RESUMEN
BACKGROUND/PURPOSE: To determine whether dual-phase 18F-florbetapir positron emission tomography imaging with perfusion-like and amyloid deposition information can distinguish among primary progressive aphasia (PPA), Alzheimer's disease (AD), and healthy controls (HCs). METHODS: Patients diagnosed with PPA, including four semantic dementia (SD) and two progressive nonfluent aphasia (PNFA), as well as one logopenic variant (LV) of PPA, were studied. All PPA patients, and age-/sex-matched patients with probable AD (n=8) and HCs (n=8) were subjected to dual-phase 18F-florbetapir imaging. Atlas-based quantitative volumes of interest (VOIs) analysis for six cortical areas and whole cerebellum was performed. The standardized uptake value ratios were calculated by normalizing the dual-phase-integrated activities of the six VOIs to whole cerebellum counts. RESULTS: Early phase 18F-florbetapir image showed significantly lower global perfusion index in six PPA patients as compared with HCs. According to VOI analysis, the hypoperfusion lesions were identified in the frontal, anterior cingulate, parietal, precuneus, and temporal regions. Similar findings were confirmed by voxel-base image comparison. 18F-florbetapir late-phase image showed significantly increased amyloid burden in the global cortex index and all six brain regions of eight AD and LV patients when compared with the other six PPA patients and eight HCs. There was no apparent uptake of amyloid tracer in both six PPA patients and eight HCs. CONCLUSION: Dual-phase 18F-florbetapir images of six PPA (SD and PNFA) patients showed hypoperfusion in the frontotemporal cortex, and little global amyloid uptake, which may be a distinct image pattern for differentiation among HC, AD, and PPA patients.
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Enfermedad de Alzheimer/diagnóstico por imagen , Afasia Progresiva Primaria/diagnóstico por imagen , Encéfalo/patología , Tomografía de Emisión de Positrones , Anciano , Compuestos de Anilina/administración & dosificación , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Glicoles de Etileno/administración & dosificación , Femenino , Fluorodesoxiglucosa F18/administración & dosificación , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , TaiwánRESUMEN
OBJECTIVE: Lactacystin has been used to establish rodent models of Parkinson disease (PD), with cerebral α-synuclein inclusions. This study evaluated the uptake of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ), a vesicular monoamine transporter type 2 (VMAT2)-targeting radiotracer, through positron emission tomography (PET) in lactacystin-treated rat brains. METHODS: Adult male Sprague-Dawley rats were randomly treated with a single intracranial dose of lactacystin (2 or 5 µg) or saline (served as the sham control) into the left medial forebrain bundle. A 30-min static [18F]FP-(+)-DTBZ brain PET scan was performed following an intravenous [18F]FP-(+)-DTBZ dose (approximately 22 MBq) in each animal at 2 and 3 weeks after lactacystin treatment. Upon completing the last PET scans, the animals were killed, and their brains were dissected for ex vivo autoradiography (ARG) and immunohistochemical (IHC) staining of tyrosine hydroxylase (TH) as well as VMAT2. RESULTS: Both the 2- and 5-µg lactacystin-treated groups exhibited significantly decreased specific [18F]FP-(+)-DTBZ uptake in the ipsilateral striata (I-ST) at 2 weeks (1.51 and 1.16, respectively) and 3 weeks (1.36 and 1.00, respectively) after lactacystin treatment, compared with the uptake in the corresponding contralateral striata (C-ST) (3.48 and 3.08 for the 2- and 5-µg lactacystin-treated groups, respectively, at 2 weeks; 3.36 and 3.11 for the 2- and 5-µg lactacystin-treated groups, respectively, at 3 weeks) and the sham controls (3.34-3.53). Lactacystin-induced decline in I-ST [18F]FP-(+)-DTBZ uptake was also demonstrated through ex vivo ARG, and the corresponding dopaminergic neuron damage was confirmed by the results of TH- and VMAT2-IHC studies. CONCLUSIONS: In this PD model, lactacystin-induced dopaminergic terminal damage in the ipsilateral striatum could be clearly visualized through in vivo [18F]FP-(+)-DTBZ PET imaging. This may serve as a useful approach for evaluating the effectiveness of new treatments for PD.
