Identify glioma recurrence and treatment effects with triple-tracer PET/CT.

BACKGROUND: Differential diagnosis of tumour recurrence (TuR) from treatment effects (TrE), mostly induced by radiotherapy and chemotherapy, is still difficult by using conventional computed tomography (CT) or magnetic resonance (MR) imaging. We have investigated the diagnostic performance of PET/CT with 3 tracers, 13N-NH3, 18F-FDOPA, and 18F-FDG, to identify TuR and TrE in glioma patients following treatment. METHODS: Forty-three patients with MR-suspected recurrent glioma were included. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the lesion and the lesion-to-normal grey-matter cortex uptake (L/G) ratio were obtained from each tracer PET/CT. TuR or TrE was determined by histopathology or clinical MR follow-up for at least 6 months. RESULTS: In this cohort, 34 patients were confirmed to have TuR, and 9 patients met the diagnostic standard of TrE. The SUVmax and SUVmean of 13N-NH3 and 18F-FDOPA PET/CT at TuR lesions were significantly higher compared with normal brain tissue (13N-NH3 0.696 ± 0.558, 0.625 ± 0.507 vs 0.486 ± 0.413; 18F-FDOPA 0.455 ± 0.518, 0.415 ± 0.477 vs 0.194 ± 0.203; both P < 0.01), but there was no significant difference in 18F-FDG (6.918 ± 3.190, 6.016 ± 2.807 vs 6.356 ± 3.104, P = 0.290 and 0.493). L/G ratios of 13N-NH3 and 18F-FDOPA were significantly higher in TuR than in TrE group (13N-NH3, 1.573 ± 0.099 vs 1.025 ± 0.128, P = 0.008; 18F-FDOPA, 2.729 ± 0.131 vs 1.514 ± 0.141, P < 0.001). The sensitivity, specificity and AUC (area under the curve) by ROC (receiver operating characteristic) analysis were 57.7%, 100% and 0.803, for 13N-NH3; 84.6%, 100% and 0.938, for 18F-FDOPA; and 80.8%, 100%, and 0.952, for the combination, respectively. CONCLUSION: Our results suggest that although multiple tracer PET/CT may improve differential diagnosis efficacy, for glioma TuR from TrE, 18F-FDOPA PET-CT is the most reliable. The combination of 18F-FDOPA and 13N-NH3 does not increase the diagnostic efficiency, while 18F-FDG is not worthy for differential diagnosis of glioma TuR and TrE.

Visual interpretation, not SUV ratios, is the ideal method to interpret 18F-DOPA PET scans to aid in the cure of patients with focal congenital hyperinsulinism.

INTRODUCTION: Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18F-DOPA PET scans and how this can influence outcomes. MATERIALS AND METHODS: After 18F-Fluoro-L-DOPA was injected intravenously into 50 subjects' arm at a dose of 2.96-5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. RESULTS: Visual interpretation had the combination of the best sensitivity and positive prediction values. CONCLUSIONS: In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.

Prediction of MGMT Status for Glioblastoma Patients Using Radiomics Feature Extraction From 18F-DOPA-PET Imaging.

PURPOSE: Methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is associated with improved treatment response and survival in patients with glioblastoma (GB), but the necessary pathologic specimen can be nondiagnostic. In this study, we assessed whether radiomics features from pretreatment 18F-DOPA positron emission tomography (PET) imaging could be used to predict pathologic MGMT status. METHODS AND MATERIALS: This study included 86 patients with newly diagnosed GB, split into 3 groups (training, validating, and predicting). We performed a radiomics analysis on 18F-DOPA PET images by extracting features from 2 tumor-based contours: a "Gold" contour of all abnormal uptake per expert nuclear medicine physician and a high-grade glioma (HGG) contour based on a tumor-to-normal hemispheric ratio >2.0, representing the most aggressive components. Feature selection was performed by comparing the weighted feature importance and filtering with bivariate analysis. Optimization of model parameters was explored using grid search with selected features. The stability of the model with increasing input features was also investigated for model robustness. The model predictions were then applied by comparing the overall survival probability of the patients with GB and unknown MGMT status versus those with known MGMT status. RESULTS: A radiomics signature was constructed to predict MGMT methylation status. Using features extracted from HGG contour alone with a random forest model, we achieved 80% ± 10% accuracy for 95% confidence level in predicting MGMT status. The prediction accuracy was not improved with the addition of the Gold contour or with more input features. The model was applied to the patients with unknown MGMT methylation status. The prediction results are consistent with what is expected using overall survival as a surrogate. CONCLUSIONS: This study suggests that 3 features from radiomics modeling of 18F-DOPA PET imaging can predict MGMT methylation status with reasonable accuracy. These results could provide valuable therapeutic guidance for patients in whom MGMT testing is inconclusive or nondiagnostic.

