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Epidemiological studies have identified prior traumatic brain injury (TBI) as a risk factor for developing Alzheimer's disease (AD). Neurofibrillary tangles (NFTs) are common to AD and chronic traumatic encephalopathy following repetitive mild TBI. However, it is unclear if a single TBI is sufficient to cause accumulation of NFTs. We performed a [ 18 F]MK-6240 positron emission tomography (PET) imaging study to assess NFTs in patients who had sustained a single TBI at least 2 years prior to study inclusion. Fourteen TBI patients (49 ± 20 years; 5 M/9 F; 8 moderate-severe, 1 mild-probable, 5 symptomatic-possible TBI) and 40 demographically similar controls (57 ± 19 years; 19 M/21 F) underwent simultaneous [ 18 F]MK-6240 PET and magnetic resonance imaging (MRI) as well as neuropsychological assessment including the Cambridge Neuropsychological Test Automated Battery (CANTAB). A region-based voxelwise partial volume correction was applied, using parcels obtained by FreeSurfer v6.0, and standardized uptake value ratios (SUVR) were calculated relative to the cerebellar gray matter. Group differences were assessed on both a voxel- and a volume-of-interest-based level and correlations of [ 18 F]MK-6240 SUVR with time since injury as well as with clinical outcomes were calculated. Visual assessment of TBI images did not show global or focal increases in tracer uptake in any subject. On a group level, [ 18 F]MK-6240 SUVR was not significantly different in patients versus controls or between subgroups of moderate-severe TBI versus less severe TBI. Within the TBI group, One Touch Stockings problem solving and spatial working memory (executive function), reaction time (attention), and Mini-Mental State Examination (MMSE) (global cognition) were associated with [ 18 F]MK-6240 SUVR. We found no group-based increase of [ 18 F]MK-6240 brain uptake in patients scanned at least 2 years after a single TBI compared with healthy volunteers, which suggests that no NFTs are building up in the first years after a single TBI. Nonetheless, correlations with cognitive outcomes were found that warrant further investigation.

Background: Somatostatin receptor (SSTR) positron emission tomography (PET) is a cornerstone of neuroendocrine tumor (NET) management. Hybrid PET/magnetic resonance imaging (MRI) is now available for NET-imaging, next to PET/computed tomography (CT)., Objectives: To determine whether CT or MRI is the best hybrid partner for [ 68 Ga]Ga-DOTATATE PET., Design: Monocentric, prospective study., Methods: Patients received a same-day [ 68 Ga]Ga-DOTATATE PET/CT and subsequent PET/MRI, for suspicion of NET, (re)staging or peptide receptor radionuclide therapy-selection. The union (PET union ) of malignant lesions detected on PET CT and PET MRI was the reference standard. Concordance of detection of malignant lesions in an organ was measured between PET union and CT and PET union and MRI. Seven bins were used to categorize the number of malignant lesions, containing following ordinal variables: 0, 1, 2-5, 6-10, 11-20, >20 countable and diffuse/uncountable. The difference in number of malignant lesions was obtained as the difference in bin level ('Δbin') between PET union and CT and PET union and MRI with a Δbin closer to zero implying a higher concordance rate., Results: Twenty-nine patients were included. Primary tumors included 17 gastroenteropancreatic-NETs, 1 colon neuroendocrine carcinoma, 7 lung-NETs and 2 meningiomas. Patient level concordance with PET union was 96% for MRI and 67% for CT ( p = 0.039). Organ level concordance with PET union was 74% for MRI and 40% for CT ( p < 0.0001). In bone, there was a higher concordance rate for MRI compared to CT, 92% and 33%, respectively ( p = 0.016). Overall, a mean Δbin of 0.5 ± 1.1 for PET union /MRI and 1.4 ± 1.2 for PET union /CT ( p < 0.0001) was noted. In liver, a mean Δbin of 0.0 ± 1.1 for PET union /MRI and 1.7 ± 1.2 for PET union /CT was observed ( p = 0.0078). In bone, a mean Δbin closer to zero was observed for PET union /MRI compared to PET union /CT, 0.6 ± 1.4 and 2.0 ± 1.5, respectively ( p = 0.0098)., Conclusions: Compared to SSTR PET/CT, SSTR PET/MRI had a higher patient and organ level concordance for malignant tumoral involvement and number of malignant lesions, with a clear added value in bone and liver specifically., Competing Interests: No conflicts of interest relevant to this work exist. CMD has been a consultant for Terumo, Ipsen, Sirtex, Bayer and PSI CRO. KVL has received speaker fees from GE Healthcare., (© The Author(s), 2023.)

With the increasing success of mapping brain networks and availability of multiple MR- and PET-based connectivity measures, the need for novel methodologies to unravel the structure and function of the brain at multiple spatial and temporal scales is emerging. Therefore, in this work, we used hybrid PET-MR data of healthy volunteers ( n = 67) to identify multiplex core nodes in the human brain. First, monoplex networks of structural, functional and metabolic connectivity were constructed, and consequently combined into a multiplex SC-FC-MC network by linking the same nodes categorically across layers. Taking into account the multiplex nature using a tensorial approach, we identified a set of core nodes in this multiplex network based on a combination of eigentensor centrality and overlapping degree. We introduced a coreness coefficient, which mitigates the effect of modeling parameters to obtain robust results. The proposed methodology was applied onto young and elderly healthy volunteers, where differences observed in the monoplex networks persisted in the multiplex as well. The multiplex core showed a decreased contribution to the default mode and salience network, while an increased contribution to the dorsal attention and somatosensory network was observed in the elderly population. Moreover, a clear distinction in eigentensor centrality was found between young and elderly healthy volunteers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Devrome, Van Laere and Koole.)

Purpose: The aim of this study was to develop a convolutional neural network (CNN) for the automatic detection and segmentation of gliomas using [ 18 F]fluoroethyl-L-tyrosine ([ 18 F]FET) PET., Methods: Ninety-three patients (84 in-house/7 external) who underwent a 20-40-min static [ 18 F]FET PET scan were retrospectively included. Lesions and background regions were defined by two nuclear medicine physicians using the MIM software, such that delineations by one expert reader served as ground truth for training and testing the CNN model, while delineations by the second expert reader were used to evaluate inter-reader agreement. A multi-label CNN was developed to segment the lesion and background region while a single-label CNN was implemented for a lesion-only segmentation. Lesion detectability was evaluated by classifying [ 18 F]FET PET scans as negative when no tumor was segmented and vice versa, while segmentation performance was assessed using the dice similarity coefficient (DSC) and segmented tumor volume. The quantitative accuracy was evaluated using the maximal and mean tumor to mean background uptake ratio (TBR max /TBR mean ). CNN models were trained and tested by a threefold cross-validation (CV) using the in-house data, while the external data was used for an independent evaluation to assess the generalizability of the two CNN models., Results: Based on the threefold CV, the multi-label CNN model achieved 88.9% sensitivity and 96.5% precision for discriminating between positive and negative [ 18 F]FET PET scans compared to a 35.3% sensitivity and 83.1% precision obtained with the single-label CNN model. In addition, the multi-label CNN allowed an accurate estimation of the maximal/mean lesion and mean background uptake, resulting in an accurate TBR max /TBR mean estimation compared to a semi-automatic approach. In terms of lesion segmentation, the multi-label CNN model (DSC = 74.6 ± 23.1%) demonstrated equal performance as the single-label CNN model (DSC = 73.7 ± 23.2%) with tumor volumes estimated by the single-label and multi-label model (22.9 ± 23.6 ml and 23.1 ± 24.3 ml, respectively) closely approximating the tumor volumes estimated by the expert reader (24.1 ± 24.4 ml). DSCs of both CNN models were in line with the DSCs by the second expert reader compared with the lesion segmentations by the first expert reader, while detection and segmentation performance of both CNN models as determined with the in-house data were confirmed by the independent evaluation using external data., Conclusion: The proposed multi-label CNN model detected positive [ 18 F]FET PET scans with high sensitivity and precision. Once detected, an accurate tumor segmentation and estimation of background activity was achieved resulting in an automatic and accurate TBR max /TBR mean estimation, such that user interaction and potential inter-reader variability can be minimized., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Fluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [ 18 F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [ 18 F]AlF-OC PET/CT outperforms [ 68 Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [ 18 F]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [ 18 F]AlF-OC ("incremental lesions")., Methods: Ten patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [ 68 Ga]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [ 18 F]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient., Results: In total, 195 unique lesions were detected: 167 with [ 68 Ga]Ga-DOTATATE and 193 with [ 18 F]AlF-OC. The DR for [ 18 F]AlF-OC was 99.1% versus 91.4% for [ 68 Ga]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [ 18 F]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [ 18 F]AlF-OC, of which 91% were confirmed by MRI and considered true positives., Conclusion: The DR of [ 18 F]AlF-OC was numerically higher and non-inferior to the DR of [ 68 Ga]Ga-DOTATATE. [ 18 F]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [ 18 F]AlF-OC as a new alternative for SSTR PET in clinical practice. Trial registration ClinicalTrials.gov: NCT04552847. Registered 17 September 2020, https://beta., Clinicaltrials: gov/study/NCT04552847., (© 2023. The Author(s).)

