Longitudinal Synaptic Density PET with 11 C-UCB-J 6 Months After Ischemic Stroke.

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.

Preclinical SPECT and PET: Joint EANM and ESMI procedure guideline for implementing an efficient quality control programme.

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.

A multi-label CNN model for the automatic detection and segmentation of gliomas using [18F]FET PET imaging.

PURPOSE: The aim of this study was to develop a convolutional neural network (CNN) for the automatic detection and segmentation of gliomas using [18F]fluoroethyl-L-tyrosine ([18F]FET) PET. METHODS: Ninety-three patients (84 in-house/7 external) who underwent a 20-40-min static [18F]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 [18F]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 (TBRmax/TBRmean). 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 [18F]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 TBRmax/TBRmean 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 [18F]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 TBRmax/TBRmean estimation, such that user interaction and potential inter-reader variability can be minimized.

[18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]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 [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) 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 [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern.

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 18F-MK-6240 for tau and 11C-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.

Visual ensemble selection of deep convolutional neural networks for 3D segmentation of breast tumors on dynamic contrast enhanced MRI.

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.

Long-term test-retest of cerebral [18F]MK-6240 binding and longitudinal evaluation of extracerebral tracer uptake in healthy controls and amnestic MCI patients.

PURPOSE: Neurofibrillary tangles (NFTs) in Alzheimer's disease can be accurately quantified in vivo using [18F]MK-6240 PET. Short-term [18F]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, [18F]MK-6240 shows variable extracerebral uptake (ECU) assumed to represent off-target binding to leptomeningeal melanocytes. Here, we examined 6-month TRT of [18F]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 [18F]MK-6240 PET-MR (GE Signa), 90-120 min post injection. [18F]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 [18F]MK-6240 to assess TRT. Also, 10 aMCI (72 ± 6 years, 5F/5 M) underwent a 2-year follow-up [18F]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 [18F]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 (rs = - 0.48; p < 0.0001), and a multivariate analysis also showed sex differences (higher ECU in women). CONCLUSION: [18F]MK-6240 shows excellent 6-month TRT, which confirms its suitability for quantification of longitudinal NFT changes. The ECU of [18F]MK-6240 is variable between subjects, influenced by age and sex, but remains stable within subjects over a 2-year time period.

Regional glucose metabolic decreases with ageing are associated with microstructural white matter changes: a simultaneous PET/MR study.

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.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

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 [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]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 [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]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 [11C]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 [11C]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 [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. CONCLUSION: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]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).

Innate immune cells and myelin profile in multiple sclerosis: a multi-tracer PET/MR study.

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)-[11C]PK11195 and [11C]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)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]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, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT 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)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]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)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). CONCLUSIONS: Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.

Prospective comparison of simultaneous [68Ga]Ga-PSMA-11 PET/MR versus PET/CT in patients with biochemically recurrent prostate cancer.

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 [68Ga]Ga-PSMA-11 PET/CT, followed by simultaneous PET/MR. All PET (PETCT, PETMR), 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: PETCT and PETMR scans were positive in 19 and 20 patients, detecting 73 and 79 lesions respectively. All lesions detected on PETCT were also detected on PETMR. CT and MRI only were positive in 14 and 17 patients, detecting 38 and 50 lesions, respectively, which was significantly lower than PETCT and PETMR 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. SUVmean and SUVmax values were significantly higher on PETMR than on PETCT in local recurrence and lymph node metastases. CONCLUSIONS: [68Ga]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.

Cannabinoid receptor availability modulates the magnitude of dopamine release in vivo in the human reward system: A preliminary multitracer positron emission tomography study.

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 (CB1 Rs). Although considerable preclinical evidence has demonstrated several functional CB1 R-DA interactions, the relation between human CB1 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 CB1 R expression levels and DA release capacity in a normo-DAergic state, relating in vivo AMPH-induced DA release to CB1 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 CB1 R levels. Compared with placebo, AMPH significantly reduced [18 F]fallypride binding potential (hence increase DA release; ΔBPND 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 CB1 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 CB1 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 CB1 R availability in the ACC (c' = -0.76; p = 0.01). Our small preliminary study reports for the first time that the human prefrontal CB1 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 CB1 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.

Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study.

RATIONALE: 11C-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 11C-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 11C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric 11C-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 11C-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 11C-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 11C-UCB-J SUVR, nor an interaction between aging and sex for this parameter. CONCLUSION: In vivo, PET using 11C-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.

Synthetic Pept-Ins as a Generic Amyloid-Like Aggregation-Based Platform for In Vivo PET Imaging of Intracellular Targets.

Amyloid-like aggregation of proteins is induced by short amyloidogenic sequence segments within a specific protein sequence resulting in self-assembly into ß-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 [68Ga]Ga-NODAGA-PEG4-vascin (targeting VEGFR2) and [68Ga]Ga-NODAGA-PEG2-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.

