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Purpose: Quantification of PSMA expression via PSMA PET is well-established, however quantification of PSMA via immunohistochemistry (IHC) is not standardized. Our aim was to determine the most optimal PSMA IHC scoring system to quantify PSMA expression with PSMA PET as reference standard., Methods: Primary intermediate- and high-risk prostate cancer patients received an [ 18 F]PSMA-1007 PET/MRI followed by radical prostatectomy. SUV max , SUV mean and K i of the prostate tumor was determined. Prostate tumors were stained with anti-PSMA antibodies and scored by 2 readers via 10 IHC scoring systems: histochemical score (H-score), immunoreactivity score predominant intensity (IRS predominant intensity ), IRS classification predominant intensity , IRS mean intensity , IRS classification mean intensity , Allred score, predominant expression pattern, Shannon diversity index (SDI), percentage negatively stained cells and total percentage positively stained cells. Spearman's rank correlation coefficients (ρ) were calculated between PET parameters and IHC scoring systems. Interreader agreement for the IHC scoring systems was measured by the intraclass correlation coefficient (ICC)., Results: Fifty tumors in 46 patients were analysed. H-score had the best correlation with SUV max (ρ 0.615 p < 0.0001) and SUV mean (ρ 0.570, p < 0.0001) and the second best correlation with K i (ρ 0.411, p = 0.0030). SDI had the best correlation with K i (ρ -0.440, p = 0.0014) and the second best correlation with SUV max (ρ -0.516, p = 0.0001) and SUV mean (ρ -0.490, p = 0.0003). A moderate interreader agreement was observed for H-score (ICC 0.663, 95% CI 0.495-0.797) and SDI (ICC 0.546, 95% CI 0.354-0.725)., Conclusion: H-score had the best correlation with PSMA PET quantification and an acceptable interreader agreement. Therefore, we deem H-score the most optimal PSMA IHC scoring system., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Preclinical data have shown that 161 Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their 177 Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose-response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [ 161 Tb]Tb- and [ 177 Lu]Lu-DOTATATE (agonist) and with [ 161 Tb]Tb- and [ 177 Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β - particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [ 161 Tb]Tb-DOTATATE and [ 161 Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their 177 Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by 161 Tb. When activity concentrations were considered, both [ 161 Tb]Tb-DOTATATE and [ 161 Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with 177 Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose-response curves for [ 161 Tb]Tb- and [ 177 Lu]Lu-DOTATATE. [ 161 Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [ 161 Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by 161 Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [ 161 Tb]Tb-DOTATATE and [ 161 Tb]Tb-DOTA-LM3 than for the 177 Lu-labeled analogs. In contrast, [ 161 Tb]Tb-DOTATATE showed no higher dose response than [ 177 Lu]Lu-DOTATATE, whereas for [ 161 Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [ 161 Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [ 161 Tb]Tb-DOTATATE for labeling with 161 Tb., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

[ 18 F]AlF-NOTA-octreotide ([ 18 F]AlF-OC) is a promising alternative for [ 68 Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [ 18 F]AlF-OC PET/CT and [ 68 Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [ 18 F]AlF-OC and [ 68 Ga]Ga-DOTA-TATE or [ 68 Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [ 68 Ga]Ga-DOTA-SSA or [ 18 F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [ 18 F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [ 68 Ga]Ga-DOTA-SSA, the use of [ 18 F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [ 18 F]AlF-OC. The use of [ 18 F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [ 18 F]AlF-OC PET/CT as an alternative for [ 68 Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15., (© 2024 British Society for Neuroendocrinology.)

