Magnetic Resonance Positron Emission Tomography Research Articles

Degeneration of gray and white matter differs between hypometabolic and hypermetabolic brain regions in a patient with ALS-FTD: a longitudinal MRI − PET multimodal study

Objective [18F]-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) imaging and magnetic resonance imaging (MRI) of brain in ALS patients with frontotemporal lobe dementia (ALS-FTD) reveal hypometabolism and hypermetabolism, as well as gray matter (GM) and white matter (WM) abnormalities in different brain regions, respectively. Hypometabolism arising from neuronal dysfunction or loss is the most recognized pathophysiologic change in neurodegeneration, whereas mechanisms underlying hypermetabolism remain unclear. We hypothesize that hypometabolic and hypermetabolic brain regions in ALS-FTD represent differential degeneration of GM and WM structures, as revealed by co-registered MRI in a two time-point longitudinal multimodal study. Methods: A 69-year-old female with ALS-FTD underwent 18F-FDG PET, diffusion tensor imaging (DTI), and T1-weighted MRI at baseline (15 months after symptom onset), and 20.4 months later. Cerebral glucose metabolism rate, cortical thickness, cortical area, and WM network changes were measured longitudinally. Results and conclusion: The patient had symptoms and signs of bulbar-onset upper motor neuron (UMN)-predominant ALS with language and behavioral dysfunction. Evaluation at baseline showed bulbar dysfunction, and impaired language and executive function. At follow-up, worsened bulbar and other motor functions, and prominent FTD both reflected significant progression. Cortical thickness and surface area showed differential involvement in the hypometabolic and hypermetabolic regions. WM connections from frontal regions to other brain regions were completely absent by graph theory-based network analysis when compared to temporal regions indicating prominent frontal lobe degeneration. Structural neuroimaging reveals different patterns of GM and WM involvement in the hypometabolic and hypermetabolic brain regions in a patient with ALS-FTD.

GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes.

Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Isolated metachronous splenic multiple metastases after colon cancer surgery: A case report and literature review

BACKGROUNDIsolated splenic metastasis is a rare clinical entity. Multiple metastases in the spleen after radical colon resection in a patient who subsequently underwent a second local resection for isolated metachronous splenic metastasis are exceedingly rare.CASE SUMMARYWe report a colon cancer patient who underwent laparoscopic radical colon resection 14 mo previously, and subsequently underwent a second local resection due to local recurrence detected by elevated serum carcinoembryonic antigen (CEA) and positron emission tomography (PET). However, multiple metastases in the spleen were found 7 mo later by elevated serum CEA and PET-magnetic resonance imaging. Then the patient underwent total laparoscopic splenectomy. Local tumor recurrence and splenic metastasis from colorectal cancer (CRC) were found by postoperative pathology. Genetic analysis of these recurrent and metastatic tissues showed KRAS exon2, APC exon16 and TP53 exon6 missense mutations, but no mutations of NRAS, KRAF, EGFR, ERBB2, MET, MLH1, MSH2 and MSH6 were detected. Chemotherapy and target therapy were administered after multiple disciplinary team (MDT) consultation, and no tumor recurrence has been observed to date. We also reviewed the literature by conducting a search of the PubMed database using the following key words: CRC, splenic metastasis, isolated, and review. We identified 34 relevant papers, which included 28 cases of metachronous metastasis and 6 cases of simultaneous metastasis.CONCLUSIONClose monitoring of serum CEA levels is crucial for the detection of isolated splenic metastases after colon surgery. In terms of overall survival and progression-free survival, MDT plays an important role in the entire process of disease management.

Diagnostic Performance of PET Imaging Using Different Radiopharmaceuticals in Prostate Cancer According to Published Meta-Analyses.

