Clinical Positron Emission Tomography Studies Research Articles

Automated, Transferable, and Ethanol-Free Radiosynthesis of [11C]Butanol.

Cerebral blood flow and blood-brain barrier permeability assessment are crucial hemodynamic parameters to measure under neurological conditions. In conjunction with positron emission tomography (PET), oxygen-15-labeled water has emerged as a gold standard for measuring cerebral perfusion; however, at higher flow rates, [15O]water extraction becomes nonlinear. In such a scenario, freely diffusible [11C]butanol can provide a truer estimate. Radiosyntheses of [11C]butanol reported to date are protracted, are not automated, or require ethanol in the final formulation. By using a flow-based, captive solvent approach on a commercially available radiosynthesizer, we automated and reduced the synthesis time to 28 min. Forgoing cartridge-based purification for an aqueous high-performance liquid chromatography method, we obtained high purity [11C]butanol in ethanol-free phosphate buffered saline in sufficient yields for clinical PET studies. We here report our expedited, automated, and ethanol-free radiosynthesis of [11C]butanol along with preliminary imaging of a porcine subject.

Developing a PET normal brain template using diffusion tensor imaging images: A proof of concept

Background: Registered Positron emission tomography (PET) brain images to the standard normal PET brain templates can be performed to diagnosis dementia by using a vendor software, in which the brain template is based on T1-Weighted (T1W) images. However, the imperfection of an overlap between PET images and the PET-T1W based brain template could be observed. Objectives: This pilot study aimed to develop a new PET brain template and compare the accuracy of image registration between a conventional PET-T1W based brain template and our proposed PET-DTI based brain template. Materials and methods: The new PET-DTI based brain template was developed from twenty-four normal volunteers (age ranged 42-79 years old) who underwent 11C-Pittsburgh compound B PET scans and both T1W and diffusion tensor image (DTI) magnetic resonance imaging brain scans. The correction of Eddy-Current distortions and related artifact removing in DTI images were performed using the open-source FMRIB Software Library (FSL) to generate whole-brain probabilistic tractography maps (MRI-Probtract). MRI-Probtract map was then deformably registered and normalized to PET images, which were used for brain boundary guidance. The accuracy of image registration was assessed by applying the newly developed PET-DTI brain template to PET images of four mild cognitive impairment patients who underwent the same brain-scanning protocols. The accuracy of image registrations using the conventional PET-T1 and PET-DTI templates was evaluated qualitatively by three nuclear medicine physicians. Wilcoxon Signed Ranks test was used to compare registration scores of the two methods. Additionally, the dice similarly coefficient was obtained to quantitatively evaluate the accuracy of image registration. Results: The registration scores of the PET images registered with the PET-DTI template were significantly higher than the PET-T1 template at p-value < 0.05. This result is consistent with the dice similarly coefficient where the value of PET-DTI template was higher. Conclusion: Result of this pilot study showed that new PET-DTI brain template provides higher registration quality, suggesting the feasibility of using PET-DTI template in a clinical PET study of the brain.

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds.

The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies

A panel of radiochemicals has enabled invivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. Invitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the invivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

Fully automated radiosynthesis and quality control of estrogen receptor targeting radiopharmaceutical 16α-[18F]fluoroestradiol ([18F]FES) for human breast cancer imaging

16α-[18F]Fluoroestradiol ([18F]FES) is the most successful estrogen receptor (ER) targeting radiopharmaceutical to date. [18F]FES has been extensively used for positron emission tomography (PET) to assess the ER expression in breast cancer and to monitor the response of breast cancer to antiestrogen therapy. To address local investigator needs for [18F]FES-PET, we sought to adapt established literature methods to our in-house multi-purpose 18F-radiosynthesis module for [18F]FES production. Here we describe facile fully automated radiosynthesis and quality control (QC) of [18F]FES using our home-built automated multi-purpose 18F-radiosynthesis module. [18F]FES was produced via two-step-one-pot synthesis using cyclic sulfate precursor, and purified by semi-preparative reversed-phase (RP) high performance liquid chromatography (HPLC) with a C18 column followed by solid-phase extraction (SPE) with a C18 Plus Sep-Pak cartridge trap/release formulation. The overall synthesis time was 75–80 min, and the radiochemical yield was 30–35% decay corrected to end of bombardment (EOB), based on H[18F]F. The radiochemical purity was >99%, and the molar activity (Am) was 182–470 GBq/μmol at EOB. The [18F]FES dose meets all QC criteria for clinical use, and is suitable for clinical PET study of breast cancer.