Objective: The purpose of this study was to explore longitudinal changes in synaptic density after ischemic stroke in vivo with synaptic vesicle protein 2A (SV2A) positron emission tomography (PET)., Methods: We recruited patients with an ischemic stroke to undergo 11 C-UCB-J PET/MR within the first month and 6 months after the stroke. We investigated longitudinal changes of partial volume corrected 11 C-UCB-J standardized uptake value ratio (SUVR; relative to centrum semiovale) within the ischemic lesion, peri-ischemic area and unaffected ipsilesional and contralesional grey matter. We also explored crossed cerebellar diaschisis at 6 months. Additionally, we defined brain regions potentially influencing upper limb motor recovery after stroke and studied 11 C-UCB-J SUVR evolution in comparison to baseline., Results: In 13 patients (age = 67 ± 15 years) we observed decreasing 11 C-UCB-J SUVR in the ischemic lesion (ΔSUVR = -1.0, p = 0.001) and peri-ischemic area (ΔSUVR = -0.31, p = 0.02) at 6 months after stroke compared to baseline. Crossed cerebellar diaschisis as measured with 11 C-UCB-J SUVR was present in 11 of 13 (85%) patients at 6 months. The 11 C-UCB-J SUVR did not augment in ipsilesional or contralesional brain regions associated with motor recovery. On the contrary, there was an overall trend of declining 11 C-UCB-J SUVR in these brain regions, reaching statistical significance only in the nonlesioned part of the ipsilesional supplementary motor area (ΔSUVR = -0.83, p = 0.046)., Interpretation: At 6 months after stroke, synaptic density further declined in the ischemic lesion and peri-ischemic area compared to baseline. Brain regions previously demonstrated to be associated with motor recovery after stroke did not show increases in synaptic density. ANN NEUROL 2023;93:911-921., (© 2022 American Neurological Association.)

18 F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68 Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, 18 F-AlF-NOTA-octreotide ( 18 F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68 Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18 F-AlF-OC compared with 68 Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68 Ga-DOTATATE ( n = 56) or 68 Ga-DOTANOC ( n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18 F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18 F-AlF-OC and 68 Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUV max and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68 Ga-DOTATATE/NOC and 4,278 with 18 F-AlF-OC. The mean DR with 18 F-AlF-OC was significantly higher than with 68 Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10 -5 ). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68 Ga-DOTATATE and 68 Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUV max were observed ( P = 0.067), but mean tumor-to-background ratio was significantly higher with 18 F-AlF-OC than with 68 Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18 F-AlF-OC is noninferior and even superior to 68 Ga-DOTATATE/NOC PET in NET patients. This validates 18 F-AlF-OC as an option for clinical practice somatostatin receptor PET., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. In 10% of patients, the disorder runs in the family. Our aim was to study the impact of ALS-causing gene mutations on cerebral glucose metabolism. Between October 2010 and October 2022, 538 patients underwent genetic testing for mutations with strong evidence of causality for ALS and 18 F-2-fluoro-2-deoxy-D-glucose-PET (FDG PET), at University Hospitals Leuven. We identified 48 C9orf72 -ALS and 22 SOD1 -ALS patients. After propensity score matching, two cohorts of 48 and 21 matched sporadic ALS patients, as well as 20 healthy controls were included. FDG PET images were assessed using a voxel-based and volume-of-interest approach. We observed widespread frontotemporal involvement in all ALS groups, in comparison to healthy controls. The degree of relative glucose metabolism in SOD1 -ALS in motor and extra-motor regions did not differ significantly from matched sporadic ALS patients. In C9orf72 -ALS, we found more pronounced hypometabolism in the peri-rolandic region and thalamus, and hypermetabolism in the medulla extending to the pons, in comparison to matched sporadic ALS patients. Our study revealed C9orf72 -dependent differences in glucose metabolism in the peri-rolandic region, thalamus, and brainstem (i.e., medulla, extending to the pons) in relation to matched sporadic ALS patients.

Purpose: Despite its limitations, [ 123 I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [ 18 F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [ 18 F]MFBG and perform a head-to-head comparison with [ 123 I]MIBG in neural crest tumour patients., Methods: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [ 123 I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [ 18 F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [ 18 F]MFBG. Normal organ uptake (SUV mean ) and lesion uptake (SUV max ; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (V T ) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [ 18 F]MFBG and [ 123 I]MIBG., Results: [ 18 F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [ 123 I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median V T was 37.4 mL/cm 3 (range: 18.0-144.8) with an excellent correlation between V T and SUV mean at all 3 time points (R 2 : 0.92-0.94). Mean lesion SUV max and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [ 123 I]MIBG were also observed with [ 18 F]MFBG. The mean DR with [ 123 I]MIBG was significantly lower than with [ 18 F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043)., Conclusion: [ 18 F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [ 123 I]MIBG scintigraphy., Trial Registration: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We present guidelines by the European Association of Nuclear Medicine (EANM) for routine quality control (QC) of PET-CT and PET-MR systems. These guidelines are partially based on the current EANM guidelines for routine quality control of Nuclear Medicine instrumentation but focus more on the inherent multimodal aspect of the current, state-of-the-art PET-CT and PET-MR scanners. We briefly discuss the regulatory context put forward by the International Electrotechnical Commission (IEC) and European Commission (EC) and consider relevant guidelines and recommendations by other societies and professional organizations. As such, a comprehensive overview of recommended quality control procedures is provided to ensure the optimal operational status of a PET system, integrated with either a CT or MR system. In doing so, we also discuss the rationale of the different tests, advice on the frequency of each test and present the relevant MR and CT tests for an integrated system. In addition, we recommend a scheme of preventive actions to avoid QC tests from drifting out of the predefined range of acceptable performance values such that an optimal performance of the PET system is maintained for routine clinical use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier GmbH.)

Objectives: To develop a visual ensemble selection of deep convolutional neural networks (CNN) for 3D segmentation of breast tumors using T1-weighted dynamic contrast-enhanced (T1-DCE) MRI., Methods: Multi-center 3D T1-DCE MRI (n = 141) were acquired for a cohort of patients diagnosed with locally advanced or aggressive breast cancer. Tumor lesions of 111 scans were equally divided between two radiologists and segmented for training. The additional 30 scans were segmented independently by both radiologists for testing. Three 3D U-Net models were trained using either post-contrast images or a combination of post-contrast and subtraction images fused at either the image or the feature level. Segmentation accuracy was evaluated quantitatively using the Dice similarity coefficient (DSC) and the Hausdorff distance (HD95) and scored qualitatively by a radiologist as excellent, useful, helpful, or unacceptable. Based on this score, a visual ensemble approach selecting the best segmentation among these three models was proposed., Results: The mean and standard deviation of DSC and HD95 between the two radiologists were equal to 77.8 ± 10.0% and 5.2 ± 5.9 mm. Using the visual ensemble selection, a DSC and HD95 equal to 78.1 ± 16.2% and 14.1 ± 40.8 mm was reached. The qualitative assessment was excellent (resp. excellent or useful) in 50% (resp. 77%)., Conclusion: Using subtraction images in addition to post-contrast images provided complementary information for 3D segmentation of breast lesions by CNN. A visual ensemble selection allowing the radiologist to select the most optimal segmentation obtained by the three 3D U-Net models achieved comparable results to inter-radiologist agreement, yielding 77% segmented volumes considered excellent or useful., Key Points: • Deep convolutional neural networks were developed using T1-weighted post-contrast and subtraction MRI to perform automated 3D segmentation of breast tumors. • A visual ensemble selection allowing the radiologist to choose the best segmentation among the three 3D U-Net models outperformed each of the three models. • The visual ensemble selection provided clinically useful segmentations in 77% of cases, potentially allowing for a valuable reduction of the manual 3D segmentation workload for the radiologist and greatly facilitating quantitative studies on non-invasive biomarker in breast MRI., (© 2022. The Author(s).)