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Acetilcisteína/análogos & derivados , Enfermedad de Parkinson/diagnóstico por imagen , Tetrabenazina/análogos & derivados , Acetilcisteína/farmacología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Radioisótopos de Flúor/metabolismo , Procesamiento de Imagen Asistido por Computador , Masculino , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Tetrabenazina/metabolismoRESUMEN
18F-9-Fluoropropyl-(+)-dihydrotetrabenazine [18F-FP-(+)-DTBZ] positron emission tomography (PET) has been shown to detect dopaminergic neuron loss associated with Parkinson's disease (PD) in human and neurotoxin-induced animal models. A polyphenol compound, magnolol, was recently proposed as having a potentially restorative effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 6-hydroxydopamine-treated animal models. In this study, 18F-FP-(+)-DTBZ PET was used to determine the therapeutic efficacy of magnolol in an MPTP-PD mouse model that was prepared by giving an intraperitoneally (i.p.) daily dose of 25 mg/kg MPTP to male C57BL/6 mice for 5 consecutive days. Twenty-minute static 18F-FP-(+)-DTBZ PET scans were performed before MPTP treatment and 5 days after the termination of MPTP treatment to set up the baseline control. Half of the MPTP-treated mice then received a daily dose of magnolol (10 mg/kg dissolved in corn oil, i.p.) for 6 days. 18F-FP-(+)-DTBZ PET imaging was performed the day after the final treatment. All 18F-FP-(+)-DTBZ PET images were analysed and the specific uptake ratio (SUr) was calculated. Ex vivo autoradiography (ARG) and corresponding immunohistochemistry (IHC) studies were conducted to confirm the distribution of dopaminergic terminals in the striatum. The striatal SUr ratios of 18F-FP-(+)-DTBZ PET images for the Sham, the MPTP, and the MPTP + Magnolol-treated groups were 1.25 ± 0.05, 0.75 ± 0.06, and 1.00 ± 0.11, respectively (n = 4 for each group). The ex vivo 18F-FP-(+)-DTBZ ARG and IHC results correlated favourably with the PET imaging results. 18F-FP-(+)-DTBZ PET imaging suggested that magnolol post-treatment may reverse the neuronal damage in the MPTP-lesioned PD mice. In vivo imaging of the striatal vesicular monoamine transporter type 2 (VMAT2) distribution using 18F-FP-(+)-DTBZ animal PET is a useful method to evaluate the efficacy of therapeutic drugs i.e., magnolol, for the management of PD.
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Compuestos de Bifenilo/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Lignanos/administración & dosificación , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Radioisótopos de Flúor/administración & dosificación , Humanos , Ratones , Neuronas/efectos de los fármacos , Neuronas/patología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnóstico por imagen , Tomografía de Emisión de Positrones , Tetrabenazina/administración & dosificación , Tetrabenazina/análogos & derivadosRESUMEN
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.
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Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Adulto , Anciano , Femenino , Radioisótopos de Flúor , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Rigidez Muscular/diagnóstico , Tomografía de Emisión de Positrones/métodos , Tetrabenazina/análogos & derivados , Temblor/diagnósticoRESUMEN
UNLABELLED: (99m)Tc-TRODAT-1 is the first clinical routine (99m)Tc radiopharmaceutical to evaluate dopamine neurons loss in Parkinson's disease (PD). (18)F-AV-133 is a novel PET radiotracer targeting the vesicular monoamine transporter type 2 (VMAT2) to detect monoaminergic terminal reduction in PD patients. The aim of this study is to compare both images in the same health control (HC) and PD subjects. METHODS: Eighteen subjects (8 HC and 10 PD) were recruited for (99m)Tc-TRODAT-1 SPECT, (18)F-AV-133 PET and MRI scans within two weeks. The SPECT images were performed at 4-h post-injection for 45 min, and the PET images were performed at 90 min post-injection for 10 min. Each PET and SPECT image was normalized into Montreal Neurological Institute template aided from individual MRI for comparison. For regional analysis, volume of interest (VOIs) of bilateral caudate nuclei, anterior, posterior putamen and occipital cortex (as reference region) were delineated from the normalized MRI. The specific uptake ratio (SUR) was calculated as (regional mean counts/reference mean counts-1). The nonparametric Mann-Whitney U test was used to evaluate the power of differentiating control from PD subjects for both image modalities. The correlations of the SURs to the clinical parameters were examined. For voxelwise analysis, two-sample t-test for group comparison between HC and PD was computed in both image modalities. RESULTS: The SURs of caudate nucleus and putamen correlated well between two image modalities (r = 0.81, p<0.001), and showed significant different between HC and PD subjects. Of note, the (18)F-AV-133 SUR displayed a better correlation to PD clinical laterality index as compared to (99m)Tc-TRODAT-1 (r = 0.73 vs. r = 0.33). Voxelwise analysis showed more lesions for PD subjects from (18)F-AV-133 image as compared to (99m)Tc-TRODAT-1 especially at the substantia nigra region. CONCLUSION: (18)F-AV-133 PET demonstrated similar performance in differentiation PD from control, and a better correlation to clinical characteristics than that of (99m)Tc-TRODAT-1 SPECT. (18)F-AV-133 PET also showed additional information in substantia nigra integrity in PD subjects by voxelwise analysis. Collectively, (18)F-AV-133 could be a promising and better tracer for clinical use to detect monoaminergic terminal reduction in PD patients.