Clinical validation of the novel HDAC6 radiotracer [18F]EKZ-001 in the human brain.

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 [18F]EKZ-001 ([18F]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 (VT) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. VT 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 VT were in agreement with 2TCM VT, however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional VT 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 VT than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported. CONCLUSION: [18F]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.

Combined brain and spinal FDG PET allows differentiation between ALS and ALS mimics.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with on average a 1-year delay between symptom onset and diagnosis. Studies have demonstrated the value of [18F]-FDG PET as a sensitive diagnostic biomarker, but the discriminatory potential to differentiate ALS from patients with symptoms mimicking ALS has not been investigated. We investigated the combination of brain and spine [18F]-FDG PET-CT for differential diagnosis between ALS and ALS mimics in a real-life clinical diagnostic setting. METHODS: Patients with a suspected diagnosis of ALS (n = 98; 64.8 ± 11 years; 61 M) underwent brain and spine [18F]-FDG PET-CT scans. In 62 patients, ALS diagnosis was confirmed (67.8 ± 10 years; 35 M) after longitudinal follow-up (average 18.1 ± 8.4 months). In 23 patients, another disease was diagnosed (ALS mimics, 60.9 ± 12.9 years; 17 M) and 13 had a variant motor neuron disease, primary lateral sclerosis (PLS; n = 4; 53.6 ± 2.5 years; 2 M) and progressive muscular atrophy (PMA; n = 9; 58.4 ± 7.3 years; 7 M). Spine metabolism was determined after manual and automated segmentation. VOI- and voxel-based comparisons were performed. Moreover, a support vector machine (SVM) approach was applied to investigate the discriminative power of regional brain metabolism, spine metabolism and the combination of both. RESULTS: Brain metabolism was very similar between ALS mimics and ALS, whereas cervical and thoracic spine metabolism was significantly different (in standardised uptake values; cervical: ALS 2.1 ± 0.5, ALS mimics 1.9 ± 0.4; thoracic: ALS 1.8 ± 0.3, ALS mimics 1.5 ± 0.3). As both brain and spine metabolisms were very similar between ALS mimics and PLS/PMA, groups were pooled for accuracy analyses. Mean discrimination accuracy was 65.4%, 80.0% and 81.5%, using only brain metabolism, using spine metabolism and using both, respectively. CONCLUSION: The combination of brain and spine FDG PET-CT with SVM classification is useful as discriminative biomarker between ALS and ALS mimics in a real-life clinical setting.

Quantification and discriminative power of 18F-FE-PE2I PET in patients with Parkinson's disease.

RATIONALE: Dopamine transporter (DAT) imaging is an important adjunct in the diagnostic workup of patients with Parkinsonism. 18F-FE-PE2I is a suitable PET radioligand for DAT quantification and imaging with good pharmacokinetics. The aim of this study was to determine a clinical optimal simplified reference tissue-based image acquisition protocol and to compare the discriminatory value and effect size for 18F-FE-PE2I to that for 123I-FP-CIT scan currently used in clinical practice. METHODS: Nine patients with early Parkinson's disease (PD, 64.3 ± 6.8 years, 3M), who had previously undergone a 123I-FP-CIT scan as part of their diagnostic workup, and 34 healthy volunteers (HV, 47.7 ± 16.8 years, 13M) underwent a 60-min dynamic 18F-FE-PE2I PET-MR scan on a GE Signa 3T PET-MR. Based on dynamic data and MR-based VOI delineation, BPND, semi-quantitative uptake ratio and SUVR[t1-t2] images were calculated using either occipital cortex or cerebellum as reference region. For start-and-end time of the SUVR interval, three time frames [t1-t2] were investigated: [15-40] min, [40-60] min, and [50-60] min postinjection. Data for putamen (PUT) and caudate nucleus-putamen ratio (CPR) were compared in terms of quantification bias versus BPND and discriminative power. RESULTS: Using occipital cortex as reference region resulted in smaller bias of SUVR with respect to BPND + 1 and higher correlation between SUVR and BPND + 1 compared with using cerebellum, irrespective of SUVR [t1-t2] interval. Smallest bias was observed with the [15-40]-min time window, in accordance with previous literature. The correlation between BPND + 1 and SUVR was slightly better for the late time windows. Discriminant analysis between PD and HV using both PUT and CPR SUVRs showed an accuracy of ≥ 90%, for both reference regions and all studied time windows. Semi-quantitative 123I-FP-CIT and 18F-FE-PE2I values and relative decrease in the striatum for patients were highly correlated, with a higher effect size for 18F-FE-PE2I for PUT and CPR SUVR. CONCLUSION: 18F-FE-PE2I is a suitable radioligand for in vivo DAT imaging with high discriminative power between early PD and healthy controls. Whereas a [15-40]-min window has lowest bias with respect to BPND, a [50-60]-min time window at pseudoequilibrium can be advocated in terms of clinical feasibility with optimal discriminative power. The occipital cortex may be slightly preferable as reference region because of the higher time stability, stronger correlation of SUVR with BPND + 1, and lower bias. Moreover, the data suggest that the diagnostic accuracy of a 10-min static 18F-FE-PE2I scan is non-inferior compared with 123I-FP-CIT scan used in standard clinical practice.

