Positron Emission Tomography Analysis Research Articles

Towards a standardized pipeline for tau PET analysis under a GAAIN/LONI and CPAD collaborative framework

AbstractBackgroundImaging tau burden in vivo using Positron Emission Tomography (PET) has tremendous potential for advancing our biological understanding of Alzheimer’s disease. Towards this direction, there is a need for post‐acquisition imaging data ‘harmonization’ tools and analysis methods that reduce variance across studies, sites, and scanners, while retaining the power to study complex disease related effects. The Global Alzheimer’s Association Interactive Network (GAAIN), the Laboratory of Neuro Imaging (LONI), and the Critical Path for Alzheimer’s Disease (CPAD) Consortium have undertaken a collaborative effort to provide a harmonized approach to the analysis of tau PET images.MethodThe GAAIN/LONI Pipeline is a software suite that allows the design and execution of neuroimaging workflows through flexible integration of different image preprocessing software and parallel processing via a computer grid. Each workflow has a distinct fingerprint that can be executed locally on different platforms or remotely via GAAIN, thus increasing interoperability and allowing the use of “harmonized” workflows across different datasets. Tau PET workflows were designed and deployed on the GAAIN/LONI Pipeline based on existing literature. In turn, these tau PET workflows were executed on CPAD tau PET to derive tau PET burden. Clinical validation was performed by quantifying tau PET burden on different clinical groups. Analytical validation was performed by correlating the LONI Pipeline results with independently developed pipelines.ResultWe first show feasibility results as the tau PET workflows are deployed and executed on CPAD data. For clinical validation, we tested whether derived metrics can distinguish between clinical groups. For analytical validation we tested correlations of results with existing methods that have been independently developed. These results provide a unified analysis model that can be utilized from GAAIN/LONI and CPAD to conduct harmonized analyses on multiple datasets. The full capabilities of this model will be explored in subsequent work.ConclusionThe proposed pipeline, which is going to be part of the publicly available GAAIN/LONI platform, should provide researchers with an optimized roadmap that describes how tau PET imaging data should be processed and analyzed for reliability and reproducibility in the context of drug development and regulatory decision making.

Challenges and innovations in brain PET analysis of neurodegenerative disorders: a mini-review on partial volume effects, small brain region studies, and reference region selection.

Positron Emission Tomography (PET) brain imaging is increasingly utilized in clinical and research settings due to its unique ability to study biological processes and subtle changes in living subjects. However, PET imaging is not without its limitations. Currently, bias introduced by partial volume effect (PVE) and poor signal-to-noise ratios of some radiotracers can hamper accurate quantification. Technological advancements like ultra-high-resolution scanners and improvements in radiochemistry are on the horizon to address these challenges. This will enable the study of smaller brain regions and may require more sophisticated methods (e.g., data-driven approaches like unsupervised clustering) for reference region selection and to improve quantification accuracy. This review delves into some of these critical aspects of PET molecular imaging and offers suggested strategies for improvement. This will be illustrated by showing examples for dopaminergic and cholinergic nerve terminal ligands.

Exploring HD-tDCS Effect on μ-opioid Receptor and Pain Sensitivity in Temporomandibular Disorder: A Pilot Randomized Clinical Trial Study

This study explored the association between experimentally-induced pain sensitivity and µ-opioid receptor (μOR) availability in patients with temporomandibular disorder (TMD) and further investigated any changes in the pain and μOR availability following high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) with pilot randomized clinical trials. Seven patients with TMD completed either active (n = 3) or sham treatment (n = 4) for 10 daily sessions and underwent positron emission tomography (PET) scans with [11C]carfentanil, a selective μOR agonist, a week before and after treatment. PET imaging consisted of an early resting and late phase with the sustained masseteric pain challenge by computer-controlled injection of 5% hypertonic saline. We also included 12 patients with TMD, obtained from our previous study, for baseline PET analysis. We observed that patients with more sensitivity to pain, indicated by lower infusion rate, had less μOR availability in the right amygdala during the late phase. Moreover, active M1 HD-tDCS, compared to sham, increased μOR availability post-treatment in the thalamus during the early resting phase and the amygdala, hippocampus, and parahippocampal gyrus during the late pain challenge phase. Importantly, increased μOR availability post-treatment in limbic structures including the amygdala and hippocampus was associated with decreased pain sensitivity. The findings underscore the role of the μOR system in pain regulation and the therapeutic potential of HD-tDCS for TMD. Nonetheless, large-scale studies are necessary to establish the clinical significance of these results. Trial registrationClinicalTrial.gov (NCT03724032) PerspectiveThis study links pain sensitivity and µ-opioid receptors in patients with TMD. HD-tDCS over M1 improved µOR availability, which was associated with reduced pain sensitivity. Implications for TMD pain management are promising, but larger clinical trials are essential for validation.