An Accurate Ensemble Classifier for Medical Volume Analysis: Phantom and Clinical PET Study

The predominant application of positron emission tomography (PET) in the field of oncology and radiotherapy and the significance of medical imaging research have led to an urgent need for effective approaches to PET volume analysis and the development of accurate and robust volume analysis techniques to support oncologists in their clinical practice, including diagnosis, arrangement of appropriate radiotherapy treatment, and evaluation of patients' response to therapy. This paper proposes an efficient optimized ensemble classifier to tackle the problem of analysis of squamous cell carcinoma in patient PET volumes. This optimized classifier is based on an artificial neural network (ANN), fuzzy C-means (FCM), an adaptive neuro-fuzzy inference system (ANFIS), K-means, and a self-organizing map (SOM). Four ensemble classifier machines are proposed in this study. The first three are built using a voting approach, an averaging technique, and weighted averaging, respectively. The fourth, novel ensemble classifier machine is based on the combination of a modified particle swarm optimization (PSO) approach and weighted averaging. Experimental National Electrical Manufacturers Association and International Electrotechnical Commission (NEMA IEC) body phantom and clinical PET studies of participants with laryngeal squamous cell carcinoma are used for the evaluation of the proposed approach. Superior results were achieved using the new optimized ensemble classifier when compared with the results from the investigated classifiers and the non-optimized ensemble classifiers. The proposed approach identified the region of interest class (tumor) with an average accuracy of 98.11% in clinical datasets of patients with laryngeal tumors. This system supports the expertise of clinicians in PET tumor analysis.

Positron Emission Tomography: Updates on Imaging of Addiction.

Positron Emission Tomography: Updates on Imaging of Addiction.

Facile fully automated radiosynthesis and quality control of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) for human brain tumor imaging

O-(2-[18F]Fluoroethyl)-l-tyrosine ([18F]FET) has become one of the most successful amino acid tracers for human brain tumor imaging with positron emission tomography (PET). Facile fully automated radiosynthesis and quality control (QC) of [18F]FET using our home-built automated multi-purpose 18F-radiosynthesis module are described. [18F]FET was produced in 75–80 min overall synthesis time with 20–25% radiochemical yield decay corrected to end of bombardment (EOB), based on H[18F]F. The radiochemical and enantiomeric purities were >99%, and the molar activity (Am) was 189–411 GBq/μmol at EOB. The [18F]FET dose meets all QC criteria for clinical use, and is suitable for clinical PET study of brain tumor.

Internal radiation dose estimation using multiple D-shuttle dosimeters for positron emission tomography (PET): A validation study using NEMA body phantom.

Internal radiation dosimetry plays an important role in ensuring the safe use of positron emission tomography (PET) technology and is a legal requirement in most countries. We propose a new technique to estimate the internal radiation dose in PET studies by means of multiple D-shuttle dosimeters attached on the body surface of the patient. Radioactivity in a source organ was estimated iteratively using measurements from multiple D-shuttle dosimeters with a maximum-likelihood expectation-maximization (MLEM) algorithm with dose response from a source to a D-shuttle dosimeter computed by Monte Carlo simulation. To validate our technique, we performed a phantom study using a National Electrical Manufacturers Association (NEMA) body phantom. The fillable compartments (torso cavity and six spheres) of the phantom were filled with 18 F-FDG mixed with pure water using an 800:1 sphere-to-background radioactivity concentration ratio. The radioactivity concentrations present in the torso cavity and six spheres were 0.00165 MBq/mL and 1.32 MBq/mL, respectively. The initial radioactivities of the torso cavity and six spheres (treated as source organs) were 15.9 MBq (torso cavity), 34.7 MBq (37 mm sphere), 15.1 MBq (28 mm sphere), 7.27 MBq (22 mm sphere), 3.26 MBq (17 mm sphere), 1.54 MBq (13 mm sphere), and 0.697 MBq (10 mm sphere). Eleven D-shuttle dosimeters were attached to the NEMA body phantom surface to obtain information on body surface dose and a mathematical NEMA body phantom has been modeled in the Heavy Ion Transport Code System (PHITS) Monte Carlo simulation code. Radioactivity was estimated in 2 min intervals over a 110-min total dose time using our proposed technique. A significant correlation (R2 = 0.992) was found between actual radioactivity and estimated radioactivity at every 2 min interval for each source organ. The estimated initial radioactivity (mean with standard deviation) was 16.5 ± 0.311 MBq (torso cavity), 33.0 ± 0.624 MBq (37 mm sphere), 15.7 ± 0.189 MBq (28 mm sphere), 7.11 ± 0.738 MBq (22 mm sphere), 4.17 ± 0.083 MBq (17 mm sphere), 1.48 ± 0.469 MBq (13 mm sphere), and 0.865 ± 0.313 MBq (10 mm sphere), which were very close to the actual initial radioactivity measurements for each source organ. The phantom study showed that our technique worked successfully. This technique could be used to estimate internal radiation dosimetry in a clinical PET study.

Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts

Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq × 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of 64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease.

In Vivo [18F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates.

As one of the major excitatory ion channels in the brain, NMDA receptors have been a leading research target for neuroscientists, physicians, medicinal chemists, and pharmaceutical companies for decades. Molecular imaging of NMDA receptors by means of positron emission tomography (PET) with [18F]GE-179 quickly progressed to clinical PET studies, but a thorough understanding of its binding specificity has been missing and has thus limited signal interpretation. Here a preclinical study with [18F]GE-179 in rodents and nonhuman primates (NHPs) is presented in an attempt to characterize [18F]GE-179 signal specificity. Rodent PET/CT was used to study drug occupancy and functional manipulation in rats by pretreating animals with NMDA targeted blocking/modulating drug doses followed by a single bolus of [18F]GE-179. Binding competition with GE-179, MK801, PCP, and ketamine, allosteric inhibition by ifenprodil, and brain activation with methamphetamine did not alter the [18F]GE-179 brain signal in rats. In addition, multimodal imaging with PET/MRI in NHPs was used to evaluate changes in radiotracer binding as a function of pharmacological challenges. Drug-induced hemodynamic changes were monitored simultaneously using functional MRI (fMRI). Comparisons of baseline and signal after drug challenge in NHPs demonstrated that the [18F]GE-179 signal cannot be manipulated in a predictable fashion in vivo. fMRI data acquired simultaneously with PET data supported this finding and provided evidence that radiotracer delivery is not altered by blood flow changes. In conclusion, the [18F]GE-179 brain signal is not readily interpretable in the context of NMDA receptor binding on the basis of the results shown in this study.

Tau Positron Emission Tomography

Accumulation of fibrillar tau protein aggregates is a neuropathological hallmark of Alzheimer's disease (AD) and related neurodegenerative dementias, including a subgroup of frontotemporal lobar degeneration (FTLD). Visualization of tau lesions in the brains of living subjects enables a pathology-based diagnosis of dementing illnesses in the prodromal stage, and offers objective measures of disease progression and outcomes of disease-modifying therapies. With this rationale, diverse classes of low-molecular-weight chemicals capable of binding to a β-pleated sheet structure have been developed to be used for in vivo positron emission tomography (PET) of tau pathologies. Clinical PET studies of AD patients with such tau probes have provided the following insights: (1) Tau fibrils accumulate in the hippocampal formation in an age-dependent manner that is independent of amyloid-beta peptide (Aβ) pathology; (2) The deposition of Aβ may trigger a spatial expansion of tau pathology, in transition from normal aging to advanced AD; and (3) Tau accumulation is intimately associated with local neuronal loss, leading to cortical atrophy and focal symptoms. In contrast, studies of FTLD have shown a limited performance of first-generation PET probes in capturing non-AD-type tau lesions. New compounds have accordingly been developed and clinically tested, proving to yield a high contrast for tau deposits with high specificity. These second-generation probes are being evaluated primarily by pharmaceutical companies, in line with their growing demands for neuroimaging-based biomarkers serving for clinical trials of anti-Aβ and anti-tau therapies. Meanwhile, a consortium flexibly linking academia and industry to facilitate the utilization of research tools, including tau PET probes, has been established in Japan, for the ultimate purpose of elucidating the molecular etiology of tauopathies and creating diagnostic and therapeutic agents based on such an understanding.

A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data

The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration–time profiles and P-glycoprotein (Pgp)–mediated brain drug–drug interactions between the model Pgp substrate (R)-[11C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [11C]tariquidar (TQD), and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration–time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration–time profiles and rank the magnitude of the Pgp-mediated brain drug–drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.

Representativeness of clinical PET study participants with schizophrenia: A systematic review

While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D2 receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D2 receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor.

BackgroundThe availability of GABAA receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [18F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [18F]flumazenil to GABAA receptors in mice.MethodsBrain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [18F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [18F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.ResultsPET images showed persistence of high [18F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.ConclusionsAnesthesia has pronounced effects on the binding and blood-brain distribution of [18F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAA receptors involving the use of anesthesia.

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models.

The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ((89)Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after (89)Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant (89)Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of (89)Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of (89)Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by (89)Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166-74. ©2016 AACR.

