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1.  Neurophysiological Effects of Sleep Deprivation in Healthy Adults, a Pilot Study 
PLoS ONE  2015;10(1):e0116906.
Total sleep deprivation (TSD) may induce fatigue, neurocognitive slowing and mood changes, which are partly compensated by stress regulating brain systems, resulting in altered dopamine and cortisol levels in order to stay awake if needed. These systems, however, have never been studied in concert. At baseline, after a regular night of sleep, and the next morning after TSD, 12 healthy subjects performed a semantic affective classification functional magnetic resonance imaging (fMRI) task, followed by a [11C]raclopride positron emission tomography (PET) scan. Saliva cortisol levels were acquired at 7 time points during both days. Affective symptoms were measured using Beck Depression Inventory (BDI), Spielberger State Trait Anxiety Index (STAI) and visual analogue scales. After TSD, perceived energy levels, concentration, and speed of thought decreased significantly, whereas mood did not. During fMRI, response speed decreased for neutral words and positive targets, and accuracy decreased trendwise for neutral words and for positive targets with a negative distracter. Following TSD, processing of positive words was associated with increased left dorsolateral prefrontal activation. Processing of emotional words in general was associated with increased insular activity, whereas contrasting positive vs. negative words showed subthreshold increased activation in the (para)hippocampal area. Cortisol secretion was significantly lower after TSD. Decreased voxel-by-voxel [11C]raclopride binding potential (BPND) was observed in left caudate. TSD induces widespread cognitive, neurophysiologic and endocrine changes in healthy adults, characterized by reduced cognitive functioning, despite increased regional brain activity. The blunted HPA-axis response together with altered [11C]raclopride binding in the basal ganglia indicate that sustained wakefulness requires involvement of additional adaptive biological systems.
doi:10.1371/journal.pone.0116906
PMCID: PMC4301911  PMID: 25608023
2.  Positron emission tomography to assess hypoxia and perfusion in lung cancer 
In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed.
doi:10.5306/wjco.v5.i5.824
PMCID: PMC4259945  PMID: 25493221
Molecular imaging; Positron emission tomography; Hypoxia; Perfusion; Quantification; Lung cancer
3.  FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0 
The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient is examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardised imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardised uptake value harmonisation in multicentre settings.
doi:10.1007/s00259-014-2961-x
PMCID: PMC4315529  PMID: 25452219
FDG; PET/CT; Imaging procedure; Tumour; Oncology; Quantification
4.  Effects of Reusing Baseline Volumes of Interest by Applying (Non-)Rigid Image Registration on Positron Emission Tomography Response Assessments 
PLoS ONE  2014;9(1):e87167.
Objectives
Reusing baseline volumes of interest (VOI) by applying non-rigid and to some extent (local) rigid image registration showed good test-retest variability similar to delineating VOI on both scans individually. The aim of the present study was to compare response assessments and classifications based on various types of image registration with those based on (semi)-automatic tumour delineation.
Methods
Baseline (n = 13), early (n = 12) and late (n = 9) response (after one and three cycles of treatment, respectively) whole body [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT) scans were acquired in subjects with advanced gastrointestinal malignancies. Lesions were identified for early and late response scans. VOI were drawn independently on all scans using an adaptive 50% threshold method (A50). In addition, various types of (non-)rigid image registration were applied to PET and/or CT images, after which baseline VOI were projected onto response scans. Response was classified using PET Response Criteria in Solid Tumors for maximum standardized uptake value (SUVmax), average SUV (SUVmean), peak SUV (SUVpeak), metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and the area under a cumulative SUV-volume histogram curve (AUC).
Results
Non-rigid PET-based registration and non-rigid CT-based registration followed by non-rigid PET-based registration (CTPET) did not show differences in response classifications compared to A50 for SUVmax and SUVpeak,, however, differences were observed for MATV, SUVmean, TLG and AUC. For the latter, these registrations demonstrated a poorer performance for small lung lesions (<2.8 ml), whereas A50 showed a poorer performance when another area with high uptake was close to the target lesion. All methods were affected by lesions with very heterogeneous tracer uptake.