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [ 11 C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195., Competing Interests: JS, JK, MD, SR, AC, and TM, were employees of or paid consultants to Syndesi Therapeutics SA when the study was conducted and the manuscript prepared. DG, and KD’O were empoyed by the company Aepodia SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Botermans, Koole, Van Laere, Savidge, Kemp, Sunaert, Duffy, Ramael, Cesura, D’Ostilio, Gossen, Madsen, Lodeweyckx and de Hoon.)

Background and Objectives: The risk of developing Alzheimer disease is increased after stroke, and this association may not solely be driven by traditional vascular risk factors. Neuronal death leads to the release of tau proteins, which can become dephosphorylated, rephosphorylated, or hyperphosphorylated in the setting of ischemia, possibly leading to formation of neurofibrillary tangles (NFT). Therefore, a potential synergistic effect between development of tauopathy and cerebrovascular lesion burden may contribute to cognitive decline after stroke. We explored the spatial and temporal distribution of NFT after ischemic stroke in vivo by using 18 F-MK-6240 PET., Methods: We included patients with a first ischemic stroke to undergo longitudinal 18 F-MK-6240 PET/MR within 2-4 weeks and 6 months after stroke. For cross-sectional analyses, we also included age-matched healthy controls. We delineated 5 volumes of interest based on T2 FLAIR and T1 MR data: the ischemic lesion, 3 consecutive peri-ischemic areas, and the remaining ipsilesional hemisphere. We performed region-based voxel-wise partial volume correction on the PET data and calculated standardized uptake value ratios (SUVRs) with the cerebellum as the reference region., Results: We did not quantify PET scans of patients within the first month after stroke (n = 17; median age 73 years [interquartile range {IQR}: 62-82 years]) because the signal intensity was influenced by blood-brain barrier breakdown hampering a reliable data analysis. At 6 months after the event (n = 13; median age 71 years [IQR: 60-79 years]), 18 F-MK-6240 SUVR was increased in the ischemic lesion compared with 20 age-matched healthy controls (median age 71.5 years [IQR: 66-76 years]; ratio lesion/controls = 1.62 ± 0.54; 1-sample t test: p = 0.0015) and gradually decreased in the surrounding tissue (1-way within-subject analysis of variance [F{1.2, 14.8} = 18.0, p = 0.00043])., Discussion: These findings suggest that NFT may form after ischemic stroke and spread in the peri-ischemic brain parenchyma. Further follow-up is required to gain more insight into the spatial and temporal dynamics of this tauopathy after ischemic stroke., (© 2022 American Academy of Neurology.)

Purpose: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [ 11 C]CHDI-00485180-R ([ 11 C]CHDI-180R) and [ 11 C]CHDI-00485626 ([ 11 C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models., Methods: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [ 11 C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [ 11 C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1., Results: There were no clinically relevant adverse events. The mean effective dose (ED) for [ 11 C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [ 11 C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [ 11 C]CHDI-180R, but for [ 11 C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite., Conclusion: [ 11 C]CHDI-180R and [ 11 C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11 C-ligands. While [ 11 C]CHDI-180R has promising kinetic properties in the brain, [ 11 C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma., Trial Registration: EudraCT number 2020-002129-27., Clinicaltrials: gov NCT05224115 (retrospectively registered)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Neurofibrillary tangles (NFTs) in Alzheimer's disease can be accurately quantified in vivo using [ 18 F]MK-6240 PET. Short-term [ 18 F]MK-6240 test-retest (TRT) is about 6%, but also long-term stability of cerebral uptake is of importance for longitudinal studies. Furthermore, although there is very little cerebral off-target binding, [ 18 F]MK-6240 shows variable extracerebral uptake (ECU) assumed to represent off-target binding to leptomeningeal melanocytes. Here, we examined 6-month TRT of [ 18 F]MK-6240 in healthy controls (HC) and investigated ECU in HC and patients with amnestic mild cognitive impairment (aMCI) with up to 2 years of follow-up. We also explored demographic factors that may be associated to ECU, including age, sex, education, smoking, and disease status., Methods: A total cohort of 40 HC (57 ± 19 years, 21F/19 M) and 24 aMCI (72 ± 8 years, 14F/10 M) underwent baseline [ 18 F]MK-6240 PET-MR (GE Signa), 90-120 min post injection. [ 18 F]MK-6240 was quantified by standardized uptake value ratios (SUVR) in predefined volumes-of-interest relative to the cerebellar cortex. Ten HC (56 ± 12 years, 8F/2 M) underwent a 6-month follow-up [ 18 F]MK-6240 to assess TRT. Also, 10 aMCI (72 ± 6 years, 5F/5 M) underwent a 2-year follow-up [ 18 F]MK-6240 PET-MR. Longitudinal changes in ECU were assessed in both cohorts. ECU was quantified as the mean SUVR of the skull parcel (FreeSurfer 6.0) that includes the meninges., Results: The mean gray matter [ 18 F]MK-6240 SUVR TRT and absolute TRT in HC were 1.6 ± 3.4% and 2.4 ± 2.8%, respectively. We found no significant 6-month or 2-year differences in ECU in HC (4.4 ± 20%) and aMCI (7.9 ± 19%), respectively. In the total cohort, ECU was significantly correlated to age (r s  =  - 0.48; p < 0.0001), and a multivariate analysis also showed sex differences (higher ECU in women)., Conclusion: [ 18 F]MK-6240 shows excellent 6-month TRT, which confirms its suitability for quantification of longitudinal NFT changes. The ECU of [ 18 F]MK-6240 is variable between subjects, influenced by age and sex, but remains stable within subjects over a 2-year time period., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity., Methods: We used the 18-kDa translocator protein (TSPO) tracer (R)-[ 11 C]PK11195 and [ 11 C]PIB PET images acquired in a hybrid PET/MR 3 T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[ 11 C]PK11195 distribution volume (V T ) was determined for each subject using a metabolite-corrected arterial plasma input function while [ 11 C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT)., Results: In the VOI-based analysis, [ 11 C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[ 11 C]PK11195 V T were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[ 11 C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [ 11 C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[ 11 C]PK11195 V T and lower [ 11 C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T 2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [ 11 C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[ 11 C]PK11195 V T (P = 0.013)., Conclusions: Widespread innate immune cells profile and marked loss of myelin in T 2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Quantification of actinium-225 through gamma counter measurements, when there is no secular equilibrium between actinium-225 and its gamma emitting daughters bismuth-213 and/or francium-221, can provide valuable information regarding the possible relocation of recoiled daughters such that related radiotoxicity effects can be evaluated. This study proposes a multiple time-point protocol using the bismuth-213 photopeak with measurements before secular equilibrium between actinium-225 and bismuth-213, and a single time-point protocol using both the francium-221 and bismuth-213 photopeak while assuming secular equilibrium between actinium-225 and francium-221 but not between bismuth-213 and actinium-225., Results: Good agreement (i.e. 3% accuracy) was obtained when relying on a multiple time-points measurement of bismuth-213 to quantify both actinium-225 and excess of bismuth-213. Following scatter correction, actinium-225 can be accurately quantified using the francium-221 in a single time-point measurement within 3% of accuracy. The analysis performed on the stability data of [ 225 Ac]Ac-DEPA and [ 225 Ac]Ac-DOTA complexes, before secular equilibrium between bismuth-213 and actinium-225 was formed, revealed considerable amounts of unbound bismuth-213 (i.e. more than 90%) after 24 h of the radiolabeling most likely due to the recoiled daughter effect., Conclusion: Both protocols were able to accurately estimate 225 Ac-activities provided the francium-221 energy window was corrected for the down scatter of the higher-energy gamma-emissions by bismuth-213. This could prove beneficial to study the recoiled daughter effect and redistribution of free bismuth-213 by monitoring the accumulation or clearance of bismuth-213 in different tissues during biodistribution studies or in patient samples during clinical studies. On the other hand, the single gamma counter measurement protocol, although required a 30 min waiting time, is more time and cost efficient and therefore more appropriate for standardized quality control procedures of 225 Ac-labeled radiopharmaceuticals., (© 2022. The Author(s).)