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Compuestos de Organotecnecio , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tetrabenazina/análogos & derivados , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tropanos , Anciano , Estudios de Casos y Controles , Femenino , Radioisótopos de Flúor , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana EdadRESUMEN
UNLABELLED: PET with (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine ((18)F-DTBZ), a novel radiotracer targeting vesicular monoamine transporter type 2 (VMAT2), has been proven as a useful imaging marker to measure dopaminergic integrity. METHODS: The aim of this study was to evaluate the capability of (18)F-DTBZ PET in detecting the monoaminergic degeneration in early Parkinson disease (PD) in vivo. Seventeen age-matched healthy subjects and 30 PD patients at early stage of disease (duration of disease ≤ 5 y) with mild and unilateral motor symptoms underwent (18)F-DTBZ PET scans. The severity of disease, including Unified Parkinson Disease Rating Scale and modified Hoehn and Yahr Stage (mHY), were recorded at off-medication states. The standardized volumes of interest were applied to the spatial normalized image for quantification analysis. The specific uptake ratios (SURs) were calculated according to the formula (specific volumes-of-interest counts/occipital cortex counts) - 1. SUR measurements were summarized for each brain region. RESULTS: The mean duration of disease in the PD group was 3.2 ± 2.1 y (range, 0.5-5 y). The mean mHY was 1.0 ± 0.1 (range, 1-1.5). The SURs of bilateral caudate, anterior putamen, posterior putamen, substantia nigra, and nucleus accumbens were significantly lower in PD patients than those of healthy subjects. The reduction of SURs was most severe in the contralateral (the brain regions that are located opposite to the symptomatic side) posterior putamen (-81%), followed by the ipsilateral posterior putamen (-67%). Receiver-operating-characteristic curve analysis showed that the SURs of the bilateral posterior putamen and contralateral anterior putamen had a sensitivity of 100% and specificity of 100% in differentiating PD patients from healthy subjects. CONCLUSION: (18)F-DTBZ PET was as an excellent tool for the early diagnosis of PD. The obvious decline of (18)F-DTBZ uptake in the ipsilateral (asymptomatic) striatum suggested that (18)F-DTBZ PET might serve as an in vivo biomarker to detect the monoaminergic degeneration in the premotor phase of PD.
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Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Tetrabenazina/análogos & derivados , Adulto , Anciano , Aminas/química , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Sensibilidad y Especificidad , Factores de Tiempo , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
UNLABELLED: (18)F-FP-(+)-DTBZ is a novel PET radiotracer targeting vesicular monoamine transporter type 2 (VMAT2). The goal was to explore the image features in normal human brains with (18)F-FP-(+)-DTBZ as a reference of molecular landmark for clinical diagnosis in Parkinson's disease (PD) and related disorders. MATERIALS AND METHODS: A total of 22 healthy subjects (59.3±6.0 years old) including 7 men and 15 women were recruited for MRI and (18)F-FP-(+)-DTBZ PET scans. A total number of 55 brain VOIs were selected for quantitation analysis. The regional specific uptake ratio (SUR) was calculated with occipital as reference from MRI-based spatially normalized (18)F-FP-(+)-DTBZ images. Regional percentage SUR to that of anterior putamen was calculated. Average SUR images were displayed in 2D and 3D space to illustrate the image patterns. The correlation between age and regional VMAT2 uptake was also examined. RESULTS: Visual assessment showed symmetric uptake of (18)F-FP-(+)-DTBZ and obviously highest in striatum, followed by nucleus accumbens, hypothalamus, substantia nigra, and raphe nuclei. Quantification analysis revealed striatal VMAT2 density of anterior putamen>posterior putamen>caudate nucleus. Other subcortical regions were with moderate VMAT2 distribution (6â¼51% SUR of anterior putamen), while slightly lower VMAT2 was observed in cerebellum (10.60% SUR) and much lower in neocortex (<5% SUR). No significant correlation of SUR to age was found in subcortical regions. CONCLUSION: Using (18)F-FP-(+)-DTBZ PET, we showed the 2D and 3D imaging features of the VMAT2 distribution in vivo in healthy aging brains. The in vivo imaging characteristics of VMAT2 is consistent with the expression of VMAT2 in a recent autopsy study. Therefore, 3D visualization and higher image quality of (18)F-FP-(+)-DTBZ PET imaging might potentially be a powerful biomarker in detecting VMAT2 distribution of subcortical regions, and for Parkinson's disease and related neuropsychiatric disorders involving related monoaminergic systems.