Conclusions
Non-rigid PET- and CTPET-based image registrations may be used to classify response based on SUVmax and SUVpeak. For other quantitative measures future studies should assess which method is valid for response evaluations by correlating with survival data.
doi:10.1371/journal.pone.0087167
PMCID: PMC3904976  PMID: 24489860
5.  18 F-FDG PET standard uptake values of the normal pons in children: establishing a reference value for diffuse intrinsic pontine glioma 
EJNMMI Research  2014;4:8.
Background
Positron emission tomography (PET) scanning with [18 F]fluorodeoxyglucose (18 F-FDG) is a useful diagnostic and prediction tool in brain tumors, but its value in childhood diffuse intrinsic pontine glioma (DIPG) is still unclear. For interpretation of 18 F-FDG PET results in DIPG, uptake values of the normal pons of children of increasing ages are mandatory. The aim of this study was to determine 18 F-FDG standard uptake value ratios (SUVr) of the normal pons and to compare these to those of DIPG.
Methods
We studied 36 subjects with a normal, non-affected pons (aged 5 to 23 years) and 6 patients with DIPG (aged 4 to 17 years) who underwent 18 F-FDG PET scanning. Magnetic resonance imaging (MRI) was co-registered to define the regions of interest. SUVr and SUVrmax for the pons/cerebellum (SUVrp/c) and the pons/occipital lobe (SUVrp/o) were calculated. Independent-samples t tests and Mann–Whitney U tests were used to compare the mean SUVr and Pearson’s test for correlations.
Results
For the normal pons, mean SUVrp/c and SUVrp/o were 0.65 (±0.054) and 0.51 (±0.056), respectively. No significant correlations were found between the SUVr of the normal pons and sex, age, nor pontine volume. A modest but statistically significant correlation was found between SUVr and post-injection time acquisition timing. For DIPG, mean SUVrp/c and SUVrp/o were 0.74 (±0.20) and 0.65 (±0.30), respectively, while mean SUVrp(max)/c and SUVrp(max)/o were 1.95 (±0.48) and 1.81 (±0.20), respectively.
Conclusion
The SUVr of the unaffected pons are strikingly constant between children, irrespective of sex and age, and can therefore be well used as a reference value for 18 F-FDG PET studies in DIPG.
doi:10.1186/2191-219X-4-8
PMCID: PMC3910228  PMID: 24472395
Positron emission tomography; [18 F]fluorodeoxyglucose; Pontine glioma; Brain neoplasms; Reference values; Pons
6.  Intervention versus standard medical treatment in patients with symptomatic occlusion of the internal carotid artery: a randomised oxygen-15 PET study 
EJNMMI Research  2013;3:79.
Background
The aim of this randomised pilot study was to investigate the haemodynamic effects measured by oxygen-15 positron emission tomography (PET) of interventional treatment consisting of either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication in comparison with standard medical treatment alone in patients with symptomatic internal carotid artery (ICA) occlusion.
Methods
Twenty-three patients with symptomatic ICA occlusion underwent PET scanning at baseline and after 3 months. Twelve patients were randomised to intervention (either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication) and 11 to standard medical treatment alone. Primary outcome was a change in cerebral blood flow (CBF), cerebral blood volume (CBV) and/or oxygen extraction fraction (OEF) after 3 months measured by PET.
Results
There were no differences in changes in CBF, CBV or OEF between the two groups. Only patients with compromised perfusion at presentation showed a borderline significant increase in CBF of 2.8 mL/min/100 mL (95% confidence interval 0.0 to 5.7) after intervention (n = 7).
Conclusion
This pilot study shows that in patients with symptomatic ICA occlusion, oxygen-15 PET did not detect differences in improvement of CBF, CBV or OEF between interventional and standard treatment.
doi:10.1186/2191-219X-3-79
PMCID: PMC4029781  PMID: 24308868
Carotid artery diseases; Haemodynamics; Other cerebrovascular disease/stroke; PET
7.  Optimized dose regimen for whole-body FDG-PET imaging 
EJNMMI Research  2013;3:63.
Background
The European Association of Nuclear Medicine procedure guidelines for whole-body fluorodeoxyglucose positron-emission tomography (FDG-PET) scanning prescribe a dose proportional to the patient’s body mass. However, clinical practice shows degraded image quality in obese patients indicating that using an FDG dose proportional to body mass does not overcome size-related degradation of the image quality. The aim of this study was to optimize the administered FDG dose as a function of the patient’s body mass or a different patient-dependent parameter, providing whole-body FDG-PET images of a more constant quality.
