Prognostic Value of Baseline Tumor Burden and Tumor Dissemination Extracted From 18 F-FDG PET/CT in a Cohort of Adult Patients With Early or Advanced Hodgkin Lymphoma.

PURPOSE: We aimed to assess the prognostic value of baseline tumor burden and dissemination parameters extracted from 18 F-FDG PET/CT in patients with early or advanced Hodgkin lymphoma (HL) treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated BEACOPP (increased bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). PATIENTS AND METHODS: Patients aged ≥18 years with classical Hodgkin lymphoma were retrospectively included. Progression-free survival (PFS) analysis of dichotomized clinicobiological and PET/CT parameters (SUV max , TMTV, TLG, D max , and D bulk ) was performed. Optimal cutoff values for quantitative metrics were defined as the values maximizing the Youden index from receiver operating characteristic analysis. PFS rates were estimated with Kaplan-Meier curves, and the log-rank test was used to assess statistical significance. Hazard ratios were calculated using Cox proportional hazards models. RESULTS: With a median age of 32 years, 166 patients were enrolled. A total of 111 patients had ABVD or ABVD-like treatment with or without radiotherapy and 55 patients with escalated BEACOPP treatment. The median follow-up was 55 months. Only International Prognostic Score (IPS >1), TMTV >107 cm 3 , and TLG >1628 were found to be significant prognostic factors for PFS on univariate analysis. Multivariate analysis revealed that IPS and TLG were independently prognostic and, combined, identified 4 risk groups ( P < 0.001): low (low TLG and low IPS; 4-year PFS, 95%), intermediate-low (high IPS and low TLG; 4-year PFS, 79%), intermediate-high (low IPS and high TLG; 4-year PFS, 78%), and high (high TLG and high IPS; 4-year PFS, 71%). CONCLUSIONS: Combining baseline TLG with IPS could improve PFS prediction.

Added value of [18F]FDOPA PET to the management of high-grade glioma patients after their initial treatment: a prospective multicentre study.

BACKGROUND: Diagnostic value of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine ([18F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG). METHODS: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [18F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [18F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured. RESULTS: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively. CONCLUSION: [18F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions.

Dissemination patterns of Hodgkin lymphoma using a probability network model based on [18F]-FDG PET/CT.

PURPOSE: The preferred hypothesis for the dissemination patterns of Hodgkin lymphoma (HL) is the contiguity hypothesis. However, this hypothesis is based on studies performed before the advent of [18F]-FDG PET/CT which is now the established reference for HL staging. This study aims to extract the dissemination patterns of HL using [18F]-FDG PET/CT and a probability network model. METHODS: We retrospectively analyzed [18F]-FDG PET/CT performed for initial staging of patients with classical HL. The HL involvement status (presence of absence) was reported for 19 supra- and infra-diaphragmatic lymph node regions and 4 extranodal regions (lung, spleen, liver, and osteo- medullary). The analysis of HL dissemination was carried out using HL involvement status for all regions through 3 distinct methods: comparison of nearby lymph node regions, correlation assessment between all regions and relationship strength between all regions using Ising network model. RESULTS: A total of 196 patients were included. Our results showed strong relationships between nearby involved lymph node regions (for example between the left pelvic and the abdominal lymph node regions (relationship strength = 0.980)) and between more distant regions (for example between right and left axillary lymph node regions (strength = 0.714)). Furthermore, involvement of the infra-diaphragmatic lymph node regions was significantly correlated with Ann Arbor stage IV (phi = 0.56, p < 0.001). CONCLUSION: This study confirms the hypothesis of lymphatic dissemination of HL in a contiguous mode, with additional links between more distant regions. These predictable dissemination patterns could be useful for the initial staging assessment of patients with HL using [18F]-FDG PET/CT.

Delayed [ 18 F]-FDG PET Imaging Increases Diagnostic Performance and Reproducibility to Differentiate Recurrence of Brain Metastases From Radionecrosis.

