In-vivo measurement of LDOPA uptake, dopamine reserve and turnover in the rat brain using [18F]FDOPA PET.
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ABSTRACT:
SUBMITTER: Walker MD
PROVIDER: S-EPMC3597374 | biostudies-other | 2013 Jan
REPOSITORIES: biostudies-other
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Project description:Using positron emission tomography, we measured in vivo uptake of (18)F-fluorodeoxyglucose (FDG) in the brain and heart of C57Bl/6 mice at intervals across a 24-hour light-dark cycle. Our data describe a significant, high amplitude rhythm in FDG uptake throughout the whole brain, peaking at the mid-dark phase of the light-dark cycle, which is the active phase for nocturnal mice. Under these conditions, heart FDG uptake did not vary with time of day, but did show biological variation throughout the 24-hour period for measurements within the same mice. FDG uptake was scanned at different times of day within an individual mouse, and also compared to different times of day between individuals, showing both biological and technical reproducibility of the 24-hour pattern in FDG uptake. Regional analysis of brain FDG uptake revealed especially high amplitude rhythms in the olfactory bulb and cortex, while low amplitude rhythms were observed in the amygdala, brain stem and hypothalamus. Low amplitude 24-hour rhythms in regional FDG uptake may be due to multiple rhythms with different phases in a single brain structure, quenching some of the amplitude. Our data show that the whole brain exhibits significant, high amplitude daily variation in glucose uptake in living mice. Reports applying the 2-deoxy-D[(14)C]-glucose method for the quantitative determination of the rates of local cerebral glucose utilization indicate only a small number of brain regions exhibiting a day versus night variation in glucose utilization. In contrast, our data show 24-hour patterns in glucose uptake in most of the brain regions examined, including several regions that do not show a difference in glucose utilization. Our data also emphasizes a methodological requirement of controlling for the time of day of scanning FDG uptake in the brain in both clinical and pre-clinical settings, and suggests waveform normalization of FDG measurements at different times of the day.
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Project description:Previous evidence indicates that transcranial direct stimulation (tDCS) is a neuromodulatory brain stimulation technique. Easy applicability, low side-effects and negligible costs facilitated its wide-spread application in efforts to modulate brain function, however neuronal mechanisms of tDCS are insufficiently understood. Hence, we investigated the immediate impact of tDCS on the brain's glucose consumption in a continuous infusion protocol with the radioligand 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET). This novel functional PET (fPET) method is capable to reliably detect area-specific and dynamic absolute glucose demand related to neuronal activity in a single molecular imaging session. Fifteen healthy subjects underwent tDCS at 0.5, 1 and 2 mA (mA) at the bilateral dorsolateral prefrontal cortex (dlPFC, cathodal right) for 10 min during functional [18F]FDG-PET lasting 70 min. Active stimulation compared to sham did not yield significant changes in glucose consumption at any tested stimulation intensity in this paradigm. Exploratory investigation of aftereffects provided hints for increased glucose consumption with a delay of 5 min at 1 mA in the right posterior temporal cortex. This is the first study investigating changes of glucose consumption in the brain during tDCS. The lack of immediately increased glucose consumption indicates that energy demanding processes in the brain such as glutamatergic signaling might not be immediately increased by tDCS. However, our results implicate the need of fPET investigations for medium-term and long-term effects.
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Project description:Background and purposeFluorine-18 florbetapir is a recently developed β-amyloid plaque positron-emission tomography imaging agent with high sensitivity, specificity, and accuracy in the detection of moderate-to-frequent cerebral cortical β-amyloid plaque. However, the FDA has expressed concerns about the consistency of interpretation of [(18)F] florbetapir PET brain scans. We hypothesized that incorporating automated cerebral-to-whole-cerebellar standardized uptake value ratios into [(18)F] florbetapir PET brain scan interpretation would reduce this interreader variability.Materials and methodsThis randomized, blinded-reader study used previously acquired [(18)F] florbetapir scans from 30 anonymized patients who were enrolled in the Alzheimer's Disease Neuroimaging Initiative 2. In 4 separate, blinded-reading sessions, 5 readers classified 30 cases as positive or negative for significant β-amyloid deposition either qualitatively alone or qualitatively with additional adjunct software that determined standardized uptake value ratios. A κ coefficient was used to calculate interreader agreement with and without the use of standardized uptake value ratios.ResultsThere was complete interreader agreement on 20/30 cases of [(18)F] florbetapir PET brain scans by using qualitative interpretation and on 27/30 scans interpreted with the adjunct use of standardized uptake value ratios. The κ coefficient for the studies read with standardized uptake value ratios (0.92) was significantly higher compared with the qualitatively read studies (0.69, P = .006).ConclusionsUse of standardized uptake value ratios improves interreader agreement in the interpretation of [(18)F] florbetapir images.
