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(+)-DTBZ (18F-AV-133) Brain PET Scan

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(+)-DTBZ (18F-AV-133) Brain PET Scan Journal of the Neurological Sciences 353 (2015) 102–106 Contents lists available at ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns Chronic manganism: A long-term follow-up study with a new dopamine terminal biomarker of 18F-FP-(+)-DTBZ (18F-AV-133) brain PET scan Chu-Yun Huang a,b, Chi-Hung Liu a,c, Eusden Tsao d,e, Chia-Ju Hsieh f,g,Yi-HsinWenga,h, Ing-Tsung Hsiao f,g, Tzu-Chen Yen f,g, Kun-Ju Lin f,g, Chin-Chang Huang a,h,⁎ a Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan b College of Pharmacy, Taipei Medical University, Taipei, Taiwan c Graduate Institute of Clinical Medical Sciences, Division of Medical Education, College of Medicine, Chang Gung University, Taoyuan, Taiwan d Department of Family Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan e Department of Environmental and Occupational Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan f Molecular Imaging Center and Nuclear Medicine, Chang Gung University, Chang Gung Memorial Hospital, Taoyuan, Taiwan g Healthy Aging Research Center Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan h Department of Neurology, College of Medicine, Chang Gung University, Taoyuan, Taiwan article info abstract Article history: Recent experimental studies revealed that dopamine neuron dysfunction in chronic manganism may be due to a Received 12 January 2015 reduced capacity of dopamine release in the striatum. The findings imposed further difficulty in the differential Received in revised form 8 April 2015 diagnosis between manganism and IPD. We conducted a long-term clinical follow-up study of 4 manganism pa- Accepted 9 April 2015 tients, applying a new tracer 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV-133) with positron emission Available online 17 April 2015 tomography (PET). Twenty age-matched subjects including 4 manganism patients, 8 idiopathic Parkinson's dis- ease (IPD) patients, and 8 healthy controls were enrolled for comparison. Volumes of interest of the bilateral pu- Keywords: 18F-FP-(+)-DTBZ tamen, caudate nuclei and occipital cortex as the reference region were delineated from individual magnetic 18F-AV-133 resonance images. The clinical features of the manganism patients still progressed, with increased scores on IPD the Unified Parkinson Disease Rating Scale. The 18F-AV-133 uptake in the IPD patients decreased at the bilateral Manganese striatum, compared with the healthy controls. In the manganism patients, there was no decreased uptake of ra- Positron emission tomography dioactivity involving the bilateral striatum, except Patient 4, who had a stroke with decreased uptake in the right Type 2 vesicle monoamine transporter posterior putamen. The 18F-AV-133 PET finding reveals that nigrostriatum neurons are not degenerated in chron- ic manganism and can provide a useful neuroimage biomarker in the differential diagnosis. © 2015 Elsevier B.V. All rights reserved. 1. Introduction clinical tools to differentiate manganism from IPD. In brain MRI studies, high signal intensities can be found in T1-weighted images in the early Chronic excessive exposure to manganese (Mn) fumes or dust may stage of manganese exposure and then disappear 3 months to 1 year induce the neurological abnormality of manganism, with symptoms after cessation of exposure [11]. Brain PET with [18F]-6-fluoro-dopa or very similar to idiopathic Parkinson's disease (IPD) [1,2]. Typical symp- dopamine transporter binding (DAT) with either TRODAT-1 or [123I]- toms of manganism patients are different from those of patients with beta-CIT showed a normal or nearly normal uptake in manganism IPD [3,4], but some atypical symptoms of manganism patients create a patients [3,12,13]. However, in recent studies, a decrease in dopamine up- diagnostic challenge [5–7]. In addition, several epidemiological studies take in the putamen and caudate areas, similar to IPD, may develop after have revealed that the inhalation of Mn fumes among welders may exposure to manganese fumes among welders or in psychostimulant accelerate the onset of IPD or even induce IPD [8–10]. These findings drug (ephedrone) abusers [6,9,10]. Lately 18F-9-fluoropropyl-(+)- have enlarged the gray zone between diagnoses of manganism and IPD. dihydrotetrabenazine (18F-AV-133), a novel PET tracer, has been devel- Neuroimaging studies such as brain magnetic resonance images oped for imaging the type 2 vesicle monoamine transporter (VMAT2) in (MRI) and brain positron emission tomography (PET) scans may provide dopaminergic neuron degeneration and can provide better resolution, especially for IPD patients [14,15]. We previously reported 6 patients with chronic Mn intoxication at ⁎ Corresponding author at: Department of Neurology, College of Medicine, Chang Gung a ferromanganese alloy factory in Taiwan in 1985 [2]. In the current University and Chang Gung Memorial Hospital, No. 199, Tung Hwa North Road, Taipei study, we investigated brain 18F-dihydrotetrabenazine (18F-DTBZ) 10507, Taiwan. Tel.: +886 3 3281200x8413; fax: +886 3 3287226. 