PURPOSE: Differentiating brain metastasis recurrence from radiation necrosis can be challenging during MRI follow-up after stereotactic radiotherapy. [ 18 F]-FDG is the most available PET tracer, but standard images performed 30 to 60 minutes postinjection provide insufficient accuracy. We compared the diagnostic performance and interobserver agreement of [ 18 F]-FDG PET with delayed images (4-5 hours postinjection) with the ones provided by standard and dual-time-point imaging. METHODS: Consecutive patients referred for brain [ 18 F]-FDG PET after inconclusive MRI were retrospectively included between 2015 and 2020 in 3 centers. Two independent nuclear medicine physicians interpreted standard (visually), delayed (visually), and dual-time-point (semiquantitatively) images, respectively. Adjudication was applied in case of discrepancy. The final diagnosis was confirmed histologically or after 6 months of MRI follow-up. Areas under the receiver operating characteristic curves were pairwise compared. RESULTS: Forty-eight lesions from 46 patients were analyzed. Primary tumors were mostly located in the lungs (57%) and breast (23%). The median delay between radiotherapy and PET was 15.7 months. The final diagnosis was tumor recurrence in 24 of 48 lesions (50%), with histological confirmation in 19 of 48 lesions (40%). Delayed images provided a larger area under the receiver operating characteristic curve (0.88; 95% confidence interval [CI], 0.75-0.95) than both standard (0.69; 95% CI, 0.54-0.81; P = 0.0014) and dual-time-point imaging (0.77; 95% CI, 0.63-0.88; P = 0.045), respectively. Interobserver agreement was almost perfect with delayed images ( κ = 0.83), whereas it was moderate with both standard ( κ = 0.48) and dual-time-point images ( κ = 0.61). CONCLUSIONS: [ 18 F]-FDG PET with delayed images is an accurate and reliable alternative to differentiate metastasis recurrence from radiation necrosis in case of inconclusive MRI after brain stereotactic radiotherapy.

Impact of point-spread function reconstruction on dynamic and static 18F-DOPA PET/CT quantitative parameters in glioma.

BACKGROUND: Quantification of dynamic and static parameters extracted from 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA, FDOPA) positron emission tomography (PET)/computed tomography (CT) plays a critical role for glioma assessment. The objective of the present study was to investigate the impact of point-spread function (PSF) reconstruction on these quantitative parameters. METHODS: Fourteen patients with untreated gliomas and investigated with FDOPA PET/CT were analyzed. The distribution of the 14 cases was as follows: 6 astrocytomas-isocitrate dehydrogenase-mutant; 2 oligodendrogliomas/1p19q-codeleted-isocitrate dehydrogenase-mutant; and 6 isocitrate dehydrogenase-wild-type glioblastomas. A 0-20-min dynamic images (8×15, 2×30, 2×60, and 3×300 s post-injection) and a 0-20-min static image were reconstructed with and without PSF. Tumoral volumes-of-interest were generated on all of the PET series and the background volumes-of-interest were generated on the 0-20-min static image with and without PSF. Static parameters (SUVmax and SUVmean) of the tumoral and the background volumes-of-interest and kinetic parameters (K1 and k2) of the tumoral volumes-of-interest extracted from using full kinetic analysis were provided. PSF and non-PSF quantitative parameters values were compared. RESULTS: Thirty-three tumor volumes-of-interest and 14 background volumes-of-interest were analyzed. PSF images provided higher tumor SUVmax than non-PSF images for 23/33 VOIs [median SUVmax =3.0 (range, 1.4-10.2) with PSF vs. 2.7 (range, 1.4-9.1) without PSF; P<0.001] and higher tumor SUVmean for 13/33 volumes-of-interest [median SUVmean =2.0 (range, 0.8-7.6) with PSF vs. 2.0 (range, 0.8-7.4) without PSF; P=0.002]. K1 and k2 were significantly lower with PSF than without PSF [respectively median K1 =0.077 mL/ccm/min (range, 0.043-0.445 mL/ccm/min) with PSF vs. 0.101 mL/ccm/min (range, 0.055-0.578 mL/ccm/min) without PSF; P<0.001 and median k2 =0.070 min-1 (range, 0.025-0.146 min-1) with PSF vs. 0.081 min-1 (range, 0.027-0.180 min-1) without PSF; P<0.001]. Background SUVmax and SUVmean were statistically unaffected [respectively median SUVmax =1.7 (range, 1.3-2.0) with PSF vs. 1.7 (range, 1.3-1.9) without PSF; P=0.346 and median SUVmean =1.5 (range, 1.0-1.8) with PSF vs. 1.5 (range, 1.0-1.7) without PSF; P=0.371]. CONCLUSIONS: The present study confirms that PSF significantly increases tumor activity concentrations measured on PET images. PSF algorithms for quantitative PET/CT analysis should be used with caution, especially for quantification of kinetic parameters.