Methods
Using a linear relation between administered dose and body mass, FDG-PET imaging was performed on two PET/computed tomography scanners (Biograph TruePoint and Biograph mCT, Siemens). Image quality was assessed by the signal-to-noise ratio (SNR) in the liver in 102 patients with a body mass of 46 to 130 kg. Moreover, the best correlating patient-dependent parameter was derived, and an optimized FDG dose regimen was determined. This optimized dose regimen was validated on the Biograph TruePoint system in 42 new patients. Furthermore, this relation was verified by a simulation study, in which patients with different body masses were simulated with cylindrical phantoms.
Results
As expected, both PET systems showed a significant decrease in SNR with increasing patient’s body mass when using a linear dosage. When image quality was fitted to the patient-dependent parameters, the fit with the patient’s body mass had the highest R2. The optimized dose regimen was found to be Anew= c/t × m2, where m is the body mass, t is the acquisition time per bed position and c is a constant (depending on scanner type). Using this relation, SNR no longer varied with the patient’s body mass. This quadratic relation between dose and body mass was confirmed by the simulation study.
Conclusion
A quadratic relation between FDG dose and the patient’s body mass is recommended. Both simulations and clinical observations confirm that image quality remains constant across patients when this quadratic dose regimen is used.
doi:10.1186/2191-219X-3-63
PMCID: PMC3751692  PMID: 23938036
Positron-emission tomography; Image quality; Weight dependency; Signal-to-noise ratio; Dose
8.  No evidence for additional blood–brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds 
Decreased blood–brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[11C]verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[11C]verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[11C]verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
doi:10.1038/jcbfm.2012.64
PMCID: PMC3421102  PMID: 22588188
Alzheimer's disease; blood–brain barrier; cerebral amyloid angiopathy; P-glycoprotein; positron emission tomography; (R)-[11C]verapamil
9.  Pemetrexed Induced Thymidylate Synthase Inhibition in Non-Small Cell Lung Cancer Patients: A Pilot Study with 3′-Deoxy-3′-[18F]fluorothymidine Positron Emission Tomography 
PLoS ONE  2013;8(5):e63705.
Objectives
Pemetrexed is a thymidylate synthase (TS) inhibitor and is effective in non-small cell lung cancer (NSCLC). 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT), a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on 18F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients.
Methods
Fourteen NSCLC patients underwent dynamic 18F-FLT positron emission tomography (PET) scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST), time to progression (TTP) and overall survival (OS) were determined.
Results
Eleven patients had evaluable 18F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased 18F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients 18F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. 18F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0–7.4 months); median OS was 13.0 months (range 5.1–30.8 months). Changes in 18F-FLT uptake were not predictive for tumor response, TTP or OS.
Conclusions
Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in 18F-FLT uptake within the tumor. No significant association with tumor response, TTP or OS was observed.
doi:10.1371/journal.pone.0063705
PMCID: PMC3663749  PMID: 23717468
10.  Summary Report of the First International Workshop on PET/MR Imaging, March 19–23, 2012, Tübingen, Germany 
Molecular Imaging and Biology  2013;15(4):361-371.
We report from the First International Workshop on positron emission tomography/magnetic resonance imaging (PET/MRI) that was organized by the University of Tübingen in March 2012. Approximately 100 imaging experts in MRI, PET and PET/computed tomography (CT), among them early adopters of pre-clinical and clinical PET/MRI technology, gathered from March 19 to 24, 2012 in Tübingen, Germany. The objective of the workshop was to provide a forum for sharing first-hand methodological and clinical know-how and to assess the potential of combined PET/MRI in various applications from pre-clinical research to scientific as well as clinical applications in humans. The workshop was comprised of pro-active sessions including tutorials, specific discussion panels and grand rounds. Pre-selected experts moderated the sessions, and feedback from the subsequent discussions is presented here to a greater readership. Naturally, the summaries provided herein are subjective descriptions of the hopes and challenges of PET/MR imaging as seen by the workshop attendees at a very early point in time of adopting PET/MRI technology and, as such, represent only a snapshot of current approaches.
doi:10.1007/s11307-013-0623-1
PMCID: PMC3708278  PMID: 23515982
Combined imaging; Molecular imaging; PET/CT; PET/MRI; Quantification; Artifacts; MR-based attenuation correction; Workflow; Standardization
11.  Dual-Phase PET-CT to Differentiate [18F]Fluoromethylcholine Uptake in Reactive and Malignant Lymph Nodes in Patients with Prostate Cancer 
PLoS ONE  2012;7(10):e48430.