The integration of angio-IMR, QFR and FFR for the detection of ischemia

Abstract Background Fractional flow reserve (FFR) and quantitative flow ratio (QFR) are important tools to assess coronary-specific ischemia, but ischemia may be obscured in the presence of coronary microvascular dysfunction (CMD). Wire free angiography based index of microcirculatory resistance (angio-IMR) might aid in identifying ischemic territories with normal FFR or QFR. Purpose First we sought to validate angio-IMR against invasive resistance indices and [15O]H2O positron emission tomography (PET) derived resistance. Secondly, we investigated whether angio-IMR can help identifying ischemic vessels with normal FFR/QFR. Methods In this PACIFIC 1 and 2 sub study symptomatic patients underwent [15O]H2O PET and invasive coronary angiography with routine three vessel FFR. Invasive hyperemic microvascular resistance (HMR) and IMR were measured in a sub set of patients. A FFR/QFR ≤0.80 and hyperemic myocardial blood flow (hMBF) ≤2.3 ml/min/g were considered ischemic. Microvascular resistance on PET was defined as the ratio of mean distal coronary pressure to MBF. Angio-IMR, QFR and PET analyses were performed by core labs blinded to invasive angiography results. Results Among 259 patients (mean age 61 ± 9 years, 188 (73%) male) 494 vessels were included. Invasive IMR and or HMR were measured in 95 vessels. Angio-IMR did not correlate with invasive HMR/IMR for the right coronary artery (RCA) but correlated weakly with invasive HMR (r=0.39, p=0.03) and moderately (r=0.48, p<0.01) with invasive IMR for the left coronary artery (LCA). The RCA was excluded for further analysis. A very weak correlation between angio-IMR and PET resistance was observed (r=0.17, p<0.01). Territories with ischemia and a normal FFR showed a higher angio-IMR than ischemic territories with reduced FFR (31.3 ± 13.8 vs 22.2 ± 10.3, p<0.01). The same was observed after stratification by QFR/PET results (34.3 ± 15.5 vs 23.9 ± 9.9, p<0.01). Results remained consistent after stratification for diameter stenosis percentage. Conclusions A weak to moderate correlation was found between angio-IMR and invasive resistance indices for the LCA. In territories with an ischemic perfusion angio-IMR was higher in those with a normal FFR/QFR compared to patients with a reduced FFR/QFR. Integration of FFR/QFR and angio-IMR might lead to superior vessel-specific ischemia detection.

The prognostic power of [11C]methionine PET in IDH-wildtype diffuse gliomas with lower-grade histological features: venturing beyond WHO classification.