Combining 18F-DOPA PET and MRI with perfusion-weighted imaging improves delineation of high-grade subregions in enhancing and non-enhancing gliomas prior treatment: a biopsy-controlled study.

PURPOSE: We aimed to compare spatial extent of high-grade subregions detected with combined [18F]-dihydroxyphenylalanine (18F-DOPA) PET and MRI to the one provided by advanced multimodal MRI alone including Contrast-enhanced (CE) and Perfusion weighted imaging (PWI). Then, we compared the accuracy between imaging modalities, in a per biopsy analysis. METHODS: Participants with suspected diffuse glioma were prospectively included between June 2018 and September 2019. Volumes of high-grade subregions were delineated respectively on 18F-DOPA PET and MRI (CE and PWI). Up to three per-surgical neuronavigation-guided biopsies were performed per patient. RESULTS: Thirty-eight biopsy samples from sixteen participants were analyzed. Six participants (38%) had grade IV IDH wild-type glioblastoma, six (38%) had grade III IDH-mutated astrocytoma and four (24%) had grade II IDH-mutated gliomas. Three patients had intratumoral heterogeneity with coexisting high- and low-grade tumor subregions. High-grade volumes determined with combined 18F-DOPA PET/MRI (median of 1.7 [interquartile range (IQR) 0.0, 19.1] mL) were larger than with multimodal MRI alone (median 1.3 [IQR 0.0, 12.8] mL) with low overlap (median Dice's coefficient 0.24 [IQR 0.08, 0.59]). Delineation volumes were substantially increased in five (31%) patients. In a per biopsy analysis, combined 18F-DOPA PET/MRI detected high-grade subregions with an accuracy of 58% compared to 42% (p = 0.03) with CE MRI alone and 50% (p = 0.25) using multimodal MRI (CE + PWI). CONCLUSIONS: The addition of 18F-DOPA PET to multimodal MRI (CE and PWI) enlarged the delineation volumes and enhanced overall accuracy for detection of high-grade subregions. Thus, combining 18F-DOPA with advanced MRI may improve treatment planning in newly diagnosed gliomas.

Functional Role of the Cerebellum in Parkinson Disease: A PET Study.

OBJECTIVES: To test for cerebellar involvement in motor and nonmotor impairments in Parkinson disease (PD) and to determine patterns of metabolic correlations with supratentorial brain structures, we correlated clinical motor, cognitive, and psychiatric scales with cerebellar metabolism. METHODS: We included 90 patients with PD. Motor, cognitive, and psychiatric domains were assessed, and resting-state 18FDG-PET metabolic imaging was performed. The motor, cognitive, and psychiatric scores were entered separately into a principal component analysis. We looked for correlations between these 3 principal components and cerebellar metabolism. Furthermore, we extracted the mean glucose metabolism value for each significant cerebellar cluster and looked for patterns of cerebrum-cerebellum metabolic correlations. RESULTS: Severity of impairment was correlated with increased metabolism in the anterior lobes and vermis (motor domain); the right crus I, crus II, and declive (cognitive domain); and the right crus I and crus II (psychiatric domain). No results survived multiple testing corrections regarding the psychiatric domain. Moreover, we found distributed and overlapping, but not identical, patterns of metabolic correlations for motor and cognitive domains. Specific supratentorial structures (cortical structures, basal ganglia, and thalamus) were strongly correlated with each of the cerebellar clusters. CONCLUSIONS: These results confirm the role of the cerebellum in nonmotor domains of PD, with differential but overlapping patterns of metabolic correlations suggesting the involvement of cerebello-thalamo-striatal-cortical loops.