A significant number of meta-analyses reporting data on the diagnostic performance of positron emission tomography (PET) in prostate cancer (PCa) is currently available in the literature. In particular, different PET radiopharmaceuticals were used for this purpose. The aim of this review is to summarize information retrieved by published meta-analyses on this topic. The first step included a systematic search of the literature (last search date: June 2020), screening two databases (PubMed/MEDLINE and Cochrane Library). This combination of key words was used: (A) “PET” OR “positron emission tomography” AND (B) “prostate” OR “prostatic” AND (C) meta-analysis. Only meta-analyses on Positron Emission Tomography/Computed Tomography (PET/CT) or Positron Emission Tomography/Magnetic Resonance (PET/MR) in PCa were selected. We have summarized the diagnostic performance of PET imaging in PCa, taking into account 39 meta-analyses published in the literature. Evidence-based data showed the good diagnostic performance of PET/CT with several radiopharmaceuticals, including prostate-specific membrane antigen (PSMA)-targeted agents, radiolabeled choline, fluciclovine, and fluoride in restaging and staging settings. Less evidence-based data were available for PET/MR with different radiotracers. More prospective multicentric studies and cost-effectiveness analyses are warranted.

Valor adicional de la tecnología híbrida de PET/RM frente a la RM y la PET en la enfermedad cardiovascular

Introduction and objectivesHybrid positron emission tomography (PET) and magnetic resonance (MR) imaging is an emerging technology in the diagnosis of cardiovascular disease; however, there have been no reports of its use in the national clinical setting. Our objective was to evaluate the additional value of integrated PET/MR systems compared with MR and PET performed separately in this setting. MethodsWe prospectively included 49 patients, 30 to assess myocardial viability (coronary group) and 19 to assess inflammatory, infectious, and tumoral diseases (noncoronary heart disease group). All patients underwent cardiac 18F-fluorodeoxyglucose PET/MR. PET/MR studies included attenuation correction sequences, followed by simultaneous cardiac PET and cardiac MR acquisition, with protocols adapted to the clinical indication (cine, tissue characterization and/or late enhancement imaging). ResultsMost (87.8%) PET/MR studies were initially interpretable. Use of PET/MR improved diagnosis vs PET or MR performed separately in 42.1% of coronary cases and 88.9% of noncoronary cases. PET/MR enabled reclassification of 87.5% of coronary cases initially classified as showing inconclusive results on MR or PET and 70% of noncoronary cases. ConclusionsIn our series, multimodality PET/MR technology provided additional diagnostic value in some patients with cardiovascular disease compared with MR and PET performed separately, especially in cases of noncoronary heart disease and in those with inconclusive results on MR or PET. In our experience, the main benefits of PET/MR include the possibility of simultaneous acquisition, the in vivo integration of anatomical/functional/metabolic aspects, and the interaction of different experts in imaging modalities.

PET-MRI nanoparticles imaging of blood-brain barrier damage and modulation after stroke reperfusion.

In an acute ischaemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood–brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood–brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant Ktrans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10−3 min−1, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10−3 min−1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, Ktrans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10−3 min−1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, Ktrans also increased within the ischaemic growth areas, suggesting added value for AGuIX®. Finally, Ktrans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5). Ktrans quantification with AGuIX® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischaemic stroke after reperfusion.

Radiotherapy target volume definition in newly diagnosed high grade glioma using 18F-FET PET imaging and multiparametric perfusion MRI: A prospective study (IMAGG)

