duration, and Unified Parkinson Disease Rating Scale III Score

Scatterplots and fitted exponential curves of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine specific uptake ratio against modified Hoehn-Yahr stage (A), disease duration (B), and Unified Parkinson Disease Rating Scale motor scores (C) in exponential regression models. All were with significant exponential correlations (P < .05). The specific uptake ratios in the ipsilateral posterior putamen were obviously higher than those of the contralateral posterior putamen.

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Figure 3.
Bilateral Posterior Putamen [18F]9-Fluoropropyl-(+)-dihydrotetrabenazine Specific Uptake Ratio vs Subscores of Unified Parkinson Disease Rating Scale III

Scatterplots and fitted exponential curves of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine specific uptake ratio vs subscores of Unified Parkinson Disease Rating Scale motor scores for posture instability and gait disturbance (A), akinesia (B), rigidity (C), and tremor (D). All were with significant exponential correlations (P < .05) except for tremor.

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[18F]9-fluoropropyl-(+)-dihydrotetrabenazine From Normal to Advanced Parkinson Disease (PD)

This is a serial volume rendering video of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine specific uptake ratio maximum intensity projection in normal, mild PD, moderate PD, and advanced PD cases. Gradual decline of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine radioactivity began from the contralateral posterior putamen, followed by the ipsilateral posterior putamen, and then extended to the anterior putamen and caudate nuclei during PD progression.

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