The Added Value of Bloodpool SPECT/CT in Painful Non-Operated Foot and Ankle Undiagnosed With Standard Three-Phase Bone Scintigraphy.

Purpose: To evaluate the interest of adding a bloodpool SPECT/CT to standard three-phase bone scintigraphy (BS) for etiological diagnosis of subacute and chronic lower extremity pains. Methods: We prospectively included patients addressed for pain of lower extremities lasting for at least 6 weeks, without previous surgery. They underwent a standard three-phase BS including late phase SPECT/CT, modified with an additional bloodpool SPECT/CT acquisition. Two independent physicians interpreted the images provided by both protocols. Diagnostic conclusion, diagnostic confidence, and interrater agreements were compared. Results: One hundred and eighteen lower extremities from 113 patients were analyzed (71 men, median age of 53 years). Adding bloodpool SPECT/CT to standard three-phase BS changed diagnostic conclusions in 24.6% (29/118) of lower extremities. The modified protocol revealed at least one diagnostic conclusion explaining the pain in 89% of extremities, rather than 83.1% with the standard protocol (p = 0.02). Tendinopathies were diagnosed in 12.7% of lower extremities, rather than 4.2% with standard BS (p = 0.002). Adding bloodpool SPECT/CT substantially increased overall confidence of each reader (p < 0.001). Inter-reader agreement was not significantly impacted. Conclusion: Adding bloodpool SPECT/CT to standard three-phase BS impacted diagnostic conclusion in a quarter of the patients with painful lower extremities, notably by revealing significantly more tendonitis.

Increased thyroid uptake on 18F-FDG PET/CT is associated with the development of permanent hypothyroidism in stage IV melanoma patients treated with anti-PD-1 antibodies.

PURPOSE: To determine performances of 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) to detect the development of permanent thyroid dysfunction (PTD), and to evaluate the prognostic value of early increased thyroid uptake in stage IV melanoma patients treated with anti-programmed death 1 (anti-PD-1) antibodies. METHODS: Twenty-nine patients were retrospectively enrolled. PTD was defined as symptomatic thyroid disorder requiring long-term specific treatment. On the first PET performed during follow-up, maximal standardized uptake value of the thyroid (SUVmax-Th) and SUVmax-Th/SUVmax-blood-pool ratio (Th/B) were measured. Areas under ROC curves (AUC) of these parameters for the diagnostic of PTD were compared. Cutoff values were defined to maximize the Youden's index. Survival analyses were performed according to the Kaplan-Meier method and compared using the log-rank method between patients with and without enhanced thyroid uptake according to cutoff values defined with the Hothorn and Lausen method. RESULTS: Four patients presented PTD. Median SUVmax-Th and Th/B were, respectively, 2.11 and 1.00. The median follow-up period was 21.7 months. AUC were 1.0 (CI95% 0.88-1.0) for both parameters. Optimal cutoff values were, respectively, SUVmax-Th > 4.1 and Th/B > 2.0, both conferring sensitivities of 100% (CI95% 40-100%) and specificities of 100% (CI95% 86-100%). The median progression-free survival and overall survival were 11.3 months and 33.5 months, respectively. Using optimized cutoffs, there was no statistically significant difference of survival. CONCLUSION: SUVmax-Th > 4.1 and Th/B > 2.0 provided perfect diagnostic performances to detect patients that developed PTD. No significant survival difference was found between patients with and without increased thyroid uptake.

Deep brain stimulation of the internal globus pallidus does not affect the limbic circuit in patients with Parkinson's disease: a PET study.

