Higher availability of α4ß2 nicotinic receptors (nAChRs) in dorsal ACC is linked to more efficient interference control.

Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the human brain and play an important role in the neuromodulation of brain networks implicated in attentional processes. Previous work in humans showed that heteromeric α4ß2 nAChRs are abundant in the cingulo-insular network underlying attentional control. It has been proposed that cholinergic neuromodulation by α4ß2 nAChRs is involved in attentional control during demanding tasks, when additional resources are needed to minimize interference from task-irrelevant stimuli and focus on task-relevant stimuli. Here we investigate the link between the availability of α4ß2 nAChRs in the cingulo-insular network and behavioral measures of interference control using two versions of the Stroop paradigm, a task known to recruit cingulo-insular areas. We used a previously published PET dataset acquired in 24 non-smoking male subjects in the context of a larger study which investigated the brain distribution of nAChRs in two clinical groups using 2-[(18)F]F-A-85380 PET. We found that higher availability of α4ß2 nAChRs in the dorsal anterior cingulate cortex (ACC) predicted better interference control independently of group and age. In line with animal models, our results support the view that the availability of α4ß2 nAChRs in the dorsal ACC is linked with more efficient attentional control.

Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy.

PURPOSE: Mutations of cholinergic neuronal nicotinic receptors have been identified in the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), associated with changes on PET images using [18F]-F-85380-A (F-A-85380), an α4ß2 nicotinic receptor ligand. The aim of the present study was to evaluate potential changes in nicotinic receptor availability in other types of epilepsy. METHODS: We included 34 male participants, 12 patients with idiopathic generalized epilepsy (IGE), 10 with non-lesional diurnal focal epilepsy, and 12 age-matched healthy controls. All patients underwent PET/CT using F-A-85380 and [18F]-fluorodeoxyglucose (FDG), 3D T1 MRI and diffusion tensor imaging (DTI). F-A-85380 and FDG images were compared with the control group using a voxel-wise (SPM12) and a volumes of interest (VOI) analysis. RESULTS: In the group of patients with IGE, the voxel-wise and VOI analyses showed a significant increase of F-A-85380 ratio index of binding potential (BPRI, corresponding to the receptor availability) in the anterior cingulate cortex (ACC), without structural changes on MRI. At an individual level, F-A-85380 BPRI increase in the ACC could distinguish IGE patients from controls and from patients with focal epilepsy with good accuracy. CONCLUSIONS: We observed focal changes of density/availability of nicotinic receptors in IGE, namely an increase in the ACC. These data suggest that the modulation of α4ß2 nicotinic receptors plays a role not only in ADNFLE, but also in other genetic epileptic syndromes such as IGE and could serve as a biomarker of epilepsy syndromes with a genetic background.

Isolated prospective confabulation in Wernicke-Korsakoff syndrome: a case for reality filtering.

A 57-year-old man suffered severe amnesia and disorientation, accompanied by content-specific confabulation, due to an alcoholic Wernicke-Korsakoff syndrome. For months, he was deeply concerned about a single obligation that he thought he had to respond to, but which he had already assumed 20 years previously. This monothematic, prospective confabulation was associated with failures of reality filtering as previously documented in behaviorally spontaneous confabulation and disorientation: the patient failed to suppress the interference of currently irrelevant memories and to abandon anticipations that were no longer valid (impaired extinction capacity). Magnetic resonance imaging showed damage to the mamillary bodies and the dorsomedial thalamic nucleus. Positron emission tomography (FDG-PET) showed extended orbitofrontal hypometabolism. We suggest that isolated prospective confabulation shares the core feature (acts and thoughts based on currently irrelevant memory), mechanism (failure of reality filtering), and anatomical basis (orbitofrontal dysfunction) with behaviorally spontaneous confabulations.

Appropriate use criteria for dementia amyloid imaging in Switzerland - mini-review and statement on behalf of the Swiss Society of Nuclear Medicine and the Swiss Memory Clinics.

While FDG-PET imaging of the brain for the differential diagnosis of dementia has been covered by the compulsory health insurance in Switzerland for more than a decade, beta-amyloid-PET just recently has been added to the catalogue of procedures that have been cleared for routine use, provided that a set of appropriate use criteria (AUC) be followed. To provide guidance to dementia care practitioners, the Swiss Society of Nuclear Medicine and the Swiss Memory Clinics jointly report a mini-review on beta-amyloid-PET and discuss the AUC set into effect by the Swiss Federal Office of Public Health, as well as their application and limitations.