IDH-wildtype (IDH-wt) diffuse gliomas with histological features of lower-grade gliomas (LGGs) are rare and heterogeneous primary brain tumours. [11C]Methionine (MET) positron emission tomography (PET) is commonly used to evaluate glial neoplasms at diagnosis. The present study aimed to assess the prognostic value of MET PET in newly diagnosed, treatment naïve IDH-wt gliomas with histological features of LGGs. Patients with a histological diagnosis of IDH-wt LGG who underwent preoperative (< 100days) MET PET/CT and surgery were retrospectively included. Qualitative and semi-quantitative analyses of MET PET images were performed. Progression-free survival (PFS) and overall survival (OS) were analysed by Kaplan-Meier curves. Cox proportional-hazards regression was used to test the association of imaging and clinical data to PFS and OS. We included 48 patients (M:F = 25:23; median age 55). 39 lesions were positive and 9 negative at MET PET. Positive MET PET was significantly associated with shorter median PFS (15.7months vs. not reached, p = 0.0146) and OS time (32.6months vs. not reached, p = 0.0253). Incomplete surgical resection and higher TBRmean values were independent predictors of shorter PFS on multivariate analysis (p < 0.001 for both). Higher tumour grade and incomplete surgical resection were independent predictors of OS at multivariate analysis (p = 0.027 and p = 0.01, respectively). MET PET is useful for the prognostic stratification of patients with IDH-wt glial neoplasms with histological LGGs features. Considering their huge biological heterogeneity, the combination of MET PET and molecular analyses may help to improve the prognostic accuracy in these diffuse gliomas subset and influence therapeutic choices accordingly.

Radiomics for the detection of diffusely impaired myocardial perfusion: A proof-of-concept study using 13N-ammonia positron emission tomography

AimThe current proof-of-concept study investigates the value of radiomic features from normal 13N-ammonia positron emission tomography (PET) myocardial retention images to identify patients with reduced global myocardial flow reserve (MFR). MethodsData from 100 patients with normal retention 13N-ammonia PET scans were divided into two groups, according to global MFR (i.e., < 2 and ≥ 2), as derived from quantitative PET analysis. We extracted radiomic features from retention images at each of five different gray-level (GL) discretization (8, 16, 32, 64, and 128 bins). Outcome independent and dependent feature selection and subsequent univariate and multivariate analyses was performed to identify image features predicting reduced global MFR. ResultsA total of 475 radiomic features were extracted per patient. Outcome independent and dependent feature selection resulted in a remainder of 35 features. Discretization at 16 bins (GL16) yielded the highest number of significant predictors of reduced MFR and was chosen for the final analysis. GLRLM_GLNU was the most robust parameter and at a cut-off of 948 yielded an accuracy, sensitivity, specificity, negative and positive predictive value of 67%, 74%, 58%, 64%, and 69%, respectively, to detect diffusely impaired myocardial perfusion. ConclusionA single radiomic feature (GLRLM_GLNU) extracted from visually normal 13N-ammonia PET retention images independently predicts reduced global MFR with moderate accuracy. This concept could potentially be applied to other myocardial perfusion imaging modalities based purely on relative distribution patterns to allow for better detection of diffuse disease.

Profiling and predicting distinct tau progression patterns: An unsupervised data-driven approach to flortaucipir positron emission tomography.

How to detect patterns of greater tau burden and accumulation is still an open question. An unsupervised data-driven whole-brain pattern analysis of longitudinal tau positron emission tomography (PET) was used first to identify distinct tau accumulation profiles and then to build baseline models predictive of tau-accumulation type. The data-driven analysis of longitudinal flortaucipir PET from studies done by the Alzheimer's Disease Neuroimaging Initiative, Avid Pharmaceuticals, and Harvard Aging Brain Study (N=348 cognitively unimpaired, N=188 mild cognitive impairment, N=77 dementia), yielded three distinct flortaucipir-progression profiles: stable, moderate accumulator, and fast accumulator. Baseline flortaucipir levels, amyloid beta (Aβ) positivity, and clinical variables, identified moderate and fast accumulators with 81% and 95% positive predictive values, respectively. Screening for fast tau accumulation and Aβ positivity in early Alzheimer's disease, compared to Aβ positivity with variable tau progression profiles, required 46% to 77% lower sample size to achieve 80% power for 30% slowing of clinical decline. Predicting tau progression with baseline imaging and clinical markers could allow screening of high-risk individuals most likely to benefit from a specific treatment regimen.