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Project description:Zebrafish (Danio rerio) have recently emerged as useful model organism for the study of neuronal function. Here, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure locally evoked dopamine release and uptake in zebrafish whole brain preparations and results were compared with those obtained from brain slices. Evoked dopamine release ([DA]max) was similar in whole brain and sagittal brain slice preparations (0.49 ± 0.13 μM in whole brain and 0.59 ± 0.28 μM in brain slices). Treatment with α-methyl-p-tyrosine methyl ester (αMPT), an inhibitor of tyrosine hydroxylase, diminished release and the electrochemical signal reappeared after subsequent drug washout. No observed change in stimulated release current occurred after treatment with desipramine or fluoxetine in the whole brain. Treatment with the uptake inhibitors, nomifensine or GBR 12909 increased [DA]max, while treatment with sulpiride, a D2 dopamine autoreceptor antagonist, resulted in increased stimulated dopamine release in whole brain, but had no effect on release in slices. Dopamine release in whole brains increased progressively up to an electrical stimulation frequency of 25 Hz, while release in slices increased up to a frequency of only 10 Hz and then plateaued, highlighting another key difference between these preparations. We observed a lag in peak dopamine release following stimulation, which we address using diffusion models and pharmacological treatments. Collectively, these results demonstrate the electrochemical determination of dopamine release in the whole, intact brain of a vertebrate species ex vivo and are an important step for carrying out further experiments in zebrafish.
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Project description:To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD.
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Project description:BackgroundChallenges to cardiac PET-CT include patient motion, prolonged image acquisition and a reduction of counts due to gating. We compared two analytical tools, FusionQuant and OsiriX, for quantification of gated cardiac 18F-sodium fluoride (18F-fluoride) PET-CT imaging.MethodsTwenty-seven patients with aortic stenosis were included, 15 of whom underwent repeated imaging 4 weeks apart. Agreement between analytical tools and scan-rescan reproducibility was determined using the Bland-Altman method and Lin's concordance correlation coefficients (CCC).ResultsImage analysis was faster with FusionQuant [median time (IQR) 7:10 (6:40-8:20) minutes] compared with OsiriX [8:30 (8:00-10:10) minutes, p = .002]. Agreement of uptake measurements between programs was excellent, CCC = 0.972 (95% CI 0.949-0.995) for mean tissue-to-background ratio (TBRmean) and 0.981 (95% CI 0.965-0.997) for maximum tissue-to-background ratio (TBRmax). Mean noise decreased from 11.7% in the diastolic gate to 6.7% in motion-corrected images (p = .002); SNR increased from 25.41 to 41.13 (p = .0001). Aortic valve scan-rescan reproducibility for TBRmax was improved with FusionQuant using motion correction compared to OsiriX (error ± 36% vs ± 13%, p < .001) while reproducibility for TBRmean was similar (± 10% vs ± 8% p = .252).Conclusion18F-fluoride PET quantification with FusionQuant and OsiriX is comparable. FusionQuant with motion correction offers advantages with respect to analysis time and reproducibility of TBRmax values.
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Project description:The standard treatment for head and neck squamous cell carcinoma (HNSCC) is radiotherapy, often in combination with chemotherapy or surgery. However, a novel monoclonal antibody, cetuximab (Erbitux®), has also been approved for patient therapy. The aim of present study was to develop an in vitro method for the measurement of 18F-fluoro-2deoxy-D-glucose (FDG) to determine if cellular 18F-FDG uptake is associated with response to radiotherapy or cetuximab treatment. In the current study, HNSCC cell lines were treated with radiation or with cetuximab. Next, the uptake of 18F-FDG was measured using a gamma spectrometer (GS). Thereafter, uptake after radiation was measured first with GS and then compared with positron emission tomography (PET)/computed tomography (CT) imaging. Furthermore, the mRNA expression of glucose transporter 1 (GLUT1) was measured following cetuximab treatment via reverse transcription-quantitative PCR. A study protocol was developed to measure the cellular uptake of 18F-FDG via gamma-ray spectrometry and comparable results were obtained with those of clinical PET/CT. The results revealed a decrease in 18F-FDG after radiation and cetuximab treatment. The uptake of 18F-FDG following cetuximab treatment was significantly lower in the cetuximab-sensitive cell line UT-SCC-14 compared with the cetuximab-resistant cell lines UT-SCC-2 and UT-SCC-45. Furthermore, after treatment with cetuximab for 24 and 48 h, a significant increase in GLUT1 expression was detected in the sensitive cell line compared with the two resistant cell lines. In conclusion, a novel yet reliable method for the measurement of intracellular 18F-FDG via GS has been developed, and our results indicate that 18F-FDG uptake is associated with radiation and cetuximab response in HNSCC.