[Joint DGN, OGNMB and SGNM S1 guideline for radiosynoviorthesis]. / Gemeinsame Handlungsempfehlung (S1-Leitlinie) von DGN, OGNMB und SGNM ­ Radiosynoviorthese ­ Stand: 9/2019 ­ AWMF-Registernummer: 031-023.

This recommendation is intended to provide a guideline for radiosynoviorthesis (RSO) in the effective local treatment of chronic inflammatory (non-infectious) joint diseases. It was developed in an interdisciplinary manner and describes the general objectives, definitions, clinical background information, indication and contraindications of this radionuclide therapy. The requirements to be met by a treatment center, the results of pretherapeutic examinations as well as recommendations on how the treatment should be carried out. Here, organizational and technical issues have been considered. Furthermore, information on the surveillance and follow-up of the treated patients can be found. In general, treatment and follow-up should be done in in close cooperation of the participating disciplines.

Electrical source imaging for presurgical focus localization in epilepsy patients with normal MRI.

PURPOSE: Patients with magnetic resonance (MR)-negative focal epilepsy (MRN-E) have less favorable surgical outcomes (between 40% and 70%) compared to those in whom an MRI lesion guides the site of surgical intervention (60-90%). Patients with extratemporal MRN-E have the worst outcome (around 50% chance of seizure freedom). We studied whether electroencephalography (EEG) source imaging (ESI) of interictal epileptic activity can contribute to the identification of the epileptic focus in patients with normal MRI. METHODS: We carried out ESI in 10 operated patients with nonlesional MRI and a postsurgical follow-up of at least 1 year. Five of the 10 patients had extratemporal lobe epilepsy. Evaluation comprised surface and intracranial EEG monitoring of ictal and interictal events, structural MRI, [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), ictal and interictal perfusion single photon emission computed tomography (SPECT) scans. Eight of the 10 patients also underwent intracranial monitoring. RESULTS: ESI correctly localized the epileptic focus within the resection margins in 8 of 10 patients, 9 of whom experienced favorable postsurgical outcomes. DISCUSSION: The results highlight the diagnostic value of ESI and encourage broadening its application to patients with MRN-E. If the surface EEG contains fairly localized spikes, ESI contributes to the presurgical decision process.

Nicotinic Acetylcholine Receptor Density in the "Higher-Order" Thalamus Projecting to the Prefrontal Cortex in Humans: a PET Study.

PURPOSE: The parcellation of the thalamus into different nuclei involved in different corticothalamocortical loops reflects its functional diversity. The connections between the mediodorsal nucleus and the prefrontal cortex play a major role in cognition, particularly in the rapid processing of behaviorally relevant information. The thalamus is the brain region with the highest density in α4ß2 nicotinic acetylcholine receptors, the main human nicotinic acetylcholine receptor subtype. The aim of this study was to investigate the possible role of the nicotinic cholinergic system in the thalamo-cortical loops measuring receptor density in different subregions of the thalamus, based on their cortical connectivity. PROCEDURES: We studied α4ß2 nicotinic acetylcholine receptors using positron emission tomography and [18F]Fluoro-A-85380, a radiotracer specific for this receptor subtype, in 36 non-smoking male subjects, including 12 healthy controls and 24 patients with epilepsy. [18F]Fluoro-A-85380 ratio index of binding potential was compared by a repeated measures general linear model, including the thalamic subregions and the brain hemisphere as within-subject factor and clinical groups as between-subject factor. RESULTS: The "prefrontal" thalamus, the subregion including the mediodorsal nucleus, had a significantly higher nicotinic acetylcholine receptor density than all other thalamic subregions. These findings were confirmed when analyzing solely the 12 healthy controls. CONCLUSIONS: This particular neurochemical organization of the thalamus supports a major role of the cholinergic system in the loops between the thalamus and the prefrontal cortex. The highest nicotinic acetylcholine receptor density in the « higher-order thalamus ¼ could partly explain the beneficial effect of acute nicotine on attentional and executive functions and possibly the pathophysiology of some neuropsychiatric disorders.

Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force.

BACKGROUND: The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented. RESULTS: A brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements. CONCLUSIONS: Molecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced.

Target Definition in Salvage Radiotherapy for Recurrent Prostate Cancer: The Role of Advanced Molecular Imaging.

Salvage radiotherapy (SRT) represents the main treatment option for relapsing prostate cancer in patients after radical prostatectomy. Several open questions remain unanswered in terms of target volumes definition and delivered doses for SRT: the effective dose necessary to achieve biochemical control in the SRT setting may be different if the tumor recurrence is micro- or macroscopic. At the same time, irradiation of only the prostatic bed or of the whole pelvis will depend on the localization of the recurrence, local or locoregional. In the "theragnostic imaging" era, molecular imaging using positron emission tomography (PET) constitutes a useful tool for clinicians to define the site of the recurrence, the extent of disease, and individualize salvage treatments. The best option currently available in clinical routine is the combination of radiolabeled choline PET imaging and multiparametric magnetic resonance imaging (MRI), associating the nodal and distant metastases identification based on PET with the local assessment by MRI. A new generation of targeted tracers, namely, prostate-specific membrane antigen, show promising results, with a contrast superior to choline imaging and a higher detection rate even for low prostate-specific antigen levels; validation studies are ongoing. Finally, imaging targeting bone remodeling, using whole-body SPECT-CT, is a relevant complement to molecular/metabolic PET imaging when bone involvement is suspected.

Comparison of voxel-based 3-D MRI analysis and subtraction ictal SPECT coregistered to MRI in focal epilepsy.

While voxel-based 3-D MRI analysis methods as well as assessment of subtracted ictal versus interictal perfusion studies (SISCOM) have proven their potential in the detection of lesions in focal epilepsy, a combined approach has not yet been reported. The present study investigates if individual automated voxel-based 3-D MRI analyses combined with SISCOM studies contribute to an enhanced detection of mesiotemporal epileptogenic foci. Seven consecutive patients with refractory complex partial epilepsy were prospectively evaluated by SISCOM and voxel-based 3-D MRI analysis. The functional perfusion maps and voxel-based statistical maps were coregistered in 3-D space. In five patients with temporal lobe epilepsy (TLE), the area of ictal hyperperfusion and corresponding structural abnormalities detected by 3-D MRI analysis were identified within the same temporal lobe. In two patients, additional structural and functional abnormalities were detected beyond the mesial temporal lobe. Five patients with TLE underwent epileptic surgery with favourable postoperative outcome (Engel class Ia and Ib) after 3-5 years of follow-up, while two patients remained on conservative treatment. In summary, multimodal assessment of structural abnormalities by voxel-based analysis and SISCOM may contribute to advanced observer-independent preoperative assessment of seizure origin.

Qualitative and Quantitative Evaluation of Blob-Based Time-of-Flight PET Image Reconstruction in Hybrid Brain PET/MR Imaging.

PURPOSE: Many neurological diseases affect small structures in the brain and, as such, reliable visual evaluation and accurate quantification are required. Recent technological developments made the clinical use of hybrid positron emission tomography/magnetic resonance (PET/MR) systems possible, providing both functional and anatomical information in a single imaging session. Nevertheless, there is a trade-off between spatial resolution and image quality (contrast and noise), which is dictated mainly by the chosen acquisition and reconstruction protocols. Image reconstruction algorithms using spherical symmetric basis functions (blobs) for image representation have a number of additional parameters that impact both the qualitative and quantitative image characteristics. Hence, a detailed investigation of the blob-based reconstruction characteristics using different parameters is needed to achieve optimal reconstruction results. PROCEDURES: This work evaluated the impact of a range of blob parameters on image quality and quantitative accuracy of brain PET images acquired on the Ingenuity Time-of-Flight (TOF) PET/MR system. Two different phantoms were used to simulate brain imaging applications. Image contrast and noise characteristics were assessed using an image quality phantom. Quantitative performance in a clinical setting was investigated using the Hoffman 3D brain phantom at various count levels. Furthermore, the visual quality of four clinical studies was scored blindly by two experienced physicians to qualitatively evaluate the influence of different reconstruction protocols, hereby providing indications on parameters producing the best image quality. RESULTS: Quantitative evaluation using the image quality phantom showed that larger basis function radii result in lower contrast recovery (∼2%) and lower variance levels (∼15%). The brain phantom and clinical studies confirmed these observations since lower contrast was seen between anatomical structures. High and low count statistics gave comparable values. The qualitative evaluation of the clinical studies, based on the assessment performed by the physicians, showed a preference towards lower image variance levels with a slightly lower contrast, favoring higher radii and four iterations. CONCLUSION: This study systematically evaluated a number of basis function parameters and their quantitative and qualitative effect within PET image reconstruction in the context of brain imaging. A range of blob parameters can minimize error and provided optimal image quality, where the anatomical structures could be recognized but the exact delineation of these structures is simplified in scans with lower image variance levels and thus, higher radii should be preferred. With the optimization of blob parameters, the reconstructed images were found to be qualitatively improved (optimum parameters {d = 2.0375, alpha = 10.4101, radius = 3.9451}) as assessed by the physicians compared to the current clinical protocol. However, this qualitative improvement is task specific, depending on the desired image characteristics to be extracted. Finally, this work could be used as a guide for application-specific optimal parameter selection.

