Heinz H. Coenen

Mesolimbic Functional Magnetic Resonance Imaging Activations during Reward Anticipation Correlate with Reward-Related Ventral Striatal Dopamine Release

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [11C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [11C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas

PurposeThe aim of the study was to compare presurgical 18F-fluoroethyl-L-tyrosine (18F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas.Methods18F-FET positron emission tomography (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumour areas that were positive or negative for 18F-FET or Gd and checked for 5-ALA fluorescence. 18F-FET uptake with a mean tumour to brain ratio ≥1.6 was rated as positive.ResultsOf 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, 18F-FET PET was positive in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was observed in 6 of 21 cases of HGG biopsy samples (3 Gd-positive/5-ALA-negative and 3 Gd-negative/5-ALA-positive). In biopsies corresponding to LGG, 18F-FET was positive in 41% (7/17), while 5-ALA and Gd were negative in all but one instance. All tumour areas with 5-ALA fluorescence were positive on 18F-FET PET.ConclusionThere are differences between 18F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumour tissue especially in LGG. 18F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an additional tool in resection planning.

Combined MRI–PET dissects dynamic changes in plant structures and functions

Unravelling the factors determining the allocation of carbon to various plant organs is one of the great challenges of modern plant biology. Studying allocation under close to natural conditions requires non-invasive methods, which are now becoming available for measuring plants on a par with those developed for humans. By combining magnetic resonance imaging (MRI) and positron emission tomography (PET), we investigated three contrasting root/shoot systems growing in sand or soil, with respect to their structures, transport routes and the translocation dynamics of recently fixed photoassimilates labelled with the short-lived radioactive carbon isotope (11)C. Storage organs of sugar beet (Beta vulgaris) and radish plants (Raphanus sativus) were assessed using MRI, providing images of the internal structures of the organs with high spatial resolution, and while species-specific transport sectoralities, properties of assimilate allocation and unloading characteristics were measured using PET. Growth and carbon allocation within complex root systems were monitored in maize plants (Zea mays), and the results may be used to identify factors affecting root growth in natural substrates or in competition with roots of other plants. MRI-PET co-registration opens the door for non-invasive analysis of plant structures and transport processes that may change in response to genomic, developmental or environmental challenges. It is our aim to make the methods applicable for quantitative analyses of plant traits in phenotyping as well as in understanding the dynamics of key processes that are essential to plant performance.

Efficient routine production of the 18F-labelled amino acid O-(2-[18F]fluoroethyl)-l-tyrosine

A convenient remotely controlled no-carrier-added synthesis of enantiomerically pure O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is described. This allows the distribution of the radiotracer to other laboratories according to the satellite concept. The radiochemical yield obtained within 80 min is about 60%. The FET containing HPLC fraction can be used immediately (after adding sodium chloride) for human application.

Prognostic Value of O-(2-18F-Fluoroethyl)-l-Tyrosine PET and MRI in Low-Grade Glioma

In glioma of World Health Organization (WHO) grade II (low-grade glioma), the natural course of a particular patient is not predictable and the treatment strategy is controversial. We determined prognostic factors in adult patients with untreated, nonenhancing, supratentorial low-grade glioma with special regard to PET using the amino acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) and MRI. Methods: In a prospective study, baseline 18F-FET PET and MRI analyses were performed on 33 consecutive patients with histologically confirmed low-grade glioma. None of the patients had radiation or chemotherapy. Clinical, histologic, therapeutic (initial cytoreduction vs. biopsy), 18F-FET uptake, and MRI morphologic parameters were analyzed for their prognostic significance. Statistical endpoints were clinical or radiologic tumor progression, malignant transformation to glioma of WHO grade III or IV (high-grade glioma), and death. Results: Baseline 18F-FET uptake and a diffuse versus circumscribed tumor pattern on MRI were highly significant predictors of prognosis (P < 0.01). By the combination of these prognostically significant variables, 3 major prognostic subgroups of low-grade glioma patients could be identified. The first of these subgroups was patients with circumscribed low-grade glioma on MRI without 18F-FET uptake (n = 11 patients, progression in 18%, no malignant transformation and no death). The second subgroup was patients with circumscribed low-grade glioma with 18F-FET uptake (n = 13 patients, progression in 46%, malignant transformation to a high-grade glioma in 15%, and death in 8%). The third subgroup was patients with diffuse low-grade glioma with 18F-FET uptake (n = 9 patients, progression in 100%, malignant transformation to a high-grade glioma in 78%, and death in 56%). Conclusion: We conclude that baseline amino acid uptake on 18F-FET PET and a diffuse versus circumscribed tumor pattern on MRI are strong predictors for the outcome of patients with low-grade glioma.

