Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle. METHODS: In this longitudinal case-control study, we acquired 118 [11C]DASB positron emission tomography scans measuring 5-HTT nondisplaceable binding potential (BPND) in 30 patients with PMDD and 29 controls during 2 menstrual cycle phases (periovulatory, premenstrual). The primary outcome was midbrain and prefrontal cortex 5-HTT BPND. We tested whether BPND changes correlated with depressed mood. RESULTS: Linear mixed effects modeling (significant group × time × region interaction) showed a mean increase of 18% in midbrain 5-HTT BPND (mean [SD] periovulatory = 1.64 [0.40], premenstrual = 1.93 [0.40], delta = 0.29 [0.47]: t29 = -3.43, p = .0002) in patients with PMDD, whereas controls displayed a mean 10% decrease in midbrain 5-HTT BPND (periovulatory = 1.65 [0.24] > premenstrual = 1.49 [0.41], delta = -0.17 [0.33]: t28 = -2.73, p = .01). In patients, increased midbrain 5-HTT BPND correlated with depressive symptom severity (R2 = 0.41, p < .0015) across the menstrual cycle. CONCLUSIONS: These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD. These neurochemical findings argue for systematic testing of pre-symptom-onset dosing of selective serotonin reuptake inhibitors or nonpharmacological strategies to augment extracellular serotonin in people with PMDD.

HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls.

BACKGROUND: Alterations of hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. OBJECTIVE: To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). STUDY PARTICIPANTS: Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. METHODS: HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. RESULTS: OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = -0.49, p = 0.009). CONCLUSION: The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

Central Noradrenergic Neurotransmission and Weight Loss 6 Months After Gastric Bypass Surgery in Patients with Severe Obesity.

PURPOSE: Roux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission. MATERIALS AND METHODS: We longitudinally studied 10 individuals with severe obesity (8 females; age 43.9 ± 13.1 years; body mass index (BMI) 46.5 ± 4.8 kg/m2) using (S,S)-[11C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex). RESULTS: The participants responded to RYGB surgery with a reduction in BMI of 12.0 ± 3.5 kg/m2 (p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01). CONCLUSION: Reductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI.

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study.

PURPOSE: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. METHODS: Using [18F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. RESULTS: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). CONCLUSIONS: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

Characterization of laser-driven proton acceleration from water microdroplets.

We report on a proton acceleration experiment in which high-intensity laser pulses with a wavelength of 0.4 µm and with varying temporal intensity contrast have been used to irradiate water droplets of 20 µm diameter. Such droplets are a reliable and easy-to-implement type of target for proton acceleration experiments with the potential to be used at very high repetition rates. We have investigated the influence of the laser's angle of incidence by moving the droplet along the laser polarization axis. This position, which is coupled with the angle of incidence, has a crucial impact on the maximum proton energy. Central irradiation leads to an inefficient coupling of the laser energy into hot electrons, resulting in a low maximum proton energy. The introduction of a controlled pre-pulse produces an enhancement of hot electron generation in this geometry and therefore higher proton energies. However, two-dimensional particle-in-cell simulations support our experimental results confirming, that even slightly higher proton energies are achieved under grazing laser incidence when no additional pre-plasma is present. Illuminating a droplet under grazing incidence generates a stream of hot electrons that flows along the droplet's surface due to self-generated electric and magnetic fields and ultimately generates a strong electric field responsible for proton acceleration. The interaction conditions were monitored with the help of an ultra-short optical probe laser, with which the plasma expansion could be observed.

Noradrenaline transporter availability on [11C]MRB PET predicts weight loss success in highly obese adults.

PURPOSE: Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention. METHODS: We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 ± 3.7 kg/m2 (age 34 ± 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m2, age 33 ± 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[11C]O-methylreboxetine (MRB) before and 6 months after dietary intervention. RESULTS: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BPND) in the insula and the hippocampus of obese individuals, which correlated well with changes in BMI (-3.3 ± 5.3%; p = 0.03) following completion of the dietary intervention. Furthermore, voxel-wise regression analyses showed that lower BPND in these regions, but also in the midbrain and the prefrontal cortex, at baseline was associated with higher achieved weight loss (e.g., hippocampal area R2 = 0.80; p < 0.0001). No changes were observed in non-obese controls. CONCLUSION: These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention.

Validation of Noninvasive Tracer Kinetic Analysis of 18F-Florbetaben PET Using a Dual-Time-Window Acquisition Protocol.