[18F]AlF-NOTA-octreotide PET imaging: biodistribution, dosimetry and first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour patients.

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 [18F]AlF-NOTA-octreotide ([18F]AlF-OC). This prospective trial aimed to evaluate safety, dosimetry, biodistribution, pharmacokinetics and lesion targeting of [18F]AlF-OC and perform the first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour (NET) patients. METHODS: Six healthy volunteers and six NET patients with a previous clinical [68Ga]Ga-DOTATATE PET were injected with an IV bolus of 4 MBq/kg [18F]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 (SUVmean) and tumour lesion uptake (SUVmax 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: [18F]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 [18F]AlF-OC was comparable to [68Ga]Ga-DOTATATE. Mean tumour SUVmax was lower for [18F]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 [68Ga]Ga-DOTATATE vs. 90.1% for [18F]AlF-OC at 2 h post-injection; p = 0.68). CONCLUSION: [18F]AlF-OC shows favourable kinetic and imaging characteristics in patients that warrant further head-to-head comparison to validate [18F]AlF-OC as a fluorine-18-labelled alternative for gallium-68-labelled SSA clinical PET. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03883776, EudraCT: 2018-002827-40.

Loss of Presynaptic Terminal Integrity in the Substantia Nigra in Early Parkinson's Disease.

BACKGROUND: It has been hypothesized that the pathology of Parkinson's disease (PD) primarily affects presynaptic terminals and spreads trans-synaptically. OBJECTIVES: The main objective of this study was to assess the magnitude and anatomical extent of presynaptic terminal loss across the brain in early PD. A second objective was to compare loss of presynaptic terminals and cell bodies within the nigrostriatal tract. METHODS: A total of 30 patients with early PD and 20 age- and gender-matched healthy controls underwent positron emission tomography with 11 C-UCB-J, a ligand for the universal presynaptic terminal marker synaptic vesicle protein 2A (SV2A), and with the dopamine transporter ligand 18 F-FE-PE2I, as well as a detailed clinical assessment. Volumes of interest were delineated based on individual 3-dimensional T1 magnetic resonance imaging. BPND images were calculated. RESULTS: Patients with PD showed significant loss of SV2A binding in the substantia nigra only. Loss of dopamine transporter binding in the PD group was much greater in the putamen than in the substantia nigra. We found no correlations between SV2A or dopamine transporter binding and any of the clinical motor or nonmotor scores. Homologous voxel-based analysis in the PD group showed significant correlations between SV2A and dopamine transporter binding in the caudate and substantia nigra. CONCLUSIONS: Presynaptic terminals appear to be the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. Moreover, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic boutons in the substantia nigra may reflect an axonal response to target deprivation or could possibly point to a trans-synaptic mode of propagation of the disease process. © 2020 International Parkinson and Movement Disorder Society.

Targeted alpha therapy: a critical review of translational dosimetry research with emphasis on actinium-225.

This review provides a general overview of the current achievements and challenges in translational dosimetry for targeted alpha therapy (TAT). The concept of targeted radionuclide therapy (TRNT) is described with an overview of its clinical applicability and the added value of TAT is discussed. For TAT, we focused on actinium-225 (225Ac) as an example for alpha particle emitting radionuclides and their features, such as limited range within tissue and high linear energy transfer, which make alpha particle emissions more effective in targeted killing of tumour cells compared to beta radiation. Starting with the state-of-the-art dosimetry for TRNT and TAT, we then describe the challenges that still need to be met in order to move to a personalized dosimetry approach for TAT. Specifically for 225Ac, we discuss the recoiled daughter effect which may provoke significant damage to healthy tissue or organs and should be considered. Next, a broad overview is given of the pre-clinical research on 225Ac-TAT with an extensive description of tools which are only available in a pre-clinical setting and their added value. In addition, we review the preclinical biodistribution and dosimetry studies that have been performed on TAT-agents and more specifically of 225Ac and its multiple progeny, and describe their potential role to better characterize the pharmacokinetic (PK) profile of TAT-agents and to optimize the use of theranostic approaches for dosimetry. Finally, we discuss the support pre-clinical studies may provide in understanding dose-effect relationships, linking radiation dose quantities to biological endpoints and even moving away from macro- to microdosimetry. As such, the translation of pre-clinical findings may provide valuable information and new approaches for improved clinical dosimetry, thus paving the way to personalized TAT.