Evaluation of the 18F-labeled analog of the therapeutic all-D-enantiomeric peptide RD2 for amyloid β imaging

Positron emission tomography (PET) imaging with radiotracers that bind to fibrillary amyloid β (Aβ) deposits is an important tool for the diagnosis of Alzheimer's disease (AD) and for the recruitment of patients into clinical trials. However, it has been suggested that rather than the fibrillary Aβ deposits, it is smaller, soluble Aβ aggregates that exert a neurotoxic effect and trigger AD pathogenesis. The aim of the current study is to develop a PET probe that is capable of detecting small aggregates and soluble Aβ oligomers for improved diagnosis and therapy monitoring. An 18F-labeled radioligand was prepared based on the Aβ-binding d-enantiomeric peptide RD2, which is currently being evaluated in clinical trials as a therapeutic agent to dissolve Aβ oligomers. 18F-labeling was carried out using palladium-catalyzed S-arylation of RD2 with 2-[18F]fluoro-5-iodopyridine ([18F]FIPy). Specific binding of [18F]RD2-cFPy to brain material from transgenic AD (APP/PS1) mice and AD patients was demonstrated with in vitro autoradiography. In vivo uptake and biodistribution of [18F]RD2-cFPy were evaluated using PET analyses in wild-type and transgenic APP/PS1 mice. Although brain penetration and brain wash-out kinetics of the radioligand were low, this study provides proof of principle for a PET probe based on a d-enantiomeric peptide binding to soluble Aβ species.

Impact of framing scheme optimization and smoking status on binding potential analysis in dynamic PET with [11C]ABP688

BackgroundFor positron emission tomography (PET) ligands, such as [11C]ABP688, to be able to provide more evidence about the glutamatergic hypothesis in schizophrenia (SZ), quantification bias during dynamic PET studies and its propagation into the estimated values of non-displaceable binding potential (BPND) must be addressed. This would enable more accurate quantification during bolus + infusion (BI) neuroreceptor studies and further our understanding of neurological diseases. Previous studies have shown BPND-related biases can often occur due to overestimated cerebellum activity (reference region). This work investigates whether an alternative framing scheme can minimize quantification biases propagated into BPND, whether confounders, such as smoking status, need to be controlled for during the study, and what the consequences for the data interpretation following analysis are. A group of healthy controls (HC) and a group of SZ patients (balanced and unbalanced number of smokers) were investigated with [11C]ABP688 and a BI protocol. Possible differences in BPND quantification as a function of smoking status were tested with constant 5 min (‘Const 5 min’) and constant true counts (‘Const Trues’) framing schemes. In order to find biomarkers for SZ, the differences in smoking effects were compared between groups. The normalized BPND and the balanced number of smokers and non-smokers for both framing schemes were evaluated.ResultsWhen applying F-tests to the ‘Const 5 min’ framing scheme, effect sizes (η2p) and brain regions which showed significant effects fluctuated considerably with F = 50.106 ± 54.948 (9.389 to 112.607), P-values 0.005 to < 0.001 and η2p = 0.514 ± 0.282 (0.238 to 0.801). Conversely, when the ‘Const Trues’ framing scheme was applied, the results showed much smaller fluctuations with F = 78.038 ± 8.975 (86.450 to 68.590), P < 0.001 for all conditions and η2p = 0.730 ± 0.017 (0.742 to 0.710), and regions with significant effects were more robustly reproduced. Further, differences, which would indicate false positive identifications between HC and SZ groups in five brain regions when using the ‘Const 5 min’ framing scheme, were not observed with the ‘Const Trues’ framing.ConclusionsBased on an [11C]ABP688 PET study in SZ patients, the results show that non-consistent BPND outcomes can be propagated by the framing scheme and that potential bias can be minimized using ‘Const Trues’ framing.