Sleep Deprivation Increases A1 Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study

It is currently hypothesized that adenosine is involved in the induction of sleep after prolonged wakefulness. This effect is partially reversed by the application of caffeine, which is a nonselective blocker of adenosine receptors. Here, we report that the most abundant and highly concentrated A1 subtype of cerebral adenosine receptors is upregulated after 24 h of sleep deprivation. We used the highly selective A1 adenosine receptor (A1AR) radioligand [18F]CPFPX ([18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine) and quantitative positron emission tomography to assess cerebral A1ARs before and after sleep deprivation in 12 healthy volunteers and a control group (n = 10) with regular sleep. In sleep deprived subjects, we found an increase of the apparent equilibrium total distribution volume in a region-specific pattern in all examined brain regions with a maximum increase in the orbitofrontal cortex (15.3%; p = 0.014). There were no changes in the control group with regular sleep. This is the first molecular imaging study that provides in vivo evidence for an A1AR upregulation in cortical and subcortical brain regions after prolonged wakefulness, indicating that A1AR expression is contributing to the homeostatic sleep regulation.

Comparison of 18F-FET and 18F-FDG PET in brain tumors

UNLABELLED The purpose of this study was to compare the diagnostic value of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose ((18)F-FDG) and O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) in patients with brain lesions suspicious of cerebral gliomas. METHODS Fifty-two patients with suspicion of cerebral glioma were included in this study. From 30 to 50 min after injection of 180 MBq (18)F-FET, a first PET scan ((18)F-FET scan) was performed. Thereafter, 240 MBq (18)F-FDG was injected and a second PET scan was acquired from 30 to 60 min after the second injection ((18)F-FET/(18)F-FDG scan). The cerebral accumulation of (18)F-FDG was calculated by decay corrected subtraction of the (18)F-FET scan from the (18)F-FET/(18)F-FDG scan. Tracer uptake was evaluated by visual scoring and by lesion-to-background (L/B) ratios. The imaging results were compared with the histological results and prognosis. RESULTS Histology revealed 24 low-grade gliomas (LGG) of World Health Organization (WHO) Grade II and 19 high-grade gliomas (HGG) of WHO Grade III or IV, as well as nine others, mainly benign histologies. The gliomas showed increased (18)F-FET uptake (>normal brain) in 86% and increased (18)F-FDG uptake (>white matter) in 35%. (18)F-FET PET provided diagnostically useful delineation of tumor extent while this was impractical with (18)F-FDG due to high tracer uptake in the gray matter. A local maximum in the tumor area for biopsy guidance could be identified with (18)F-FET in 76% and with (18)F-FDG in 28%. The L/B ratios showed significant differences between LGG and HGG for both tracers but considerable overlap so that reliable preoperative grading was not possible. A significant correlation of tracer uptake with overall survival was found with (18)F-FDG only. In some benign lesions like abscesses, increased uptake was observed for both tracers indicating a limited specificity of both techniques. CONCLUSIONS (18)F-FET PET is superior to (18)F-FDG for biopsy guidance and treatment planning of cerebral gliomas. The uptake of (18)F-FDG is associated with prognosis, but the predictive value is limited and a histological evaluation of tumor tissue remains necessary. Therefore, amino acids like (18)F-FET are the preferred PET tracers for the clinical management of cerebral gliomas.

Comparison of fluorotyrosines and methionine uptake in F98 rat gliomas

The transport mechanisms of O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) and 2-[(18)F]fluoro-L-tyrosine (FTyr) were compared to those of [(3)H]-Methyl-L-methionine (MET) in F98 rat glioma cells in vitro and by tumor imaging by ex vivo dual tracer autoradiography in F98 rat gliomas. Both, FET and FTyr exhibited similar transport characteristics in F98 glioma cells compared to MET, i.e. mainly a sodium dependent transport similar to system B(0,+) and sodium independent transport via system L. Radioactivity of FET in the acid precipitable fraction was <1% after 120 min incubation time while FTyr and MET exhibited a 15-18% incorporation into proteins. Comparison of FET and FTyr with MET uptake in F98 rat gliomas demonstrated a significant correlation of tumor to brain ratios and a similar intratumoral tracer distribution pattern.

