Brown Adipose Tissue: A Protective Mechanism Against "Preprediabetes"?

Brown adipose tissue (BAT) is present in a significant number of adult humans and has been postulated to exert beneficial metabolic effects. Lean, nondiabetic patients undergoing clinical PET/CT imaging are more likely to exhibit incidental BAT activation. The aim of this study was to assess metabolic changes associated with the cold activation of BAT and to compare baseline blood metabolites in participants with varying amounts of active BAT. Methods: Serum blood samples were collected from healthy adult volunteers (body mass index, 18.0-25.0, and age ≤ 35 y) before and after 2 h of exposure to cold. 18F-FDG PET/CT imaging was performed immediately after cold exposure. Activated BAT was segmented, and fasting glucose, insulin, lipid, and other blood metabolite levels were correlated with volume and intensity of active BAT. Using a median cutoff, subjects were classified as high-BAT (BAThigh) or low-BAT (BATlow). Results: A higher volume of activated BAT was associated with significantly higher precooling glucose and insulin levels (P < 0.001 for each). Precooling thyroid-stimulating hormone and triglyceride levels were significantly higher in the BAThigh than the BATlow group (P = 0.002 and P < 0.001, respectively). Triglyceride levels tended to increase over the cooling period in both BAT groups but increased significantly more in the BAThigh group (15.7 ± 13.2 mg/dL; P < 0.001) than in the BATlow group (4.5 ± 12.2 mg/dL; P = 0.061). Conclusion: These findings may indicate that BAT is recruited to counteract incipient "preprediabetic" states, potentially serving as a first-line protective mechanism against very early metabolic or hormonal variations.

Perspectives on Brown Adipose Tissue Imaging: Insights from Preclinical and Clinical Observations from the Last and Current Century.

Brown adipose tissue (BAT) was first described in the 16th century, but until late last century had mainly been considered a tissue with the function of nonshivering thermogenesis, maintaining body temperature in key organs in newborns who have high body surface areas relative to their weight and thus marked radiative heat loss. BAT was believed to have substantially disappeared by adulthood. Molecular imaging with 18F-FDG PET and PET combined with CT, as well as imaging with 131I-metaiodobenzylguanidine (MIBG) beginning late last century have shown BAT to be present and active well into adulthood. This review highlights key aspects of BAT biology, early empiric observations misidentifying BAT, pitfalls in image interpretation, and methods to intentionally reduce BAT uptake, and outlines multiple imaging methods used to identify BAT in vivo. The therapeutic potential of increasing the amount or activity of BAT for weight loss and improvement of glucose and lipid profiles is highlighted as a major opportunity. Molecular imaging can help dissect the physiology of this complex dynamic tissue and offers the potential for addressing challenges separating "active BAT" from "total BAT." Research in BAT has grown extensively, and 18F-FDG PET is the key imaging procedure against which all other BAT imaging methods must be compared. Given the multiple functions of BAT, it is reasonable to consider it a previously unrecognized endocrine tissue and thus an appropriate topic for review in this supplement to The Journal of Nuclear Medicine.

Repeatability of Radiomic Features of Brown Adipose Tissue.

The aim of this study was to assess the repeatability of activated brown adipose tissue (BAT) radiomic features. To decipher radiomic features that may provide useful information on BAT, the impact of reconstruction methods and imaging modality choice was also evaluated. Methods: Twenty-seven healthy adults enrolled in this study. After a cooling procedure to activate BAT, volunteers underwent 18F-FDG imaging. Participants underwent repeat imaging using the same imaging protocols and a similar 18F-FDG dose within 14 d. Active BAT was segmented using the BARCIST 1.0 methods. Radiomic features were extracted from each region of interest on high-definition PET (HD PET), non-HD PET, and CT images. Lin's concordance correlation coefficient was used to estimate the repeatability of the extracted radiomic features. To determine whether BAT radiomic feature repeatability correlates with BAT SUVmax repeatability, participants were stratified based on the relative difference in SUVmax between sessions. Non-HD PET repeatable features were clustered together using hierarchical clustering, and the normalized dynamic range of each feature was computed to identify the most informative feature within each cluster. Results: Eighteen of the 27 volunteers had sufficient BAT activity for radiomic analysis. Sixty-six HD PET, 66 non-HD PET, and 6 CT features showed high repeatability (concordance correlation coefficient ≥ 0.80). Feature repeatability was significantly higher for PET than for CT, but there was no statistically significant difference between HD and non-HD PET in radiomic feature repeatability. The repeatability of radiomic features extracted from each modality and reconstruction method type followed the trend in SUVmax, as participants with lower relative differences in SUVmax between initial and repeated imaging sessions had higher radiomic feature repeatability. Hierarchical clustering of the high-repeatability PET features resulted in 10 highly correlated clusters (R2 ≥ 0.95). Seven features, including SUVmax, did not cluster with any other features. Conclusion: Several clusters of highly repeatable BAT radiomic features derived from 18F-FDG PET/CT appear to provide information regarding BAT activity distinct from SUVmax These features might be explored as quantitative imaging biomarkers of BAT activity in future studies.

