GPi-DBS-induced brain metabolic activation in cervical dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia. METHODS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR<0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen. CONCLUSIONS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.

Bone marrow metabolism is affected by body weight and response to exercise training varies according to anatomical location.

AIM: High body weight is a protective factor against osteoporosis, but obesity also suppresses bone metabolism and whole-body insulin sensitivity. However, the impact of body weight and regular training on bone marrow (BM) glucose metabolism is unclear. We studied the effects of regular exercise training on bone and BM metabolism in monozygotic twin pairs discordant for body weight. METHODS: We recruited 12 monozygotic twin pairs (mean ± SD age 40.4 ± 4.5 years; body mass index 32.9 ± 7.6, mean difference between co-twins 7.6 kg/m2 ; eight female pairs). Ten pairs completed the 6-month long training intervention. We measured lumbar vertebral and femoral BM insulin-stimulated glucose uptake (GU) using 18 F-FDG positron emission tomography, lumbar spine bone mineral density and bone turnover markers. RESULTS: At baseline, heavier co-twins had higher lumbar vertebral BM GU (p < .001) and lower bone turnover markers (all p < .01) compared with leaner co-twins but there was no significant difference in femoral BM GU, or bone mineral density. Training improved whole-body insulin sensitivity, aerobic capacity (both p < .05) and femoral BM GU (p = .008). The training response in lumbar vertebral BM GU was different between the groups (time × group, p = .02), as GU tended to decrease in heavier co-twins (p = .06) while there was no change in leaner co-twins. CONCLUSIONS: In this study, regular exercise training increases femoral BM GU regardless of weight and genetics. Interestingly, lumbar vertebral BM GU is higher in participants with higher body weight, and training counteracts this effect in heavier co-twins even without reduction in weight. These data suggest that BM metabolism is altered by physical activity.

The effects of a 6-month intervention aimed to reduce sedentary time on skeletal muscle insulin sensitivity: a randomized controlled trial.

Sedentary behavior (SB) and physical inactivity associate with impaired insulin sensitivity. We investigated whether an intervention aimed at a 1-h reduction in daily SB during 6 mo would improve insulin sensitivity in the weight-bearing thigh muscles. Forty-four sedentary inactive adults [mean age 58 (SD 7) yr; 43% men] with metabolic syndrome were randomized into intervention and control groups. The individualized behavioral intervention was supported by an interactive accelerometer and a mobile application. SB, measured with hip-worn accelerometers in 6-s intervals throughout the 6-mo intervention, decreased by 51 (95% CI 22-80) min/day and physical activity (PA) increased by 37 (95% CI 18-55) min/day in the intervention group with nonsignificant changes in these outcomes in the control group. Insulin sensitivity in the whole body and in the quadriceps femoris and hamstring muscles, measured with hyperinsulinemic-euglycemic clamp combined with [18F]fluoro-deoxy-glucose PET, did not significantly change during the intervention in either group. However, the changes in hamstring and whole body insulin sensitivity correlated inversely with the change in SB and positively with the changes in moderate-to-vigorous PA and daily steps. In conclusion, these results suggest that the more the participants were able to reduce their SB, the more their individual insulin sensitivity increased in the whole body and in the hamstring muscles but not in quadriceps femoris. However, according to our primary randomized controlled trial results, this kind of behavioral interventions targeted to reduce sedentariness may not be effective in increasing skeletal muscle and whole body insulin sensitivity in people with metabolic syndrome at the population level.NEW & NOTEWORTHY Aiming to reduce daily SB by 1 h/day had no impact on skeletal muscle insulin sensitivity in the weight-bearing thigh muscles. However, successfully reducing SB may increase insulin sensitivity in the postural hamstring muscles. This emphasizes the importance of both reducing SB and increasing moderate-to-vigorous physical activity to improve insulin sensitivity in functionally different muscles of the body and thus induce a more comprehensive change in insulin sensitivity in the whole body.

Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients.

PURPOSE: Short-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [18F]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism. METHODS: Twenty-five men with newly diagnosed treatment-naïve metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [18F]PSMA-1007 PET/CT immediately before and 3-4 weeks after ADT initiation (degarelix). Before ADT, [18F]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as ΔSUVmax. RESULTS: All the patients reached castration levels of testosterone at the time of the second [18F]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (≥ 20%) in PSMA uptake, with a median ΔSUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [18F]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA ΔSUVmax and FDG SUVmax (p < 0.0001). Moreover, a negative correlation between the ΔSUVmax and the decrease in serum PSA after ADT was noted (p < 0.0001). CONCLUSIONS: A heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive. TRIAL REGISTRATION: NCT03876912, registered 15 March 2019.