Purpose: To investigate the short-term cerebral metabolic effects of intravenous chemotherapy and their association with long-term fatigue/cognitive complaints., Experimental Design: Using [ 18 F]-FDG-PET/CT whole-body scans, we retrospectively quantified relative cerebral glucose metabolism before and after neoadjuvant chemotherapy in a cohort of patients treated for non-metastatic breast cancer (2009-2019). Self-report of cognitive complaints and fatigue were prospectively assessed 7 ± 3 years after therapy. Metabolic changes were estimated with i) robust mixed-effects modelling in regions-of-interest (frontal, parietal, temporal, occipital, and insular cortex) and ii) general-linear modelling of whole-brain voxel-wise outcomes. iii) The association between metabolic changes and self-reported outcomes was evaluated using linear regression-analysis., Results: Of the 667 screened patients, 263 underwent PET/CT before and after chemotherapy and 183 (48 ± 9 years) met the inclusion criteria. After chemotherapy, decreased frontal and increased parietal and insular metabolism were observed (|ß|>0.273, p FDR <0.008). Separately, additional increased occipital metabolism after epiribucin+ cyclophosphamide (EC) and temporal metabolism after EC+ fluorouracil chemotherapy were observed (ß>0.244, p FDR ≤0.048). Voxel-based analysis ( p cluster-FWE <0.001) showed decreased metabolism in the paracingulate gyrus (-3.2 ± 3.9%) and putamen (3.1 ± 4.1%) and increased metabolism in the lateral cortex (L=2.9 ± 3.1%) and pericentral gyri (3.0 ± 4.4%). Except for the central sulcus, the same regions showed changes in EC, but not in FEC patients. Of the 97 self-reported responders, 23% and 27% experienced extreme fatigue and long-term cognitive complaints, respectively, which were not associated with metabolic changes., Conclusion: Both hyper- and hypometabolism were observed after chemotherapy for breast cancer. Combined with earlier findings, this study could support inflammatory mechanisms resulting in relative hypermetabolism, mainly in the parietal/occipital cortices. As early metabolic changes did not precede long-term complaints, further research is necessary to identify vulnerable patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schroyen, Schramm, Van Weehaeghe, Leenaerts, Vande Casteele, Blommaert, Koole, Smeets, Van Laere, Sunaert and Deprez.)

Next to amyloid and tau, synaptic loss is a key pathological hallmark in Alzheimer's disease, closely related to cognitive dysfunction and neurodegeneration. Tau is thought to cause synaptic loss, but this has not been experimentally verified in vivo. In a 2-year follow-up study, dual tracer PET-MR was performed in 12 amnestic MCI patients using 18 F-MK-6240 for tau and 11 C-UCB-J for SV2A as a proxy for synaptic density. Tau already accumulated in the neocortex at baseline with progression in Braak V/VI at follow-up. While synaptic loss was limited to limbic regions at baseline, it followed the specific tau pattern to stage IV/V regions two years later, indicating that tau spread might drive synaptic vulnerability. Moreover, synaptic density changes correlated to changes in cognitive function. This study shows for the first time in vivo that synaptic loss regionally follows tau accumulation after two years, providing a disease-modifying window of opportunity for (combined) tau-targeting therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Gallium-68 ( 68 Ga) is characterized by relatively high positron energy compared to Fluorine-18 ( 18 F), causing substantial image quality degradation. Furthermore, the presence of statistical noise can further degrade image quality. The aim of this literature review is to identify the recently developed positron range correction techniques for 68 Ga, as well as noise reduction methods to enhance the image quality of low count 68 Ga PET imaging. The search engines PubMed and Scopus were employed, and we limited our research to published results from January 2010 until 1 August 2022. Positron range correction was achieved by using either deblurring or deep learning approaches. The proposed techniques improved the image quality and, in some cases, achieved an image quality comparable to 18 F PET. However, none of these techniques was validated in clinical studies. PET denoising for 68 Ga-labeled radiotracers was reported using either reconstruction-based techniques or deep learning approaches. It was demonstrated that both approaches can substantially enhance the image quality by reducing the noise levels of low count 68 Ga PET imaging. The combination of 68 Ga-specific positron range correction techniques and image denoising approaches may enable the application of low-count, high-quality 68 Ga PET imaging in a clinical setting.

Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.

Background: The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products., Main Body: To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as "non-clinical" or "preclinical" are mandatory. This document is an outcome of a Technical Meeting of the International Atomic Energy Agency. It summarises the considerations necessary for non-clinical studies to accommodate the regulatory requirements for clinical translation of radiopharmaceuticals. These considerations include non-clinical pharmacology, radiation exposure and effects, toxicological studies, pharmacokinetic modelling, and imaging studies. Additionally, standardisation of different specific clinical applications is discussed., Conclusion: This document is intended as a guide for radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation process in a safe and effective way., (© 2022. The Author(s).)

Convolutional neural networks (CNNs) for brain tumor segmentation are generally developed using complete sets of magnetic resonance imaging (MRI) sequences for both training and inference. As such, these algorithms are not trained for realistic, clinical scenarios where parts of the MRI sequences which were used for training, are missing during inference. To increase clinical applicability, we proposed a cross-modal distillation approach to leverage the availability of multi-sequence MRI data for training and generate an enriched CNN model which uses only single-sequence MRI data for inference but outperforms a single-sequence CNN model. We assessed the performance of the proposed method for whole tumor and tumor core segmentation with multi-sequence MRI data available for training but only T 1 -weighted ([Formula: see text]) sequence data available for inference, using BraTS 2018, and in-house datasets. Results showed that cross-modal distillation significantly improved the Dice score for both whole tumor and tumor core segmentation when only [Formula: see text] sequence data were available for inference. For the evaluation using the in-house dataset, cross-modal distillation achieved an average Dice score of 79.04% and 69.39% for whole tumor and tumor core segmentation, respectively, while a single-sequence U-Net model using [Formula: see text] sequence data for both training and inference achieved an average Dice score of 73.60% and 62.62%, respectively. These findings confirmed cross-modal distillation as an effective method to increase the potential of single-sequence CNN models such that segmentation performance is less compromised by missing MRI sequences or having only one MRI sequence available for segmentation.

[ 18 F]MK-6240 is a second-generation tau PET-tracer to quantify neurofibrillary tangles in-vivo. However, individually variable levels of meningeal uptake induce spill-in-effects into the cortex, complicating [ 18 F]MK-6240 PET quantification. Group SUVR differences between age-matched HC subgroups with varying extracerebral uptake (EC-low/mixed/high), and between aMCI and each HC subgroup were assessed without and with partial volume correction (PVC). Both Müller-Gartner (MG-)PVC and region-based voxelwise (RBV-)PVC, with the latter also correcting for extracerebral spill-in-effects, were implemented. Between HC groups, where no differences are to be expected, HC EC-high showed spill-in differences compared to HC EC-low when no PVC was applied while for MG-PVC, differences were reduced and, for RBV-PVC, no statistically significant differences were observed. Between aMCI and HC, cortical SUVR differences were statistically significant, both without and with PVC, but modulated by the varying meningeal uptake in HC subgroups when no PVC was applied. After applying PVC, correlations to clinical parameters improved and effect sizes between HC and aMCI increased, independent of the HC-subgroup. Therefore, appropriate PVC with correction for extracerebral spill-in-effects is recommended to minimize the impact of varying meningeal uptake on cortical differences between HC and aMCI.