The role of 18F-DOPA PET/CT in the diagnosis of the congenital focal form of hyperinsulinism in children. / Papel de la PET/TC con 18F-DOPA en el diagnóstico de la forma congénita focal del hiperinsulinismo en niños.

BACKGROUND: Congenital hyperinsulinism (CHI) is a neuroendocrine disease with focal or diffuse abnormalities in pancreas. While drug-resistant diffuse forms require near-total pancreatectomy or prolonged pharmacotherapy, focal CHI may be treated by targeted surgical resection. We evaluated the usefulness of 18F-DOPA PET/CT to identify the focal pancreatic form. SUBJECTS AND METHODS: Nineteen children (11 boys, 8 girls, aged 2-54 months) with clinical signs of neonatal CHI and positive genetic examinations were enrolled in the study. After i.v. administration of 18F-DOPA, early PET and late PET/CT acquisition covering one-bed length over thoraco-abdominal region were performed. Both acquisitions were done in dynamic mode to allow exclusion of frames with motion artefacts. Standardized uptake values were adjusted to bodyweight (SUVbw). The finding was considered as focal when the ratio of SUVbwmax between the suspicious region and the rest of pancreas was greater than 1.2. RESULTS: Focal forms were recorded in 10/19 children and 4 of them underwent surgical resection with complete recovery. Focal uptake was significantly higher than the uptake in the normal pancreatic tissue (p=0.0059). Focal and diffuse forms of CHI did not differ significantly in normal pancreatic tissue uptake. We found no advantage in the measurement of SUVbwmean ratio compared to SUVbwmax ratio (p=0.50). CONCLUSION: 18F-DOPA PET/CT is a useful tool for the localization of focal CHI and planning of surgical treatment.

Intrastriatal gradient analyses of 18F-FDOPA PET scans for differentiation of Parkinsonian disorders.

AIM: L -3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA PET may be used to distinguish subjects with Parkinsonism from those with symptoms not originating from impaired dopaminergic transmission. However, it is not routinely utilized to discriminate Idiopathic Parkinson's disease (IPD) from Atypical Parkinsonian Disorders (APD). We investigated the potential of FDOPA PET to discriminate between IPD and APD, with a focus on the anterior-to-posterior decline in het striatum, considered to be more specific for IPD. MATERIALS AND METHODS: 18F-DOPA PET data from a total of 58 subjects were retrospectively analyzed. 28 subjects had idiopathic Parkinson's disease (14 male, 14 female; age at scan 61 +- 11,5), 13 atypical Parkinsonian disease (7 male, 6 females; age at scan: 69,6 +- 6,4) and 17 were controls (6 male, 11 female; age at scan 65,3 +-8,6). Regional striatal-to-occipital ratio's (RSOR's) were calculated, as well as multiple in-line VOI's from the caudate nucleus to the posterior part of the putamen. The linearity of anteroposterior decline was determined by a linear regression fit and associated R squared values. ROC curves were calculated to assess the diagnostic performance of these measurements. Data contralateral to the clinically most affected side were used for analysis. RESULTS: ROC curve analysis for differentiation between controls and Parkinsonism patients showed the highest AUC for the caudate nucleus-to-posterior putamen ratio (AUC = 0.930; p < 0.00) and for the R squared value for the linear regression fit (AUC = 0.948; p = 0.006). For discrimating IPD from APD, the highest AUC was found for the caudate nucleus-to-anterior putamen ratio (0.824; p < 0.001) CONCLUSIONS: Subregional analysis of the striatum in F-DOPA PET scans may provide additional diagnostic information in patients screened for a  presynaptic dopaminergic deficit. A more linear decrease from the head of the caudate nucleus to the posterior putamen was  present in patients with IPD, although this feature did not have additional diagnostic value over the RSOR analysis.