Purpose
To investigate whether time-trends of enhanced [18F]Fluoromethylcholine ([18F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice.
Procedures
25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [18F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUVmax and SUVmeanA50, determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [18F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant.
Results
Analysis of 54 nodes showed that LN status, time-trends, and ‘late’ (30 min p.i.) SUVmax and SUVmeanA50 parameters were strongly associated (P<0.0001). SUVmax relative difference was the best LN status predictor. All but one inguinal LN showed a decreasing [18F]FCH uptake over time (pattern A), while 95% of the pelvic nodes presented a stable or increasing uptake (pattern B) type.
Conclusions
Time-trends of enhanced [18F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes.
doi:10.1371/journal.pone.0048430
PMCID: PMC3485217  PMID: 23119014
12.  Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology 
EJNMMI Research  2012;2:56.
Background
Positron emission tomography (PET) may be useful for defining the gross tumour volume for radiation treatment planning and for response monitoring of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to compare tumour sizes obtained from CT- and various more commonly available PET-based tumour delineation methods to pathology findings.
Methods
Retrospective non-respiratory gated whole body [18F]-fluoro-2-deoxy-D-glucose PET/CT studies from 19 NSCLC patients were used. Several (semi-)automatic PET-based tumour delineation methods and manual CT-based delineation were used to assess the maximum tumour diameter.
Results
50%, adaptive 41% threshold-based and contrast-oriented delineation methods showed good agreement with pathology after removing two outliers (R2=0.82). An absolute SUV threshold of 2.5 also showed a good agreement with pathology after the removal of 5 outliers (R2: 0.79), but showed a significant overestimation in the maximum diameter (19.8 mm, p<0.05). Adaptive 50%, relative threshold level and gradient-based methods did not show any outliers, provided only small, non-significant differences in maximum tumour diameter (<4.7 mm, p>0.10), and showed fair correlation (R2>0.62) with pathology. Although adaptive 70% threshold-based methods showed underestimation compared to pathology (36%), it provided the best precision (SD: 14%) together with good correlation (R2=0.81). Good correlation between CT delineation and pathology was observed (R2=0.77). However, CT delineation showed a significant overestimation compared with pathology (3.8 mm, p<0.05).
Conclusions
PET-based tumour delineation methods provided tumour sizes in agreement with pathology and may therefore be useful to define the (metabolically most) active part of the tumour for radiotherapy and response monitoring purposes.
doi:10.1186/2191-219X-2-56
PMCID: PMC3502476  PMID: 23034289
Tumour delineation; Tumour diameter; FDG PET; Non-small cell lung cancer
13.  Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C]PK11195 brain PET studies 
Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer's disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPMVb). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions (Vb) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of Vb in RPM improved both parametric images and binding potential contrast between groups. Incorporation of Vb within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies.
doi:10.1038/jcbfm.2012.59
PMCID: PMC3421099  PMID: 22588187
clustering; parametric analysis; (R)-[11C]PK11195; reference tissue
14.  Comparison of oxygen-15 PET and transcranial Doppler CO2-reactivity measurements in identifying haemodynamic compromise in patients with symptomatic occlusion of the internal carotid artery 
EJNMMI Research  2012;2:30.
Background
Transcranial Doppler (TCD) CO2-reactivity and oxygen-15 positron emission tomography (PET) have both been used to measure the cerebral haemodynamic state in patients who may have a compromised blood flow. Our purpose was to investigate whether PET and TCD identify the same patients with an impaired flow state of the brain in patients with internal carotid artery (ICA) occlusion.
Methods
Patients with recent transient ischaemic attack or minor ischaemic stroke associated with ICA occlusion underwent TCD with measurement of CO2-reactivity and oxygen-15 PET within a median time interval of 6 days.