Experimental validation of gallium production and isotope-dependent positron range correction in PET

Positron range (PR) is one of the important factors that limit the spatial resolution of positron emission tomography (PET) preclinical images. Its blurring effect can be corrected to a large extent if the appropriate method is used during the image reconstruction. Nevertheless, this correction requires an accurate modelling of the PR for the particular radionuclide and materials in the sample under study. In this work we investigate PET imaging with 68Ga and 66Ga radioisotopes, which have a large PR and are being used in many preclinical and clinical PET studies. We produced a 68Ga and 66Ga phantom on a natural zinc target through (p,n) reactions using the 9-MeV proton beam delivered by the 5-MV CMAM tandetron accelerator. The phantom was imaged in an ARGUS small animal PET/CT scanner and reconstructed with a fully 3D iterative algorithm, with and without PR corrections. The reconstructed images at different time frames show significant improvement in spatial resolution when the appropriate PR is applied for each frame, by taking into account the relative amount of each isotope in the sample. With these results we validate our previously proposed PR correction method for isotopes with large PR. Additionally, we explore the feasibility of PET imaging with 68Ga and 66Ga radioisotopes in proton therapy.

Accelerated time-of-flight (TOF) PET image reconstruction using TOF bin subsetization and TOF weighting matrix pre-computation

Time-of-flight (TOF) positron emission tomography (PET) technology has recently regained popularity in clinical PET studies for improving image quality and lesion detectability. Using TOF information, the spatial location of annihilation events is confined to a number of image voxels along each line of response, thereby the cross-dependencies of image voxels are reduced, which in turns results in improved signal-to-noise ratio and convergence rate. In this work, we propose a novel approach to further improve the convergence of the expectation maximization (EM)-based TOF PET image reconstruction algorithm through subsetization of emission data over TOF bins as well as azimuthal bins. Given the prevalence of TOF PET, we elaborated the practical and efficient implementation of TOF PET image reconstruction through the pre-computation of TOF weighting coefficients while exploiting the same in-plane and axial symmetries used in pre-computation of geometric system matrix. In the proposed subsetization approach, TOF PET data were partitioned into a number of interleaved TOF subsets, with the aim of reducing the spatial coupling of TOF bins and therefore to improve the convergence of the standard maximum likelihood expectation maximization (MLEM) and ordered subsets EM (OSEM) algorithms. The comparison of on-the-fly and pre-computed TOF projections showed that the pre-computation of the TOF weighting coefficients can considerably reduce the computation time of TOF PET image reconstruction. The convergence rate and bias-variance performance of the proposed TOF subsetization scheme were evaluated using simulated, experimental phantom and clinical studies. Simulations demonstrated that as the number of TOF subsets is increased, the convergence rate of MLEM and OSEM algorithms is improved. It was also found that for the same computation time, the proposed subsetization gives rise to further convergence. The bias-variance analysis of the experimental NEMA phantom and a clinical FDG-PET study also revealed that for the same noise level, a higher contrast recovery can be obtained by increasing the number of TOF subsets. It can be concluded that the proposed TOF weighting matrix pre-computation and subsetization approaches enable to further accelerate and improve the convergence properties of OSEM and MLEM algorithms, thus opening new avenues for accelerated TOF PET image reconstruction.

Differential effects of amyloid-beta 1–40 and 1–42 fibrils on 5-HT1A serotonin receptors in rat brain

Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT1AR) after intrahippocampal injections of amyloid-beta 1–40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [18F]MPPF revealing an overexpression of 5-HT1AR in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT1AR reactivity by injecting them, separately, into the hippocampus or striatum of rats. [18F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT1AR in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils–induced 5-HT1AR expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed.

The impact of the rs6971 polymorphism in TSPO for quantification and study design

Second-generation translocator protein (TSPO) radioligands were developed to circumvent the technical short comings of 11C-PK11195, the first TSPO targeting tracer. However, in early clinical positron emission tomography (PET) studies they displayed greater inter- and intra-subject variability than was expected given the promising characteristics they showed in preclinical and in vitro studies. A great deal of this variability, although not all, can be explained by the rs6971 polymorphism in the gene encoding TSPO. This polymorphism causes a single amino acid substitution in the TSPO which, for all second-generation tracers tested in man hitherto, reduces binding affinity in mutants relative to wild type. This has obvious implications for interpretation of data, because inter-subject comparisons in PET studies are predicated on the assumption that binding affinity is consistent across all subjects. In this paper, we discuss the implications of the rs6971 polymorphism on study design, analysis and interpretation of data for clinical PET studies using second-generation TSPO radioligands.