Rate of change in maximum 18F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.

PURPOSE: To examine whether the rate of change in maximum 18F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial 18F-FDOPA PET and MRI scans. METHODS: 27 LGG patients with ≥ 2 18F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized 18F-FDOPA specific uptake value (nSUVmax/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS. RESULTS: A GLM using patient age, treatment, the rate of change in FLAIR and 18F-FDOPA nSUVmax could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS. CONCLUSIONS: The change in maximum normalized 18F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.

Olfactory dysfunction correlates with putaminal dopamine turnover in early de novo Parkinson's disease.

Although olfactory dysfunction is one of the most well-established prodromal symptoms in Parkinson's disease (PD), its correlation with clinical disease progression or dopaminergic dysfunction still remains unclear. We here evaluated the association of striatal dopamine metabolism and olfactory function in a homogenous cohort of 30 patients with early untreated de novo PD. Striatal dopamine metabolism was assessed by the extended 18Fluorodopa PET scanning protocol to measure 18Fluorodopa uptake (Kocc) and the effective dopamine distribution volume ratio (EDVR) as the inverse of dopamine turnover. Olfactory function was estimated by the "Sniffin' Sticks" test including odor threshold (T), discrimination (D) and identification (I) assessment. We detected moderate correlations of the EDVR in the posterior putamen with the TDI composite score (r = 0.412; p = 0.024; Pearson's correlation test) and the odor identification score (r = 0.444; p = 0.014). These correlations were confirmed by multivariate regression analyses using age, sex, symptom duration and disease severity as measured by UPDRSIII motor score as candidate covariates. No other associations were observed between olfaction measures and Kocc and EDVR in all striatal regions. Together, olfactory dysfunction in early PD is not correlated with striatal 18Fluorodopa uptake as a measure for dopaminergic degeneration, but with putaminal dopamine turnover as a marker for dopaminergic presynaptic compensatory processes in early PD. These results should be treated as hypothesis generating and require confirmation by larger multicenter studies.

The role of exposure to pesticides in the etiology of Parkinson's disease: a 18F-DOPA positron emission tomography study.

Susceptibility to Parkinson's disease (PD) is believed to involve an interaction between genetic and environmental factors. The role of pesticides as a risk factor of PD and neurodegeneration remains controversial. An asymmetric decrease in ligand uptake on 18F-DOPA positron emission tomography (PET), especially in the dorsal putamen, is a sensitive marker of PD. The aim of this study was to examine the pattern of ligand uptake on 18F-DOPA PET in patients with PD exposed or not exposed to pesticides. The main sample included 26 Israeli patients with PD, 13 who were exposed to pesticides and 13 who were not, matched for age and disease duration. All underwent 18F-DOPA PET imaging, and an asymmetry index of ligand uptake between the ipsilateral and contralateral caudate, putamen, and whole striatum was calculated. No significant between-group differences were found in demographic variables, clinical asymmetry index (P = 0.15), or asymmetry index of ligand uptake in the putamen (P = 0.84), caudate (P = 0.78) and striatum (P = 0.45). Comparison of the 18F-DOPA results of the Israeli cohort with those of 17 non-pesticide-exposed patients with PD from Austria yielded no significant differences, further validating our findings. Our observations suggest that although exposure to pesticides might be a risk factor for PD, it does not have an effect on the asymmetry pattern in the nigrostriatal system over non-exposure. We assume that once the disease process is initiated in pesticide-exposed patients, the pathogenic mechanism does not differ from that of idiopathic PD.

False-positive findings on 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (18F-FDOPA-PET) performed for imaging of neuroendocrine tumors.