Accurate amyloid PET quantification is necessary for monitoring amyloid-ß accumulation and response to therapy. Currently, most of the studies are analyzed using the static SUV ratio (SUVR) approach because of its simplicity. However, this approach may be influenced by changes in cerebral blood flow (CBF) or radiotracer clearance. Full tracer kinetic models require arterial blood sampling and dynamic image acquisition. The objectives of this work were, first, to validate a noninvasive kinetic modeling approach for 18F-florbetaben PET using an acquisition protocol with the best compromise between quantification accuracy and simplicity and, second, to assess the impact of CBF changes and radiotracer clearance on SUVRs and noninvasive kinetic modeling data in 18F-florbetaben PET. Methods: Using data from 20 subjects (10 patients with probable Alzheimer dementia and 10 healthy volunteers), the nondisplaceable binding potential (BPND) obtained from the full kinetic analysis was compared with the SUVR and with noninvasive tracer kinetic methods (simplified reference tissue model and multilinear reference tissue model 2). Various approaches using shortened or interrupted acquisitions were compared with the results of the full acquisition (0-140 min). Simulations were performed to assess the effect of CBF and radiotracer clearance changes on SUVRs and noninvasive kinetic modeling outputs. Results: An acquisition protocol using time windows of 0-30 and 120-140 min with appropriate interpolation of the missing time points provided the best compromise between patient comfort and quantification accuracy. Excellent agreement was found between BPND obtained using the full protocol and BPND obtained using the dual-window protocol (for multilinear reference tissue model 2, BPND [dual-window] = 0.01 + 1.00·BPND [full], R2 = 0.97; for simplified reference tissue model, BPND [dual-window] = 0.05 + 0.92·BPND [full], R2 = 0.93). Simulations showed a limited impact of CBF and radiotracer clearance changes on multilinear reference tissue model parameters and SUVR. Conclusion: This study demonstrated accurate noninvasive kinetic modeling of 18F-florbetaben PET data using a dual-window acquisition, thus providing a good compromise between quantification accuracy, scan duration, and patient burden. The influence of CBF and radiotracer clearance changes on amyloid-ß load estimates was small. For most clinical research applications, the SUVR approach is appropriate. However, for longitudinal studies in which maximum quantification accuracy is desired, this noninvasive dual-window acquisition with kinetic analysis is recommended.

54 J pulses with 18 nm bandwidth from a diode-pumped chirped-pulse amplification laser system.

We report on results from the fully diode-pumped chirped-pulse amplification laser system Polaris. Pulses were amplified to a maximum energy of 54.2 J before compression. These pulses have a full width at half-maximum spectral bandwidth of 18 nm centered at 1033 nm and are generated at a repetition rate of 0.02 Hz. To the best of our knowledge, these are the most energetic broadband laser pulses generated by a diode-pumped laser system so far. Due to the limited size of our vacuum compressor, only attenuated pulses could be compressed to a duration of 98 fs containing an energy of 16.7 J, which leads to a peak power of 170 TW. These pulses could be focused to a peak intensity of 1.3×1021 W/cm2. Having an ultra-high temporal contrast of 1012 with respect to amplified spontaneous emission these laser pulses are well suited for high-intensity laser-matter experiments.

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain µ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

Brain µ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [11C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [11C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.

Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[(18)F]Flubatine in humans.

INTRODUCTION: (-)-[(18)F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine α4ß2 receptor subtype. A clinical trial assessing the availability of this subtype of nAChRs was performed. From a total participant number of 21 Alzheimer's disease (AD) patients and 20 healthy controls (HCs), the following parameters were determined: plasma protein binding, metabolism and activity distribution between plasma and whole blood. METHODS: Plasma protein binding and fraction of unchanged parent compound were assessed by ultracentrifugation and HPLC, respectively. The distribution of radioactivity (parent compound+metabolites) between plasma and whole blood was determined ex vivo at different time-points after injection by gamma counting after separation of whole blood by centrifugation into the cellular and non-cellular components. In additional experiments in vitro, tracer distribution between these blood components was assessed for up to 90min. RESULTS: A fraction of 15%±2% of (-)-[(18)F]Flubatine was found to be bound to plasma proteins. Metabolic degradation of (-)-[(18)F]Flubatine was very low, resulting in almost 90% unchanged parent compound at 90min p.i. with no significant difference between AD and HC. The radioactivity distribution between plasma and whole blood changed in vivo only slightly over time from 0.82±0.03 at 3min p.i. to 0.87±0.03 at 270min p.i. indicating the contribution of only a small amount of metabolites. In vitro studies revealed that (-)-[(18)F]Flubatine was instantaneously distributed between cellular and non-cellular blood parts. DISCUSSION: (-)-[(18)F]Flubatine exhibits very favourable characteristics for a PET radiotracer such as slow metabolic degradation and moderate plasma protein binding. Equilibrium of radioactivity distribution between plasma and whole blood is reached instantaneously and remains almost constant over time allowing both convenient sample handling and facilitated fractional blood volume contribution assessment.