Associations of sedentary time, physical activity, and fitness with muscle glucose uptake in adults with metabolic syndrome.

OBJECTIVE: The objective of the study was to investigate the associations of sedentary time, physical activity, and cardiorespiratory fitness with skeletal muscle glucose uptake (GU). METHODS: Sedentary time and physical activity were measured with accelerometers and VO2 max with cycle ergometry in 44 sedentary adults with metabolic syndrome. Thigh muscle GU was determined with [18 F]FDG-PET imaging. RESULTS: Sedentary time (ß = -0.374), standing (ß = 0.376), steps (ß = 0.351), and VO2 max (ß = 0.598) were associated with muscle GU when adjusted for sex, age, and accelerometer wear time. Adjustment for body fat-% turned all associations non-significant. CONCLUSION: Body composition is a more important determinant of muscle GU in this population than sedentary time, physical activity, or fitness.

Novel effects of the gastrointestinal hormone secretin on cardiac metabolism and renal function.

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography. Kidney function was measured with [18F]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means ± SD, 15.5 ± 7.4 vs. 9.7 ± 4.9 µmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [18F]FDG renal clearance (44.5 ± 5.4 vs. 39.5 ± 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 ± 9.8 vs. 6.0 ± 5.2 ΔmL/min/1.73 m2, 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure.NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.

Hydroxysteroid (17ß) dehydrogenase 12 is essential for metabolic homeostasis in adult mice.

Hydroxysteroid 17ß dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within 6 days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides, and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.

Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques.

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR-/-ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR-/-ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.

Prospective evaluation of 18F-FACBC PET/CT and PET/MRI versus multiparametric MRI in intermediate- to high-risk prostate cancer patients (FLUCIPRO trial).

PURPOSE: The purpose of this study was to evaluate 18F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa). METHODS: Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 ± 10 MBq 18F-FACBC (fluciclovine) followed by PET/MRI started 55 ± 7 min from injection. Maximum standardized uptake values (SUVmax) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (VT). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455. RESULTS: In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUVmax and VT of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes. CONCLUSIONS: Quantitative 18F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. 18F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI.

Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.

BACKGROUND: Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aß) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. FINDINGS: Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aß burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aß42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. CONCLUSIONS: JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aß burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Prognostic value of tumour blood flow, [¹8F]EF5 and [¹8F]FDG PET/CT imaging in patients with head and neck cancer treated with radiochemotherapy.

PURPOSE: In order to improve the treatment of squamous cell carcinoma of the head and neck, precise information on the treated tumour's biology is required and the prognostic importance of different biological parameters needs to be determined. The aim of our study was to determine the predictive value of pretreatment PET/CT imaging using [(18)F]FDG, a new hypoxia tracer [(18)F]EF5 and the perfusion tracer [(15)O]H2O in patients with squamous cell cancer of the head and neck treated with radiochemotherapy. METHODS: The study group comprised 22 patients with confirmed squamous cell carcinoma of the head and neck who underwent a PET/CT scan using the above tracers before any treatment. Patients were later treated with a combination of radiochemotherapy and surgery. Parametric blood flow was calculated from dynamic [(15)O]H2O PET images using a one-tissue compartment model. [(18)F]FDG images were analysed by calculating standardized uptake values (SUV) and metabolically active tumour volumes (MATV). [(18)F]EF5 images were analysed by calculating tumour-to-muscle uptake ratios (T/M ratio). A T/M ratio of 1.5 was considered a significant threshold and used to determine tumour hypoxic subvolumes (HS) and hypoxic fraction area. The findings were finally correlated with the pretreatment clinical findings (overall stage and TNM stage) as well as the outcome following radiochemotherapy in terms of local control and overall patient survival. RESULTS: Tumour stage and T-classification did not show any significant differences in comparison to the patients' metabolic and functional characteristics measured on PET. Using the Cox proportional hazards model, a shorter overall survival was associated with MATV (p = 0.008, HR = 1.108), maximum [(18)F]EF5 T/M ratio (p = 0.0145, HR = 4.084) and tumour HS (p = 0.0047, HR = 1.112). None of the PET parameters showed a significant effect on patient survival in the log-rank test, although [(18)F]EF5 maximum T/M ratio was the closest (p = 0.109). By contrast, tumour blood flow was not correlated with any of the clinical endpoints. There were no statistically significant correlations among [(18)F]FDG SUVmax, [(18)F]EF5 T/M ratio and blood flow. CONCLUSION: Our study in a limited number of patients confirmed the importance of MATV in the prognosis of locally advanced squamous cell carcinoma of the head and neck. It is of interest that high uptake of the hypoxia tracer [(18)F]EF5 showed a stronger correlation with a poor clinical outcome than [(18)F]FDG uptake. This confirms the importance of hypoxia in treatment outcome and suggests that [(18)F]EF5 may act as a surrogate marker of radioresistance.

Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET.

BACKGROUND: The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC). METHODS: [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome. RESULTS: None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = -618, p =0.019) and apoptosis with Ki-67 (rs = -638, p =0.014). CONCLUSIONS: A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.

Evaluation of PET imaging as a tool for detecting neonatal hypoxic-ischemic encephalopathy in a preclinical animal model.

Hypoxic-ischemic encephalopathy due to insufficient oxygen delivery to brain tissue is a leading cause of death or severe morbidity in neonates. The early recognition of the most severely affected individuals remains a clinical challenge. We hypothesized that hypoxic-ischemic injury can be detected using PET radiotracers for hypoxia ([18F]EF5), glucose metabolism ([18F]FDG), and inflammation ([18F]F-DPA). METHODS: A preclinical model of neonatal hypoxic-ischemic brain injury was made in 9-d-old rat pups by permanent ligation of the left common carotid artery followed by hypoxia (8% oxygen and 92% nitrogen) for 120 min. In vivo PET imaging was performed immediately after injury induction or at different timepoints up to 21 d later. After imaging, ex vivo brain autoradiography was performed. Brain sections were stained with cresyl violet to evaluate the extent of the brain injury and to correlate it with [18F]FDG uptake. RESULTS: PET imaging revealed that all three of the radiotracers tested had significant uptake in the injured brain hemisphere. Ex vivo autoradiography revealed high [18F]EF5 uptake in the hypoxic hemisphere immediately after the injury (P < 0.0001), decreasing to baseline even 1 d postinjury. [18F]FDG uptake was highest in the injured hemisphere on the day of injury (P < 0.0001), whereas [18F]F-DPA uptake was evident after 4 d (P = 0.029), peaking 7 d postinjury (P < 0.0001), and remained significant 21 d after the injury. Targeted evaluation demonstrated that [18F]FDG uptake measured by in vivo imaging 1 d postinjury correlated positively with the brain volume loss detected 21 d later (r = 0.72, P = 0.028). CONCLUSION: Neonatal hypoxic-ischemic brain injury can be detected using PET imaging. Different types of radiotracers illustrate distinct phases of hypoxic brain damage. PET may be a new useful technique, worthy of being explored for clinical use, to predict and evaluate the course of the injury.

Evaluation of bone marrow glucose uptake and adiposity in male rats after diet and exercise interventions.

Objectives: Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their morphology and number. Here we evaluated whether diet or exercise intervention could improve the high-fat diet (HFD) associated impairment in BM glucose uptake (BMGU) and whether this associates with the morphology of BM adipocytes (BMAds) in rats. Methods: Eight-week-old male Sprague-Dawley rats were fed ad libitum either HFD or chow diet for 24 weeks. Additionally after 12 weeks, HFD-fed rats switched either to chow diet, voluntary intermittent running exercise, or both for another 12 weeks. BMAd morphology was assessed by perilipin-1 immunofluorescence staining in formalin-fixed paraffin-embedded tibial sections. Insulin-stimulated sternal and humeral BMGU were measured using [18F]FDG-PET/CT. Tibial microarchitecture and mineral density were measured with microCT. Results: HFD rats had significantly higher whole-body fat percentage compared to the chow group (17% vs 13%, respectively; p = 0.004) and larger median size of BMAds in the proximal tibia (815 µm2 vs 592 µm2, respectively; p = 0.03) but not in the distal tibia. Switch to chow diet combined with running exercise normalized whole-body fat percentage (p < 0.001) but not the BMAd size. At 32 weeks of age, there was no significant difference in insulin-stimulated BMGU between the study groups. However, BMGU was significantly higher in sternum compared to humerus (p < 0.001) and higher in 8-week-old compared to 32-week-old rats (p < 0.001). BMAd size in proximal tibia correlated positively with whole-body fat percentage (r = 0.48, p = 0.005) and negatively with humeral BMGU (r = -0.63, p = 0.02). HFD significantly reduced trabecular number (p < 0.001) compared to the chow group. Switch to chow diet reversed this as the trabecular number was significantly higher (p = 0.008) than in the HFD group. Conclusion: In this study we showed that insulin-stimulated BMGU is age- and site-dependent. BMGU was not affected by the study interventions. HFD increased whole-body fat percentage and the size of BMAds in proximal tibia. Switching from HFD to a chow diet and running exercise improved glucose homeostasis and normalized the HFD-induced increase in body fat but not the hypertrophy of BMAds.