Repeatability of 18F-FDG PET Radiomic Features in Cervical Cancer.

Knowledge of the intrinsic variability of radiomic features is essential to the proper interpretation of changes in these features over time. The primary aim of this study was to assess the test-retest repeatability of radiomic features extracted from 18F-FDG PET images of cervical tumors. The impact of different image preprocessing methods was also explored. Methods: Patients with cervical cancer underwent baseline and repeat 18F-FDG PET/CT imaging within 7 d. PET images were reconstructed using 2 methods: ordered-subset expectation maximization (PETOSEM) or ordered-subset expectation maximization with point-spread function (PETPSF). Tumors were segmented to produce whole-tumor volumes of interest (VOIWT) and 40% isocontours (VOI40). Voxels were either left at the default size or resampled to 3-mm isotropic voxels. SUV was discretized to a fixed number of bins (32, 64, or 128). Radiomic features were extracted from both VOIs, and repeatability was then assessed using the Lin concordance correlation coefficient (CCC). Results: Eleven patients were enrolled and completed the test-retest PET/CT imaging protocol. Shape, neighborhood gray-level difference matrix, and gray-level cooccurrence matrix features were repeatable, with a mean CCC value of 0.81. Radiomic features extracted from PETOSEM images showed significantly better repeatability than features extracted from PETPSF images (P < 0.001). Radiomic features extracted from VOI40 were more repeatable than features extracted from VOIWT (P < 0.001). For most features (78.4%), a change in bin number or voxel size resulted in less than a 10% change in feature value. All gray-level emphasis and gray-level run emphasis features showed poor repeatability (CCC values < 0.52) when extracted from VOIWT but were highly repeatable (mean CCC values > 0.96) when extracted from VOI40Conclusion: Shape, gray-level cooccurrence matrix, and neighborhood gray-level difference matrix radiomic features were consistently repeatable, whereas gray-level run length matrix and gray-level zone length matrix features were highly variable. Radiomic features extracted from VOI40 were more repeatable than features extracted from VOIWT Changes in voxel size or SUV discretization parameters typically resulted in relatively small differences in feature value, though several features were highly sensitive to these changes.

Human Radiation Dosimetry for Orally and Intravenously Administered 18F-FDG.

Intravenous access is difficult in some patients referred for 18F-FDG PET imaging. Extravasation at the injection site and accumulation in central catheters can lead to limited tumor 18F-FDG uptake, erroneous quantitation, and significant image artifacts. In this study, we compared the human biodistribution and dosimetry for 18F-FDG after oral and intravenous administrations sequentially in the same subjects to ascertain the dosimetry and potential suitability of orally administered 18F-FDG as an alternative to intravenous administration. We also compared our detailed intravenous 18F-FDG dosimetry with older dosimetry data. Methods: Nine healthy volunteers (6 male and 3 female; aged 19-32 y) underwent PET/CT imaging after oral and intravenous administration of 18F-FDG. Identical preparation and imaging protocols (except administration route) were used for oral and intravenous studies. During each imaging session, 9 whole-body PET scans were obtained at 5, 10, 20, 30, 40, 50, 60, 120, and 240 min after 18F-FDG administration (370 ± 16 MBq). Source organ contours drawn using CT were overlaid onto registered PET images to extract time-activity curves. Time-integrated activity coefficients derived from time-activity curves were given as input to OLINDA/EXM for dose calculations. Results: Blood uptake after orally administered 18F-FDG peaked at 45-50 min after ingestion. The oral-to-intravenous ratios of 18F-FDG uptake for major organs at 45 min were 1.07 ± 0.24 for blood, 0.94 ± 0.39 for heart wall, 0.47 ± 0.12 for brain, 1.25 ± 0.18 for liver, and 0.84 ± 0.24 for kidneys. The highest organ-absorbed doses (µGy/MBq) after oral 18F-FDG administration were observed for urinary bladder (75.9 ± 17.2), stomach (48.4 ± 14.3), and brain (29.4 ± 5.1), and the effective dose was significantly higher (20%) than after intravenous administration (P = 0.002). Conclusion:18F-FDG has excellent bioavailability after oral administration, but peak organ activities occur later than after intravenous injection. These data suggest PET at 2 h after oral 18F-FDG administration should yield images that are comparable in biodistribution to conventional clinical images acquired 1 h after injection. Oral 18F-FDG is a palatable alternative to intravenous 18F-FDG when venous access is problematic.