PET quantification of 18F-florbetaben binding to ß-amyloid deposits in human brains.

UNLABELLED: (18)F-florbetaben is a novel (18)F-labeled tracer for PET imaging of ß-amyloid deposits in the human brain. We evaluated the kinetic model-based approaches to the quantification of ß-amyloid binding in the brain from dynamic PET data. The validity of the practically useful tissue ratio was also evaluated against the model-based parameters. METHODS: (18)F-florbetaben PET imaging was performed with concurrent multiple arterial sampling after tracer injection (300 MBq) in 10 Alzheimer disease (AD) patients and 10 age-matched healthy controls. Regional brain-tissue time-activity curves for 90 min were analyzed by a 1-tissue-compartment model and a 2-tissue-compartment model (2TCM) with metabolite-corrected plasma data estimating the specific distribution volume (VS) and distribution volume ratio (DVR [2TCM]) and a multilinear reference tissue model estimating DVR (DVR [MRTM]) using the cerebellar cortex as the reference tissue. Target-to-reference tissue standardized uptake value ratios (SUVRs) at 70-90 min were also calculated. RESULTS: All brain regions required 2TCM to describe the time-activity curves. All ß-amyloid binding parameters in the cerebral cortex (VS, DVR [2TCM], DVR [MRTM], and SUVR) were significantly increased in AD patients (P < 0.05), and there were significant linear correlations among these parameters (r(2) > 0.83). Effect sizes in group discrimination between 8 ß-amyloid-positive AD scans and 9 ß-amyloid-negative healthy control scans for all binding parameters were excellent, being largest for DVR (2TCM) (4.22) and smallest for VS (3.25) and intermediate and the same for DVR (MRTM) and SUVR (4.03). CONCLUSION: These results suggest that compartment kinetic model-based quantification of ß-amyloid binding from (18)F-florbetaben PET data is feasible and that all ß-amyloid binding parameters including SUVR are excellent in discriminating between ß-amyloid-positive and -negative scans.

Measurement of the alpha4beta2* nicotinic acetylcholine receptor ligand 2-[(18)F]Fluoro-A-85380 and its metabolites in human blood during PET investigation: a methodological study.

2-[(18)F]fluoro-A-85380 (2-[(18)F]FA) is a new radioligand for noninvasive imaging of alpha4beta2* nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET) in human brain. In most cases, quantification of 2-[(18)F]FA receptor binding involves measurement of free nonmetabolized radioligand concentration in blood. This requires an efficient and reliable method to separate radioactive metabolites from the parent compound. In the present study, three analytical methods, thin layer chromatography (TLC), high-performance liquid chromatography (HPLC) and solid phase extraction (SPE) have been tested. Reversed-phase TLC of deproteinized aqueous samples of plasma provides good estimates of 2-[(18)F]FA and its metabolites. However, because of the decreased radioactivity in plasma samples, this method can be used in humans over the first 2 h after radioligand injection only. Reliable quantification of the parent radioligand and its main metabolites was obtained using reversed-phase HPLC, followed by counting of eluted fractions in a well gamma counter. Three main and five minor metabolites of 2-[(18)F]FA were detected in human blood using this method. On average, the unchanged 2-[(18)F]FA fraction in plasma of healthy volunteers measured at 14, 60, 120, 240 and 420 min after radioligand injection was 87.3+/-2.2%, 74.4+/-3%, 68.8+/-5%, 62.3+/-8% and 61.0+/-8%, respectively. In patients with neurodegenerative disorders, the values corresponding to the three last time points were significantly lower. The fraction of nonmetabolized 2-[(18)F]FA in plasma determined using SPE did not differ significantly from that obtained by HPLC (+gamma counting) (n=73, r=.95). Since SPE is less time-consuming than HPLC and provides comparable results, we conclude that SPE appears to be the most suitable method for measurement of 2-[(18)F]FA parent fraction during PET investigations.

A priori identifiability of a one-compartment model with two input functions for liver blood flow measurements.

An extended dual-input Kety-Schmidt model can be applied to positron emission tomography data for the quantification of local arterial (f(a)) and local portal-venous blood flow (f(p)) in the liver by freely diffusible tracers (e.g., [15O]H2O). We investigated the a priori identifiability of the three-parameter model (f(a), f(p) and distribution volume (Vd)) under ideal (noise-free) conditions. The results indicate that the full identifiability of the model depends on the form of the portal-venous input function (c(p)(t)), which is assumed to be a sum of m exponentials convolved with the arterial input function (c(a)(t)). When m>or=2, all three-model parameters are uniquely identifiable. For m=1 identifiability of f(p) fails if c(p)(t) coincides with tissue concentration (q(t)/Vd), which occurs if c(p)(t) is generated from an intestinal compartment with transit time Vd/f(a). Any portal input, f(p) c(p)(t), is balanced by the portal contribution, f(p) q(t)/Vd, to the liver efflux, leaving q(t) unchanged by f(p) and only f(a) and Vd are a priori uniquely identifiable. An extension to this condition of unidentifiability is obtained if we leave the assumption of a generating intestinal compartment system and allow for an arbitrary proportionality constant between c(p)(t) and q(t). In this case, only f(a) remains a priori uniquely identifiable. These findings provide important insights into the behaviour and identifiability of the model applied to the unique liver environment.