The International Commission on Radiological Protection (ICRP), recently expressed concern that "a shortage of investment in training, education, research, and infrastructure seen in many sectors and countries may compromise society's ability to properly manage radiation risks" and in 2022 announced the "Vancouver call for action to strengthen expertise in radiological protection worldwide". As representatives of organisations in formal relations with ICRP, we decided to promote this position paper to declare and emphasise that strengthening the expertise in radiological protection is a collective priority for all of us., 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 © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate whether tau accumulation is higher in late life depression (LLD) compared to non-depressed cognitively unimpaired (CU) older adults. To situate these findings in the neurodegeneration model of LLD by assessing group differences in tau and grey matter volume (GMV) between LLD, non-depressed CU and mild cognitive impairment due to Alzheimer's Disease (MCI)., Design: Monocentric, cross-sectional study., Setting: University Psychiatric hospital, memory clinic and outpatient neurology practice., Participants: A total of 102 adults over age 60, of whom 19 currently depressed participants with LLD, 19 with MCI and 36 non-depressed CU participants completed neuropsychological testing and tau PET-MR imaging., Measurements: PET-MRI: 18F-MK-6240 tracer SUVR for tau assessment; 3D T1-weighted structural MRI derived GMV in seven brain regions (temporal, cingulate, prefrontal and parietal regions); amyloid PET to assess amyloid positivity; Neuropsychological test scores: MMSE, RAVLT, GDS, MADRS. ANCOVA and Spearman's rank correlations to investigate group differences in tau and GMV, and correlations with neuropsychological test scores respectively., Results: Compared to non-depressed CU participants, LLD patients showed lower GMV in temporal and anterior cingulate regions but similar tau accumulation and amyloid positivity rate. In contrast, MCI patients had significantly higher tau accumulation in all regions. Tau did not correlate with any neuropsychological test scores in LLD., Conclusion: Our findings suggest AD-type tau is not higher in LLD compared to non-depressed, cognitively unimpaired older adults and appears unlikely to contribute to lower gray matter volume in LLD, further underscoring the need to distinguish major depressive disorder from depressive symptoms occurring in early AD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this guideline is to provide recommendations for the implementation of an effective and efficient quality control (QC) programme for SPECT and PET systems in a preclinical imaging lab. These recommendations aim to strengthen the translational power of preclinical imaging results obtained using preclinical SPECT and PET. As for clinical imaging, reliability, reproducibility, and repeatability are essential when groups of animals are used in a longitudinal imaging experiment. The larger the variability of the imaging endpoint, the more animals are needed to be able to observe statistically significant differences between groups. Therefore, preclinical imaging requires quality control procedures to maintain reliability, reproducibility, and repeatability of imaging procedures, and to ensure the accuracy and precision of SPECT and PET quantification. While the Physics Committee of the European Association of Nuclear Medicine (EANM) has already published excellent procedure guidelines for Routine Quality Control Recommendations for Nuclear Medicine Instrumentation that also includes procedures for small animal PET systems, and important steps have already been made concerning preclinical quality control aspects, this new guideline provides a review and update of these previous guidelines such that guidelines are also adapted to new technological developments., (© 2024. The Author(s).)

Background: Although the importance of quantitative SPECT has increased tremendously due to newly developed therapeutic radiopharmaceuticals, there are still no accreditation programs to harmonize SPECT imaging. Work is currently underway to develop an accreditation for quantitative 177 Lu SPECT/CT. The aim of this study is to verify whether the positioning of the spheres within the phantom has an influence on the recovery and thus needs to be considered in SPECT harmonization. In addition, the effects of these recovery coefficients on a potential partial volume correction as well as absorbed-dose estimates are investigated., Methods: Using a low-dose CT of a SPECT/CT acquisition, a computerized version of the NEMA body phantom was created using a semi-automatic threshold-based method. Based on the mass-density map, the detector orbit, and the sphere centers, realistic SPECT acquisitions of all possible 720 sphere configurations of both the PET and the SPECT versions of the NEMA Body Phantom were generated using Monte Carlo simulations. SPECT reconstructions with different numbers of updates were performed without (CASToR) and with resolution modeling (STIR). Recovery coefficients were calculated for all permutations, reconstruction methods, and phantoms, and their dependence on the sphere positioning was investigated. Finally, the simulation-based findings were validated using SPECT/CT acquisitions of six different sphere configurations., Results: Our analysis shows that sphere positioning has a significant impact on the recovery for both of the reconstruction methods and the phantom type. Although resolution modeling resulted in significantly higher recovery, the relative variation in recovery within the 720 permutations was even larger. When examining the extreme values of the recovery, reconstructions without resolution modeling were influenced primarily by the sphere position, while with resolution modeling the volume of the two adjacent spheres had a larger influence. The SPECT measurements confirmed these observations, and the recovery curves showed good overall agreement with the simulated data., Conclusion: Our study shows that sphere positioning has a significant impact on the recovery obtained in NEMA sphere phantom measurements and should therefore be considered in a future SPECT accreditation. Furthermore, the single-measurement method normally performed for PVC should be reconsidered to account for the position dependency., (© 2024. The Author(s).)