Loading enhances glucose uptake in muscles, bones, and bone marrow of lower extremities in humans.

CONTEXT: Increased standing time has been associated with improved health, but the underlying mechanism is unclear. OBJECTIVES: We herein investigate if increased weight loading increases energy demand and thereby glucose uptake (GU) locally in bone and/or muscle in the lower extremities. METHODS: In this single-center clinical trial with randomized crossover design (ClinicalTrials.gov ID, NCT05443620), we enrolled 10 men with body mass index (BMI) between 30 and 35 kg/m2. Participants were treated with both high load (standing with weight vest weighing 11% of body weight) and no load (sitting) on the lower extremities. GU was measured using whole-body quantitative positron emission tomography/computed tomography (PET/CT) imaging. The primary endpoint was the change in GU ratio between loaded bones (i.e. femur and tibia) and non-loaded bones (i.e. humerus). RESULTS: High load increased the GU ratio between lower and upper extremities in cortical diaphyseal bone (e.g. femur/humerus ratio increased by 19%, p = 0.029), muscles (e.g. m. quadriceps femoris/m. triceps brachii ratio increased by 28%, p = 0.014) and in certain bone marrow regions (femur/humerus diaphyseal bone marrow region ratio increased by 17%, p = 0.041). Unexpectedly, we observed the highest GU in the bone marrow region of vertebral bodies, but its GU was not affected by high load. CONCLUSIONS: Increased weight-bearing loading enhances GU in muscles, cortical bone, and bone marrow of the exposed lower extremities. This could be interpreted as increased local energy demand in bone and muscle caused by increased loading. The physiological importance of the increased local GU by static loading remains to be determined.

Daily standing time, dietary fiber, and intake of unsaturated fatty acids are beneficially associated with hepatic insulin sensitivity in adults with metabolic syndrome.

Background: Obesity is associated with impaired glucose metabolism and hepatic insulin resistance. The aim was to investigate the associations of hepatic glucose uptake (HGU) and endogenous glucose production (EGP) to sedentary behavior (SB), physical activity (PA), cardiorespiratory fitness, dietary factors, and metabolic risk markers. Methods: Forty-four adults with metabolic syndrome (mean age 58 [SD 7] years, BMI ranging from 25-40kg/; 25 females) were included. HGU was measured by positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated by subtracting the glucose infusion rate during clamp from the glucose rate of disappearance. SB and PA were measured with hip-worn accelerometers (26 [SD3] days). Fitness was assessed by maximal bicycle ergometry with respiratory gas measurements and dietary intake of nutrients by 4-day food diaries. Results: HGU was not associated with fitness or any of the SB or PA measures. When adjusted for sex, age, and body fat-%, HGU was associated with whole-body insulin sensitivity (ß=0.58), water-insoluble dietary fiber (ß=0.29), energy percent (E%) of carbohydrates (ß=-0.32), saccharose (ß=-0.32), mono- and polyunsaturated fatty acids (ß=0.35, ß=0.41, respectively). EGP was associated with whole-body insulin sensitivity (ß=-0.53), and low-density lipoprotein cholesterol [ß=-0.31], and when further adjusted for accelerometry wear time, EGP was associated with standing [ß=-0.43]. (p-value for all< 0.05). Conclusions: Standing more, consuming a diet rich in fiber and unsaturated fatty acids, and a lower intake of carbohydrates, especially sugar, associate beneficially with hepatic insulin sensitivity. Habitual SB, PA, or fitness may not be the primary modulators of HGU and EGP. However, these associations need to be confirmed with intervention studies.

Thermogenic Capacity of Human Supraclavicular Brown Fat and Cold-Stimulated Brain Glucose Metabolism.

Human brain metabolism is susceptible to temperature changes. It has been suggested that the supraclavicular brown adipose tissue (BAT) protects the brain from these fluctuations by regulating heat production through the presence of uncoupling protein 1 (UCP-1). It remains unsolved whether inter-individual variation in the expression of UCP-1, which represents the thermogenic capacity of the supraclavicular BAT, is linked with brain metabolism during cold stress. Ten healthy human participants underwent 18F-FDG PET scanning of the brain under cold stimulus to determine brain glucose uptake (BGU). On a separate day, an excision biopsy of the supraclavicular fat-the fat proximal to the carotid arteries supplying the brain with warm blood-was performed to determine the mRNA expression of the thermogenic protein UCP-1. Expression of UCP-1 in supraclavicular BAT was directly related to the whole brain glucose uptake rate determined under cold stimulation (rho = 0.71, p = 0.03). In sub-compartmental brain analysis, UCP-1 expression in supraclavicular BAT was directly related to cold-stimulated glucose uptake rates in the hypothalamus, medulla, midbrain, limbic system, frontal lobe, occipital lobe, and parietal lobe (all rho ≥ 0.67, p < 0.05). These relationships were independent of body mass index and age. When analysing gene expressions of BAT secretome, we found a positive correlation between cold-stimulated BGU and DIO2. These findings provide evidence of functional links between brain metabolism under cold stimulation and UCP-1 and DIO2 expressions in BAT in humans. More research is needed to evaluate the importance of these findings in clinical outcomes, for instance, in examining the supporting role of BAT in cognitive functions under cold stress.