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Neuroimagen/métodos , Enfermedad de Parkinson/diagnóstico , Tomografía de Emisión de Positrones/métodos , Proteínas de Transporte Vesicular de Monoaminas/ultraestructura , Femenino , Radioisótopos de Flúor , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Estándares de Referencia , Estadísticas no ParamétricasRESUMEN
BACKGROUND: To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD) subjects with [(18)F]AV-45 positron emission tomography (PET). MATERIALS AND METHODS: [(18)F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [(18)F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed. RESULTS: The global cortical [(18)F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (pâ=â0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment. CONCLUSIONS: Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [(18)F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [(18)F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.
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Enfermedad de Alzheimer/metabolismo , Amnesia/metabolismo , Amiloide/metabolismo , Disfunción Cognitiva/metabolismo , Tomografía de Emisión de Positrones/métodos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Amnesia/diagnóstico , Pueblo Asiatico , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Amyloid positron emission tomography (PET) is an important noninvasive method for detecting amyloid burden in Alzheimer's disease (AD) patients. As amyloid PET images have limited anatomical information, magnetic resonance (MR) imaging is usually acquired to perform reliable spatial normalization needed for large-scale analysis. This work proposed and evaluated the performance of new MR-free spatial normalization methods using a perfusion-like template for amyloid PET imaging. METHODS: Amyloid PET and MR images were collected in 35 subjects (cohort 1: 8 AD patients and 6 controls; cohort 2: 15 AD patients and 6 controls). Three ligand-related templates (AD, control, mixed group) and a perfusion-like template (pAV-45) from early time frames of amyloid PET images were constructed from cohort 1. The variations of (18)F-AV-45 standardized uptake value ratios (SUVRs) among AD patients, controls, and all subjects were tested with repeated two-way (template × brain region) analysis of variance (ANOVA) in cohort 2. (18)F-AV-45 SUVRs by region of interest analysis and voxelwise analysis between MR-based and MR-free approaches were compared and correlated to clinical and image parameters. Effect size (group mean SUVR difference between AD and control/standard deviation) was also evaluated for each template method. RESULTS: Significantly different (18)F-AV-45 SUVRs between MR-free spatial normalization and MR-based reference images were found among AD patients, controls, and all subjects by the effect of template and brain regions. The highest correlation (r=0.991) of (18)F-AV-45 SUVR to MR-based reference was found in the pAV-45 group. The SUVR percentage difference to MR-based reference showed the least variation and bias (control: -1.31±3.47 %; AD: -0.36±2.50 %) in the pAV-45 group as well. The voxelwise analysis showed the smallest t statistic value in pAV-45 followed by mixed, control, and AD groups when compared to MR-based reference images. Moreover, an overall larger effect size but compatible to that of MR-based reference result was observed in the pAV-45 group as compared to those of the other MR-free template. CONCLUSION: The novel MR-free template based on the early-phase perfusion images pAV-45 approach for amyloid imaging showed significantly better performance in quantitation accuracy, effect size, and stability when compared with other MR-free PET templates and thus has potential for large-scale clinical applications.
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Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Glicoles de Etileno , Radioisótopos de Flúor/farmacología , Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Amiloide/análisis , Estudios de Casos y Controles , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Perfusión , Reproducibilidad de los ResultadosRESUMEN
The formation and deposition of ß-amyloid (Aß) plaques are the earliest pathological changes in Alzheimer's disease (AD). Molecular imaging of Aß plaques could serve as a surrogate marker in early diagnosis and neuropathogenesis studies of AD. Several radionuclide labeled ligands have recently been developed for noninvasive visualization of Aß plaques in the brains of AD patients using single photon emission computed tomography or positron emission tomography (PET). There has been rapid progress in the field of imaging for plaque pathology. AV-45 was the first plaque imaging agent to enter multi-center, investigational new drug clinical trials in the US, and has now been studied in dozens of trials with more than 1,000 subjects ranging from cognitively normal individuals to those with AD dementia. "Imaging to autopsy" phase III studies further confirmed and validated the specific imaging signal correlated to the plaque burden in living subjects. With these promising and confirmed characteristics of AV-45, the Alzheimer's Disease Neuroimaging Initiative (ADNI) under common consensus decided on AV-45 as the emerging standard PET imaging agent for evaluating the progression of plaque pathology in patients with AD or mild cognition impairment, and even healthy controls. With the wide availability of AV-45 for plaque imaging, the ultimate goal of the ADNI is global clinical trials for disease detection and progression. This review presents recent experience with Aß-targeting radiotracers at Chang Gung University and Chang Gung Memorial Hospital.