PurposeThe aim of this study was to prospectively investigate tumor volume delineation by amino acid PET and multiparametric perfusion magnetic resonance imaging (MRI) in patients with newly diagnosed, untreated high grade glioma (HGG). Materials and methodsThirty patients with histologically confirmed HGG underwent O-(2-[18F]-fluoroethyl)-l-tyrosine (18F-FET) positron emission tomography (PET), conventional Magnetic Resonance Imaging (MRI) as contrast-enhanced (CE) and fluid-attenuated inversion recovery (FLAIR) and multiparametric MRI as relative cerebral blood volume (rCBV) and permeability estimation map (K2). Areas of MRI volumes were semi-automatically segmented. The percentage overlap volumes, Dice and Jaccard spatial similarity coefficients (OV, DSC, JSC) were calculated. ResultsThe 18F-FET tumor volume was significantly larger than the CE volume (median 43.5 mL (2.5–124.9) vs. 23.8 mL (1.4–80.3), p = 0.005). The OV between 18F-FET uptake and CE volume was low (median OV 0.59 (0.10–1)), as well as spatial similarity (median DSC 0.52 (0.07–0.78); median JSC 0.35 (0.03–0.64)). Twenty-five patients demonstrated both rCBV and CE on MRI: The median rCBV tumor volume was significantly smaller than the median CE volume (p < 0.001). The OV was high (median 0.83 (0.54–1)), but the spatial similarity was low (median DSC 0.45 (0.04–0.83); median JSC 0.29 (0.07–0.71)). Twenty-eight patients demonstrated both K2 and CE on MRI. The median K2 tumor volume was not significantly larger than the median CE volume. The OV was high (median OV 0.90 (0.61–1)), and the spatial similarity was moderate (median DSC 0.75 (0.01–0.83); median JSC 0.60 (0.11–0.89)). ConclusionWe demonstrated that multiparametric perfusion MRI volumes (rCBV, K2) were highly correlated with CE T1 gadolinium volumes whereas 18F-FET PET provided complementary information, suggesting that the metabolically active tumor volume in patients with newly diagnosed untreated HGG is critically underestimated by contrast enhanced MRI. 18F-FET PET imaging may help to improve target volume delineation accuracy for radiotherapy planning.

1050-P: Enhanced Release of Glucose into the Intraluminal Space of the Intestine Associated with Metformin Treatment as Revealed by 18F FDG-Based PET-MRI

Objective: In addition to the inhibition of gluconeogenesis in the liver, metformin exerts various effects on the gut that likely contribute to the lowering of blood glucose levels. Positron emission tomography (PET)-computed tomography recently has revealed that metformin promotes the intestinal accumulation of [18F]fluorodeoxyglucose (FDG), a nonmetabolizable glucose derivative, indicating that the drug affects glucose handling in the intestine. It has remained unknown, however, whether this accumulation occurs in the wall or intraluminal space of the intestine. We here addressed this question with the use of [18F]FDG-based PET-magnetic resonance imaging (MRI), a recently developed imaging modality with increased accuracy of registration and high soft-tissue contrast. Methods: Among 244 individuals with type 2 diabetes who underwent PET-MRI, we extracted 24 pairs of subjects matched for age, BMI, and HbA1c level who were (metformin group) or were not (control group) receiving treatment with metformin. We evaluated accumulation of [18F]FDG in different portions of the intestine with both a visual scale and measurement of maximum standardized uptake value (SUVmax), and such accumulation within the intestinal wall or lumen was discriminated on the basis of SUVmax. Results: SUVmax of the jejunum, ileum, and right or left hemicolon was greater in the metformin group than in the control group. [18F]FDG accumulation in the ileum and right or left hemicolon as assessed with the visual scale was also greater in the metformin group. SUVmax for the intraluminal space of the ileum and right or left hemicolon, but not that for the intestinal wall, was greater in the metformin group than in the control group. Conclusions: Metformin treatment was associated with increased accumulation of [18F]FDG in the intraluminal space of the intestine, suggesting that this drug promotes the transport of glucose from the circulation into stool. Disclosure K. Sakaguchi: Other Relationship; Self; AstraZeneca, Novartis AG, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Morita: None. M. Nogami: None. Y. Okada: None. Y. Hirota: Other Relationship; Self; Sanofi. K. Sugawara: None. Y. Tamori: None. T. Murakami: None. W. Ogawa: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharma GmbH &amp; Co.KG, Eli Lilly Japan K.K., Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

Long-term Ashtanga yoga practice decreases medial temporal and brainstem glucose metabolism in relation to years of experience