Repeatability of Quantitative Brown Adipose Tissue Imaging Metrics on Positron Emission Tomography with 18F-Fluorodeoxyglucose in Humans.

Brown adipose tissue (BAT) is a promising target for anti-obesity interventions. This prospective test-retest study assessed the repeatability of several important quantitative BAT metrics. After cold activation, 24 subjects underwent positron emission tomography (PET)/computed tomography (CT) and PET/magnetic resonance imaging (MRI), utilizing 18F-fluorodeoxyglucose. Repeat imaging occurred within 14 days per an identical protocol. BAT volumes were strongly correlated between sessions for PET/CT (intraclass correlation coefficient [ICC], 0.85) and PET/MRI (ICC, 0.82). BAT maximum lean-body-mass-adjusted standardized uptake values (SULmax) were also strongly correlated between sessions for both PET/CT (ICC, 0.74) and PET/MRI (ICC, 0.83). Much longitudinal variability in BAT metrics was likely due to biological factors intrinsic to BAT, whole-body metabolic fluctuations, or temporal differences in cold-activation efficacy, rather than imaging factors. Future studies utilizing these imaging metrics to track the response BAT to interventions should incorporate this variation into sample-size considerations and response criteria.

Repeatability of brown adipose tissue measurements on FDG PET/CT following a simple cooling procedure for BAT activation.

Brown Adipose Tissue (BAT) is present in a significant number of adult humans and can be activated by exposure to cold. Measurement of active BAT presence, activity, and volume are desirable for determining the efficacy of potential treatments intended to activate BAT. The repeatability of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of BAT presence, activity, and volume under controlled conditions has not been extensively studied. Eleven female volunteers underwent double baseline FDG PET imaging performed following a simple, regional cold intervention intended to activate brown fat. The cold intervention involved the lightly-clothed participants intermittently placing their feet on a block of ice while sitting in a cooled room. A repeat study was performed under the same conditions within a target of two weeks. FDG scans were obtained and maximum standardized uptake value adjusted for lean body mass (SULmax), CT Hounsfield units (HU), BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were determined according to the Brown Adipose Reporting Criteria in Imaging STudies (BARCIST) 1.0. A Lin's concordance correlation (CCC) of 0.80 was found for BMV between test and retest imaging. Intersession BAT SULmax was significantly correlated (r = 0.54; p < 0.05). The session #1 mean SULmax of 4.92 ± 4.49 g/mL was not significantly different from that of session #2 with a mean SULmax of 7.19 ± 7.34 g/mL (p = 0.16). BAT SULmax was highly correlated with BMV in test and retest studies (r ≥ 0.96, p < 0.001). Using a simplified ice-block cooling method, BAT was activated in the majority (9/11) of a group of young, lean female participants. Quantitative assessments of BAT SUL and BMV were not substantially different between test and retest imaging, but individual BMV could vary considerably. Intrasession BMV and SULmax were strongly correlated. The variability in estimates of BAT activity and volume on test-retest with FDG should inform sample size choice in studies quantifying BAT physiology and support the dynamic metabolic characteristics of this tissue. A more sophisticated cooling method potentially may reduce variations in test-retest BAT studies.

Measurement Repeatability of 18F-FDG PET/CT Versus 18F-FDG PET/MRI in Solid Tumors of the Pelvis.

Knowledge of the within-subject variability of 18F-FDG PET/MRI measurements is necessary for proper interpretation of quantitative PET or MRI metrics in the context of therapeutic efficacy assessments with integrated PET/MRI scanners. The goal of this study was to determine the test-retest repeatability of these metrics on PET/MRI, with comparison to similar metrics acquired by PET/CT. Methods: This prospective study enrolled subjects with pathology-proven pelvic malignancies. Baseline imaging consisted of PET/CT immediately followed by PET/MRI, using a single 370-MBq 18F-FDG dose. Repeat imaging was performed within 7 d using an identical imaging protocol, with no oncologic therapy between sessions. PET imaging on both scanners consisted of a list-mode acquisition at a single pelvic station. The MRI consisted of 2-point Dixon imaging for attenuation correction, standard sequences for anatomic correlation, and diffusion-weighted imaging. PET data were statically reconstructed using various frame durations and minimizing uptake time differences between sessions. SUV metrics were extracted for both PET/CT and PET/MRI in each imaging session. Apparent diffusion coefficient (ADC) metrics were extracted for both PET/MRI sessions. Results: The study cohort consisted of 14 subjects (13 female, 1 male) with various pelvic cancers (11 cervical, 2 rectal, 1 endometrial). For SUVmax, the within-subject coefficient of variation (wCV) appeared higher for PET/CT (8.5%-12.8%) than PET/MRI (6.6%-8.7%) across all PET reconstructions, though with no significant repeatability differences (all P values ≥ 0.08) between modalities. For lean body mass-adjusted SUVpeak, the wCVs appeared similar for PET/CT (9.9%-11.5%) and PET/MRI (9.2%-11.3%) across all PET reconstructions, again with no significant repeatability differences (all P values ≥ 0.14) between modalities. For PET/MRI, the wCV for ADCmedian of 3.5% appeared lower than the wCVs for SUVmax (6.6%-8.7%) and SULpeak (9.2%-11.3%), though without significant repeatability differences (all P values ≥ 0.23). Conclusion: For solid tumors of the pelvis, the repeatability of the evaluated SUV and ADC metrics on 18F-FDG PET/MRI is both acceptably high and similar to previously published values for 18F-FDG PET/CT and MRI, supporting the use of 18F-FDG PET/MRI for quantitative oncologic treatment response assessments.

