Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.

We present a new rodent SPECT system (U-SPECT-II) that enables molecular imaging of murine organs down to resolutions of less than half a millimeter and high-resolution total-body imaging. Methods: The U-SPECT-II is based on a triangular stationary detector set-up, an XYZ stage that moves the animal during scanning, and interchangeable cylindric collimators (each containing 75 pinhole apertures) for both mouse and rat imaging. A novel graphical user interface incorporating preselection of the field of view with the aid of optical images of the animal focuses the pinholes to the area of interest, thereby maximizing sensitivity for the task at hand. Images are obtained from list-mode data using statistical reconstruction that takes system blurring into account to increase resolution. Results: For 99m Tc, resolutions determined with capillary phantoms were smaller than 0.35 and 0.45 mm using the mouse collimator with 0.35-and 0.6-mm pinholes, respectively, and less than 0.8 mm using the rat collimator with 1.0-mm pinholes. Peak geometric sensitivity is 0.07% and 0.18% for the mouse collimator with 0.35-and 0.6-mm pinholes, respectively, and 0.09% for the rat collimator. Resolution with 111 In, compared with that with 99m Tc, was barely degraded, and resolution with 125 I was degraded by about 10%, with some additional distortion. In vivo, kidney, tumor, and bone images illustrated that U-SPECT-II could be used for novel applications in the study of dynamic biologic systems and radiopharmaceuticals at the suborgan level. Conclusion: Images and movies obtained with U-SPECT-II provide high-resolution radiomolecule visualization in rodents. Discrimination of molecule concentrations between adjacent volumes of about 0.04 mL in mice and 0.5 mL in rats with U-SPECT-II is readily possible.

SUMMARYPurpose: Fifteen percent to 25% of patients with refractory epilepsy require invasive video-electroencephalography (EEG) monitoring (IVEM) to precisely delineate the ictal-onset zone. This delineation based on the recorded intracranial EEG (iEEG) signals occurs visually by the epileptologist and is therefore prone to human mistakes. The purpose of this study is to investigate whether effective connectivity analysis of intracranially recorded EEG during seizures provides an objective method to localize the ictal-onset zone. Methods: In this study data were analyzed from eight patients who underwent IVEM at Ghent University Hospital in Belgium. All patients had a focal ictal onset and were seizure-free following resective surgery. The effective connectivity pattern was calculated during the first 20 s of ictal rhythmic iEEG activity. The outdegree, which is reflective of the number of outgoing connections, was calculated for each electrode contact for every single seizure during these 20 s. The seizure specific out-degrees were summed per patient to obtain the total out-degree. The electrode contact with the highest total out-degree was considered indicative of localization of the ictal-onset zone. This result was compared to the conclusion of the visual analysis of the epileptologist and the resected brain region segmented from postoperative magnetic resonance imaging (MRI). Key findings: In all eight patients the electrode contact with the highest total out-degree was among the contacts identified by the epileptologist as the ictal onset. This contact, that we named "the driver," always laid within the resected brain region. Furthermore, the patient-specific connectivity patterns were consistent over the majority of seizures. Significance: In this study we demonstrated the feasibility of correctly localizing the ictal-onset zone from iEEG recordings by using effective connectivity analysis during the first 20 s of ictal rhythmic iEEG activity.

TSPO expression was dynamically upregulated during epileptogenesis, persisted in the chronic phase and correlated with microglia activation rather than reactive astrocytes. TSPO expression was correlating with spontaneous seizures and its high expression during the latent phase might possibly suggest being an important switching point in disease ontogenesis which could be further investigated by PET imaging.

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18 F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18 F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18 F-FDG SUVR. CSF measures included Aβ 1–42 , Aβ 1–40 , T-tau, P-tau 181 , and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [ p < 0.001] and + 0.37 [ p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = −0.28 [ p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or 18 F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters.

Electroencephalographic source localization (ESL) relies on an accurate model representing the human head for the computation of the forward solution. In this head model, the skull is of utmost importance due to its complex geometry and low conductivity compared to the other tissues inside the head. We investigated the influence of using different skull modeling approaches on ESL. These approaches, consisting in skull conductivity and geometry modeling simplifications, make use of X-ray computed tomography (CT) and magnetic resonance (MR) images to generate seven different head models. A head model with an accurately segmented skull from CT images, including spongy and compact bone compartments as well as some air-filled cavities, was used as the reference model. EEG simulations were performed for a configuration of 32 and 128 electrodes, and for both noiseless and noisy data. The results show that skull geometry simplifications have a larger effect on ESL than those of the conductivity modeling. This suggests that accurate skull modeling is important in order to achieve reliable results for ESL that are useful in a clinical environment. We recommend the following guidelines to be taken into account for skull modeling in the generation of subject-specific head models: (i) If CT images are available, i.e., if the geometry of the skull and its different tissue types can be accurately segmented, the conductivity should be modeled as isotropic heterogeneous. The spongy bone might be segmented as an erosion of the compact bone; (ii) when only MR images are available, the skull base should be represented as accurately as possible and the conductivity can be modeled as isotropic heterogeneous, segmenting the spongy bone directly from the MR image; (iii) a large number of EEG electrodes should be used to obtain high spatial sampling, which reduces the localization errors at realistic noise levels.

Background: Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelatorlinker systems. Here, we report squaric acid (SA) containing bifunctional DATA 5m and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA 5m .SA.FAPi with their non-radioactive derivatives were characterized for in vitro inhibitory efficiency to FAP and PREP, respectively and radiochemical investigated with gallium-68. Further, first proof-ofconcept in vivo animal study followed by ex vivo biodistribution were determined with [ 68 Ga]Ga-DOTA.SA.FAPi. Results: [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DATA 5m .SA.FAPi showed high complexation > 97% radiochemical yields after already 10 min and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and DATA 5m .SA.FAPi and its nat Ga and nat Lu-labeled derivatives were excellent resulting in low nanomolar IC 50 values of 0.7-1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC 50 with 1.7-8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [ 68 Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor (SUV mean of 0.75) and low background signal. Ex vivo biodistribution showed highest uptake in tumor (5.2%ID/g) at 60 min post injection with overall low uptake in healthy tissues.