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Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Glicoles de Etileno , Placa Amiloide/diagnóstico por imagen , Pirazoles , Animales , Humanos , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
UNLABELLED: [¹8F]AV-133 is a novel PET tracer for targeting the vesicular monoamine transporter 2 (VMAT2). The aim of this study is to characterize and quantify the loss of monoamine neurons with [¹8F]AV-133 in the MPTP-lesioned PD mouse model using animal PET imaging and ex vivo quantitative autoradiography (QARG). METHODS: Optimal imaging time window of [¹8F]AV-133 was first determined in normal C57BL/6 mice (n = 3) with a 90-min dynamic scan. The reproducibility of [¹8F]AV-133 PET imaging was evaluated by performing a test-retest study within 1 week for the normal group (n = 6). For MPTP-lesioned studies, normal, and MPTP-treated [25 mg mg/kg once (Group A) and twice (Group B), respectively, daily for 5 days, i.p., groups of four normal and MPTP-treated] mice were used. PET imaging studies at baseline and at Day 4 post-MPTP injections were performed at the optimal time window after injection of 11.1 MBq [¹8F]AV-133. Specific uptake ratio (SUr) of [¹8F]AV-133 was calculated by [(target uptake-cerebellar uptake)/cerebellar uptake] with cerebellum as the reference region. Ex vitro QARG and immunohistochemistry (IHC) studies with tyrosine hydroxylase antibody were carried out to confirm the abundance of dopaminergic neurons. RESULTS: The variability between [¹8F]AV-133 test-retest striatal SUr was 6.60 ± 3.61% with less than 5% standard deviation between animals (intervariability). The percentages of MPTP lesions were Group A 0.94 ± 0.29, -42.1% and Group B 0.65 ± 0.09, -60.4%. By QARG, specific binding of [¹8F]AV-133 was reduced relative to the control groups by 50.6% and 60.7% in striatum and by 30.6% and 46.4% in substantia nigra (Groups A and B, respectively). Relatively small [¹8F]AV-133 SUr decline was noted in the serotonin and norepinephrine-enriched regions (7.9% and 9.4% in mid-brain). Results obtained from IHC consistently confirmed the sensitivity and selectivity of dopaminergic neuron loss after MPTP treatment. CONCLUSIONS: [¹8F]AV-133 PET SUr displayed a high test-retest stability. The SUr significantly declined in the caudate putamen but not in the hypothalamus and midbrain regions after MPTP treatment in the mouse brain. The results obtained for QARG and IHC were consistent and correlated well with the PET imaging studies. On the basis of these concordant results, we find that [¹8F]AV-133 should serve as a useful and reliable PET tracer for evaluating nigrostriatal degeneration.
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Intoxicación por MPTP/diagnóstico por imagen , Tetrabenazina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/análisis , Animales , Sitios de Unión , Encéfalo/diagnóstico por imagen , Modelos Animales de Enfermedad , Radioisótopos de Flúor/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones/métodos , Tetrabenazina/farmacocinéticaRESUMEN
PURPOSE: (18)F-Florbetapir (AV-45/Amyvid) is a novel positron emission tomography (PET) tracer for imaging plaque pathology in Alzheimer's disease (AD), while PET images of fluorodeoxyglucose (FDG) for cerebral glucose metabolism can provide complementary information to amyloid plaque images for diagnosis of AD. The goal of this preliminary study was to investigate the perfusion-like property of relative cerebral blood flow estimates (R(1)) and summed early-phase AV-45 images [perfusion AV-45 (pAV-45)] and optimize the early time frame for pAV-45. METHODS: Dynamic AV-45 PET scans (0-180 min) were performed in seven subjects. pAV-45, late-phase AV-45, and FDG images were spatially normalized to the Montreal Neurological Institute template aided by individual MRI images, and the corresponding standardized uptake value ratio (SUVR) was computed. The R(1) images were derived from a simplified reference tissue model. Correlations between regional and voxelwise R(1) and the corresponding FDG images were calculated. An optimization of time frames of pAV-45 was conducted in terms of correlation to FDG images. The optimal early time frame was validated in a separate cohort. RESULTS: The regional distribution in the R(1) images correlated well (R = 0.91) to that of the FDG within subjects. Consistently high correlation was noted across a long range of time frames. The maximal correlation of pAV-45 to FDG SUVR of R = 0.95 was observed at the time frame of 1-6 min, while the peak correlation of R = 0.99 happened at 0-2 min between pAV-45 and R(1). A similar result was achieved in the validation cohort. CONCLUSION: Preliminary results showed that the distribution patterns of R(1) and pAV-45 images are highly correlated with normalized FDG images, and the initial 5-min early time frame of 1-6 min is potentially useful in providing complementary FDG-like information to the amyloid plaque density by late-phase AV-45 images.