The established role of dopamine (DA) in the mediation of reward and positive reinforcement, reward processing is strongly influenced by the type 1 cannabinoid receptors (CB 1 Rs). Although considerable preclinical evidence has demonstrated several functional CB 1 R-DA interactions, the relation between human CB 1 R availability, DA release capacity and drug-reinforcing effects has been never investigated so far. Here, we perform a multitracer [ 18 F]MK-9470 and [ 18 F]fallypride positron emission tomography (PET) study in 10 healthy male subjects using a placebo-controlled and single-blinded amphetamine (AMPH) (30 mg) administration paradigm to (1) investigate possible functional interactions between CB 1 R expression levels and DA release capacity in a normo-DAergic state, relating in vivo AMPH-induced DA release to CB 1 R availability, and (2) to test the hypothesis that the influence of striatal DAergic signalling on the positive reinforcing effects of AMPH may be regulated by prefrontal CB 1 R levels. Compared with placebo, AMPH significantly reduced [ 18 F]fallypride binding potential (hence increase DA release; ΔBP ND ranging from -6.1% to -9.6%) in both striatal (p < 0.005, corrected for multiple comparisons) and limbic extrastriatal regions (p ≤ 0.04, uncorrected). Subjects who reported a greater dopaminergic response in the putamen also showed higher CB 1 R availability in the medial and dorsolateral prefrontal cortex (r = 0.72; p = 0.02), which are regions involved in salience attribution, motivation and decision making. On the other hand, the magnitude of DA release was greater in those subjects with lower CB 1 R availability in the anterior cingulate cortex (ACC) (r = -0.66; p = 0.03). Also, the correlation between the DA release in the nucleus accumbens with the subjective AMPH effect liking was mediated through the CB 1 R availability in the ACC (c' = -0.76; p = 0.01). Our small preliminary study reports for the first time that the human prefrontal CB 1 R availability is a determinant of DA release within both the ventral and dorsal reward corticostriatal circuit, contributing to a number of studies supporting the existence of an interaction between CB 1 R and DA receptors at the molecular and behavioural level. These preliminary findings warrant further investigation in pathological conditions characterized by hypo/hyper excitability to DA release such as addiction and schizophrenia., (© 2022 Society for the Study of Addiction.)

Introduction: Indigenous peoples in Canada face numerous health needs and challenges and often have poor health status due to inequitable access to care. Providing culturally appropriate support for health conditions, particularly chronic conditions that require self-management, can assist in averting complications and morbidity. Mobile health is a useful medium for delivering health education across different populations. However, meaningful user involvement is necessary because mobile health interventions suitable for one population may not be appropriate for another. Indigenous people's views will inform the use of mobile health interventions in Indigenous communities., Objective: The study explored the perception of Indigenous women on using mobile health as a tool for receiving health information., Methods: This was a qualitative study, and participants comprised of 22 Indigenous women (First Nations and Métis) with or at risk of diabetes, aged 18-69 years in Saskatoon, Canada. After 12 weeks of disseminating diabetic eye care information via text messaging, data were collected via sharing circle discussions and analyzed using thematic analysis., Results: Participants indicated that the nature of messages such as the use of Indigenous languages, the message content, frequency of messages, group activities, and delivery formats such as voice messages, mobile applications, Internet, two-way messaging, and text messages were essential considerations in using mobile health as a tool for receiving health information., Conclusion: Different factors need to be considered in using mobile health as a tool for health education among Indigenous peoples. These factors could be applicable in implementing mobile health solutions in other populations for the management of health conditions., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Contrary to group-based brain connectivity analyses, the aim of this study was to construct individual brain metabolic networks to determine age-related effects on brain metabolic connectivity. Static 40-60 min [ 18 F]FDG positron emission tomography (PET) images of 67 healthy subjects between 20 and 82 years were acquired with an integrated PET-MR system. Network nodes were defined by brain parcellation using the Schaefer atlas, while connectivity strength between two nodes was determined by comparing the distribution of PET uptake values within each node using a Kullback-Leibler divergence similarity estimation (KLSE). After constructing individual brain networks, a linear and quadratic regression analysis of metabolic connectivity strengths within- and between-networks was performed to model age-dependency. In addition, the age dependency of metrics for network integration (characteristic path length), segregation (clustering coefficient and local efficiency), and centrality (number of hubs) was assessed within the whole brain and within predefined functional subnetworks. Overall, a decrease of metabolic connectivity strength with healthy aging was found within the whole-brain network and several subnetworks except within the somatomotor, limbic, and visual network. The same decrease of metabolic connectivity was found between several networks across the whole-brain network and the functional subnetworks. In terms of network topology, a less integrated and less segregated network was observed with aging, while the distribution and the number of hubs did not change with aging, suggesting that brain metabolic networks are not reorganized during the adult lifespan. In conclusion, using an individual brain metabolic network approach, a decrease in metabolic connectivity strength was observed with healthy aging, both within the whole brain and within several predefined networks. These findings can be used in a diagnostic setting to differentiate between age-related changes in brain metabolic connectivity strength and changes caused by early development of neurodegeneration., Competing Interests: NM is Ph.D. mandate holder of the Fund for Scientific Research, Flanders, Belgium (FWO, 1S57420N). KVL has conducted this study as senior clinical research fellow for the Research Foundation Flanders (FWO). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mertens, Sunaert, Van Laere and Koole.)

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11 C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11 C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11 C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11 C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratio lesion/controls  = 0.67 ± 0.28, p = 0.00023). Moreover, 11 C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = -0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11 C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = -0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.

Objectives: PSMA-PET has become the PET technique of choice to localise the site of biochemically recurrent prostate cancer (PCa). With hybrid PET/MRI, the advantages of MRI are added to molecular characteristic of PET. The aim of this study was to investigate the incremental value of PET/MR versus PET/CT in patients with biochemically recurrent PCa by head-to-head comparison., Methods: Thirty-four patients with biochemically recurrent PCa were prospectively included. They underwent [ 68 Ga]Ga-PSMA-11 PET/CT, followed by simultaneous PET/MR. All PET (PET CT , PET MR ), CT and MR images were evaluated for number of lesions and location. The number of lesions at specific sites was compared using Wilcoxon-sign-rank test. For PET, the maximum and mean standardised uptake values (SUVs) were calculated for each lesion compared using a two-sided paired t test., Results: PET CT and PET MR scans were positive in 19 and 20 patients, detecting 73 and 79 lesions respectively. All lesions detected on PET CT were also detected on PET MR . CT and MRI only were positive in 14 and 17 patients, detecting 38 and 50 lesions, respectively, which was significantly lower than PET CT and PET MR respectively. Combined interpretation showed more lesions on PET/MR than on PET/CT (88 vs 81). No significant difference in detection of presence of local recurrence nor distant metastases was found. SUV mean and SUV max values were significantly higher on PET MR than on PET CT in local recurrence and lymph node metastases., Conclusions: [ 68 Ga]Ga-PSMA-11 PET/MR was able to detect biochemically recurrent PCa at least as accurately as PET/CT for local recurrence, lymph node metastasis and distant metastasis., Key Points: • PSMA PET/MRI detects the location of biochemical recurrence at least as accurately as PET/CT. • Substitution of PET/CT by PET/MRI adds sensitivity in PSMA lesion detection also in the setting of distant recurrence due to both the MR and TOF PET components., (© 2021. European Society of Radiology.)

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [ 11 C]MK-6884 from rhesus monkeys to patients with Alzheimer’s disease (AD). [ 3 H]MK-6884/[ 11 C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [ 11 C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [ 11 C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BP ND ) of [ 11 C]MK-6884. These results suggest that [ 11 C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Background and Objectives: Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo . METHODS: In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with 11 C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed 18 F-fluorodeoxyglucose ( 18 F-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for 11 C-UCB-J with the centrum semiovale as reference region. 18 F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and 11 C-UCB-J PET data were calculated., Results: Eighteen HD mutation carriers (age 51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced 18 F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, 11 C-UCB-J and 18 F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment., Discussion: Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. 11 C-UCB-J PET is more sensitive than 18 F-FDG-PET for detection of extrastriatal changes in early HD., Classification of Evidence: This study provides Class III evidence that 11 C-UCB-J PET accurately discriminates individuals HD from normal controls., (© 2021 American Academy of Neurology.)