BackgroundYoga is increasingly popular worldwide with several physical and mental benefits, but the underlying neurobiology remains unclear. Whereas many studies have focused on pure meditational aspects, the triad of yoga includes meditation, postures, and breathing. We conducted a cross-sectional study comparing experienced yoga practitioners to yoga-naive healthy subjects using a multiparametric 2 × 2 design with simultaneous positron emission tomography/magnetic resonance (PET/MR) imaging.Methods18F-FDG PET, morphometric and diffusion tensor imaging, resting state fMRI, and MR spectroscopy were acquired in 10 experienced (4.8 ± 2.3 years of regular yoga experience) yoga practitioners and 15 matched controls in rest and after a single practice (yoga practice and physical exercise, respectively).ResultsIn rest, decreased regional glucose metabolism in the medial temporal cortex, striatum, and brainstem was observed in yoga practitioners compared to controls (p < 0.0001), with a significant inverse correlation of resting parahippocampal and brainstem metabolism with years of regular yoga practice (ρ < − 0.63, p < 0.05). A single yoga practice resulted in significant hypermetabolism in the cerebellum (p < 0.0001). None of the MR measures differed, both at rest and after intervention.ConclusionsExperienced yoga practitioners show regional long-term decreases in glucose metabolism related to years of practice. To elucidate a potential causality, a prospective longitudinal study in yoga-naive individuals is warranted.

PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson's Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy.

The adenosine A2A receptor (A2AR) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson’s disease (PD). An increased A2AR availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A2AR upregulation in PD. For that purpose, we selected the known A2AR-specific radiotracer [18F]FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [18F]FESCH in the mouse striatum. Concomitantly, metabolism studies with [18F]FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A2AR binding of [18F]FESCH was found. Nonetheless, the correlation between the increased A2AR levels within the proposed PD animal model remains to be further investigated.

Improving the CT (140kVp) to PET (511keV) conversion in PET/MR hardware component attenuation correction.

Today, attenuation correction (AC) of positron emission tomography/magnetic resonance (PET/MR) hardware components is performed by using an established method from PET/CT hybrid imaging. As shown in previous studies, the established mathematical conversion from computed tomography (CT) to PET attenuation coefficients may, however, lead to incorrect results in PET quantification when applied to AC of hardware components in PET/MR. The purpose of this study is to systematically investigate the attenuating properties of various materials and electronic components frequently used in the context of PET/MR hybrid imaging. The study, thus, aims at improving hardware component attenuation correction in PET/MR. Overall, 38 different material samples were collected; a modular phantom was used to for CT, PET, and PET/MR scanning of all samples. Computed tomography-scans were acquired with a tube voltage of 140kVp to determine Hounsfield Units (HU). PET transmission scans were performed with 511keV to determine linear attenuation coefficients (LAC) of all materials. The attenuation coefficients were plotted to obtain a HU to LAC correlation graph, which was then compared to two established conversions from literature. Hardware attenuation maps of the different materials were created and applied to PET data reconstruction following a phantom validation experiment. From these measurements, PET difference maps were calculated to validate and compare all three conversion methods. For each material, the HU and corresponding LAC could be determined and a bi-linear HU to LAC conversion graph was derived. The corresponding equation was . While the two established conversions lead to a mean quantification PET bias of 4.69%±0.27% and -2.84%±0.72% in a phantom experiment, PET difference measurements revealed only 0.5% bias in PET quantification when applying the new conversion resulting from this study. An optimized method for the conversion of CT to PET attenuation coefficients has been derived by systematic measurement of 38 different materials. In contrast to established methods, the new conversion also considers highly attenuating materials, thus improving attenuation correction of hardware components in PET/MR hybrid imaging.

Performance of Multiparametric Functional Imaging and Texture Analysis in Predicting Synchronous Metastatic Disease in Pancreatic Ductal Adenocarcinoma Patients by Hybrid PET/MR: Initial Experience.

