Ing-Tsung Hsiao1, Yi-Hsin Weng2, Chia-Ju Hsieh3, Wey-Yil Lin4, Shiaw-Pyng Wey1, Mei-Ping Kung5, Tzu-Chen Yen6, Chin-Song Lu7, Kun-Ju Lin1. 1. Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan2Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan3Department of Nuclear Medicine and Molecular Imaging Center, Chang G. 2. Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan5Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan6School of Medicine, Chang Gung University, Taoyuan, Taiwan. 3. Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan2Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. 4. Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan5Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 5. Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan2Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan7Department of Radiology, University of Pennsylvania, Philadelphia. 6. Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan3Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 7. Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan4Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan5Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Abstract
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[Parkinson disease];60.75%, 79.49%,and 39.87%formoderate PD; and63.94%,83.20%, and 44.00% for advanced PD, respectively [corrected]. 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.
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[Parkinson disease];60.75%, 79.49%,and 39.87%formoderatePD; and63.94%,83.20%, and 44.00% for advanced PD, respectively [corrected]. 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.
Authors: D Campbell Dewey; Svjetlana Miocinovic; Ira Bernstein; Pravin Khemani; Richard B Dewey; Ross Querry; Shilpa Chitnis; Richard B Dewey Journal: J Neurol Sci Date: 2014-07-19 Impact factor: 3.181