Measurement of Brown Adipose Tissue Activity Using Microwave Radiometry and 18F-FDG PET/CT.

The aim of this study was to evaluate the operating characteristics of a microwave radiometry system in the noninvasive assessment of activated and nonactivated brown adipose tissue (BAT) and normal-tissue temperatures, reflecting metabolic activity in healthy human subjects. The radiometry data were compared with 18F-FDG PET/CT images in the same subjects. Methods: Microwave radiometry and 18F-FDG PET/CT were sequentially performed on 19 participants who underwent a cold intervention to maximize BAT activation. The cold intervention involved the participants' intermittently placing their feet on an ice block while sitting in a cool room. Participants exhibiting BAT activity qualitatively on PET/CT were scanned again with both modalities after undergoing a BAT minimization protocol (exposure to a warm room and a 20-mg dose of propranolol). Radiometry was performed every 5 min for 2 h before PET/CT imaging during both the warm and the cold interventions. A grid of 15-20 points was drawn on the participant's upper body (data were collected at each point), and a photograph was taken for comparison with PET/CT images. Results: PET/CT identified increased signal consistent with BAT activity in 11 of 19 participants. In 10 of 11 participants with active BAT, radiometry measurements collected during the cold study were modestly, but significantly, higher on points located over areas of active BAT on PET/CT than on points not exhibiting BAT activity (P < 0.01). This difference lessened during the warm studies: 7 of 11 participants showed radiometry measurements that did not differ significantly between the same set of points. The mean radiometry result collected during BAT maximization was 33.2°C ± 1.5°C at points designated as active and 32.7°C ± 1.3°C at points designated as inactive (P < 0.01). Conclusion: Passive microwave radiometry was shown to be feasible and, with substantial improvements, has the potential to noninvasively detect active brown adipose tissue without a radiotracer injection.

A comparison of FLT to FDG PET/CT in the early assessment of chemotherapy response in stages IB-IIIA resectable NSCLC.

BACKGROUND: The aim of this study was to compare the percentage change in 18F-fluorothymidine (FLT) standard uptake value (SUV) between baseline and after one cycle of chemotherapy in patients categorized by RECIST 1.1 computed tomography (CT) as responders or non-responders after two cycles of therapy. Change in 18F-fluorodeoxyglucose (FDG) uptake was also compared between these time points. Nine patients with newly diagnosed, operable, non-small cell lung cancer (NSCLC) were imaged with FDG positron emission tomography/CT (PET), FLT PET/CT, and CT at baseline, following one cycle of neoadjuvant therapy (75 mg/m2 docetaxel + 75 mg/m2 cisplatin), and again after the second cycle of therapy. All patients had a biopsy prior to enrollment and underwent surgical resection within 4 weeks of post-cycle 2 imaging. RESULTS: Between baseline and post-cycle 1, non-responders had mean SULmax (maximum standard uptake value adjusted for lean body mass) increases of 7.0 and 3.4% for FDG and FLT, respectively. Responders had mean decreases of 44.8 and 32.0% in FDG and FLT SULmax, respectively, between baseline and post-cycle 1 imaging. On post-cycle 1 imaging, primary tumor FDG SUL values were significantly lower in responders than in non-responders (P = 0.016). Primary tumor FLT SUL values did not differ significantly between these groups. Using the change from baseline to post-cycle 1, receiver-operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.94 for FDG and 0.78 for FLT in predicting anatomic tumor response after the second cycle of therapy. CONCLUSIONS: Fractional decrease in FDG SULmax from baseline to post-cycle 1 imaging was significantly different between anatomic responders and non-responders, while percentage changes in FLT SULmax were not significantly different between these groups over the same period of time.