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Project description:BackgroundThe activation of microglia, in general, and the upregulation of the translocator protein (18 kDa) (TSPO) system, in particular, are key features of neuroinflammation, of which the in vivo visualization and quantitative assessment are still challenging due to the lack of appropriate molecular imaging biomarkers. Recent positron emission tomography (PET) studies using TSPO radioligands such as [11C]PK11195 and [11C]PBR28 have indicated the usefulness of these PET biomarkers in patients with neuroinflammatory diseases, including multiple sclerosis (MS). [18F]FEDAA1106 is a recently developed PET radioligand for the in vivo quantification of TSPO. In the present study, we aimed at investigating the diagnostic usefulness of [18F]FEDAA1106 in patients with MS.MethodsNine patients (three on the interferon beta therapy and six without immunomodulatory therapy; seven females/two males; age 34.2 ± 9.1 years old) with relapsing-remitting MS in acute relapse and with gadolinium (Gd)-enhancing lesion(s) in the magnetic resonance imaging (MRI) scans and five healthy controls (four females/one male, age 38.0 ± 9.7 years old) were investigated in this study. Genetic information about the TSPO binding could not be obtained because knowledge about the importance of genetic background for TSPO binding was not available at the time the study was performed. Dynamic PET measurements were performed using an ECAT EXACT HR system (CTI/Siemens, Knoxville, TN, USA) for a total of 150 min, with a 30-min break after the injection of 153.4 ± 10.2 MBq of [18F]FEDAA1106. Metabolite-corrected arterial plasma samples were used to calculate the input function. PET data were analyzed in the following ways: (1) region-of-interest analysis for cortical and subcortical regions was performed using a two-tissue compartment kinetic model in order to estimate binding potentials (BPND) and distribution volume (VT), (2) the feasibility of the estimation of BPND and VT was investigated for MS lesions, and (3) VT parametric images by a Logan plot and standard uptake value (SUV) images were visually compared with the corresponding MRI, focusing on MRI-identified MS lesions.ResultsThere were no significant differences in the BPND or VT values between patients with MS and healthy controls. Robust BPND and VT values could not be obtained for most MS lesions due to noisy time-activity curves. Visual inspection of VT and SUV images in all nine patients did not reveal high uptake of the radioligand inside and beyond MRI-identified active MS lesions with the exception of one Gd-enhanced MS lesion in the whole patient population.ConclusionsIn our study, [18F]FEDAA1106 as a PET radioligand could neither differentiate patients with MS from healthy controls nor detect active plaques in the brain of MS patients. Stratification with respect to genetics and binder status might help to uncover the differences between the groups, which could not be detected here.Trial registrationClinicalTrials.gov, NCT01031199.
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Project description:Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging.FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high-fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to-blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake.At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm(3) of the HX4-HV was outside the FDG-HV; for 37%, this volume was 1.9 to 12 cm(3). Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV.Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment.
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Project description:BACKGROUND:Currently, [18F] altanserin is the most frequently used PET-radioligand for serotonin2A (5-HT2A) receptor imaging in the human brain but has never been validated in dogs. In vivo imaging of this receptor in the canine brain could improve diagnosis and therapy of several behavioural disorders in dogs. Furthermore, since dogs are considered as a valuable animal model for human psychiatric disorders, the ability to image this receptor in dogs could help to increase our understanding of the pathophysiology of these diseases. Therefore, five healthy laboratory beagles underwent a 90-min dynamic PET scan with arterial blood sampling after [18F] altanserin bolus injection. Compartmental modelling using metabolite corrected arterial input functions was compared with reference tissue modelling with the cerebellum as reference region. RESULTS:The distribution of [18F] altanserin in the canine brain corresponded well to the distribution of 5-HT2A receptors in human and rodent studies. The kinetics could be best described by a 2-Tissue compartment (2-TC) model. All reference tissue models were highly correlated with the 2-TC model, indicating compartmental modelling can be replaced by reference tissue models to avoid arterial blood sampling. CONCLUSIONS:This study demonstrates that [18F] altanserin PET is a reliable tool to visualize and quantify the 5-HT2A receptor in the canine brain.
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