Radiochemical Synthesis of 4-[18F]FluorobenzylAzide and Its Conjugation with EGFR-Specific Aptamers

Central nervous system tumors related to gliomas are of neuroectodermal origin and cover about 30% of all primary brain tumors. Glioma is not susceptible to any therapy and surgical attack remains one of the main approaches to its treatment. Preoperative tumor imaging methods, such as positron emission tomography (PET), are currently used to distinguish malignant tissue to increase the accuracy of glioma removal. However, PET is lacking a specific visualization of cells possessing certain molecular markers. Here, we report an application of aptamers to enhancing specificity in imaging tumor cells bearing the epidermal growth factor receptor (EGFR). Glioblastoma is characterized by increased EGFR expression, as well as mutations of this receptor associated with active division, migration, and adhesion of tumor cells. Since 2021, EGFR has been included into the WHO classification of gliomas as a molecular genetic marker. To obtain conjugates of aptamers GR20 and GOL1-specific to EGFR, a 4-[18F]fluorobenzylazide radiotracer was used as a synthon. For the production of the synthon, a method of automatic synthesis on an Eckert & Ziegler research module was adapted and modified using spirocyclic iodonium ylide as a precursor. Conjugation of 4-[18F]fluorobenzylazide and alkyne-modified aptamers was carried out using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with/without the TBTA ligand. As a result, it was possible to obtain 18F-labelled conjugates with 97% radiochemical purity for [18F]FB-GR20 and 98% for [18F]FB-GOL1. The obtained conjugates can be used for further studies in PET analysis on model animals with grafted glioblastoma.

Preoperative Detection of Subtle Focal Cortical Dysplasia in Children by Combined Arterial Spin Labeling, Voxel-Based Morphometry, Electroencephalography-Synchronized Functional MRI, Resting-State Regional Homogeneity, and 18F-fluorodeoxyglucose Positron Emission Tomography.

Focal cortical dysplasia (FCD) causes drug-resistant epilepsy in children that can be cured surgically, but the lesions are often unseen by imaging. To assess the efficiency of arterial spin labeling (ASL), voxel-based-morphometry (VBM), fMRI electroencephalography (EEG), resting-state regional homogeneity (ReHo), 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their combination in detecting pediatric FCD. We prospectively included 10 children for whom FCD was localized by surgical resection. They underwent 3T MR acquisition with concurrent EEG, including ASL perfusion, resting-state BOLD fMRI (allowing the processing of EEG-fMRI and ReHo), 3D T1-weighted images processed using VBM, and FDG PET-CT coregistered with MRI. Detection was assessed visually and by comparison with healthy controls (for ASL and VBM). Eight children had normal MRI, and 2 had asymmetric sulci. Using MR techniques, FCD was accurately detected by ASL for 6/10, VBM for 5/10, EEG-fMRI for 5/8 (excluding 2 with uninterpretable results), and ReHo for 4/10 patients. The combination of ASL, VBM, and ReHo allowed correct FCD detection for 9/10 patients. FDG PET alone showed higher accuracy than the other techniques (7/9), and its combination with VBM allowed correct FCD detection for 8/9 patients. The detection efficiency was better for patients with asymmetric sulci (2/2 for all techniques), but advanced MR techniques and PET were useful for MR-negative patients (7/8). A combination of multiple imaging techniques, including PET, ASL, and VBM analysis of T1-weighted images, is effective in detecting subtle FCD in children.

586 BODY WEIGHT AND MICROVASCULAR DYSFUNCTION IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY AT LOW CARDIOVASCULAR RISK REFERRED TO POSITRON EMISSION TOMOGRAPHY