Objectives: To assess the imaging biomarkers of glucose metabolic activity and diffusion-weighted imaging (DWI) derived from pretreatment integrated 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET/MR) imaging as potential predictive factors of metastasis in patients with pancreatic ductal adenocarcinoma (PDAC).Patients and Methods: We retrospectively included 17 consecutive patients with pathologically confirmed PDAC by pretreatment 18F-FDG PET/MR. The study subjects were divided into a non-metastatic group (M0, six cases) and a metastatic group (M1, 11 cases). The 18F-FDG PET/MR images were reviewed independently by two board certificated nuclear medicine physicians and one radiologist. Conventional characteristics and quantitative parameters from both PET and apparent diffusion coefficient (ADC) were assessed. The texture features were extracted from LIFEx packages (www.lifexsoft.org), and a 3D tumor volume of interest was manually drawn on fused PET/ADC images. Chi-square tests, independent-samples t-tests and Mann–Whitney U-tests were used to compare the differences in single parameters between the two groups. A logistic regression analysis was performed to determine independent predictors. A receiver operating characteristic (ROC) curve analysis was performed to assess the discriminatory power of the selected parameters. Correlations between metabolic parameters and ADC features were calculated with Spearman's rank correlation coefficient test.Results: For conventional parameters, univariable analysis demonstrated that the M1 group had a significantly larger size and a higher peak of standardized uptake value (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) than those of the M0 group (p < 0.05 for all). TLG remained significant predictor in the multivariable analysis, but there were no significant differences for the area under the ROC curve (AUC) among the four conventional features in differential diagnoses (p > 0.05 for all). For the texture features, there were four features from the PET image and 13 from the ADC map that showed significant differences between the two groups. Multivariate analysis indicated that one feature from PET and three from the ADC were significant predictors. TLG was associated with ADC-GLRLM_GLNU (r = 0.659), ADC-GLRLM_LRHGE (r = 0.762), and PET-GLRLM_LRHGE (r = 0.806).Conclusions: Multiple parameters and texture features of primary tumors from 18F-FDG PET/MR images maybe reliable biomarkers to predict synchronous metastatic disease for the pretreatment PDAC.

Usefulness of Hybrid PET/MRI in Clinical Evaluation of Head and Neck Cancer Patients.

(1) Background: The novel hybrid of positron emission tomography/magnetic resonance (PET/MR) examination has been introduced to clinical practice. The aim of our study was to evaluate PET/MR usefulness in preoperative staging of head and neck cancer (HNC) patients (pts); (2) Methods: Thirty eight pts underwent both computed tomography (CT) and PET/MR examination, of whom 21 pts underwent surgical treatment as first-line therapy and were further included in the present study. Postsurgical tissue material was subjected to routine histopathological (HP) examination with additional evaluation of p16, human papillomavirus (HPV), Epstein-Barr virus (EBV) and Ki67 status. Agreement of clinical and pathological T staging, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of CT and PET/MR in metastatic lymph nodes detection were defined. The verification of dependences between standardized uptake value (SUV value), tumor geometrical parameters, number of metastatic lymph nodes in PET/MR and CT, biochemical parameters, Ki67 index, p16, HPV and EBV status was made with statistical analysis of obtained results; (3) Results: PET/MR is characterized by better agreement in T staging, higher specificity, sensitivity, PPV and NPV of lymph nodes evaluation than CT imaging. Significant correlations were observed between SUVmax and maximal tumor diameter from PET/MR, between SUVmean and CT tumor volume, PET/MR tumor volume, maximal tumor diameter assessed in PET/MR. Other correlations were weak and insignificant; (4) Conclusions: Hybrid PET/MR imaging is useful in preoperative staging of HNC. Further studies are needed.

Magnetic Resonance-Based Attenuation Correction and Scatter Correction in Neurological Positron Emission Tomography/Magnetic Resonance Imaging—Current Status With Emerging Applications

In this review, we will summarize the past and current state-of-the-art developments in attenuation and scatter correction approaches for hybrid positron emission tomography (PET) and magnetic resonance (MR) imaging. The current status of the methodological advances for producing accurate attenuation and scatter corrections on positron emission tomography/magnetic resonance (PET/MR) systems are described, in addition to emerging clinical and research applications. Future prospects and potential applications which benefit from accurate data corrections to improve the quantitative accuracy and clinical applicability of PET/MR are also discussed. Novel clinical and research applications where improved attenuation and scatter correction methods are beneficial are highlighted.

CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis-Driven Hepatocarcinogenesis via ERK-Dependent PKM2 Nuclear Relocalization and Activation.

Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain-of-function and loss-of-function in vitro studies in patient-derived organoid and cell cultures as well as in vivo positron emission tomography-magnetic resonance imaging animal models, we showed that protein arginine N-methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal-regulated kinase (ERK)-mediated PKM2 translocation into the nucleus. This altered PRMT6-ERK-PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1-silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2-deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Our findings indicate that the PRMT6-ERK-PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.

Potential Clinical Applications of PET/MR

Since the introduction of simultaneous positron emission tomography magnetic resonance imaging (PET/MR) in 2010, technological advances led to improved image quality, improved attenuation correction, and reduced scan time, leading to an increasing number of clinical applications for this new technology. Lower radiation exposure and higher soft-tissue contrast are the main advantages of PET/MR over PET/CT. However, its real added value in clinical applications is still under investigation. This short review is focusing on three PET/MR applications that had an increasing clinical acceptance in our institution and where we believe that PET/MR will play an important role in the future: prostate cancer, head and neck cancer, and cardiac imaging.

Fibroblast Growth Factor-21, Leptin, and Adiponectin Responses to Acute Cold-Induced Brown Adipose Tissue Activation.

BackgroundAdipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored.ObjectiveOur study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults.DesignNineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity.Main Outcome MeasuresPlasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA).ResultsPlasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P = 0.03), and inversely correlated with MR sFF (coefficient, −404; P = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects.ConclusionHigher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.HighlightsA higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.

Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer\u2019s disease

BackgroundPlasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects.MethodsTwenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics.ResultsStatistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping.ConclusionWe conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases—possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.

Preclinical and first-in-human-brain-cancer applications of [18F]poly (ADP-ribose) polymerase inhibitor PET/MR.

BackgroundWe report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [18F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.MethodsWe applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [18F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [18F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.ResultsIn a preclinical mouse model, we illustrated that [18F]PARPi crossed the blood–brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [18F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood–brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.ConclusionsAlthough larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

(18F)-Fluorodeoxyglucose positron emission tomography/magnetic resonance imaging assessment of hypometabolism patterns in clinical phenotypes of suspected corticobasal degeneration

Corticobasal degeneration (CBD) is a rare neurodegenerative disorder presenting with atypical parkinsonian symptoms that characteristically involves the frontoparietal region including the primary sensorimotor cortex, ipsilateral basal ganglia, and thalamus, typically in an asymmetric pattern. We aim to evaluate the metabolic and volumetric abnormalities in patients with clinically suspected CBD phenotypes utilizing hybrid 18F-fluorodeoxyglucose (FDG) positron emission tomography–magnetic resonance (PET/MR) brain imaging. A retrospective analysis was performed on 75 patients (mean age 74 years, 31 males and 44 females) who underwent 18F-FDG PET/MR imaging (MRI) as part of their clinical dementia workup. Images were obtained using an integrated Siemens mMR 3T PET/MRI scanner. Two board-certified neuroradiologists and a nuclear medicine physician evaluated the metabolic and volumetric data of each hemisphere to assess for symmetric or asymmetric involvement of regions of interest in the subset of patients with suspected CBD. Of the 75 patients, 12 were diagnosed with suspected CBD based on a combination of clinical symptoms, neurocognitive testing, and hybrid neuroimaging findings. Ten of 12 patients (87%) demonstrated asymmetrically decreased FDG uptake involving a single cerebral hemisphere and ipsilateral subcortical structures, whereas two of 12 patients (13%) demonstrated striking hypometabolism of the bilateral sensorimotor cortices. Our study highlights two characteristic patterns of hypometabolism in patients with clinical and neuroimaging findings suggestive of the underlying CBD. The first pattern is asymmetric hypometabolism and volume loss, particularly within the frontoparietal and occipital cortices with involvement of ipsilateral subcortical structures, including the basal ganglia and thalamus. The second, more atypical pattern, is symmetric hypometabolism with striking involvement of the bilateral sensorimotor cortices.