Background: The distance traveled by the positron before annihilation with an electron, the so-called positron range, negatively effects the positron emission tomography (PET) image quality for radionuclides emitting high-energy positrons such as Gallium-68 ( 68 Ga)., Purpose: In this study, the effect of a tissue-independent positron range correction for Gallium-68 ( 68 Ga-PRC) was investigated based on phantom measurements. The effect of the 68 Ga-PRC was also explored in four patients., Methods: The positron range distribution profile of 68 Ga in water was generated via Monte Carlo simulation. That profile was mapped to a spatially invariant 3D convolution kernel which was incorporated in the OSEM and Q.Clear reconstruction algorithms to perform the 68 Ga-PRC. In addition, each reconstruction method included point spread function (PSF) modeling and time-of-flight information. For both Fluorine-18 ( 18 F) and 68 Ga, the NEMA IQ phantom was filled with a sphere-to-background ratio of 10:1 and scanned with the GE Discovery MI 5R PET/CT system. Standard non-positron range correction (PRC) reconstructions were performed for both radionuclides, while also PRC reconstructions were performed for 68 Ga. Reconstructions parameters (OSEM: number of updates, Q.Clear: beta value) were adapted to achieve similar noise levels between the corresponding reconstructions. The effect of 68 Ga-PRC was assessed for both OSEM and Q.Clear reconstructions and compared to non-PRC reconstructions for 68 Ga and 18 F in terms of image contrast, noise, recovery coefficient (RC), and spatial resolution. For the clinical validation, 68 Ga-labeled prostate-specific membrane antigen ( 68 Ga-PSMA) and 68 Ga-DOTATOC PET scans were included of two patients each. For each PET scan, patients were injected with 1.5 MBq/kg of 68 Ga-PSMA or 68 Ga-DOTATOC and the contrast-to-noise ratio (CNR) was calculated and compared to the non-PRC reconstructions., Results: For OSEM reconstructions, including the 68 Ga-PRC improved the RC by 9.4% (3.7%-19.3%) and spatial resolution by 21.7% (4.6 mm vs. 3.6 mm) for similar noise levels. For Q.Clear reconstructions, 68 Ga-PRC modeling improved the RC by 6.7% (2.8%-10.5%) and spatial resolution by 15.3% (5.9 mm vs. 5.0 mm) while obtaining similar noise levels. In the patient data, the use of 68 Ga-PRC enhanced the CNR by 13.2%., Conclusions: Including 68 Ga-PRC in the PET reconstruction enhanced the image quality of 68 Ga PET data compared to the standard non-PRC reconstructions for similar noise levels. Limited patient results also supported this improvement., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: The C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in many cancers, e.g. multiple myeloma and acute leukemia, yet solely [ 68 Ga]PentixaFor is used for clinical PET imaging. The aim of this