BACKGROUND/AIM: PET with 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) has been shown to be a useful imaging tool with a high sensitivity for the visualization of neuroendocrine tumors (NETs). 18F-FDOPA uptake in tumors other than NETs has been suggested previously, but data on this phenomenon are limited. We therefore studied the non-physiological, false-positive uptake of 18F-FDOPA in a large population of patients with a NET or with a high clinical suspicion of harboring a NET. PATIENTS AND METHODS: Retrospective single-center study among adult patients in whom 18F-FDOPA PET scintigraphy was performed between January 2004 and December 2014. The original scan report was compared with the original pathology report corresponding with the 18F-FDOPA PET-positive lesion. In case this was inconsistent with the diagnosis of a NET, both the scan and the pathology slides were reassessed. Specimens of these non-NET tissues were immunohistochemically stained for AADC. RESULTS: 1070 18F-FDOPA PET scans from 705 patients were evaluated. Focal or multiple 18F-FDOPA-avid lesions were described in 709 18F-FDOPA PET scans (66%). Histology of these 18F-FDOPA PET-positive lesions was present in 508 (72%) cases. In seven cases, the histopathology was not compatible with NET but showed squamous cell carcinoma of the cervix, multiple myeloma (two cases), hepatocellular carcinoma, Schwannoma, adrenocortical carcinoma and a skeletal myxoid chondrosarcoma, with positive immunohistochemical staining for AADC in 67%. CONCLUSIONS: Pathological uptake of 18F-FDOPA does not always indicate the presence of a NET. The possibility of 18F-FDOPA uptake by tumor types other than NETs, although rare, should be considered.

Lower dopamine tone in the striatum is associated with higher body mass index.

Existing literature suggests that striatal dopamine (DA) tone may be altered in individuals with higher body mass index (BMI), but evidence accrued so far only offers an incomplete view of their relationship. Here, we characterized striatal DA tone using more comprehensive measures within a larger sample than previously reported. In addition, we explored if there was a relationship between striatal DA tone and disinhibited eating. 60 healthy participants underwent a 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scan. Disinhibited eating was measured with the Three-Factor Eating Questionnaire on a baseline visit. Individual whole-brain PET parameter estimates, namely 18F-DOPA influx rate constant (kocc i.e. DA synthesis capacity), 18F-DA washout rate (kloss) and effective distribution volume ratio (EDVR= kocc/ kloss), were derived with a reversible-tracer graphical analysis approach. We then computed parameter estimates for three regions-of-interests (ROIs), namely the ventral striatum, putamen and caudate. Overweight/mildly obese individuals had lowered EDVR than normal weight individuals in all three ROIs. The most prominent of these associations, driven by lowered kocc (r = -.28, p = .035) and heightened kloss (r = .48, p < .001), was found in the ventral striatum (r = -.46, p < .001). Disinhibition was greater in higher-BMI individuals (r = .31, p = .015), but was unrelated to PET measures and did not explain the relationship between PET measures and BMI. In sum, our findings resonate with the notion that overweight/mildly obese individuals have lower striatal DA tone and suggest new avenues for investigating their underlying mechanisms.

Seizure-Induced Increased 18F-DOPA Uptake in a Child With Diffuse Astrocytoma and Transient Brain MRI Abnormalities Related to Status Epilepticus.

We report the finding of increased F-DOPA uptake in the brain parenchyma surrounding a temporoparietal low-grade diffuse astrocytoma and corresponding to transient seizure-induced MRI abnormalities. There was concomitant markedly increased tumoral uptake. This F-DOPA PET phenomenon may represent increased amino acid transport induced by seizures. In the setting of brain tumor imaging, increased F-DOPA uptake of low-grade epileptogenic tumors and adjacent brain parenchyma should be carefully interpreted in light of clinical and electroencephalographic findings related to seizure activity.

11 C-PE2I and 18 F-Dopa PET for assessing progression rate in Parkinson's: A longitudinal study.

BACKGROUND: 18 F-dopa PET measuring aromatic l-amino acid decarboxylase activity is regarded as the gold standard for evaluating dopaminergic function in Parkinson's disease. Radioligands for dopamine transporters are also used in clinical trials and for confirming PD diagnosis. Currently, it is not clear which imaging marker is more reliable for assessing clinical severity and rate of progression. The objective of this study was to directly compare 18 F-dopa with the highly selective dopamine transporter radioligand 11 C-PE2I for the assessment of motor severity and rate of progression in PD. METHODS: Thirty-three mild-moderate PD patients underwent 18 F-dopa and 11 C-PE2I PET at baseline. Twenty-three were followed up for 18.8 ± 3.4 months. RESULTS: Standard multiple regression at baseline indicated that 11 C-PE2I BPND predicted UPDRS-III and bradykinesia-rigidity scores (P < 0.05), whereas 18 F-dopa Ki did not make significant unique explanatory contributions. Voxel-wise analysis showed negative correlations between 11 C-PE2I BPND and motor severity across the whole striatum bilaterally. 18 F-Dopa Ki clusters were restricted to the most affected putamen and caudate. Longitudinally, negative correlations were found between striatal Δ11 C-PE2I BPND , ΔUPDRS-III, and Δbradykinesia-rigidity, whereas no significant associations were found for Δ18 F-dopa Ki . One cluster in the most affected putamen was identified in the longitudinal voxel-wise analysis showing a negative relationship between Δ11 C-PE2I BPND and Δbradykinesia-rigidity. CONCLUSIONS: Striatal 11 C-PE2I appears to show greater sensitivity for detecting differences in motor severity than 18 F-dopa. Furthermore, dopamine transporter decline is closely associated with motor progression over time, whereas no such relationship was found with aromatic l-amino acid decarboxylase. 11 C-PE2I may be more effective for evaluating the efficacy of neuroprotective treatments in PD. © 2017 International Parkinson and Movement Disorder Society.