Purpose: Human ageing is associated with a regional reduction in cerebral neuronal activity as assessed by numerous studies on brain glucose metabolism and perfusion, grey matter (GM) density and white matter (WM) integrity. As glucose metabolism may impact energetics to maintain myelin integrity, but changes in functional connectivity may also alter regional metabolism, we conducted a cross-sectional simultaneous FDG PET/MR study in a large cohort of healthy volunteers with a wide age range, to directly assess the underlying associations between reduced glucose metabolism, GM atrophy and decreased WM integrity in a single ageing cohort., Methods: In 94 healthy subjects between 19.9 and 82.5 years (mean 50.1 ± 17.1; 47 M/47F, MMSE ≥ 28), simultaneous FDG-PET, structural MR and diffusion tensor imaging (DTI) were performed. Voxel-wise associations between age and grey matter (GM) density, RBV partial-volume corrected (PVC) glucose metabolism, white matter (WM) fractional anisotropy (FA) and mean diffusivity (MD), and age were assessed. Clusters representing changes in glucose metabolism correlating significantly with ageing were used as seed regions for tractography. Both linear and quadratic ageing models were investigated., Results: An expected age-related reduction in GM density was observed bilaterally in the frontal, lateral and medial temporal cortex, striatum and cerebellum. After PVC, relative FDG uptake was negatively correlated with age in the inferior and midfrontal, cingulate and parietal cortex and subcortical regions, bilaterally. FA decreased with age throughout the entire brain WM. Four white matter tracts were identified connecting brain regions with declining glucose metabolism with age. Within these, relative FDG uptake in both origin and target clusters correlated positively with FA (0.32 ≤ r ≤ 0.71) and negatively with MD (- 0.75 ≤ r ≤  - 0.41)., Conclusion: After appropriate PVC, we demonstrated that regional cerebral glucose metabolic declines with age and that these changes are related to microstructural changes in the interconnecting WM tracts. The temporal course and potential causality between ageing effects on glucose metabolism and WM integrity should be further investigated in longitudinal cohort PET/MR studies., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The population aging increased the prevalence of brain diseases, like Alzheimer's disease (AD). Early identification of individuals with higher odds of cognitive decline is essential to maintain quality of life. Imaging evaluation of individuals at risk of cognitive decline includes biomarkers extracted from brain positron emission tomography (PET) and structural magnetic resonance imaging (MRI)., Objective: We propose investigating ensemble models to classify groups in the aging cognitive decline spectrum by combining features extracted from single imaging modalities and combinations of imaging modalities (FDG+AMY+MRI, and a PET ensemble)., Methods: We group imaging data of 131 individuals into four classes related to the individuals' cognitive assessment in baseline and follow-up: stable cognitive non-impaired; individuals converting to mild cognitive impairment (MCI) syndrome; stable MCI; and Alzheimer's clinical syndrome. We assess the performance of four algorithms using leave-one-out cross-validation: decision tree classifier, random forest (RF), light gradient boosting machine (LGBM), and categorical boosting (CAT). The performance analysis of models is evaluated using balanced accuracy before and after using Shapley Additive exPlanations with recursive feature elimination (SHAP-RFECV) method., Results: Our results show that feature selection with CAT or RF algorithms have the best overall performance in discriminating early cognitive decline spectrum mainly using MRI imaging features., Conclusion: Use of CAT or RF algorithms with SHAP-RFECV shows good discrimination of early stages of aging cognitive decline, mainly using MRI image features. Further work is required to analyze the impact of selected brain regions and their correlation with cognitive decline spectrum.

Aberrant Hsp90 has been implied in cancer and neurodegenerative disorders. The development of a suitable Hsp90 Positron emission tomography (PET) probe can provide in vivo quantification of the expression levels of Hsp90 as a biomarker for diagnosis and follow-up of cancer and central nervous system (CNS) disease progression. In this respect, [ 11 C]YC-72-AB85 was evaluated as an Hsp90 PET probe in B16.F10 melanoma bearing mice and its brain uptake was determined in rats and nonhuman primate. In vitro binding of [ 11 C]YC-72-AB85 to tissue slices of mouse B16.F10 melanoma, PC3 prostate carcinoma, and rodent brain was evaluated using autoradiography. Biodistribution of [ 11 C]YC-72-AB85 was evaluated in healthy and B16.F10 melanoma mice. In vivo brain uptake was assessed by μPET studies in rats and a rhesus monkey. In vitro binding was deemed Hsp90-specific by blocking studies with heterologous Hsp90 inhibitors onalespib and SNX-0723. Saturable Hsp90 binding was observed in brain, tumor, blood, and blood-rich organs in mice. In combined pretreatment and displacement studies, reversible and Hsp90-specific binding of [ 11 C]YC-72-AB85 was observed in rat brain. Dynamic μPET brain scans in baseline and blocking conditions in a rhesus monkey indicated Hsp90-specific binding. [ 11 C]YC-72-AB85 is a promising PET tracer for in vivo visualization of Hsp90 in tumor and brain. Clear differences of Hsp90 binding to blood and blood-rich organs were observed in tumor vs control mice. Further, we clearly demonstrate, for the first time, binding to a saturable Hsp90 pool in brain of rats and a rhesus monkey.

Interventional yoga studies with an active control group remain scarce and are important to clarify the underlying neurobiology. We conducted an interventional study in healthy controls using simultaneous positron emission tomography/magnetic resonance (PET/MR) imaging and psychometric scales. Thirty healthy, female volunteers (28.4 ± 8.4 years) participated and were randomly assigned to a 12-week yoga or indoor cycling intervention. Before and after the intervention, [ 18 F]FDG and [ 11 C]UCB-J PET was performed on a simultaneous GE Signa PET/MR with volumetric imaging. Psychometric scales were evaluated on affect, mindfulness, stress, worrying, self-compassion, and interoceptive awareness. Yoga subjects scored higher on interoceptive awareness compared to baseline ( p < 0.001). Cognitive ( P = 0.009) and overall cognitive functioning ( P = 0.01) improved after the yoga intervention compared to the cycling group. We did not observe significant differences in glucose metabolism, synaptic density, or gray matter (GM) volume. The indoor cycling group did not show changes in psychometric variables, but significant increases in relative glucose metabolism were observed in the parahippocampal/fusiform gyrus and cerebellum ( P < 0.001). In conclusion, 12 weeks of yoga practice has significant effects on interoceptive awareness and perceived cognitive function in starters. Longer interventions and/or higher frequency of yoga practice may be needed to detect cerebral metabolic and/or morphologic effects on the macroscopic level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Aalst, Jennen, Demyttenaere, Sunaert, Koole, Ceccarini and Van Laere.)

Amyloid-like aggregation of proteins is induced by short amyloidogenic sequence segments within a specific protein sequence resulting in self-assembly into β-sheets. We recently validated a technology platform in which synthetic amyloid peptides ("Pept-ins") containing a specific aggregation-prone region (APR) are used to induce specific functional knockdown of the target protein from which the APR was derived, including bacterial, viral, and mammalian cell proteins. In this work, we investigated if Pept-ins can be used as vector probes for in vivo Positron Emission Tomography (PET) imaging of intracellular targets. The radiolabeled Pept-ins [ 68 Ga]Ga-NODAGA-PEG 4 -vascin (targeting VEGFR2) and [ 68 Ga]Ga-NODAGA-PEG 2 -P2 (targeting E. coli ) were evaluated as PET probes. The Pept-in based radiotracers were cross-validated in a murine tumor and muscle infection model, respectively, and were found to combine target specificity with favorable in vivo pharmacokinetics. When the amyloidogenicity of the interacting region of the peptide is suppressed by mutation, cellular uptake and in vivo accumulation are abolished, highlighting the importance of the specific design of synthetic Pept-ins. The ubiquity of target-specific amyloidogenic sequence segments in natural proteins, the straightforward sequence-based design of the Pept-in probes, and their spontaneous internalization by cells suggest that Pept-ins may constitute a generic platform for in vivo PET imaging of intracellular targets.