INTRODUCTION: Internal globus pallidus (GPi) deep brain stimulation (DBS) is a safe and effective alternative treatment in Parkinson's disease (PD) for patients with cognitive impairment. However, no study has yet investigated metabolic changes within a large series of patients undergoing GPi stimulation. OBJECTIVE: We assessed motor, cognitive and psychiatric changes, as well as modifications in brain glucose metabolism measured with FDG-PET, before and after bilateral GPi-DBS. METHODS: In the same week, 32 patients with PD underwent a motor, cognitive and psychiatric assessment and a resting-state FDG-PET scan, 4 months before and 4 months after GPi-DBS surgery. For the voxelwise metabolic change assessment, the p value was controlled for multiple comparisons using the family wise error rate. RESULTS: After GPi-DBS surgery, patients showed a significant overall improvement in motor status. No cognitive or psychiatric changes were observed after surgery. Nor were any clusters with significantly relative metabolic changes found in the limbic circuit after surgery. Clusters with significantly relative metabolic changes were observed in the left and right Brodmann area (BA) 6, the right BA 9, the right and left BA 39 and the left BA 17. CONCLUSION: The present study confirmed that GPi-DBS is an effective treatment in patients with advanced PD, owing to metabolic changes in the areas involved in motor execution. The absence of relative metabolic decrease in the limbic circuit and the few changes affecting the associative circuit could explain why GPi-DBS is cognitively safe.

Motor symptom asymmetry in Parkinson's disease predicts emotional outcome following subthalamic nucleus deep brain stimulation.

The objective of this study was to explore the brain modifications associated with vocal emotion (i.e., emotional prosody) processing deficits in patients with Parkinson's disease after deep brain stimulation of the subthalamic nucleus, and the impact of motor asymmetry on these deficits. We therefore conducted 18-fluorodeoxyglucose positron emission tomography scans of 29 patients with left- or right-sided motor symptoms of Parkinson's disease before and after surgery, and correlated changes in their glucose metabolism with modified performances on the recognition of emotional prosody. Results were also compared with those of a matched healthy control group. Patients with more left-sided motor symptoms exhibited a deficit in vocal emotion recognition for neutral, anger, happiness and sadness in the preoperative condition that was normalized postoperatively. Patients with more right-sided motor symptoms performed comparably to controls in the preoperative condition, but differed significantly on fear postoperatively. At the metabolic level, the improvement observed among patients with left-sided motor symptoms was correlated with metabolic modifications in a right-lateralized network known to be involved in emotional prosody, while the behavioral worsening observed among patients with right-sided motor symptoms was correlated with metabolic modifications in the left parahippocampal gyrus and right cerebellum. We suggest that surgery has a differential impact on emotional processing according to motor symptom lateralization, and interpret these results as reflecting the (de)synchronization of the limbic loop in the postoperative condition.

Optimization of time frame binning for FDOPA uptake quantification in glioma.

INTRODUCTION: 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (FDOPA) uptake quantification in glioma assessment can be distorted using a non-optimal time frame binning of time-activity curves (TAC). Under-sampling or over-sampling dynamic PET images induces significant variations on kinetic parameters quantification. We aimed to optimize temporal time frame binning for dynamic FDOPA PET imaging. METHODS: Fourteen patients with 33 tumoral TAC with biopsy-proven gliomas were analysed. The mean SUVmax tumor-to-brain ratio (TBRmax) were compared at 20 min and 35 min post-injection (p.i). Five different time frame samplings within 20 min were compared: 11x10sec-6x15sec-5x20sec-3x300sec; 8x15sec- 2x30sec- 2x60sec- 3x300sec; 6x20sec- 8x60sec- 2x300sec; 10x30sec- 3x300sec and 4x45sec- 3x90sec- 5x150sec. The reversible single-tissue compartment model with blood volume parameter (VB) was selected using the Akaike information criterion. K1 values extracted from 1024 noisy simulated TAC using Monte Carlo method from the 5 different time samplings were compared to a target K1 value as the objective, which is the average of the K1 values extracted from the 33 lesions using an imaging-derived input function for each patient. RESULTS: The mean TBRmax was significantly higher at 20 min p.i. than at 35 min p.i (respectively 1.4 +/- 0.8 and 1.2 +/- 0.6; p <0.001). The target K1 value was 0.161 mL/ccm/min. The 8x15sec- 2x30sec- 2x60sec- 3x300sec time sampling was the optimal time frame binning. K1 values extracted using this optimal time frame binning were significantly different with K1 values extracted from the other time frame samplings, except with K1 values obtained using the 11x10sec- 6x15sec -5x20sec-3x300sec time frame binning. CONCLUSIONS: This optimal sampling schedule design (8x15sec- 2x30sec- 2x60sec- 3x300sec) could be used to minimize bias in quantification of FDOPA uptake in glioma using kinetic analysis.