18F-DOPA uptake parameters in glioma: effects of patients' characteristics and prior treatment history.

OBJECTIVE: In amino acid positron emission tomography brain tumour imaging, tumour-to-background uptake parameters are often used for treatment monitoring. We studied the effects of patients' characteristics and anticancer treatments on 18F-fluoro-l-phenylalanine uptake of normal brain and tumour lesions, with particular emphasis on temozolomide (TMZ) chemotherapy. METHODS: 155 studies from 120 patients with glioma were analysed. Average uptake of normal background (standardized uptake value, SUVbckgr) and basal ganglia (SUVbg), as well as tumour-to-brain ratios (TBR) were compared between positron emission tomography/CT studies acquired before (Group A, n = 48), after (Group B, n = 50) or during (Group C, n = 57) TMZ treatment, using analysis of variance. RESULTS: Overall, mean SUVbckgr and mean SUVbg were 1.06 ± 0.26 and 2.12 ± 0.47, respectively. Female had significantly higher SUVbckgr (p = 0.002) and SUVbg (p = 0.012) than male patients. Age showed a positive correlation with SUVbg (p = 0.001). In the overall cohort, there were significant effects of TMZ on SUVbckgr (p = 0.0237) and TBR (p = 0.0138). In particular, SUVbckgr was lower in Group C than in Group B (1.00 ± 0.25 vs 1.14 ± 0.31, p = 0.0173). Significant variations of SUVbckr could be observed in female only. TBR was significantly higher in Group C than in Group B (2.37 ± 0.54 vs 2.06 ± 0.38, p = 0.010). Variations of SUVbg between groups slightly missed significance (p = 0.0504). CONCLUSION: Temozolomide chemotherapy and patients' characteristics, including gender and age, affect physiological [18F]-fluoro-l-phenylalanine uptake and, consequently, the calculation of TBRs. Advances in knowledge: For the first time, the effects of past or concurrent temozolomide chemotherapy on brain physiological amino acid uptake have been investigated. Such effects are relevant and should be taken into account when evaluating tumour-to-background ratios.

A high 18F-FDOPA uptake is associated with a slow growth rate in diffuse Grade II-III gliomas.

OBJECTIVE: In diffuse Grade II-III gliomas, a high 3,4-dihydroxy-6-(18F)-fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUVmax)/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18F-FDOPA uptake in diffuse Grade II-III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year. METHODS: 20 patients (42 ± 10 years, 10 female) with newly-diagnosed diffuse Grade II-III gliomas (17 with IDH mutation) were retrospectively included. All had a 18F-FDOPA PET, quantified with SUVmax ratio, along with a serial MRI enabling VDE determination. RESULTS: SUVmax ratio was above 1.8 in 5 patients (25%) all of whom had a VDE <4 mm/year (100%) and IDH mutation (100%). Moreover, a SUVmax ratio above 1.8 was associated with higher rates of VDE <4 mm/year in the overall population (45 vs 0%, p = 0.04) and also in the subgroup of patients with IDH mutation (45 vs 0%, p = 0.10). CONCLUSION: This pilot study shows that in diffuse Grade II-III gliomas, a high 18F-FDOPA uptake would be predictive of low tumour growth, with a different prognostic significance than IDH mutation. Advances in knowledge: 18F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse Grade II-III gliomas.

Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction.