Increased sensitivity in detection of a porcine high-turnover osteopenia after total gastrectomy by dynamic 18F-fluoride ion PET and quantitative CT.

UNLABELLED: High-resolution (18)F-fluoride ion PET in combination with quantitative CT (QCT) allows the assessment of bone metabolism in relation to bone mass. This combined imaging approach was used to elucidate porcine bone metabolic changes after gastrectomy, which are frequently associated with osteopenia or osteomalacia. METHODS: Six months after total gastrectomy (n = 7) or sham operation (n = 6), bone blood flow and bone metabolic activity (K(i), K(flux)) were calculated from dynamic PET measurements from vertebral bodies and compared with corresponding QCT bone mineral density (BMD) measurements. RESULTS: Total gastrectomy resulted in a significant reduction of the BMD (-21%; P < 0.005), whereas 1,25-(OH)(2)-vitamin D, serum phosphate, and parathyroid hormone were significantly increased compared with that of sham-operated animals. Because of the significant increase of the rate constant k(3) (+325%; P < 0.05), describing chemisorption and incorporation of (18)F-fluoride onto or into the bone matrix, K(i) (+36%) and K(flux) (+37%) were significantly elevated after total gastrectomy compared with that of control animals (P < 0.01), whereas bone blood flow was not significantly different between groups. The normalization of K(i) and K(flux) values by the specific bone mass (K(i/BMD); K(flux/BMD)) largely increased the differences between groups (K(i/BMD), +74%; K(flux), +76%; P < 0.001). CONCLUSION: Dynamic (18)F-fluoride ion PET revealed that porcine bone loss after total gastrectomy is related to a high-turnover bone disease without significant changes in bone blood flow. In mini pigs, the increased bone metabolism is probably related to an elevated parathyroid hormone secretion, thus maintaining serum calcium homeostasis at the expense of the bone mineral content. Normalizing bone metabolic activity by the specific bone mass increases the sensitivity in the detection of osteopenic high-turnover bone diseases. Therefore, the combination of QCT and (18)F-fluoride ion PET seems to be the method of choice for the classification of metabolic bone diseases and for monitoring treatment effects quantitatively.

Coupling of porcine bone blood flow and metabolism in high-turnover bone disease measured by [(15)O]H(2)O and [(18)F]fluoride ion positron emission tomography.

Previously, we identified a parathyroid hormone-related high-turnover bone disease after gastrectomy in mini pigs. Dynamic [(18)F]fluoride ion positron emission tomography (PET) revealed that bone metabolism was significantly increased, but that bone blood flow derived from permeability-surface area product (PS product)-corrected K(1) values was not. Since bone blood flow and metabolism are coupled in normal bone tissues, we hypothesised that the capillary permeability and/or surface area might be altered in high-turnover bone disease. The "true" bone blood flow ( f(H2O)) was measured in vertebral bodies by dynamic [(15)O]H(2)O PET, followed by a 120-min dynamic [(18)F]fluoride ion PET study, 6 months after total gastrectomy (n=5) and compared with results in sham-operated animals (n=5). Estimates for bone blood flow based on PS-corrected K(1) values (f) and the net uptake of fluoride in bone tissue (K(i)), representing the bone metabolic activity, were calculated using standard compartmental modelling and non-linear fitting. Gastrectomy was followed by a significant elevation of K(i) and k(3) ( P<0.05), which was mainly caused by an increase of the fraction of bound tracer in tissue (P<0.01). In contrast, f(H2O), f, the single-pass extraction fraction of [(18)F]fluoride (E) and the volume of distribution (DV) of [(18)F]fluoride were not significantly different between groups. In both groups, a coupling of the mean f(H2O) and K(i) values was found, but the intercept with the y-axis was higher in high-turnover bone disease. It is concluded that in high-turnover bone disease following gastrectomy, the PS product for [(18)F]fluoride remains unchanged. Therefore, even in high-turnover bone diseases, [(18)F]fluoride ion PET can provide reliable blood flow estimates (f), as long as a proper PS product correction is applied. The increased bone metabolism in high-turnover bone disease after gastrectomy is mainly related to an up-regulation of the amount of ionic exchange of [(18)F]fluoride with the bone matrix, while tracer delivery remains unchanged.