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Compuestos de Anilina , Glicoles de Etileno , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones/métodos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Circulación Cerebrovascular , Femenino , Glucosa/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de TiempoRESUMEN
UNLABELLED: The vesicular monoamine transporter type II (VMAT2) is highly expressed in pancreatic ß-cells and thus has been proposed to be a potential target for measuring ß-cell mass (BCM) by molecular imaging. Several tracers based on the TBZ backbone, including 9-fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133), have shown some promising results as potential biomarkers for BCM despite a relatively high background signal in the pancreas. In the present study, we explore the background binding characteristics of [(18)F]AV-133 in rat pancreas. METHODS: Pancreatic exocrine cells and islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum regions, were used for in vitro binding studies of [(18)F]AV-133 under a selective masking condition. 1,3-Di-o-tolylguanidine (DTG), displaying high and roughly equal affinity for both sigma-1 and sigma-2 receptors, was chosen at 5 µM concentration for the masking/blocking studies. RESULTS: [(18)F]AV-133 binding to rat striatum homogenates was not significantly altered by the presence of DTG. In contrast, [(18)F]AV-133 showed significant competition with DTG for binding sites in rat pancreatic exocrine homogenates as well as in rat islet cell homogenates. Importantly, in the presence of DTG, [(18)F]AV-133 showed a single high-affinity binding site on islet cell homogenates with a K(d) value of 3.8 nM which is consistent with the affinity reported previously for VMAT2 sites in rat pancreas. CONCLUSIONS: [(18)F]AV-133, in addition to a high-affinity VMAT2 binding site, binds with low affinity (but high capacity) to sigma components that are present in the rat pancreas. Identification of the cause of background binding of [(18)F]AV-133 to rat pancreatic tissue may lead to improved methods for quantification.
Asunto(s)
Pancrelipasa/metabolismo , Receptores sigma/metabolismo , Tetrabenazina/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Unión Competitiva , Radioisótopos de Flúor , Guanidinas/metabolismo , Masculino , Neostriado/metabolismo , Unión Proteica , Trazadores Radiactivos , Ratas , Ratas Sprague-Dawley , Especificidad por Sustrato , Tetrabenazina/análogos & derivados , Tetrabenazina/químicaRESUMEN
UNLABELLED: (18)F-9-fluoropropyl-(+)-dihydrotetrabenazine ((18)F-AV-133) is a novel positron emission tomography tracer for imaging the vesicular monoamine transporter II in dopaminergic neuron degeneration, which might be indicative for Parkinson's disease (PD) and other parkinsonism. Studies were performed to optimize the imaging time window for calculating standardized uptake value ratio (SUVR) with correlation to distribution volume ratio (DVR) and in differentiating PD from normal controls (NCs). METHODS: Thirteen (18)F-AV-133 positron emission tomography studies were conducted on four NCs (age, 62.3±4.9 years) and nine PD patients (age, 60.8±6.0 years) with Hoehn and Yahr stages 2 to 3. Dynamic images were acquired within 180 min (0-30, 50-140 and 160-180 min) and were rearranged into 14 of 10-min scans. The contralateral striatum was defined as the opposite striatum to the predominantly affected limbs. Volumes of interest (VOIs) of bilateral putamen, caudate nuclei and occipital cortex (OC; as the reference region) were delineated from individual magnetic resonance imaging. SUVRs of striatum to OC were computed from 14 dynamic image sets. The DVRs were computed from Logan graphic analysis by using OC as the input. The performance of SUVR was evaluated based on the correlation of SUVR at each time window to DVR, as well as the Cohen effect size (group mean SUVR difference between PD and NC/standard deviation). RESULTS: (18)F-AV-133 uptake decreased in PD subjects at bilateral striatum especially at contralateral side with posterior putamen predominant as compared with NC. Consistent higher correlations of SUVRs to DVR for all VOIs were observed at later time window and reached to its maximal value of 0.9917 at 90-100 min. The group mean SUVR differences between NC and PD subjects increased and reached relatively stable values after 90 min. The effect sizes for all VOIs were stable across different time window and with the largest value around 90~120 min. CONCLUSION: The scanning time of 90-100 min for (18)F-AV-133 is considered as the optimal time window for summed uptake measurements in terms of SUVRs' correlation to DVRs, differential power, stability and clinical feasibility across and between NC and PD patients.
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Radioisótopos de Flúor , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tetrabenazina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Anciano , Estudios de Casos y Controles , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/metabolismo , Femenino , Radioisótopos de Flúor/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/metabolismo , Putamen/diagnóstico por imagen , Putamen/metabolismo , Tetrabenazina/farmacocinética , Factores de TiempoRESUMEN
UNLABELLED: Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-(18)F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-FP-(+)-dihydrotetrabenazine [DTBZ] or (18)F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use. METHODS: Nine healthy human subjects (mean age +/- SD, 58.6 +/- 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 +/- 22.9 MBq of (18)F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs. RESULTS: The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% +/- 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 +/- 23.8 microGy/MBq, was the pancreas. The effective dose equivalent and effective dose for (18)F-AV-133 were 36.5 +/- 2.8 and 27.8 +/- 2.5 microSv/MBq, respectively. These values are comparable to those reported for any other (18)F-labeled radiopharmaceutical. CONCLUSION: (18)F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.
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Imagen Molecular/métodos , Tetrabenazina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Radioisótopos de Flúor , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiometría , Tetrabenazina/efectos adversos , Tetrabenazina/farmacocinéticaRESUMEN
Sigma-2 receptors represent an endogenous marker for proliferation in solid tumors. The high affinity, high selectivity sigma(2) receptor ligand N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-fluoroethoxy)-5-iodo-3-methoxybenzamide (3) was separately radiolabeled with F-18 and I-125. The radiolabeling yield was 30% and 70% for [(18)F]3 and [(125)I]3, respectively. Studies of [(125)I]3 using murine 66 breast tumor membrane homogenates and evaluation of [(18)F]3 and [(125)I]3 in 66 tumor-bearing mice indicate that this ligand has potential as a PET or a SPECT probe for imaging sigma(2) receptors in breast cancer.
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Neoplasias de la Mama/diagnóstico , Receptores sigma/metabolismo , Animales , Femenino , Radioisótopos de Flúor/metabolismo , Radioisótopos de Yodo/metabolismo , Ligandos , Tomografía de Emisión de Positrones , Conejos , Ratas , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
We report herein the Good Manufacturing Practice (GMP)-compliant automated synthesis of (18)F-labeled styrylpyridine, AV-45 (Florbetapir), a novel tracer for positron emission tomography (PET) imaging of beta-amyloid (Abeta) plaques in the brain of Alzheimer's disease patients. [(18)F]AV-45 was prepared in 105 min using a tosylate precursor with Sumitomo modules for radiosynthesis under GMP-compliant conditions. The overall yield was 25.4+/-7.7% with a final radiochemical purity of 95.3+/-2.2% (n=19). The specific activity of [(18)F]AV-45 reached as high as 470+/-135 TBq/mmol (n=19). The present studies show that [(18)F]AV-45 can be manufactured under GMP-compliant conditions and could be widely available for routine clinical use.
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Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Glicoles de Etileno , Radioisótopos de Flúor , Adhesión a Directriz , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Automatización , Cromatografía Líquida de Alta Presión , Humanos , Tomografía de Emisión de PositronesRESUMEN
UNLABELLED: The vesicular monoamine transporter type 2 (VMAT2) is highly expressed in pancreatic beta-cells and thus has been proposed to be a potential target for measuring beta-cell mass (BCM) by molecular imaging. C-11- and F-18-labeled tetrabenazine derivatives targeting VMAT2 have shown some promising results as potential biomarkers for BCM. In the present study, we examined the binding characteristics of 9-fluoropropyl-(+)-dihydrotetrabenzazine ([(18)F]AV-133), a potential PET tracer for BCM imaging, in rat pancreas and rat brain. METHODS: Pancreatic exocrine cells and pancreatic islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum and hypothalamus regions, were used for in vitro binding studies. In vitro and ex vivo autoradiography studies with [(18)F]AV-133 were performed on rat brain and rat pancreas sections. Immunohistochemistry studies were performed to confirm the distribution of VMAT2 on islet beta-cells. RESULTS: Excellent binding affinities of [(18)F]AV-133 were observed in rat striatum and hypothalamus homogenates with K(d) values of 0.19 and 0.25 nM, respectively. In contrast to single-site binding observed in rat striatum homogenates, rat islet cell homogenates showed two saturable binding sites (site A: K(d)=6.76 nM, B(max)=60 fmol/mg protein; site B: K(d)=241 nM, B(max)=1500 fmol/mg protein). Rat exocrine pancreas homogenates showed only a single low-affinity binding site (K(d)=209 nM), which was similar to site B in islet cells. In vitro autoradiography of [(18)F]AV-133 using frozen sections of rat pancreas showed specific labeling of islets, as evidenced by co-localization with anti-insulin antibody. Ex vivo VMAT2 pancreatic autoradiography in the rat, however, was not successful, in contrast to the excellent ex vivo autoradiography of VMAT2 binding sites in the brain. In vivo/ex vivo islet labeling may be complicated by the presence of the low-affinity/high-capacity site B binding in rat pancreas. CONCLUSIONS: [(18)F]AV-133 is an excellent imaging agent for mapping VMAT2 sites in rat brain and specifically binds rat islet cells in vitro and postmortem. Additional optimization may be required to achieve ex vivo islet beta-cell labeling in rats.