To uncover mechanisms underlying chemotherapy-induced cognitive impairment in breast cancer, we studied new biomarkers of neuroinflammation and neuronal survival. This cohort study included 74 women (47 ± 10 years) from 22 October 2017 until 20 August 2020. Nineteen chemotherapy-treated and 18 chemotherapy-naïve patients with breast cancer were assessed one month after the completion of surgery and/or chemotherapy, and 37 healthy controls were included. Assessments included neuropsychological testing, questionnaires, blood sampling for 17 inflammatory and two neuronal survival markers (neurofilament light-chain (NfL), and brain-derived neurotrophic factor (BDNF) and PET-MR neuroimaging. To investigate neuroinflammation, translocator protein (TSPO) [ 18 F]DPA714-PET-MR was acquired for 15 participants per group, and evaluated by volume of distribution normalized to the cerebellum. Chemotherapy-treated patients showed higher TSPO expression, indicative for neuroinflammation, in the occipital and parietal lobe when compared to healthy controls or chemotherapy-naïve patients. After partial-volume correction, differences with healthy controls persisted ( p FWE < 0.05). Additionally, compared to healthy- or chemotherapy-naïve controls, cognitive impairment (17-22%) and altered levels in blood markers ( F ≥ 3.7, p &nbsp;≤ 0.031) were found in chemotherapy-treated patients. NfL, an axonal damage marker, was particularly sensitive in differentiating groups ( F = 105, p = 4.2 × 10 -21 ), with levels 20-fold higher in chemotherapy-treated patients. Lastly, in chemotherapy-treated patients alone, higher local TSPO expression was associated with worse cognitive performance, higher blood levels of BDNF/NfL, and decreased fiber cross-section in the corpus callosum ( p FWE < 0.05). These findings suggest that increased neuroinflammation is associated with chemotherapy-related cognitive impairment in breast cancer. Additionally, NfL could be a useful biomarker to assess neurotoxic effects of anticancer chemotherapies.

Aging is a complex process that involves changes at both molecular and morphological levels. However, our understanding of how aging affects brain anatomy and function is still poor. In addition, numerous biomarkers and imaging markers, usually associated with neurodegenerative diseases such as Alzheimer's disease (AD), have been clinically used to study cognitive decline. However, the path of cognitive decline from healthy aging to a mild cognitive impairment (MCI) stage has been studied only marginally. This review presents aspects of cognitive decline assessment based on the imaging differences between individuals cognitively unimpaired and in the decline spectrum. Furthermore, we discuss the relationship between imaging markers and the change in their patterns with aging by using neuropsychological tests. Our goal is to delineate how aging has been studied by using medical imaging tools and further explore the aging brain and cognitive decline. We find no consensus among the biomarkers to assess the cognitive decline and its relationship with the cognitive decline trajectory. Brain glucose hypometabolism was found to be directly related to aging and indirectly to cognitive decline. We still need to understand how to quantify an expected hypometabolism during cognitive decline during aging. The Aβ burden should be longitudinally studied to achieve a better consensus on its association with changes in the brain and cognition decline with aging. There exists a lack of standardization of imaging markers that highlight the need for their further improvement. In conclusion, we argue that there is a lot to investigate and understand cognitive decline better and seek a window for a suitable and effective treatment strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dartora, Borelli, Koole and Marques da Silva.)

[ 18 F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (V T ) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF). Regional postdose V T,IDIF values were compared with corresponding V T,AIF estimates using a arterial input function (AIF), in terms of absolute values, test-retest reliability and receptor occupancy. Compared to an invasive AIF approach, postdose V T,IDIF values and corresponding receptor occupancies showed only limited bias (Bland-Altman analysis: 0.06 ± 0.27 and 3.1% ± 6.4%) while demonstrating a high correlation (Spearman ρ = 0.78 and ρ = 0.98 respectively). In terms of test-retest reliability, regional intraclass correlation coefficients were 0.98 ± 0.02 for V T,IDIF compared to 0.97 ± 0.01 for V T,AIF. These results confirmed that a postdose IDIF, guided by MR angiography and using baseline blood and metabolite data, can be considered for accurate [ 18 F]JNJ-64413739 PET quantification in a repeated PET study design, thus avoiding multiple invasive arterial sampling and increasing dosing flexibility., (© 2021. The Author(s).)

Late-life depression (LLD) is associated with a risk of developing Alzheimer's disease (AD). However, the role of AD-pathophysiology in LLD, and its association with clinical symptoms and cognitive function are elusive. In this study, one hundred subjects underwent amyloid positron emission tomography (PET) imaging with [ 18 F]-flutemetamol and structural MRI: 48 severely depressed elderly subjects (age 74.1 ± 7.5 years, 33 female) and 52 age-/gender-matched healthy controls (72.4 ± 6.4 years, 37 female). The Geriatric Depression Scale (GDS) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess the severity of depressive symptoms and episodic memory function respectively. Amyloid deposition was quantified using the standardized uptake value ratio. Whole-brain voxel-wise comparisons of amyloid deposition and gray matter volume (GMV) between LLD and controls were performed. Multivariate analysis of covariance was conducted to investigate the association of regional differences in amyloid deposition and GMV with clinical factors, including GDS and RAVLT. As a result, there were no significant group differences in amyloid deposition. In contrast, LLD showed significant lower GMV in the left temporal and parietal region. GMV reduction in the left temporal region was associated with episodic memory dysfunction, but not with depression severity. Regional GMV reduction was not associated with amyloid deposition. LLD is associated with lower GMV in regions that overlap with AD-pathophysiology, and which are associated with episodic memory function. The lack of corresponding associations with amyloid suggests that lower GMV driven by non-amyloid pathology may play a central role in the neurobiology of LLD presenting as a psychiatric disorder.Trial registration: European Union Drug Regulating Authorities Clinical Trials identifier: EudraCT 2009-018064-95., (© 2021. The Author(s).)

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [ 11 C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [ 18 F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [ 11 C]UCB-J were indeed highly significantly correlated ( r  > 0.47, p  < 0.001). However, regional differences in relative [ 18 F]FDG and [ 11 C]UCB-J uptake were observed, with up to 19% higher [ 11 C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

Background: [ 18 F]MK-6240 is a PET tracer with sub-nanomolar affinity for neurofibrillary tangles. Therefore, tau quantification is possible with [ 18 F]MK-6240 PET/CT scans, and it can be used for assessment of Alzheimer's disease. However, long acquisition scans are required to provide fully quantitative estimates of pharmacokinetic parameters. Therefore, on the present study, dual-time-window (DTW) acquisitions was simulated to reduce PET/CT acquisition time, while taking into consideration perfusion changes and possible scanning protocol non-compliance. To that end, time activity curves (TACs) representing a 120-min acquisition (TAC 120 ) were simulated using a two-tissue compartment model with metabolite corrected arterial input function from 90-min dynamic [ 18 F]MK-6240 PET scans of three healthy control subjects and five subjects with mild cognitive impairment or Alzheimer's disease. Therefore, TACs corresponding to different levels of specific binding were generated and then various perfusion changes were simulated. Next, DTW acquisitions were simulated consisting of an acquisition starting at tracer injection, a break and a second acquisition starting at 90 min post-injection. Finally, non-compliance with the PET/CT scanning protocol were simulated to assess its impact on quantification. All TACs were quantified using reference Logan's distribution volume ratio (DVR) and standardized uptake value ratio (SUVR 90 ) using the cerebellar cortex as reference region., Results: It was found that DVR from a DTW protocol with a 60-min break between two 30-min dynamic scans closely approximates the DVR from the uninterrupted TAC 120 , with a regional bias smaller than 2.5%. Moreover, SUVR 90 estimates were more susceptible (regional bias ≤ 19%) to changes in perfusion compared to DVR from a DTW TAC (regional bias ≤ 10%). Similarly, SUVR 90 was affected by late-time scanning protocol delays reaching an increase of 8% for a 20-min delay, while DVR was not affected (regional bias < 1.5%) by DTW protocol non-compliance., Conclusions: Therefore, such DTW protocol has the potential to increase patient comfort and throughput without compromising quantitative accuracy and is more reliable against SUVR in terms of perfusion changes and protocol deviations, which could prove beneficial for drug effect assessment and patient follow-up using longitudinal [ 18 F]MK-6240 PET imaging.