BACKGROUND: The hypothesis that dopamine plays an important role in the pathophysiology of pathological gambling is pervasive. However, there is little to no direct evidence for a categorical difference between pathological gamblers and healthy control subjects in terms of dopamine transmission in a drug-free state. Here we provide evidence for this hypothesis by comparing dopamine synthesis capacity in the dorsal and ventral parts of the striatum in 13 pathological gamblers and 15 healthy control subjects. METHODS: This was achieved using [18F]fluoro-levo-dihydroxyphenylalanine dynamic positron emission tomography scans and striatal regions of interest that were hand-drawn based on visual inspection of individual structural magnetic resonance imaging scans. RESULTS: Our results show that dopamine synthesis capacity was increased in pathological gamblers compared with healthy control subjects. Dopamine synthesis was 16% higher in the caudate body, 17% higher in the dorsal putamen, and 17% higher in the ventral striatum in pathological gamblers compared with control subjects. Moreover, dopamine synthesis capacity in the dorsal putamen and caudate head was positively correlated with gambling distortions in pathological gamblers. CONCLUSIONS: Taken together, these results provide empirical evidence for increased striatal dopamine synthesis in pathological gambling.

[18F] FDOPA standardized uptake values of brain tumors are not exclusively dependent on LAT1 expression.

[18F]-FDOPA is a labeled amino acid (AA) analog used for positron emission tomography (PET) which is gaining increasing interest in the evaluation of brain tumors (BT). The AA-transporter LAT1 has been shown to be involved in [18F]-FDOPA uptake. The aim of this study was to determine whether the [18F]-FDOPA uptake was correlated with level of LAT1 expression in BT. Twenty-eight BT (including 19 gliomas and 9 metastases) were investigated by [18F]-FDOPA-PET prior to surgery and by anti-LAT1 immunohistochemistry on surgical specimens. The quantitative [18F]-FDOPA measured parameters were SUVmax, SUVmean and SUVpeak. LAT1 expression was quantified using a score (0 to 400). A significant [18F]-FDOPA uptake was associated with a LAT1 score ≥ 100 (p = 0.02) but there was no linear correlation between intensity of [18F]-FDOPA uptake and score of LAT1 expression whatever the parameters considered. LAT1 expression alone is not sufficient to explain variation of intensity of [18F]-FDOPA uptake in BT.

Quantitative analysis of normal and pathologic adrenal glands with 18F-FDOPA PET/CT: focus on pheochromocytomas.

INTRODUCTION: Many studies have reported the high performance of 6-fluorine-18-fluorodihydroxyphenilalanine (F-FDOPA) PET/CT in the diagnosis of pheochromocytomas but nobody seems to have investigated physiological and pathological adrenal glands from a quantitative point of view. The purpose of the present study was to assess the quantitative F-FDOPA uptake of normal and pathologic adrenal glands and to establish thresholds to characterize pheochromocytomas. We were especially interested in characterizing the remaining adrenal glands captation after an adrenalectomy. PATIENTS AND METHODS: We reviewed 112 F-FDOPA PET/CT scans taken for different indications. A total of 212 adrenal glands, of which 17 were pheochromocytomas, were analyzed on the basis of their functional and morphological features. The final diagnosis was based on histologic proof when available (six pheochromocytomas) or after synthesis of clinical, biological, morphological, and functional results. Maximum standardized uptake value (SUVmax), mediastinum, and liver ratios in case of pheochromocytomas, adenomas, and solitary adrenal glands were determined and compared with those of healthy glands. Receiver operating characteristic curves were determined and areas under the curve were compared for different cutoffs of each index. RESULTS: Pheochromocytomas demonstrated a higher F-FDOPA uptake compared with normal adrenal glands (mean SUVmax: 7.5, SD 4.0, range: 3.5-20.0 vs. mean SUVmax: 2.6, SD: 0.8, range: 1.0-6.9) (P<0.0001). An SUVmax threshold of 4.2 has a sensitivity and specificity of 94 and 98%, respectively. The areas under the curve were 0.988, 0.991, and 0.987 for an SUVmax of 4.2, a mediastinum ratio of 3.0, and a liver ratio of 1.7, respectively. A large number of nonsecreting pheochromocytomas were noticed. On the basis of the SUVmax no statistically significant difference was found between secreting (SUVmax: 8.9, SD: 5.3) and nonsecreting pheochromocytomas (SUVmax: 5.1, SD: 0.9) (P=0.141). After unilateral adrenalectomy, solitary glands presented no increased uptake compared with healthy adrenal glands. An unexpected lower captation was also observed (SUVmax: 2.0, P=0.047). CONCLUSION: We confirm the high affinity of F-FDOPA for secreting or nonsecreting pheochromocytoma. Indeed within a series of various adrenal glands, only these tumors presented a significant increased uptake compared with normal adrenal glands. Because of a high rate of nonhypersecreting lesions, F-FDOPA can act as a surrogate to biological assays. After an adrenalectomy, the remaining glands did not demonstrate compensatory accumulation of F-FDOPA. To our knowledge this last point has never been addressed.

Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [15O]-water and [18F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

Effect of Carbidopa on 18F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging.

Patient premedication with carbidopa seems to improve the accuracy of 6-18F-fluoro-3,4-dihydroxy-l-phenylalanine (18F-FDOPA) PET for insulinoma diagnosis. However, the risk of PET false-negative results in the presence of carbidopa is a concern. Consequently, we aimed to evaluate the effect of carbidopa on 18F-FDOPA uptake in insulinoma ß-cells and an insulinoma xenograft model in mice. METHODS: 18F-FDOPA in vitro accumulation was assessed in the murine ß-cell line RIN-m5F. In vivo small-animal PET experiments were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F cells. Experiments were conducted with and without carbidopa pretreatment. RESULTS: Incubation of RIN-m5F cells with 80 µM carbidopa did not significantly affect the cellular accumulation of 18F-FDOPA. Tumor xenografts were clearly detectable by small-animal PET in all cases. Insulinoma xenografts in carbidopa-treated mice showed significantly higher 18F-FDOPA uptake than those in nontreated mice. Regardless of carbidopa premedication, the xenografts were characterized by an early increase in 18F-FDOPA uptake and then a progressive reduction over time. CONCLUSION: Carbidopa did not influence in vitro 18F-FDOPA accumulation in RIN-m5F cells but improved insulinoma imaging in vivo. Our findings increase current knowledge about the 18F-FDOPA uptake profile of RIN-m5F cells and a related xenograft model. To our knowledge, the present work represents the first preclinical research specifically focused on insulinomas, with potential translational implications.

Pancreatic Uptake by 18F-FDOPA PET/CT in Patients With Hypoglycemia After Gastric Bypass Surgery Compared With Controls With or Without Carbidopa Pretreatment.

PURPOSE: The use of Fluorine-labeled dihydroxy-phenyl-alanine (F-FDOPA) PET/CT in patients with hypoglycemia suspected to be caused by pancreatic disease can be helpful to localize the source of excess insulin production. In this setting, carbidopa pretreatment is not recommended. However, quantitative comparisons of pancreatic tracer uptake in patients with or without carbidopa pretreatment and in diffuse pancreatic disease are lacking. Therefore, we aimed to describe and quantify pancreatic F-FDOPA uptake in patients without pancreatic disease with or without carbidopa pretreatment and in patients with hypoglycemia after gastric bypass surgery. PATIENTS AND METHODS: This is a retrospective data analysis of F-FDOPA PET/CT scans performed at a university medical center in the period from 2009 to 2015. All scans were reconstructed and calculated based on the European Association of Nuclear Medicine/EANM Research Ltd guidelines. Of 358 patients without evidence of pancreatic disease or hypoglycemic disorders, 344 received carbidopa and 14 did not. Another 9 patients had post-gastric bypass hypoglycemia. The main outcome measurement was F-FDOPA SUVmax for pancreatic head, body, and tail regions. RESULTS: Carbidopa pretreated patients had a lower median SUVmax (-1.15, -1.20, and -0.84 in pancreatic head, body, and tail [all P < 0.01]) than patients without carbidopa pretreatment. Patients with post-gastric bypass hypoglycemia scanned without carbidopa pretreatment had higher median SUVmax (+1.18, +1.39, and +1.63, all P < 0.03) compared with controls without pretreatment. CONCLUSIONS: Patients with post-gastric bypass hypoglycemia have increased uptake in all pancreatic regions. Carbidopa pretreatment lowers pancreatic F-FDOPA uptake in the nonaffected pancreas and may therefore mask disease activity in post-gastric bypass hypoglycemia.