18 E-mail addresses: [email protected], [email protected] PET ( F-AV-133 PET) using a long-term follow-up study design. To (C.-C. Huang). our knowledge, no such long-term comparative study has been http://dx.doi.org/10.1016/j.jns.2015.04.018 0022-510X/© 2015 Elsevier B.V. All rights reserved. C.-Y. Huang et al. / Journal of the Neurological Sciences 353 (2015) 102–106 103 conducted among manganism patients, and this is the first to inves- measured with a matrix size of 400 × 400 × 148 and a voxel size of tigate manganism patients using VMAT2 PET. 0.68 × 0.68 × 1.5 mm3. 2.2. Image analysis 2. Materials and methods All image data were processed and analyzed using PMOD image anal- Four out of the original 6 patients participated in the follow-up ysis software (version 3.3, PMOD Technologies Ltd., Zurich, Switzerland). study; 1 of the 6 patients was unavailable and another expired in Each PET image was co-registered to the corresponding MRI, and the in- 1990 [2,16]. All patients developed Parkinsonian features in a smelting dividual MRI was spatially normalized to the Montreal Neurological Insti- department of a ferromanganese alloy factory in Taiwan. The patients tute (MNI) MRI template [19]. The spatial normalization parameters were were investigated using the Unified Parkinson Disease Rating Scale then applied to the corresponding PET image to obtain the normalized (UPDRS) and the clinical features were charted using video-recording. PET image in the MNI domain. VOIs of bilateral caudate nuclei, anterior/ Brain 18F-AV-133 PET studies were conducted with these 4 manganism posterior putamen, nucleus accumbens, substantia nigra, raphe, amygda- patients (age: 67.8 ± 5.3 years). Eight IPD patients (age: 66.3 ± la, hippocampus, thalamus, hypothalamus, locus coeruleus, brain stem 2.9 years) served as abnormal controls and 8 age-matched volunteers and occipital cortex were defined on the MRI template. The occipital (age: 65.5 ± 3.6 years) were also included as healthy controls (HCs) cortex was included as the reference region to calculate the standard up- for the brain 18F-AV-133 PET scan. The modified Hoehn and Yahr stages take value ratio (SUVR). In the IPD group, the contralateral VOIs were (mH &Y) scores for IPD were in the range of 1 to 3, and the symptomatic defined as the striatum opposite the predominantly affected limbs, and durations of illness were between 1 and 21 years. The study protocol were evaluated separately from the ipsilateral VOIs. VOIs in the HCs was approved by the Institutional Review Board of Chang Gung Memo- and Mn intoxication patients were defined as the left and right sides for rial Hospital and the Governmental Department of Health, with written future analysis. informed consent obtained prior to all procedures for each participant. Neurologic examinations were performed for all subjects including as- 2.3. Statistical analysis sessment of duration of illness and mH &Y stages. Regional SUVRs computed from 18F-FP-(+)-DTBZ images were 2.1. Data acquisition statistically compared among HCs, IPD patients, and Mn intoxication patients using nonparametric Kruskal–Wallis tests with Dunn's multi- 18F-FP-(+)-DTBZ was prepared and synthesized at the cyclotron fa- ple comparison post hoc test in GraphPad Prism (version 5.0, GraphPad cility of Chang Gung Memorial Hospital as described previously [17].All software, San Diego, CA). A p value of 0.05 was selected as the threshold subjects were studied in a Biograph mCT PET/CT System (Siemens Med- of statistical significance in each test. ical Solutions, Malvern, PA, USA) with a 3-dimensional (3D) acquisition mode. All subjects underwent MRI for screening of other diseases, 3. Results obtaining structural information and delineating volumes of interest (VOIs), and for performing spatial normalization with PET images. Sub- The ages of the patients that underwent 18F-AV-133 PET ranged jects were then imaged on a 3T Siemens Magnetom TIM Trio scanner from 62 to 73 years, and the ages of manganism onset ranged from 36 (Siemens Medical Solutions, Malvern, PA, USA). to 48 years, with duration of exposure from 5 to 13 years. The main clin- After injection of 380.1 ± 11.8 MBq of 18F-FP-(+)-DTBZ, a single 10- ical manifestations included micrographia, masked face/dystonic smile, min PET scan was acquired 90 min post-injection in 3D mode [18].PET hypophonia/stuttering speech, dystonic foot, wide-based gait, difficulty images were then reconstructed using the 3-D OSEM algorithm (4 iter- in turning, difficulty in walking backwards, postural instability, and ri- ations, 24 subsets; Gaussian filter: 2 mm; zoom: 3) with CT-based at- gidity. Tremor was not prominent and presented in 2 patients only tenuation correction, and also scatter and random corrections as (Patient 1 in the hands while walking, and patients 1 and 4 in the tongue provided by the manufacturer.
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