study was to develop and assess a second generation Al 18 F-labeled D-amino acid peptide based on the viral macrophage inflammatory protein II for CXCR4 targeted molecular imaging., Methods: We designed a library of monomer and multimer constructs and evaluated their binding affinity for human and mouse CXCR4. Based on these results, we selected the best vector molecule for development of an Al 18 F-labeled ligand, [ 18 F]AlF-NOTA-2xDV1(c11sc12s), which was further evaluated in a cell-based binding assay to assess its binding properties and specificity for CXCR4. Next, pharmacokinetics and tumor uptake of [ 18 F]AlF-NOTA-2xDV1(c11sc12s) were evaluated in naïve mice and mice with xenografts derived from U87.CXCR4 cells. Finally, we performed an imaging study in a non-human primate to assess the in vivo distribution of this novel radioligand in a species closely related to humans., Results: The lead ligand AlF-NOTA-2xDV1(c11sc12s) showed six-fold higher affinity for human CXCR4 compared to Ga-Pentixafor. The corresponding radiotracer was obtained in a good radiochemical yield of 40.1 ± 13.5 % (n = 4) and apparent molar activity of 20.4 ± 3.3 MBq/nmol (n = 4) after optimization. In U87.CD4.CXCR4 cell binding assays, the total bound fraction of [ 18 F]AlF-NOTA-(2×)DV1(c11sc12s) was 32.4 ± 1.8 %. This fraction could be reduced by 82.5 % in the presence of 75 μM AMD3100. In naïve mice, [ 18 F]AlF-NOTA-2xDV1(c11sc12s) accumulated in organs expressing mouse CXCR4, e.g. the liver (SUV mean (mean standardized uptake value) 75 min p.i. 11.7 ± 0.6), which was blockable by co-injecting AMD3100 (5 mg/kg). In U87.CXCR4 xenografted tumor mice, the tumor uptake of [ 18 F]AlF-NOTA-2xDV1(c11sc12s) remained low (SUV mean 0.5 ± 0.1), but was reduced by co-administration of AMD3100. Surprisingly, [ 18 F]AlF-NOTA-2xDV1(c11sc12s) exhibited a similar biodistribution in a non-human primate as in mice indicating off-target binding of [ 18 F]AlF-NOTA-2xDV1(c11sc12s) in liver tissue. We confirmed that [ 18 F]AlF-NOTA-2xDV1(c11sc12s) is taken up by hepatocytes using in vitro studies and that the uptake can be blocked with AMD3100 and rifampicin, a potent organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 inhibitor., Conclusion: The second generation D-peptide AlF-NOTA-2xDV1(c11sc12s) showed high affinity for human CXCR4 and the corresponding radiotracer was produced in good radiochemical yields. However, [ 18 F]AlF-NOTA-2xDV1(c11sc12s) is not specific for CXCR4 and is also a substrate for OATP1B1 and/or OATP1B3, known to mediate hepatic uptake. Therefore, D-amino acid peptides, based on the viral macrophage inflammatory protein II, are not the prefered vector molecule for the development of CXCR4 targeting molecular imaging tools., 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 © 2024 Elsevier Inc. All rights reserved.)