Assessment of Treatment Response in Patients with Glioblastoma Using O-(2-18F-Fluoroethyl)-l-Tyrosine PET in Comparison to MRI

The assessment of treatment response in glioblastoma is difficult with MRI because reactive blood–brain barrier alterations with contrast enhancement can mimic tumor progression. In this study, we investigated the predictive value of PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET PET) during treatment. Methods: In a prospective study, 25 patients with glioblastoma were investigated by MRI and 18F-FET PET after surgery (MRI-/FET-1), early (7–10 d) after completion of radiochemotherapy with temozolomide (RCX) (MRI-/FET-2), and 6–8 wk later (MRI-/FET-3). Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) were determined by region-of-interest analyses. Furthermore, gadolinium contrast-enhancement volumes on MRI (Gd-volume) and tumor volumes in 18F-FET PET images with a tumor-to-brain ratio greater than 1.6 (Tvol 1.6) were calculated using threshold-based volume-of-interest analyses. The patients were grouped into responders and nonresponders according to the changes of these parameters at different cutoffs, and the influence on progression-free survival and overall survival was tested using univariate and multivariate survival analyses and by receiver-operating-characteristic analyses. Results: Early after completion of RCX, a decrease of both TBRmax and TBRmean was a highly significant and independent statistical predictor for progression-free survival and overall survival. Receiver-operating-characteristic analysis showed that a decrease of the TBRmax between FET-1 and FET-2 of more than 20% predicted poor survival, with a sensitivity of 83% and a specificity of 67% (area under the curve, 0.75). Six to eight weeks later, the predictive value of TBRmax and TBRmean was less significant, but an association between a decrease of Tvol 1.6 and PFS was noted. In contrast, Gd-volume changes had no significant predictive value for survival. Conclusion: In contrast to Gd-volumes on MRI, changes in 18F-FET PET may be a valuable parameter to assess treatment response in glioblastoma and to predict survival time.

Role of O-(2-18 F-Fluoroethyl)-L-Tyrosine PET for differentiation of local recurrent brain metastasis from radiation necrosis

The aim of this study was to investigate the potential of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation necrosis after radiation therapy because the use of contrast-enhanced MRI for this issue is often difficult. Methods: Thirty-one patients (mean age ± SD, 53 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 40) on MRI after radiation therapy of brain metastases were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively; 20–40 min after injection) of 18F-FET uptake were determined. Time–activity curves were generated, and the time to peak (TTP) was calculated. Furthermore, time–activity curves of each lesion were assigned to one of the following curve patterns: (I) constantly increasing 18F-FET uptake, (II) 18F-FET uptake peaking early (TTP ≤ 20 min) followed by a plateau, and (III) 18F-FET uptake peaking early (TTP ≤ 20 min) followed by a constant descent. The diagnostic accuracy of the TBRmax and TBRmean of 18F-FET uptake and the curve patterns for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or Fisher exact test for 2 × 2 contingency tables using subsequent histologic analysis (11 lesions in 11 patients) or clinical course and MRI findings (29 lesions in 20 patients) as reference. Results: Both TBRmax and TBRmean were significantly higher in patients with recurrent metastasis (n = 19) than in patients with radiation necrosis (n = 21) (TBRmax, 3.2 ± 0.9 vs. 2.3 ± 0.5, P < 0.001; TBRmean, 2.1 ± 0.4 vs. 1.8 ± 0.2, P < 0.001). The diagnostic accuracy of 18F-FET PET for the correct identification of recurrent brain metastases reached 78% using TBRmax (area under the ROC curve [AUC], 0.822 ± 0.07; sensitivity, 79%; specificity, 76%; cutoff, 2.55; P = 0.001), 83% using TBRmean (AUC, 0.851 ± 0.07; sensitivity, 74%; specificity, 90%; cutoff, 1.95; P < 0.001), and 92% for curve patterns II and III versus curve pattern I (sensitivity, 84%; specificity, 100%; P < 0.0001). The highest accuracy (93%) to diagnose local recurrent metastasis was obtained when both a TBRmean greater than 1.9 and curve pattern II or III were present (AUC, 0.959 ± 0.03; sensitivity, 95%; specificity, 91%; P < 0.001). Conclusion: Our findings suggest that the combined evaluation of the TBRmean of 18F-FET uptake and the pattern of the time–activity curve can differentiate local brain metastasis recurrence from radionecrosis with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.