90Yttrium PET/MR-based dosimetry after liver radioembolization (SIRT).

Biodistribution and dosimetric aspects are important issues in the preparation realization of radionuclide therapies and thus play an emerging role in radioembolization of liver malignancies. Biodistribution assessment of liver selective internal radiotherapy (SIRT) has been shown feasible using PET/CT PET/magnetic resonance (MR). Whereas prospective dosimetry using 99mTc macroaggregated albumin SPECT/CT is discussed controversially, retrospective 90Y PET/CT has been shown feasible for dosimetry of SIRT in recent studies. Considering the advantages of PET/MR with regard to lesion detection radiation dose reduction compared to PET/CT, especially when repeated scanning is intended, we investigated the use of PET/MR for dosimetry of liver SIRT.

Localization of the epileptogenic tuber with electric source imaging in patients with tuberous sclerosis.

PURPOSE: Patients with tuberous sclerosis complex (TSC) often suffer from medically refractory epilepsy. Despite the multifocality of the disease, resection of the most epileptogenic tuber can lead to major improvement of seizure control. Therefore, non-invasive imaging methods are needed for detecting epileptogenic sources. We assessed the utility of electric source imaging (ESI) in the presurgical work-up of TSC patients and its combination with Positron Emission Tomography (PET) and ictal/interictal Single Photon Emission Computed Tomography (SISCOM). METHODS: Thirteen patients underwent high density ESI (8/13) and/or low density ESI (13/13). We investigated the concordance between ESI, PET, SISCOM and the resection area in the 11 operated patients (nine seizure-free). RESULTS: High resolution ESI was partially or completely concordant with the resected area in 5/5 seizure free patients. Low resolution ESI was partially or completely concordant in 7/9 seizure free patients. PET and SPECT were concordant (partially or completely) in 8/9 and 6/9 cases, respectively. We found multifocal ESI sources in 2/9 seizure free patients, marked multifocal PET hypometabolism in 3/9 and multifocal SISCOM in 4/9. The region of concordant ESI and PET accurately predicted the dominant epileptogenic source in 6/9 patients. The same was true for concordant ESI and SISCOM in 4/9 patients, whereas the coregistration of only PET and SISCOM was insufficient in 3/9 successfully operated cases. The combination of all three imaging modalities could successfully identify the resection area in all but one patient with a favorable post-operation outcome. CONCLUSION: ESI is an important tool for the pre-surgical evaluation of TSC patients. It complements PET and SPECT results and can improve the management of candidates for surgery when integrated with electro-clinical information.

Concentrations of Gd-BOPTA in cholestatic fatty rat livers: role of transport functions through membrane proteins.