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Tetrabenazina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Autorradiografía , Encéfalo/citología , Encéfalo/metabolismo , Radioisótopos de Flúor , Inmunohistoquímica , Masculino , Imagen Molecular , Páncreas/citología , Páncreas/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Tetrabenazina/metabolismoRESUMEN
PURPOSE: The compound (E)-4-(2-(6-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy) pyridin-3-yl)vinyl)-N-methylbenzenamine ([(18)F]AV-45) is a novel radiopharmaceutical capable of selectively binding to beta-amyloid (A beta) plaques. This pilot study reports the safety, biodistribution, and radiation dosimetry of [(18)F]AV-45 in human subjects. METHODS: In vitro autoradiography and fluorescent staining of postmortem brain tissue from patients with Alzheimer's disease (AD) and cognitively healthy subjects were performed to assess the specificity of the tracer. Biodistribution was assessed in three healthy elderly subjects (mean age: 60.0+/-5.2 years) who underwent 3-h whole-body positron emission tomography (PET)/computed tomographic (CT) scans after a bolus injection of 381.9+/-13.9 MBq of [(18)F]AV-45. Another six subjects (three AD patients and three healthy controls, mean age: 67.7+/-13.6 years) underwent brain PET studies. Source organs were delineated on PET/CT. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. RESULTS: In vitro autoradiography revealed exquisitely high specific binding of [(18)F]AV-45 to postmortem AD brain sections, but not to the control sections. There were no serious adverse events throughout the study period. The peak uptake of the tracer in the brain was 5.12+/-0.41% of the injected dose. The highest absorbed organ dose was to the gallbladder wall (184.7+/-78.6 microGy/MBq, 4.8 h voiding interval). The effective dose equivalent and effective dose values for [(18)F]AV-45 were 33.8+/-3.4 microSv/MBq and 19.3+/-1.3 microSv/MBq, respectively. CONCLUSION: [(18)F]AV-45 binds specifically to A beta in vitro, and is a safe PET tracer for studying A beta distribution in human brain. The dosimetry is suitable for clinical and research application.
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Amiloide/metabolismo , Compuestos de Anilina/farmacocinética , Encéfalo/diagnóstico por imagen , Glicoles de Etileno/farmacocinética , Radioisótopos de Flúor , Tomografía de Emisión de Positrones/métodos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Compuestos de Anilina/metabolismo , Benzotiazoles , Encéfalo/metabolismo , Estudios de Casos y Controles , Glicoles de Etileno/metabolismo , Femenino , Colorantes Fluorescentes/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Radiometría , Tiazoles/metabolismoRESUMEN
AIM: Recently, the feasibility of detecting amyloid plaques in the living brain by positron emission tomography (PET) imaging has been successfully demonstrated. As such, imaging beta-amyloid (A beta) plaques in the brain may further advance the differential diagnosis of the disease and allow clinicians to measure the effectiveness of therapeutic drugs aimed at lowering plaques in the brain. We report herein the preclinical validation of a potential (18)F-labeled biphenylalkyne, AV-138, as a preliminary step toward developing the imaging agent for patients suspected of having Alzheimer's disease. METHODS: In vitro binding was carried out in the homogenates prepared from postmortem AD brains with [(125)I]IMPY as the radioligand. [(18)F]AV-138 was successfully prepared using a tosylate precursor and Sumitomo modules for radiosynthesis. Similarly, specific binding of [(18)F]AV-138 (0.02-0.05 nM) to homogenates, prepared from gray and white matters of pooled AD patients and control subjects, was performed. Specific binding to A beta plaques was measured by autoradiography in AD brain sections (n=11), and the same brain sections were fluorescently stained with thioflavin-S (TF-S). Images of both radiolabeling and fluorescent staining of plaques obtained by a phosphor imager were used for correlation image analysis. RESULTS: As expected, AV-138 displayed a high binding affinity (K(i)=2.4+/-0.7 nM) in AD gray matter homogenates (due to its high level of A beta plaque accumulation). Specific binding can be clearly measured in the AD gray matter homogenates, but not in the AD white matters. Control brain homogenates, due to a lack of A beta plaques, also showed no specific binding. Furthermore, in vitro autoradiography of postmortem AD brain sections showed that the high binding signal of [(18)F]AV-138 was specifically due to A beta plaques. Fluorescent staining of plaques with TF-S correlated well with the radiolabeling of [(18)F]AV-138 in AD brain sections (r>0.90). CONCLUSION: Taken together, these preliminary results strongly suggest that [(18)F]AV-138 is potentially useful for imaging A beta plaques in the living human brain.