Prognostic Value of Baseline Total Metabolic Tumor Volume Measured on FDG PET in Patients With Richter Syndrome.

PURPOSE: We evaluated the prognostic value of baseline total metabolic tumor volume (TMTV) measured using pretreatment FDG PET for patients with transformation of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 28 patients with transformation of CLL into DLBCL who had undergone FDG PET before treatment were retrospectively reviewed. Univariate and multivariate analysis of conventional clinicopathologic variables (sex, age, World Health Organization performance status score, International Prognostic Index score, Binet stage, lactate dehydrogenase serum level [LDH], platelet count, presence or not of prior therapies for CLL, the time from CLL to Richter syndrome, Ann Arbor stage, Bulky or not) and metabolic parameters (SUVmax, SUVmean, TMTV, and total lesion glycolysis) at the time of the transformation of CLL into DLBCL were tested for overall survival (OS). RESULTS: Of the 28 patients, 14 patients (50%) died during the follow-up period. Low platelet count, World Health Organization performance status score >1, high LDH, and high TMTV were found to be significant prognostic factors for OS on univariate analysis. The 5-year estimates of OS were 63% in the low metabolic burden group (TMTV ≤1200 cm) and 0% in the high metabolic burden group (TMTV >1200 cm). Multivariate analysis revealed that only high LDH was a significant predictor after adjustment for other variables of OS. CONCLUSIONS: TMTV extracted from FDG PET at the time of the transformation of CLL into DLBCL is a predictor of OS.

Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience.

Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, ß-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings.

The Story of the Dopamine Transporter PET Tracer LBT-999: From Conception to Clinical Use.

The membrane dopamine transporter (DAT) is involved in a number of brain disorders and its exploration by positron emission tomography (PET) imaging is highly relevant for the early and differential diagnosis, follow-up and treatment assessment of these diseases. A number of carbon-11 and fluor-18 labeled tracers are to date available for this aim, the majority of them being derived from the chemical structure of cocaine. The development of such a tracer, from its conception to its use, is a long process, the expected result being to obtain the best radiopharmaceutical adapted for clinical protocols. In this context, the cocaine derivative (E)-N-(4-fluorobut-2-enyl)2ß-carbomethoxy-3ß-(4'-tolyl)nortropane, or LBT-999, has passed all the required stages of the development that makes it now a highly relevant imaging tool, particularly in the context of Parkinson's disease. This review describes the different steps of the development of LBT-999 which initially came from its non-fluorinated derivative (E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methylphenyl) nortropane, or PE2I, because of its high promising properties. [18F]LBT-999 has been extensively characterized in rodent and non-human primate models, in which it demonstrated its capability to explore in vivo the DAT localized at the dopaminergic nerve endings as well as at the mesencephalic cell bodies, in physiological conditions. In lesion-induced rat models of Parkinson's disease, [18F]LBT-999 was able to precisely quantify in vivo the dopaminergic neuron loss, and to assess the beneficial effects of therapeutic approaches such as pharmacological treatment and cell transplantation. Finally recent clinical data demonstrated the efficiency of [18F]LBT-999 in the diagnosis of Parkinson's disease.

Comparison of 18F-Choline PET/CT and MRI functional parameters in prostate cancer.