Gd-BOPTA (gadobenate dimeglumine) is a magnetic resonance (MR) contrast agent that, after i.v. administration, distributes within the extracellular space, enters rat hepatocytes through the sinusoidal transporters organic anion transporting peptides (Oatps) and is excreted unchanged into bile through the multidrug resistance-associated protein 2 (Mrp2). It is unclear how the hepatobiliary contrast agent would accumulate in cholestatic fatty livers from obese rats with bile flow impairment. Indeed, the expression of both Oatps and Mrp2 transporters is decreased in cholestatic hepatocytes. To assess this question, we measured on-line the hepatic concentrations of ¹5³Gd-BOPTA with a gamma probe placed over perfused rat livers. During the perfusion of ¹5³Gd-BOPTA, we obtained a similar maximal hepatic concentration in normal and fatty livers despite the decreased expression and function of membrane transporters in fatty livers. By pharmacokinetic modeling and mathematical simulations, we show how changes of transport into and out of hepatocytes modify the concentrations of ¹5³Gd-BOPTA within hepatocytes. Mathematical simulations help to understand how each parameter (entry into hepatocytes, bile excretion, or efflux back to sinusoids) interferes with the hepatic concentrations. The hepatic concentrations of ¹5³Gd-BOPTA within hepatocytes rely on the entry into hepatocytes through the sinusoidal membrane and on two paths of exit, the efflux back to sinusoids and the elimination into bile. Understanding how ¹5³Gd-BOPTA accumulates in hepatocytes is then complex. However, such understanding is important to analyze liver imaging with hepatobiliary contrast agents in cholestatic fatty livers.

Clinical applications of hybrid PET/MRI in neuroimaging.

PURPOSE: We tested the performance and clinical applicability of combined protocols for brain imaging studies acquired on a new whole-body hybrid PET/MR scanner. PATIENTS AND METHODS: Fifteen patients [6 male and 9 female patients; mean (SD) age, 51 (30) y; range, 6-89 y] were scanned on a Philips Ingenuity TF PET/MR. Standard imaging protocols of both modalities were combined, using a "head coil" and contrast-enhanced fully diagnostic MR protocols. Attenuation correction of the PET images was performed using tissue segmentation of the MR image and incorporation of attenuation templates measured for coils and table.The clinical indications evaluated are as follows: patients with cognitive disturbance of suspected neurodegenerative origin, presurgical evaluation of drug-refractory epilepsy, and brain tumor staging. For the first 2 indications, FDG PET imaging was performed, whereas for the last, fluoroethyltyrosine, an amino acid tracer, was used. RESULTS: In all cases (4 patients with neurodegenerative disease, 6 patients with epilepsy, and 5 patients with high-grade tumor), we obtained full diagnostic quality of both modalities and the total duration of the examination remained within a tolerable range (<2 hours). Twelve subjects had pathological findings: 11 of which were confirmed by clinical follow-up as true positive and 1 was confirmed as a false-positive result. For the 3 normal studies, the clinical follow-up confirmed the imaging findings as true-negative. CONCLUSIONS: Acquiring both PET and MR in a single session on a hybrid system minimized patient discomfort while maximizing clinical information and optimizing registration of both modalities. In addition, in comparison to PET/CT, the effective dose (related to CT) was reduced, and this is particularly beneficial in the pediatric population.

Breathing adapted radiotherapy: a 4D gating software for lung cancer.

PURPOSE: Physiological respiratory motion of tumors growing in the lung can be corrected with respiratory gating when treated with radiotherapy (RT). The optimal respiratory phase for beam-on may be assessed with a respiratory phase optimizer (RPO), a 4D image processing software developed with this purpose. METHODS AND MATERIALS: Fourteen patients with lung cancer were included in the study. Every patient underwent a 4D-CT providing ten datasets of ten phases of the respiratory cycle (0-100% of the cycle). We defined two morphological parameters for comparison of 4D-CT images in different respiratory phases: tumor-volume to lung-volume ratio and tumor-to-spinal cord distance. The RPO automatized the calculations (200 per patient) of these parameters for each phase of the respiratory cycle allowing to determine the optimal interval for RT. RESULTS: Lower lobe lung tumors not attached to the diaphragm presented with the largest motion with breathing. Maximum inspiration was considered the optimal phase for treatment in 4 patients (28.6%). In 7 patients (50%), however, the RPO showed a most favorable volumetric and spatial configuration in phases other than maximum inspiration. In 2 cases (14.4%) the RPO showed no benefit from gating. This tool was not conclusive in only one case. CONCLUSIONS: The RPO software presented in this study can help to determine the optimal respiratory phase for gated RT based on a few simple morphological parameters. Easy to apply in daily routine, it may be a useful tool for selecting patients who might benefit from breathing adapted RT.