Purpose: Next-generation SPECT/CT systems with CdZnTe (CZT) digital detectors in a ring-like setup are emerging to perform quantitative Lu-177 SPECT imaging in clinical routine. It is essential to assess how the shorter acquisition time might affect the image quality and uncertainty on the mean absorbed dose of the tumors and organs at risk compared to a conventional system., Methods: A NEMA Image Quality phantom was scanned with a 3D CZT SPECT/CT system (Veriton, by Spectrum Dynamics) using 6 min per bed position and with a conventional SPECT/CT system (Symbia T16, by Siemens) using 16 min per bed position. The sphere-to-background ratio was 12:1 and the background activity concentration ranged from 0.52 to 0.06 MBq/mL. A clinical reconstruction protocol for dosimetry purposes was determined for both systems by maximizing the sphere-to-background ratio while keeping the coefficient of variation of the background as low as possible. The corresponding image resolution was determined by the matching filter method and used for a dose uncertainty assessment of both systems following an established uncertainty model.., Results: The optimized iterative reconstruction protocol included scatter and attenuation correction for both systems and detector response modeling for the Siemens system. For the 3D CZT system, 6 iterations and 8 subsets were combined with a Gaussian post-filter of 3 mm Full Width Half Maximum (FWHM) for post-smoothing. For the conventional system, 16 iterations and 16 subsets were applied with a Gaussian post-smoothing filter of 1 mm FWHM. For these protocols, the sphere-to-background ratio was 18.5% closer to the true ratio for the conventional system compared to the 3D CZT system when considering the four largest spheres. Meanwhile, the background coefficient of variation was very similar for both systems. These protocols resulted in SPECT image resolution of 14.8 mm and 13.6 mm for the 3D CZT and conventional system respectively. Based on these resolution estimates, a 50% dose uncertainty corresponded to a lesion volume of 28 mL for the conventional system and a lesion volume of 33 mL for the 3D CZT system., Conclusions: An optimized reconstruction protocol for a Veriton system with 6 min of acquisition time per bed position resulted in slightly higher dose uncertainties than a conventional Symbia system using 16 min of acquisition time per bed position. Therefore, a 3D CZT SPECT/CT allows to significantly reduce the acquisition times with only a very limited impact on dose uncertainties such that quantitative Lu-177 SPECT/CT imaging becomes much more accessible for treatment concurrent dosimetry. Nevertheless, the uncertainty of SPECT-based dose estimates remains high., (© 2024. The Author(s).)

Late-life depression has been consistently associated with lower gray matter volume, the origin of which remains largely unexplained. Recent in-vivo PET findings in early-onset depression and Alzheimer's Disease suggest that synaptic deficits contribute to the pathophysiology of these disorders and may therefore contribute to lower gray matter volume in late-life depression. Here, we investigate synaptic density in vivo for the first time in late-life depression using the synaptic vesicle glycoprotein 2A receptor radioligand 11 C-UCB-J. We included 24 currently depressed adults with late-life depression (73.0 ± 6.2 years, 16 female, geriatric depression scale = 19.5 ± 6.8) and 36 age- and gender-matched healthy controls (70.4 ± 6.2 years, 21 female, geriatric depression scale = 2.7 ± 2.9) that underwent simultaneous 11 C-UCB-J positron emission tomography (PET) and 3D T1- and T2-FLAIR weighted magnetic resonance (MR) imaging on a 3-tesla PET-MR scanner. We used analyses of variance to test for 11 C-UCB-J binding and gray matter volumes differences in regions implicated in depression. The late-life depression group showed a trend in lower gray matter volumes in the hippocampus (p = 0.04), mesial temporal (p = 0.02) and prefrontal cortex (p = 0.02) compared to healthy control group without surviving correction for multiple comparison. However, no group differences in 11 C-UCB-J binding were found in these regions nor were any associations between 11 C-UCB-J and depressive symptoms. Our data suggests that, in contrast to Alzheimer's Disease, lower gray matter volume in late-life depression is not associated with synaptic density changes. From a therapeutic standpoint, preserved synaptic density in late-life depression may be an encouraging finding., (© 2024. The Author(s).)

Terbium features four clinically interesting radionuclides for application in nuclear medicine: terbium-149, terbium-152, terbium-155, and terbium-161. Their identical chemical properties enable the synthesis of radiopharmaceuticals with the same pharmacokinetic character, while their distinctive decay characteristics make them valuable for both imaging and therapeutic applications. In particular, terbium-152 and terbium-155 are useful candidates for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, respectively; whereas terbium-149 and terbium-161 find application in α- and β - -/Auger electron therapy, respectively. This unique characteristic makes the terbium family ideal for the "matched-pair" principle of theranostics. In this review, the advantages and challenges of terbium-based radiopharmaceuticals are discussed, covering the entire chain from radionuclide production to bedside administration. It elaborates on the fundamental properties of terbium, the production routes of the four interesting radionuclides and gives an overview of the available bifunctional chelators. Finally, we discuss the preclinical and clinical studies as well as the prospects of this promising development in nuclear medicine., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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.