AIM: 18F-Choline (FCH) uptake parameters are strong indicators of aggressive disease in prostate cancer. Functional parameters derived by magnetic resonance imaging (MRI) are also correlated to aggressive disease. The aim of this work was to evaluate the relationship between metabolic parameters derived by FCH PET/CT and functional parameters derived by MRI. MATERIALS AND METHODS: Fourteen patients with proven prostate cancer who underwent FCH PET/CT and multiparametric MRI were enrolled. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition and late whole-body acquisition. FCH PET/CT and multiparametric MRI examinations were registered and tumoral volume-of-interest were drawn on the largest lesion visualized on the apparent diffusion coefficient (ADC) map and projected onto the different multiparametric MR images and FCH PET/CT images. Concerning the FCH uptake, kinetic parameters were extracted with the best model selected using the Akaike information criterion between the one- and two-tissue compartment models with an imaging-derived plasma input function. Other FCH uptake parameters (early SUVmean and late SUVmean) were extracted. Concerning functional parameters derived by MRI scan, cell density (ADC from diffusion weighting imaging) and vessel permeability (Ktrans and Ve using the Tofts pharmakinetic model from dynamic contrast-enhanced imaging) parameters were extracted. Spearman's correlation coefficients were calculated to compare parameters. RESULTS: The one-tissue compartment model for kinetic analysis of PET images was selected. Concerning correlation analysis between PET parameters, K1 was highly correlated with early SUVmean (r = 0.83, p < 0.001) and moderately correlated with late SUVmean (r = 0.66, p = 0.010) and early SUVmean was highly correlated with late SUVmean (r = 0.90, p < 0.001). No significant correlation was found between functional MRI parameters. Concerning correlation analysis between PET and functional MRI parameters, K1 (from FCH PET/CT imaging) was moderately correlated with Ktrans (from perfusion MR imaging) (r = 0.55, p = 0.041). CONCLUSIONS: No significant correlation was found between FCH PET/CT and multiparametric MRI metrics except FCH influx which is moderately linked to the vessel permeability in prostate cancer.

Apathy alters emotional arousal in chronic schizophrenia

Background: Within the heterogeneity of schizophrenia, apathy constitutes an independent cluster of negative symptoms associated with poor outcomes. Attempts to identify an emotional deficit in patients who have schizophrenia with negative symptoms have yielded mixed results, and studies that focus on the relationship between apathy and emotional disorders are lacking. Methods: We set out to remedy this shortcoming using a validated battery of film excerpts to induce positive and negative emotions in patients with chronic schizophrenia with (n = 20) or without (n = 20) apathy, and in controls (n = 20) comparable for age, sex and socioeconomic status. We assessed emotions using an innovative but validated technique to evaluate tonic and phasic electrodermal activity and subjective feelings using a standardized visual analogue scale. Results: Using a qualitative measure of apathy, we did not find a specific decrease in tonic activity during the induction of positive emotions. However, we did observe that patients with apathy showed reduced tonic activity independent of valence (i.e., for both positive and negative emotions) compared with controls and patients without apathy. Moreover, the quantitative measure of apathy (Apathy Evaluation Scale) was the only significant factor, explaining 24% of the variance in tonic activity during induction of positive emotions after controlling for confounding factors. Limitations: Electrodermal activity was the only physiologic measure we acquired. We induced several emotions sequentially that might have overlapped with each other, but we added an emotional "washout" period and randomized the order of each film excerpt to limit this possibility. Conclusion: Taken together, these results suggest that apathy in schizophrenia could impair tonic activity during positive emotions. Treatments aimed at enhancing positive emotions may help alleviate apathy in schizophrenia.

Optimization of temporal sampling for 18F-choline uptake quantification in prostate cancer assessment.

BACKGROUND: Suboptimal temporal sampling of time-activity curves (TAC) from dynamic 18F-fluoromethylcholine (FCH) PET images may introduce bias in quantification of FCH uptake in prostate cancer assessment. We sought to define an optimal temporal sampling protocol for dynamic FCH PET imaging. Seven different time samplings were tested: 5 × 60″, 10 × 30″, 15 × 15″-1 × 75″, 6 × 10″-8 × 30″, 12 × 5″-8 × 30″; 10 × 5″-4 × 10″-3 × 20″-5 × 30″, and 8 × 3″-8 × 12″-6 × 30″. First, the irreversible and reversible one-tissue compartment model with blood volume parameter (VB) (respectively, 1T1K+VB and 1T2k+VB, with K1 = transfer coefficient from the arterial blood to the tissue compartment and k2 = transfer coefficient from the tissue compartment to the arterial blood) were compared for 37 lesions from 32 patients who underwent FCH PET imaging for initial or recurrence assessment of prostate cancer, and the model was selected using the Akaike information criterion. To determine the optimal time sampling, K1 values extracted from 1000 noisy-simulated TAC using Monte Carlo method from the seven different time samplings were compared to a target K1 value which is the average of the K1 values extracted from the 37 lesions using an imaging-derived input function for each patient. K1 values extracted with the optimal time sampling for each tumoral lesion were compared to K1 values extracted from each of the other time samplings for the 37 lesions. RESULTS: The 1T2k + VB model was selected. The target K1 value as the objective was 0.506 mL/ccm/min (range 0.216-1.246). Results showed a significant difference between K1 values from the simulated TAC with the seven different time samplings analyzed. The closest K1 value from the simulated TAC to the target K1 value was obtained by the 12 × 5″-8 × 30″ time sampling. Concerning the clinical validation, K1 values extracted from the optimal time sampling (12 × 5″-8 × 30″) were significantly different with K1 values extracted from the other time samplings, except for the comparison with K1 values extracted from the 10 × 5″-4 × 10″-3 × 20″-5 × 30″ time sampling. CONCLUSIONS: A two-phase framing of dynamic PET reconstruction with frame durations of 5 s (blood phase) and 30 s (tissue phase) could be used to sample the TAC for uptake quantification in prostate cancer assessment.