Results
We included 24 patients (mean age 64 ± 10 years). Seventeen (71%) patients had impaired CO2-reactivity (≤20%), of whom six had absent reactivity (0%) or steal (<0%) in the hemisphere ipsilateral to the ICA occlusion. PET of the perfusion state of the hemisphere ipsilateral to the ICA occlusion demonstrated stage 1 haemodynamic compromise (decreased cerebral blood flow (CBF) or increased cerebral blood volume (CBV) without increased oxygen extraction fraction (OEF)) in 13 patients and stage 2 (increased OEF) in 2 patients. In 12 patients (50%), there was agreement between TCD and PET, indicating haemodynamic compromise in 10 and a normal flow state of the brain in 2 patients. There was no significant correlation between CO2-reactivity and CBF ipsilateral/contralateral hemispheric ratio (r = 0.168, p value = 0.432), OEF ratio (r = −0.242, p value = 0.255), or CBV/CBF ratio (r = −0.368, p value = 0.077).
Conclusions
In patients with symptomatic ICA occlusion, identification of an impaired flow state of the brain by PET and TCD CO2-reactivity shows concordance in only half of the patients.
doi:10.1186/2191-219X-2-30
PMCID: PMC3444322  PMID: 22682265
carotid artery disease; haemodynamic; PET; transcranial Doppler; stroke
15.  P-Glycoprotein Function at the Blood–Brain Barrier: Effects of Age and Gender 
Molecular Imaging and Biology  2012;14(6):771-776.
Purpose
P-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood–brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females. Pgp function can be quantified in vivo using (R)-[11C]verapamil and positron emission tomography. The purpose of this study was to assess global and regional effects of both age and gender on BBB Pgp function.
Procedures
Thirty-five healthy men and women in three different age groups were included. Sixty minutes dynamic (R)-[11C]verapamil scans with metabolite-corrected arterial plasma input curves were acquired. Grey matter time–activity curves were fitted to a validated constrained two-tissue compartment plasma input model, providing the volume of distribution (VT) of (R)-[11C]verapamil as outcome measure.
Results
Increased VT of (R)-[11C]verapamil with aging was found in several large brain regions in men. Young and elderly women showed comparable VT values. Young women had higher VT compared with young men.
Conclusions
Decreased BBB Pgp is found with aging; however, effects of age on BBB Pgp function differ between men and women.
doi:10.1007/s11307-012-0556-0
PMCID: PMC3492696  PMID: 22476967
Aging; Gender; Positron emission tomography; Blood–brain barrier; P-glycoprotein; (R)-[11C]verapamil
16.  Bone formation rather than inflammation reflects Ankylosing Spondylitis activity on PET-CT: a pilot study 
Introduction
Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference.
Methods
In a stepwise approach different PET tracers were investigated. First, whole body [18F]FDG and [11C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [18F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data.
Results
No increased [18F]FDG and [11C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]Fluoride PET positive lesions.
Conclusions
Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging.
doi:10.1186/ar3792
PMCID: PMC3446444  PMID: 22471910
17.  Effects of rigid and non-rigid image registration on test-retest variability of quantitative [18F]FDG PET/CT studies 
EJNMMI Research  2012;2:10.
Background
[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) is a valuable tool for monitoring response to therapy in oncology. In longitudinal studies, however, patients are not scanned in exactly the same position. Rigid and non-rigid image registration can be applied in order to reuse baseline volumes of interest (VOI) on consecutive studies of the same patient. The purpose of this study was to investigate the impact of various image registration strategies on standardized uptake value (SUV) and metabolic volume test-retest variability (TRT).
Methods
Test-retest whole-body [18F]FDG PET/CT scans were collected retrospectively for 11 subjects with advanced gastrointestinal malignancies (colorectal carcinoma). Rigid and non-rigid image registration techniques with various degrees of locality were applied to PET, CT, and non-attenuation corrected PET (NAC) data. VOI were drawn independently on both test and retest scans. VOI drawn on test scans were projected onto retest scans and the overlap between projected VOI and manually drawn retest VOI was quantified using the Dice similarity coefficient (DSC). In addition, absolute (unsigned) differences in TRT of SUVmax, SUVmean, metabolic volume and total lesion glycolysis (TLG) were calculated in on one hand the test VOI and on the other hand the retest VOI and projected VOI. Reference values were obtained by delineating VOIs on both scans separately.
Results
Non-rigid PET registration showed the best performance (median DSC: 0.82, other methods: 0.71-0.81). Compared with the reference, none of the registration types showed significant absolute differences in TRT of SUVmax, SUVmean and TLG (p > 0.05). Only for absolute TRT of metabolic volume, significant lower values (p < 0.05) were observed for all registration strategies when compared to delineating VOIs separately, except for non-rigid PET registrations (p = 0.1). Non-rigid PET registration provided good volume TRT (7.7%) that was smaller than the reference (16%).
Conclusion
In particular, non-rigid PET image registration showed good performance similar to delineating VOI on both scans separately, and with smaller TRT in metabolic volume estimates.
doi:10.1186/2191-219X-2-10
PMCID: PMC3349514  PMID: 22404895
Positron emission tomography (PET); Test-retest variability; Image registration; Non-rigid; Rigid
18.  Kinetic analysis in human brain of [11C](R)-rolipram, a positron emission tomographic radioligand to image phosphodiesterase 4: a retest study and use of an image-derived input function 
NeuroImage  2010;54(3):1903-1909.
[11C](R)-rolipram provides a measure of the density of phosphodiesterase 4 (PDE4) in brain, an enzyme that metabolizes cAMP. The aims of this study were to perform kinetic modeling of [11C](R)-rolipram in healthy humans using an arterial input function and to replace this arterial input in humans with an image-derived input function.
Methods
Twelve humans had two injections of [11C](R)-rolipram. An image-derived input function was obtained from the carotid arteries and four blood samples. The samples were used for partial volume correction and for estimating the parent concentration using HPLC analysis.
Results
An unconstrained two-compartment model and Logan analysis measured distribution volume VT, with good identifiability but with moderately high retest variability (15%). Similar results were obtained using the image input (ratio image/arterial VT = 1.00 ± 0.06).
Conclusions
Binding of [11C](R)-rolipram to PDE4 can be quantified in human brain using kinetic modeling and an arterial input function. Image input function from carotid arteries provides an equally accurate and reproducible method to quantify PDE4.
doi:10.1016/j.neuroimage.2010.10.064
PMCID: PMC3026385  PMID: 21034834
Phosphodiesterase 4; Compartment model; Logan plot; Image-derived input function; Metabolite-corrected arterial input function; Test retest reproducibility
19.  Reproducibility of quantitative (R)-[11C]verapamil studies 
EJNMMI Research  2012;2:1.
Background
P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data.
Methods
Dynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures.
Results
Analysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data.
Conclusion
The model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model.
doi:10.1186/2191-219X-2-1
PMCID: PMC3274480  PMID: 22251281
Positron emission tomography; P-glycoprotein; reproducibility; (R)-[11C]verapamil
20.  Measurement of metabolic tumor volume: static versus dynamic FDG scans 
EJNMMI Research  2011;1:35.
Background
Metabolic tumor volume assessment using positron-emission tomography [PET] may be of interest for both target volume definition in radiotherapy and monitoring response to therapy. It has been reported, however, that metabolic volumes derived from images of metabolic rate of glucose (generated using Patlak analysis) are smaller than those derived from standardized uptake value [SUV] images. The purpose of this study was to systematically compare metabolic tumor volume assessments derived from SUV and Patlak images using a variety of (semi-)automatic tumor delineation methods in order to identify methods that can be used reliably on (whole body) SUV images.
Methods
Dynamic [18F]-fluoro-2-deoxy-D-glucose [FDG] PET data from 10 lung and 8 gastrointestinal cancer patients were analyzed retrospectively. Metabolic tumor volumes were derived from both Patlak and SUV images using five different types of tumor delineation methods, based on various thresholds or on a gradient.
Results
In general, most tumor delineation methods provided more outliers when metabolic volumes were derived from SUV images rather than Patlak images. Only gradient-based methods showed more outliers for Patlak-based tumor delineation. Median measured metabolic volumes derived from SUV images were larger than those derived from Patlak images (up to 59% difference) when using a fixed percentage threshold method. Tumor volumes agreed reasonably well (< 26% difference) when applying methods that take local signal-to-background ratio [SBR] into account.
Conclusion
Large differences may exist in metabolic volumes derived from static and dynamic FDG image data. These differences depend strongly on the delineation method used. Delineation methods that correct for local SBR provide the most consistent results between SUV and Patlak images.
doi:10.1186/2191-219X-1-35
PMCID: PMC3285530  PMID: 22214394
tumor delineation; tumor volume; FDG PET; Patlak; SUV
21.  Impact of [18F]FDG PET imaging parameters on automatic tumour delineation: need for improved tumour delineation methodology 
Purpose
Delineation of tumour boundaries is important for quantification of [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies and for definition of biological target volumes in radiotherapy. Several (semi-)automatic tumour delineation methods have been proposed, but these methods differ substantially in estimating tumour volume and their performance may be affected by imaging parameters. The main purpose of this study was to explore the performance dependence of various (semi-)automatic tumour delineation methods on different imaging parameters, i.e. reconstruction parameters, noise levels and tumour characteristics, and thereby the need for standardization or inter-institute calibration.
Methods
Six different types of delineation methods were evaluated by assessing accuracy and precision in estimating tumour volume from simulations and phantom experiments. The evaluated conditions were various tumour sizes, iterative reconstruction algorithm settings and image filtering, tumour to background ratios (TBR), noise levels and region growing initializations.
Results
The accuracy of all automatic delineation methods was influenced when imaging parameters were varied. The performance of all tumour delineation methods depends on variation of TBR, image resolution and image noise level, and to a lesser extent on number of iterations during image reconstruction or the initialization method of the region generation. For sphere sizes larger than 20 mm diameter a contrast-oriented method provided the most accurate results, on average, over all simulated conditions. For threshold-based methods the accuracy of tumour delineation improved after image denoising/filtering.
Conclusion
The accuracy and precision of all studied tumour delineation methods was affected by physiological and imaging parameters. The latter illustrates the need for optimizing imaging parameters and/or for careful calibration and optimization of delineation methods.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-011-1899-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00259-011-1899-5
PMCID: PMC3228515  PMID: 21858528
Tumour delineation; Volume of interest (VOI); [18F]FDG; Positron emission tomography (PET); Tumour volume
22.  Increased cerebral (R)-[11C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study 
Background
The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI) and to relate these findings to glutamate release.
Procedures
Sequential dynamic (R)-[11C]PK11195 PET scans were performed in rats 24 hours before (baseline), and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF) glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno)-histochemistry.
Results
Ten days after TBI, (R)-[11C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p < 0.05). ECF glutamate values were increased immediately after TBI (27.6 ± 14.0 μmol·L-1) as compared with the sham procedure (6.4 ± 3.6 μmol·L-1). Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B.
Conclusions
Increased cerebral uptake of (R)-[11C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels.
doi:10.1186/1742-2094-8-67
PMCID: PMC3132713  PMID: 21672189
23.  Evaluation of a cumulative SUV-volume histogram method for parameterizing heterogeneous intratumoural FDG uptake in non-small cell lung cancer PET studies 
Purpose
Standardized uptake values (SUV) are commonly used for quantification of whole-body [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies. Changes in SUV following therapy, however, only provide a proper measure of response in case of homogeneous FDG uptake in the tumour. The purpose of this study was therefore to implement and characterize a method that enables quantification of heterogeneity in tumour FDG uptake.
Methods
Cumulative SUV-volume histograms (CSH), describing % of total tumour volume above % threshold of maximum SUV (SUVmax), were calculated. The area under a CSH curve (AUC) is a quantitative index of tumour uptake heterogeneity, with lower AUC corresponding to higher degrees of heterogeneity. Simulations of homogeneous and heterogeneous responses were performed to assess the value of AUC-CSH for measuring uptake and/or response heterogeneity. In addition, partial volume correction and image denoising was applied prior to calculating AUC-CSH. Finally, the method was applied to a number of human FDG scans.
Results
Partial volume correction and noise reduction improved CSH curves. Both simulations and clinical examples showed that AUC-CSH values corresponded with level of tumour heterogeneity and/or heterogeneity in response. In contrast, this correspondence was not seen with SUVmax alone. The results indicate that the main advantage of AUC-CSH above other measures, such as 1/COV (coefficient of variation), is the possibility to measure or normalize AUC-CSH in different ways.