Abstract Introduction Whether obesity, a modifiable risk factor in patients with hypertrophic cardiomyopathy (HCM), can influence coronary microvascular dysfunction (CMD) is unknown. Objective To assess the relationship between body weight and CMD measured with myocardial blood flow (MBF) at positron emission tomography (PET) in patients with HCM. Methods All consecutive patients with HCM referred to PET scan from 2010 to 2020 were reviewed. Only patients with PET and cardiac magnetic resonance (CMR) analysis, &amp;lt;60 years old at diagnosis, with no history of diabetes, dyslipidemia, and hypertension were included. Patients were classified into three groups according to baseline BMI: BMI&amp;lt;25 kg/m2, BMI 25-30 kg/m2, and BMI&amp;gt;30 kg/m2. Results Of 1512 patients with HCM, 134 (8.9%) had been referred to a PET scan and 79 (5.2%) met the inclusion criteria (29% were women, median age was 44 [28-53] years). Overall, 52% had a BMI&amp;lt;25 kg/m2, 37% had a BMI 25-30 kg/m2, and 11% had a BMI &amp;gt;30 kg/m2. At PET, average MBF was 2.08 [1.52-2.40] ml/min/g and was similar among BMI groups (p=0.288) irrespective of fibrosis at CMR. Prevalence of severe microvascular dysfunction was similar (MBF &amp;lt;1.53 ml/min/g: (9 [22%] vs 8 [28%] vs 2 [22%], among study groups, p=0.833). Age at PET and atrial fibrillation were associated with MBF. Conclusions Obesity is not associated with worsening of CMD in HCM patients. These findings support the hypothesis that the worse symptomatic profile in obese HCM patients is due to increased prevalence of obstruction rather than accentuation of structural phenotype. Thus, the symptomatic handicap associated with obesity may be reversible following appropriate weight-reduction strategies

Differential cholinergic systems' changes in progressive supranuclear palsy versus Parkinson's disease: an exploratory analysis.

Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [18F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ2 = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP.

Assessment of Alzheimer's Disease Imaging Biomarkers in World Trade Center Responders with Cognitive Impairment at Midlife.

Purpose Incidence of early onset neurocognitive dysfunction has been reported in World Trade Center (WTC) responders. Ongoing studies are investigating the underlying etiology, as we are concerned that an underlying risk of neurodegenerative dementia may be occurring because of their stressful and neurotoxic exposures to particulate matter when they responded to the search and rescue efforts on September 11, 2001. The purpose of this study is to report preliminary results from two ongoing positron emission tomography (PET)/magnetic resonance imaging (MRI) imaging studies investigating the presence of Alzheimer's disease (AD) biomarkers, such as β-amyloid, tau, and neurodegeneration, and compare our findings to published norms. Methods We present findings on 12 WTC responders diagnosed with either cognitive impairment (CI) or mild cognitive impairment (MCI), now at midlife, who underwent PET/MRI brain imaging as part of ongoing studies. Six responders with CI received [ 18 F] florbetaben (FBB) to detect β-amyloidosis and six separate responders with MCI received [ 18 F] flortaucipir (FTP) to detect tauopathy. All 12 responders underwent concomitant MRI scans for gray matter volume analysis of neurodegeneration. Results PET analysis revealed 50% FBB and 50% of FTP scans were clinically read as positive and that 50% of FTP scans identified as consistent with Braak's stage I or II. Furthermore, one responder identified as centiloid positive for AD. Gray matter volumes from MRI analyses were compared with age/sex-matched norms (Neuroquant), identifying abnormally low cortical volumes in the occipital and temporal lobes, as well as the inferior temporal gyri and the entorhinal cortex. Conclusion These preliminary results suggest that WTC responders with neurocognitive dysfunction may be at increased risk for a neurodegenerative dementia process as a result of their exposures at September 11, 2001.

Imaging-Based Prevalence of Oligometastatic Disease: A Single-Center Cross-Sectional Study

Oligometastatic disease refers to a distinct state in patients with cancer characterized by a low metastatic burden, with diagnosis being informed by a limited number of distant metastases in radiologic imaging. However, oligometastasis remains poorly understood in terms of its biology and prevalence in the metastatic cascade. In the absence of clinically viable molecular biomarkers, this study examined the prevalence of oligometastasis using oncological imaging. This study is based on all consecutive [fluorine-18]-fluorodeoxyglucose (FDG)- and [gallium-68]-prostate specific membrane antigen (PSMA)-positron emission tomography (PET) scans conducted at our cancer center between January and December 2020. We identified and analyzed all PET scans from patients with a maximum of 5 distant metastases from a solid malignancy and also reviewed concurrent cranial magnetic resonance imaging (cMRI) imaging in all candidate patients. Data on the number and sites of metastases were extracted from the imaging reports and verified on imaging studies in case of uncertainties. In total, 7000 PET scans were analyzed, of which 1155 were performed in unique metastatic patients, and 637 patients showed extracranial oligometastatic disease (55%). Concurrent cMRI scans were available for 20% (130/637) of extracranial oligometastatic patients, 36 of which proved to be polymetastatic after combined PET and cMRI analysis. Prevalence of oligometastatic disease was influenced by primary tumor histology and was most frequent in pancreatic, liver and gallbladder cancers (59%), but was least frequent in cancer of unknown primary (26%). In 72% of oligometastatic cases, only 1 or 2 metastases were detected. Bone/soft tissue metastases were the most common sites of distant metastasis (41%). About 75% of patients had metachronous oligometastatic disease. Our analysis suggests that about half of patients with metastatic cancer are characterized by a limited tumor burden detectable on PET and cMRI imaging. This finding warrants intensified research efforts to better understand the biology of oligometastatic disease and to optimize multidisciplinary treatment strategies.

11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.

Quantification of myocardial blood flow and myocardial flow reserve by 13N-NH3 PET/CT is not significantly affected by pixel size.

Myocardial blood flow (MBF) and myocardial flow reserve (MFR) are measurable by 13N-NH3 positron emission tomography (PET). MFR, which is the ratio of MBF under adenosine stress to MBF at rest, is prognostically valuable. The ASNC imaging guidelines/SNMMI procedure standards recommend using 2-3mm pixels, and pixel size does differ between institutions. We sought to evaluate the effects of pixel sizes on the quantitative values calculated from 13N-NH3 PET images. Thirty consecutive patients with ischemic heart disease who underwent 13N-NH3 PET were retrospectively enrolled. Dynamic images were quantified using PMOD's cardiac PET analysis tool (pixel sizes: 3.18, 2.03, and 1.59mm). MBF under adenosine stress, MBF at rest, and MFR for the right coronary artery (RCA) region, left anterior descending artery region, and left circumflex coronary artery branch region innervation regions were calculated at each pixel size and compared. Quantitative values did not significantly differ according to pixel size in any of the regions. However, MFR values for the RCA fluctuated the most. Ischemic and non-ischemic regions remained visually discernible in qualitative images, with no variation in quantitative values, regardless of pixel size. Quantitative values were not significantly affected by pixel sizes within the recommended range of 2-3mm. Values for the RCA region may have been overestimated, but this was true for all pixel sizes.

Spatiotemporal learning of dynamic positron emission tomography data improves diagnostic accuracy in breast cancer.

Positron emission tomography (PET) can reveal metabolic activity in a voxelwise manner. PET analysis is commonly performed in a static manner by analyzing the standardized uptake value (SUV) obtained from the plateau region of PET acquisitions. A dynamic PET acquisition can provide a map of the spatiotemporal concentration of the tracer in vivo, hence conveying information about radiotracer delivery to tissue, its interaction with the target and washout. Therefore, tissue-specific biochemical properties are embedded in the shape of time activity curves (TACs), which are generally used for kinetic analysis. Conventionally, TACs are employed along with information about blood plasma activity concentration, i.e., the arterial input function (AIF), and specific compartmental models to obtain a full quantitative analysis of PET data. The main drawback of this approach is the need for invasive procedures requiring arterial blood sample collection during the whole PET scan. In this paper, we address the challenge of improving PET diagnostic accuracy through an alternative approach based on the analysis of time signal intensity patterns. Specifically, we demonstrate the diagnostic potential of tissue TACs provided by dynamic PET acquisition using various deep learning models. Our framework is shown to outperform the discriminative potential of classical SUV analysis, hence paving the way for more accurate PET-based lesion discrimination without additional acquisition time or invasive procedures. Clinical Relevance- The diagnostic accuracy of dynamic PET data exploited by deep-learning based time signal intensity pattern analysis is superior to that of static SUV imaging.

Automated semi-quantitative amyloid PET analysis technique without MR images for Alzheimer’s disease

ObjectiveAlthough beta-amyloid (Aβ) positron emission tomography (PET) images are interpreted visually as positive or negative, approximately 10% are judged as equivocal in Alzheimer’s disease. Therefore, we aimed to develop an automated semi-quantitative analysis technique using 18F-flutemetamol PET images without anatomical images.MethodsOverall, 136 cases of patients administered 18F-flutemetamol were enrolled. Of 136 cases, five PET images each with the highest and lowest values of standardized uptake value ratio (SUVr) of cerebral cortex-to-pons were used to create positive and negative templates. Using these templates, PET images of the remaining 126 cases were standardized, and SUVr images were produced with the pons as a reference region. The mean of SUVr values in the volume of interest delineated on the cerebral cortex was compared to those in the CortexID Suite (GE Healthcare). Furthermore, centiloid (CL) values were calculated for the 126 cases using data from the Centiloid Project (http://www.gaain.org/centiloid-project) and both templates. 18F-flutemetamol-PET was interpreted visually as positive/negative based on Aβ deposition in the cortex. However, the criterion "equivocal" was added for cases with focal or mild Aβ accumulation that were difficult to categorize. Optimal cutoff values of SUVr and CL maximizing sensitivity and specificity for Aβ detection were determined by receiver operating characteristic (ROC) analysis using the visual evaluation as a standard of truth.ResultsSUVr calculated by our method and CortexID were highly correlated (R2 = 0.9657). The 126 PET images comprised 84 negative and 42 positive cases of Aβ deposition by visual evaluation, of which 11 and 10 were classified as equivocal, respectively. ROC analyses determined the optimal cutoff values, sensitivity, and specificity for SUVr as 0.544, 89.3%, and 92.9%, respectively, and for CL as 12.400, 94.0%, and 92.9%, respectively. Both semi-quantitative analyses showed that 12 and 9 of the 21 equivocal cases were negative and positive, respectively, under the optimal cutoff values.ConclusionsThis semi-quantitative analysis technique using 18F-flutemetamol-PET calculated SUVr and CL automatically without anatomical images. Moreover, it objectively and homogeneously interpreted positive or negative Aβ burden in the brain as a supplemental tool for the visual reading of equivocal cases in routine clinical practice.

Development and technical validation of an ultrasound nebulizer to deliver intraperitoneal pressurized aerosols in a rat colon cancer peritoneal metastases model

Background/aimTo develop and validate a nebulizer device for anti-cancer research on pressurized intraperitoneal aerosol supply in a preclinical peritoneal metastases (PM) rat model.Material and methodsFor aerosol generation, an ultrasonic nebulizer (USN) was modified. Aerosol analyses were performed ex-vivo by laser diffraction spectrometry (LDS). Intraperitoneal (IP) 99mtechnetium sodium pertechnetate (99mTc) aerosol distribution and deposition were quantified by in-vivo single photon emission computed tomography (SPECT/CT) and compared to liquid IP instillation of equivalent volume/doses of 99mTc with and without capnoperitoneum. PM was induced by IP injection of HCT116-Luc2 human colon cancer cells in immunosuppressed RNU rats. Tumor growth was monitored by bioluminescence imaging (BLI), 18F-FDG positron emission tomography (PET) and tissues examination at necropsy.ResultsThe USN was able to establish a stable and reproducible capnoperitoneum at a pressure of 8 to 10 mmHg. LDS showed that the USN provides a polydisperse and monomodal aerosol with a volume-weighted diameter of 2.6 μm. At a CO2 flow rate of 2 L/min with an IP residence time of 3.9 s, the highest drug deposition efficiency was found to be 15 wt.-%. In comparison to liquid instillation, nebulization showed the most homogeneous IP spatial drug deposition. Compared to BLI, 18F-FDG-PET was more sensitive to detect smaller PM nodules measuring only 1–2 mm in diameter. BLI, 18F-FDG PET and necropsy analyses showed relevant PM in all animals.ConclusionsThe USN together with the PM rat model are suitable for robust and species-specific preclinical pharmacological studies regarding intraperitoneal delivery of pressurized aerosolized drugs and cancer research.