Comparison of choline influx from dynamic 18F-Choline PET/CT and clinicopathological parameters in prostate cancer initial assessment.

AIM: The aim of the study was to compare the kinetic analysis of 18F-labeled choline (FCH) uptake with static analysis and clinicopathological parameters in patients with newly diagnosed prostate cancer (PC). MATERIALS AND METHODS: Sixty-one patients were included. PSA was performed few days before FCH PET/CT. Gleason scoring (GS) was collected from systematic sextant biopsies. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition (from 0 to10 min post-injection) and late whole-body acquisition (60 min post-injection). PC volume of interest was drawn using an adaptative thresholding (40% of the maximal uptake) on the late acquisition and projected onto an early static frame of 10 min and each of the 20 reconstructed frames of 30 s. Kinetic analysis was performed using an imaging-derived plasma input function. Early kinetic parameter (K1 as influx) and static parameters (early SUVmean, late SUVmean, and retention index) were extracted and compared to clinicopathological parameters. RESULTS: K1 was significantly, but moderately correlated with early SUVmean (r = 0.57, p < 0.001) and late SUVmean (r = 0.43, p < 0.001). K1, early SUVmean, and late SUVmean were moderately correlated with PSA level (respectively, r = 0.36, p = 0.004; r = 0.67, p < 0.001; r = 0.51, p < 0.001). Concerning GS, K1 was higher for patients with GS ≥ 4 + 3 than for patients with GS < 4 + 3 (median value 0.409 vs 0.272 min- 1, p < 0.001). No significant difference was observed for static parameters. CONCLUSIONS: FCH influx index K1 seems to be related to GS and could be a non-invasive tool to gain further information concerning tumor aggressiveness.

Pre-frontal-insular-cerebellar modifications correlate with disgust feeling blunting after subthalamic stimulation: A positron emission tomography study in Parkinson's disease.

Subthalamic nucleus (STN) deep brain stimulation (DBS) has recently advanced our understanding of the major role played by this basal ganglion in human emotion. Research indicates that STN DBS can induce modifications in all components of emotion, and neuroimaging studies have shown that the metabolic modifications correlated with these emotional disturbances following surgery are both task- and sensory input-dependent. Nevertheless, to date, these modifications have not been confirmed for all emotional components, notably subjective emotional experience, or feelings. To identify the neural network underlying the modification of feelings following STN DBS, we assessed 16 patients with Parkinson's disease before and after surgery, using both subjective assessments of emotional experience and 18 [F]fluorodeoxyglucose positron emission tomography (18 FDG-PET). The patients viewed six film excerpts intended to elicit happy, angry, fearful, sad, disgusted, and neutral feelings, and they self-rated the intensity of these feelings. After DBS, there was a significant reduction in the intensity of the disgust feeling. Correlations were observed between decreased disgust experience and cerebral glucose metabolism (FDG uptake) in the bilateral pre-frontal cortices (orbitofrontal, dorsolateral, and inferior frontal gyri), bilateral insula, and right cerebellum. We suggest that the STN contributes to the synchronization process underlying the emergence of feelings.