Rationale: 11 C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as in vivo proxy of synaptic density. There are discrepancies in postmortem data on stability of synaptic density with healthy aging. In this study, healthy aging and sex as potential modifiers of 11 C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex., Methods: 80 healthy volunteers underwent 11 C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric 11 C-UCB-J standardized uptake value ratio (SUVR) images were calculated using the centrum semiovale as reference tissue. To correct for atrophy-related partial volume effects, a region-based voxel-wise type partial volume correction (PVC) was applied in FreeSurfer. The correlations of 11 C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging., Results: Full results were available for 78 participants (19-85y; 33 M/45 F). VBM grey matter concentration changes with aging were most predominant in the perisylvian and frontal regions. After PVC, no significantly decreased 11 C-UCB-J SUVR with aging was found in the voxel-based analysis, whereas the VOI-based analysis showed a slight decrease in the caudate nucleus (-1.7% decrease per decade, p= 0.0025) only. There was no association between sex and 11 C-UCB-J SUVR, nor an interaction between aging and sex for this parameter., Conclusion: In vivo, PET using 11 C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: [ 11 C]-UCB-J is an emerging tool for the noninvasive measurement of synaptic vesicle density in vivo. Here, we report human biodistribution and dosimetry estimates derived from sequential whole-body PET using two versions of the OLINDA dosimetry program., Methods: Sequential whole-body PET scans were performed in 3 healthy subjects for 2 h after injection of 254 ± 77 MBq [ 11 C]-UCB-J. Volumes of interest were drawn over relevant source organs to generate time-activity curves and calculate time-integrated activity coefficients, with effective dose coefficients calculated using OLINDA 2.1 and compared to values derived from OLINDA 1.1 and those recently reported in the literature., Results: [ 11 C]-UCB-J administration was safe and showed mixed renal and hepatobiliary clearance, with largest organ absorbed dose coefficients for the urinary bladder wall and small intestine (21.7 and 23.5 μGy/MBq, respectively). The average (±SD) effective dose coefficient was 5.4 ± 0.7 and 5.1 ± 0.8 μSv/MBq for OLINDA versions 1.1 and 2.1 respectively. Doses were lower than previously reported in the literature using either software version., Conclusions: A single IV administration of 370 MBq [ 11 C]-UCB-J corresponds to an effective dose of less than 2.0 mSv, enabling multiple PET examinations to be carried out in the same subject., Trial Registration: EudraCT number: 2016-001190-32. Registered 16 March 2016, no URL available for phase 1 trials.

Purpose: To evaluate the prognostic utility of apparent diffusion coefficient (ADC) changes at whole-body diffusion-weighted (WB-DW) MRI after one treatment cycle for aggressive non-Hodgkin lymphoma (NHL) compared with response assessment at interim and end-of-treatment fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) PET/CT., Materials and Methods: This was a secondary analysis of a prospective study (ClinicalTrials.gov identifier: NCT01231269) in which participants with aggressive NHL were recruited between March 2011 and April 2015 and underwent WB-DW MRI before and after one cycle of immunochemotherapy. Volunteers were recruited for test-retest WB-DW MRI (ClinicalTrials.gov identifier: NCT01231282) to assess ADC measurement repeatability. Response assessment was based on ADC change after one treatment cycle at WB-DW MRI and Deauville criteria at 18 F-FDG PET/CT. To evaluate prognostic factors of disease-free survival (DFS), Kaplan-Meier survival analysis and univariable and multivariable Cox regression were performed; intraclass correlation coefficient (ICC) and mean difference with limits of agreement were calculated to determine inter- and intraobserver repeatability of ADC measurements., Results: Forty-five patients (mean age, 58 years ± 17 [standard deviation]; 31 men) and nine volunteers (mean age, 22 years ± 3; seven men) were enrolled. Median DFS was 48 months (range, 2-48 months). Outcome prediction accuracy was 86.7% (39 of 45), 71.4% (30 of 42), and 73.8% (31 of 42) for WB-DW MRI and interim and end-of-treatment 18 F-FDG PET/CT, respectively. WB-DW MRI (hazard ratio [HR], 17.8; P < .001) and interim (HR, 5; P = .008) and end-of-treatment (HR, 4.3; P = .017) 18 F-FDG PET/CT were prognostic of DFS. After multivariable analysis, WB-DW MRI remained an independent predictor of outcome (HR, 26.8; P = .002). Intra- and interobserver agreement for ADC measurements were excellent (ICC = 0.85-0.99)., Conclusion: Quantitative WB-DW MRI after only one cycle of immunochemotherapy predicts DFS in aggressive NHL and is noninferior to routinely performed interim and end-of-treatment 18 F-FDG PET/CT. Keywords: MR-Diffusion Weighted Imaging, Lymphoma, Oncology, Tumor Response, Whole-Body Imaging Supplemental material is available for this article. © RSNA, 2021., Competing Interests: Disclosures of Conflicts of Interest: K.N.D.P. disclosed no relevant relationships. C.A.V.K. disclosed no relevant relationships. G.M.A. disclosed no relevant relationships. F.D.K. disclosed no relevant relationships. O.G. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: author received consultancy fees from IBA and payment for lectures including service on speakers bureaus from Pfizer. Other relationships: disclosed no relevant relationships. O.B. disclosed no relevant relationships. P.W. disclosed no relevant relationships. D.D. disclosed no relevant relationships. A.J. disclosed no relevant relationships. G.V. disclosed no relevant relationships. R.O. disclosed no relevant relationships. M.K. disclosed no relevant relationships. V.V. disclosed no relevant relationships., (2021 by the Radiological Society of North America, Inc.)

Purpose: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [ 18 F]EKZ-001 ([ 18 F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects., Methods: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (V T ) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. V T differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches., Results: The effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA V T were in agreement with 2TCM V T , however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional V T values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher V T than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported., Conclusion: [ 18 F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

Purpose: The widespread use of gallium-68-labelled somatostatin analogue (SSA) PET, the current standard for somatostatin receptor (SSTR) imaging, is limited by practical and economic challenges that could be overcome by a fluorine-18-labelled alternative, such as the recently introduced [ 18 F]AlF-NOTA-octreotide ([ 18 F]AlF-OC). This prospective trial aimed to evaluate safety, dosimetry, biodistribution, pharmacokinetics and lesion targeting of [ 18 F]AlF-OC and perform the first comparison with [ 68 Ga]Ga-DOTATATE in neuroendocrine tumour (NET) patients., Methods: Six healthy volunteers and six NET patients with a previous clinical [ 68 Ga]Ga-DOTATATE PET were injected with an IV bolus of 4 MBq/kg [ 18 F]AlF-OC. Healthy volunteers underwent serial whole-body PET scans from time of tracer injection up to 90 min post-injection, with an additional PET/CT at 150 and 300 min post-injection. In patients, a 45-min dynamic PET was acquired and three whole-body PET scans at 60, 90 and 180 min post-injection. Absorbed organ doses and effective doses were calculated using OLINDA/EXM. Normal organ uptake (SUV mean ) and tumour lesion uptake (SUV max and tumour-to-background ratio (TBR)) were measured. A lesion-by-lesion analysis was performed and the detection ratio (DR), defined as the fraction of detected lesions was determined for each tracer., Results: [ 18 F]AlF-OC administration was safe and well tolerated. The highest dose was received by the spleen (0.159 ± 0.062 mGy/MBq), followed by the urinary bladder wall (0.135 ± 0.046 mGy/mBq) and the kidneys (0.070 ± 0.018 mGy/MBq), in accordance with the expected SSTR-specific uptake in the spleen and renal excretion of the tracer. The effective dose was 22.4 ± 4.4 μSv/MBq. The physiologic uptake pattern of [ 18 F]AlF-OC was comparable to [ 68 Ga]Ga-DOTATATE. Mean tumour SUV max was lower for [ 18 F]AlF-OC (12.3 ± 6.5 at 2 h post-injection vs. 18.3 ± 9.5; p = 0.03). However, no significant differences were found in TBR (9.8 ± 6.7 at 2 h post-injection vs. 13.6 ± 11.8; p = 0.35). DR was high and comparable for both tracers (86.0% for [ 68 Ga]Ga-DOTATATE vs. 90.1% for [ 18 F]AlF-OC at 2 h post-injection; p = 0.68)., Conclusion: [ 18 F]AlF-OC shows favourable kinetic and imaging characteristics in patients that warrant further head-to-head comparison to validate [ 18 F]AlF-OC as a fluorine-18-labelled alternative for gallium-68-labelled SSA clinical PET., Trial Registration: Clinicaltrials.gov : NCT03883776, EudraCT: 2018-002827-40.