Segmentation of Dynamic Total-Body [18F]-FDG PET Images Using Unsupervised Clustering.

Clustering time activity curves of PET images have been used to separate clinically relevant areas of the brain or tumours. However, PET image segmentation in multiorgan level is much less studied due to the available total-body data being limited to animal studies. Now, the new PET scanners providing the opportunity to acquire total-body PET scans also from humans are becoming more common, which opens plenty of new clinically interesting opportunities. Therefore, organ-level segmentation of PET images has important applications, yet it lacks sufficient research. In this proof of concept study, we evaluate if the previously used segmentation approaches are suitable for segmenting dynamic human total-body PET images in organ level. Our focus is on general-purpose unsupervised methods that are independent of external data and can be used for all tracers, organisms, and health conditions. Additional anatomical image modalities, such as CT or MRI, are not used, but the segmentation is done purely based on the dynamic PET images. The tested methods are commonly used building blocks of the more sophisticated methods rather than final methods as such, and our goal is to evaluate if these basic tools are suited for the arising human total-body PET image segmentation. First, we excluded methods that were computationally too demanding for the large datasets from human total-body PET scanners. These criteria filtered out most of the commonly used approaches, leaving only two clustering methods, k-means and Gaussian mixture model (GMM), for further analyses. We combined k-means with two different preprocessing approaches, namely, principal component analysis (PCA) and independent component analysis (ICA). Then, we selected a suitable number of clusters using 10 images. Finally, we tested how well the usable approaches segment the remaining PET images in organ level, highlight the best approaches together with their limitations, and discuss how further research could tackle the observed shortcomings. In this study, we utilised 40 total-body [18F] fluorodeoxyglucose PET images of rats to mimic the coming large human PET images and a few actual human total-body images to ensure that our conclusions from the rat data generalise to the human data. Our results show that ICA combined with k-means has weaker performance than the other two computationally usable approaches and that certain organs are easier to segment than others. While GMM performed sufficiently, it was by far the slowest one among the tested approaches, making k-means combined with PCA the most promising candidate for further development. However, even with the best methods, the mean Jaccard index was slightly below 0.5 for the easiest tested organ and below 0.2 for the most challenging organ. Thus, we conclude that there is a lack of accurate and computationally light general-purpose segmentation method that can analyse dynamic total-body PET images.

Novel electrophilic synthesis of 6-[¹8F]fluorodopamine and comprehensive biological evaluation.

PURPOSE: 6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2-diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/µmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs. METHODS: 6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6-[(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs. RESULTS: 6-[(18)F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/µmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects. CONCLUSION: 6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6-[(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.

Pharmacokinetics of [¹8F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer's disease.

PURPOSE: The aim of this study was to investigate the potential of [(18)F]flutemetamol as a preclinical PET tracer for imaging ß-amyloid (Aß) deposition by comparing its pharmacokinetics to those of [(11)C]Pittsburgh compound B ([(11)C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [(18)F]flutemetamol to Aß deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease. METHODS: [(18)F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [(11)C]PIB and [(18)F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [(18)F]flutemetamol to Aß deposits was also studied using ex vivo and in vitro autoradiography. The location of Aß deposits in the brain was determined with thioflavine S staining and immunohistochemistry. RESULTS: The pharmacokinetics of [(18)F]flutemetamol resembled that of [(11)C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [(18)F]flutemetamol into radioactive metabolites was faster than that of [(11)C]PIB. [(18)F]Flutemetamol cleared more slowly from the brain than [(11)C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [(11)C]PIB and [(18)F]flutemetamol were 2.28 and 6.65 µSv/MBq, respectively. Autoradiographs showed [(18)F]flutemetamol binding to fibrillar Aß deposits in the brain of Tg2576 mice. CONCLUSION: Based on its pharmacokinetic profile, [(18)F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aß deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging.