Paolo Zanotti-Fregonara

Image-Derived Input Function for Brain PET Studies: Many Challenges and Few Opportunities:

Quantitative positron emission tomography (PET) brain studies often require that the input function be measured, typically via arterial cannulation. Image-derived input function (IDIF) is an elegant and attractive noninvasive alternative to arterial sampling. However, IDIF is also a very challenging technique associated with several problems that must be overcome before it can be successfully implemented in clinical practice. As a result, IDIF is rarely used as a tool to reduce invasiveness in patients. The aim of the present review was to identify the methodological problems that hinder widespread use of IDIF in PET brain studies. We conclude that IDIF can be successfully implemented only with a minority of PET tracers. Even in those cases, it only rarely translates into a less-invasive procedure for the patient. Finally, we discuss some possible alternative methods for obtaining less-invasive input function.

The methodology of TSPO imaging with positron emission tomography

The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for molecular strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomography (PET) has allowed the imaging of TSPO density in brain using [11C]-(R)-PK11195, a radiolabelled-specific antagonist of the TSPO that has demonstrated microglial activation in a large number pathological cohorts. The significant clinical interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising number of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodological aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers.

Reduced cannabinoid CB 1 receptor binding in alcohol dependence measured with positron emission tomography

Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and [18F]FMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3–7 days of admission from ongoing drinking, and after 2–4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20–30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2–4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2–4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.

Comparison of Eight Methods for the Estimation of the Image-Derived Input Function in Dynamic [18F]-FDG PET Human Brain Studies

The aim of this study was to compare eight methods for the estimation of the image-derived input function (IDIF) in [18F]-FDG positron emission tomography (PET) dynamic brain studies. The methods were tested on two digital phantoms and on four healthy volunteers. Image-derived input functions obtained with each method were compared with the reference input functions, that is, the activity in the carotid labels of the phantoms and arterial blood samples for the volunteers, in terms of visual inspection, areas under the curve, cerebral metabolic rates of glucose (CMRglc), and individual rate constants. Blood-sample-free methods provided less reliable results as compared with those obtained using the methods that require the use of blood samples. For some of the blood-sample-free methods, CMRglc estimations considerably improved when the IDIF was calibrated with a single blood sample. Only one of the methods tested in this study, and only in phantom studies, allowed a reliable calculation of the individual rate constants. For the estimation of CMRglc values using an IDIF in [18F]-FDG PET brain studies, a reliable absolute blood-sample-free procedure is not available yet.

Bone metastases of differentiated thyroid cancer: impact of early 131I-based detection on outcome

Bone is the second most frequent target of distant metastases in patients with differentiated thyroid cancer, and such forms carry a very poor prognosis. The impact of (131)I therapy in this setting is controversial. We describe the diagnostic circumstances and outcome of patients with bone metastases recently managed in two institutions. Among 921 consecutive thyroid cancer patients who had total thyroidectomy and (131)I ablation between January 2000 and December 2004 and who were subsequently monitored, bone metastases had been diagnosed in 16 patients. In three cases, the bone metastases were non-functioning (negative (131)I uptake) . These patients were treated with surgery and radiotherapy but progressed rapidly. The other 13 patients had functioning (positive (131)I uptake) bone metastases. In five of them, thyroid cancer was revealed by signs of distant involvement (bone pain, n = 4; dyspnea, n = 1). The bone metastases progressed in these five patients, despite local therapy and multiple courses of (131)I. The bone metastases in the remaining eight patients were discovered on the post-surgery (131)I therapy scan. Complementary radiological studies were negative except in one patient in whom one of the metastases (a 5 mm lesion of the right humerus) was visible on magnetic resonance imaging (MRI). Six of these patients showed a good response to (131)I therapy, with (131)I uptake and Tg levels becoming undetectable or showing a sharp fall. One patient refused (131)I therapy; bone metastases became visible on MRI within 1 year and the Tg level rose tenfold. The disease progressed in one patient despite (131)I therapy. Post-surgical (131)I ablation can contribute to early detection of bone metastases at a time when the Tg level may be only moderately elevated, when other radiological studies are negative, and when the disease is potentially curable by (131)I therapy.

Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein

IMPORTANCE Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES The [11C]PBR28 distribution volume (VT) corrected for free fraction (fP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. RESULTS The [11C]PBR28 VT to fp ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [11C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [11C]PBR28 was increased significantly in thalamus. Relative [11C]PBR28 and [11C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([11C]PBR28: 2%-6%; [11C]DPA-713: 4%-9%). Asymmetry of [11C]DPA-713 was greater than that of [11C]PBR28 (F = 29.4; P = .001). CONCLUSIONS AND RELEVANCE Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.

Kinetic modeling without accounting for the vascular component impairs the quantification of [11C]PBR28 brain PET data

The positron emission tomography radioligand [11C]PBR28 targets translocator protein (18 kDa) (TSPO) and is a potential marker of neuroinflammation. [11C]PBR28 binding is commonly quantified using a two-tissue compartment model and an arterial input function. Previous studies with [11C]HRJ-PK11195 demonstrated a slow irreversible binding component to the TSPO proteins localized in the endothelium of brain vessels, such as venous sinuses and arteries. However, the impact of this component on the quantification of [11C]PBR28 data has never been investigated. In this work we propose a novel kinetic model for [11C]PBR28. This model hypothesizes the existence of an additional irreversible component from the blood to the endothelium. The model was tested on a data set of 19 healthy subjects. A simulation was also performed to quantify the error generated by the standard two-tissue compartmental model when the presence of the irreversible component is not taken into account. Our results show that when the vascular component is included in the model the estimates that include the vascular component (2TCM-1K) are more than three-fold smaller, have a higher time stability and are better correlated to brain mRNA TSPO expression than those that do not include the model (2TCM).

[123I]-FP-CIT and [99mTc]-HMPAO single photon emission computed tomography in a new sporadic case of rapid-onset dystonia–parkinsonism

UNLABELLED Rapid-onset dystonia-parkinsonism (RDP) is a rare, autosomal-dominantly inherited syndrome characterized by abrupt onset, over hours to days, of dystonic and parkinsonian symptoms. To date, RDP has been described in a small number of families, and in only four sporadic cases. METHODS We here report a new sporadic case of RDP who has a novel de novo mutation in the ATP1A3 gene. Striatal dopamine transporters have been assessed quantitatively using [123I]-FP-CIT SPECT. A volume of interest (VOI) was drawn within the occipital cortex to obtain non-specific activity and specific to non-specific binding ratios (BR) were calculated. A single template of predefined VOI 3D-drawn on right and left caudate nucleus and putamen was applied to the spatially normalized BR images. BR values were compared to those obtained from an age-matched control group and from a group of patients suffering from Parkinsons disease (Hoehn and Yahr score 2 or 3). A [99mTc]-HMPAO cerebral blood flow study was also performed. RESULTS In the control group, BR values (mean+/-Standard Deviation) were 3.5+/-0.4 for the left striatum and 3.3+/-0.3 for the right one. RDP patients values were 3 and 2.7, respectively. In the Parkinson group, values were 1.6+/-0.3 and 1.7+/-0.4, respectively. [99mTc]-HMPAO scan showed homogeneous cortical and sub-cortical perfusion. CONCLUSION Quantification of striatal [123I]-FP-CIT uptake in a new sporadic case of RDP with a novel mutation in the ATP1A3 gene showed values just within the range of normality. [99mTc]-HMPAO scan was normal.

Absorbed 18F-FDG Dose to the Fetus During Early Pregnancy

We describe a rare case of a woman who underwent 18F-FDG PET/CT during early pregnancy (fetus age, 10 wk). The fetal absorbed dose was calculated by taking into account the 18F-FDG fetal self-dose, photon dose coming from the maternal tissues, and CT dose received by both mother and fetus. Methods: The patient (weight, 71 kg) had received 296 MBq of 18F-FDG. Imaging started at 1 h, with unenhanced CT acquisition, followed by PET acquisition. From the standardized uptake value measured in fetal tissues, we calculated the total number of disintegrations per unit of injected activity. Monte Carlo analysis was then used to derive the fetal 18F-FDG self-dose, including positrons and self-absorbed photons. Photon dose from maternal tissues and CT dose were added to obtain the final dose. Results: The maximum standardized uptake value in fetal tissues was 4.5. Monte Carlo simulation showed that the fetal self-dose was 3.0 × 10−2 mGy/MBq (2.7 × 10−2 mGy/MBq from positrons and 0.3 × 10−2 mGy/MBq from photons). The estimated photon dose to the fetus from maternal tissues was 1.04 × 10−2 mGy/MBq. Accordingly, the specific 18F-FDG dose to the fetus was about 4.0 × 10−2 mGy/MBq (11.8 mGy in this patient). The CT scan added a further 10 mGy. Conclusion: The dose to the fetus during early pregnancy can be as high as 4.0 × 10−2 mGy/MBq of 18F-FDG. Current dosimetric standards in early pregnancy may need to be revised.

Suggested pathway to assess radiation safety of 11C-labeled PET tracers for first-in-human studies

Dear Sir, Before a new radioactive tracer can be used in humans, many national as well as local Institutional Radiation Safety Committees often require that a biodistribution study be conducted in animals. The aim of these time-consuming and expensive studies is to assess the dose of absorbed radiation in animals so that the human dose can be extrapolated. Because of their physical similarity to humans (organ size and body weight), monkeys are arguably the best animal species to estimate radiation burden in human subjects. The extrapolation can be performed with different methods [1], for example by converting the percent administered activity in the monkey organ to percent administered activity in the same human organ. Basically, the human residence time for a given organ is derived by performing the animal to human organ mass ratio multiplication for each time point and then by integrating that time-activity curve to derive a hypothetical area under the curve for that human organ. This process is then repeated for each major source organ. The resulting residence times are then used in conjunction with an anthropomorphic human phantom to calculate the human dose. This method assumes that the metabolism of radiopharmaceuticals is similar between the two species and varies only as a function of organ mass. However, as we will describe below, it is our contention that results obtained in this manner from monkeys are misleading. This commentary will suggest a more accurate alternative that nevertheless maintains a wide safety margin. To investigate this issue, we identified a total of nine C-labeled tracers for which both monkey and human absorbed doses were reported. We compared the absorbed doses extrapolated from monkeys for that particular radioligand and the mean dose from human biodistribution data for all nine radiotracers. The results of these studies showed that, in general, doses extrapolated from monkeys overestimated the human effective dose (Table 1). Looking at all nine tracers, we found that the mean dose extrapolated from monkeys was 7.3±1.6 μSv/ MBq, while the mean dose measured in actual human studies for the same tracers was 5.7±1.2 μSv/MBq (paired t test: p< 0.001). Furthermore, such overestimates were not constant, but showed unpredictable variations; indeed, the percentage difference ranged from −72 to +11%. The most likely reason for such discrepancies is metabolic differences between different species. For instance, for C-(R)-rolipram, biodistribution in monkey poorly estimated biodistribution in humans [2]. Compared to humans, monkeys had a higher liver uptake, no hepatobiliary excretion, and higher urinary elimination. This led to an approximately 40% overestimate of the effective dose [2]. For C-PBR28, monkey data overestimated the effective human dose by 60%, with exposures to individual organs both overand underestimated [3]. Moreover, the doses measured in human studies were quite constant across the different tracers (range 4.3–7.8 μSv/MBq) (Table 1). This suggests that when predicting the human dose for a given tracer, a simple mean human value from all published studies is a better predictor of the effective dose than the value derived from monkeys for that specific tracer. We also searched the literature and found 21 other C-labeled tracers for which dosimetry in human scans had been calculated. With the exception of C-WAY-100635, whose effective dose was about 12–16 μSv/MBq, all other tracers had very similar, low estimates (range 3.0–6.8 μSv/ MBq, mean 5.1 μSv/MBq) that closely agree with the average dose of 5.8 μSv/MBq found in the first nine tracers (Table 2). P. Zanotti-Fregonara :R. B. Innis (*) Molecular Imaging Branch, NIMH, NIH, 10 Center Drive, Bethesda, MD 20892-1026, USA e-mail: robert.innis@nih.gov Eur J Nucl Med Mol Imaging (2012) 39:544–547 DOI 10.1007/s00259-011-2005-8