Conclusion
AUC-CSH might be used as a quantitative index of heterogeneity in tracer uptake. In response monitoring studies it can be used to address heterogeneity in response.
doi:10.1007/s00259-011-1845-6
PMCID: PMC3151405  PMID: 21617975
Positron emission tomography (PET); Standardized uptake value (SUV); Intratumoural heterogeneity; Cumulative SUV-volume histogram (CSH); Intensity-volume histograms (IVH)
24.  Image-Derived Input Function for Human Brain Using High Resolution PET Imaging with [11C](R)-rolipram and [11C]PBR28 
PLoS ONE  2011;6(2):e17056.
Background
The aim of this study was to test seven previously published image-input methods in state-of-the-art high resolution PET brain images. Images were obtained with a High Resolution Research Tomograph plus a resolution-recovery reconstruction algorithm using two different radioligands with different radiometabolite fractions. Three of the methods required arterial blood samples to scale the image-input, and four were blood-free methods.
Methods
All seven methods were tested on twelve scans with [11C](R)-rolipram, which has a low radiometabolite fraction, and on nineteen scans with [11C]PBR28 (high radiometabolite fraction). Logan VT values for both blood and image inputs were calculated using the metabolite-corrected input functions. The agreement of image-derived Logan VT values with the reference blood-derived Logan VT values was quantified using a scoring system. Using the image input methods that gave the most accurate results with Logan analysis, we also performed kinetic modelling with a two-tissue compartment model.
Results
For both radioligands the highest scores were obtained with two blood-based methods, while the blood-free methods generally performed poorly. All methods gave higher scores with [11C](R)-rolipram, which has a lower metabolite fraction. Compartment modeling gave less reliable results, especially for the estimation of individual rate constants.
Conclusion
Our study shows that: 1) Image input methods that are validated for a specific tracer and a specific machine may not perform equally well in a different setting; 2) despite the use of high resolution PET images, blood samples are still necessary to obtain a reliable image input function; 3) the accuracy of image input may also vary between radioligands depending on the magnitude of the radiometabolite fraction: the higher the metabolite fraction of a given tracer (e.g., [11C]PBR28), the more difficult it is to obtain a reliable image-derived input function; and 4) in association with image inputs, graphical analyses should be preferred over compartmental modelling.
doi:10.1371/journal.pone.0017056
PMCID: PMC3045425  PMID: 21364880
25.  In vivo validation of reconstruction-based resolution recovery for human brain studies 
The aim of this study was to validate in vivo the accuracy of a reconstruction-based partial volume correction (PVC), which takes into account the point spread function of the imaging system. The NEMA NU2 Image Quality phantom and five healthy volunteers (using [11C]flumazenil) were scanned on both HR+ and high-resolution research tomograph (HRRT) scanners. HR+ data were reconstructed using normalization and attenuation-weighted ordered subsets expectation maximization (NAW-OSEM) and a PVC algorithm (PVC-NAW-OSEM). HRRT data were reconstructed using 3D ordinary Poisson OSEM (OP-OSEM) and a PVC algorithm (PVC-OP-OSEM). For clinical studies, parametric volume of distribution (VT) images were generated. For phantom data, good recovery was found for both OP-OSEM (0.84 to 0.97) and PVC-OP-OSEM (0.91 to 0.98) HRRT reconstructions. In addition, for the HR+, good recovery was found for PVC-NAW-OSEM (0.84 to 0.94), corresponding well with OP-OSEM. Finally, for clinical data, good correspondence was found between PVC-NAW-OSEM and OP-OSEM-derived VT values (slope: 1.02±0.08). This study showed that HR+ image resolution using PVC-NAW-OSEM was comparable to that of the HRRT scanner. As the HRRT has a higher intrinsic resolution, this agreement validates reconstruction-based PVC as a means of improving the spatial resolution of the HR+ scanner and thereby improving the quantitative accuracy of positron emission tomography.
doi:10.1038/jcbfm.2009.225
PMCID: PMC2949117  PMID: 19844240
high-resolution PET; high-resolution research tomograph; HRRT; PET; reconstruction-based partial volume correction; resolution recovery

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