Advances In Positron Emission Tomography Research Articles

Monte Carlo simulation of two Siemens Biograph PET/CT system using GATE: Image quality performance

The utilization of Monte Carlo simulation is a highly effective method in advancing research within the field of nuclear medicine. An important software tool for simulating and modeling cutting-edge systems for Positron Emission Tomography (PET) is the Geant4 Application for Tomographic Emission (GATE). This research specifically concentrates on two Siemens PET scanners: the Siemens Biograph True point (True V) and Siemens Biograph mcT 20 excel. Our primary objective was to validate the GATE V8.2 simulation in accordance with the NEMA (National Electrical Manufacturers Association) NU 2-2018 protocol, using a parallel computing platform on a local cluster of computers. This cluster was managed by the open-source package TORQUE version 6.1.0, which is based on the original wrapper PBS.The results of this validation process for the Siemens Biograph True point (True V) scanner were highly promising. The scatter fraction (SF), peak noise equivalent count rate (NECR), and sensitivity all demonstrated a remarkable level of agreement, with deviations within 10.02%, 5.4%, and 1.57%, respectively. Additionally, the spatial resolution was found to deviate by less than 0.59 mm. Image evaluations demonstrate high-quality results for both Siemens Biograph True point (True V) and Siemens Biograph mcT 20 excel scanners, validating the GATE simulation. The study on acquisition time provides insights into optimizing computing simulation time.This research demonstrates the effectiveness of Monte Carlo simulation, facilitated by GATE, in accurately modeling advanced PET systems. The validation results affirm the reliability of GATE V8.2 in accordance with NEMA standards for the Siemens Biograph True point (True V) scanner. The high-quality images obtained from GATE-validated scanners underscore the potential of this simulation approach in advancing nuclear medicine research. Additionally, the study on acquisition time provides valuable considerations for optimizing simulation efficiency.

Reduced count pediatric whole-body 18F-FDG PET imaging reconstruction with a Bayesian penalized likelihood algorithm.

Advanced positron emission tomography (PET) image reconstruction methods promise to allow optimized PET/CT protocols with improved image quality,decreased administered activity and/or acquisition times. To evaluate the impact of reducing counts(simulating reduced acquisition time) in block sequential regularized expectation maximization (BSREM) reconstructed pediatric whole-body 18F-fluorodeoxyglucose (FDG) PET images, and to compare BSERM with ordered-subset expectation maximization (OSEM) reconstructed reduced-count images. Twenty children (16 male) underwent clinical whole-body 18F-FDG PET/CT examinations using a 25-cm axial field-of-view (FOV) digital PET/CT system at 90s per bed (s/bed) with BSREM reconstruction (β=700). Reduced count simulations with varied BSREM β levels were generated from list-mode data: 60s/bed, β=800; 50s/bed, β=900; 40s/bed, β=1000; and 30s/bed, β=1300. In addition, a single OSEM reconstruction was created at 60s/bed based on prior literature. Qualitative (Likert scores) and quantitative (standardized uptake value [SUV]) analyses were performed to evaluate image quality and quantitation across simulated reconstructions. The mean patient age was 9.0 ± 5.5 (SD) years, mean weight was 38.5 ± 24.5kg, and mean administered 18F-FDG activity was 4.5 ± 0.7 (SD) MBq/kg. Between BSREM reconstructions, no qualitative measure showed a significant difference versus the 90s/bed β=700 standard (all P>0.05). SUVmax values for lesions were significantly lower from 90s/bed, β=700 only at a simulated acquisition time of 30s/bed, β=1300 (P=0.001). In a side-by-side comparison of BSREM versus OSEM reconstructions, 40s/bed, β=1000 images were generally preferred over 60s/bed TOF OSEM images. In children who undergo whole-body 18F-FDG PET/CT on a 25-cm FOV digital PET/CT scanner, reductions in acquisition time or, by corollary, administered radiopharmaceutical activity of >50% from a clinical standard of 90s/bed may be possible while maintaining diagnostic quality when a BSREM reconstruction algorithm is used.

Advances in positron emission tomography and radiomics.

Positron emission tomography is established for staging and response evaluation in lymphoma using visual evaluation and semi-quantitative analysis. Radiomic analysis involving quantitative imaging features at baseline, such as metabolic tumor volume and markers of disease dissemination and changes in the standardized uptake value during treatment are emerging as powerful biomarkers. The combination of radiomic features with clinical risk factors and genomic analysis offers the potential to improve clinical risk prediction. This review discusses the state of current knowledge, progress toward standardization of tumor delineation for radiomic analysis and argues that radiomic features, molecular markers and circulating tumor DNA should be included in clinical trial designs to enable the development of baseline and dynamic risk scores that could further advance the field to facilitate testing of novel treatments and personalized therapy in aggressive lymphomas.

Astrocyte Signature in Alzheimer's Disease Continuum through a Multi-PET Tracer Imaging Perspective.

Reactive astrogliosis is an early event in the continuum of Alzheimer's disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity-more than one subtype of astrocyte involved-in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages.

A coordinated strategy for a simple, pragmatic approach to the early identification of the ultra-high-risk patient with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma seen in clinical practice. Despite huge strides in understanding its biology, front-line therapy has remained unchanged for decades. Roughly one-third of patients are primary refractory or relapse following the end of conventional first-line therapy. The outcome of patients with primary refractory disease and those with early relapse (defined as relapse less than one year from end of therapy) is markedly inferior to those with later relapse and is exemplified by dismal overall survival. In this article, we term patients with features that identify them as being at particularly high-risk for either primary refractory disease or early relapse, as 'ultra-high-risk'. As new treatment options become established (e.g., bispecific T-cell engagers, chimeric antigen receptor 'CAR' T-cells and antibody-drug conjugates), it is likely that there will be a push to incorporate some of these agents into the first-line setting for patients identified as ultra-high-risk. In this review, we will outline advances in positron emission tomography, widely available laboratory assays and clinical prognosticators, that can detect a high proportion of patients with ultra-high-risk disease. Since these approaches are pragmatic and able to be adopted widely, they could be incorporated into routine clinical practice. This article is protected by copyright. All rights reserved.

Abstract 3990: Imaging molecular alterations during tucatinib response in preclinical models of HER2+ breast cancer

Abstract Introduction: Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25% of breast cancers. Tucatinib, a small molecule HER2 inhibitor, was FDA approved for inoperable or metastatic HER2+ breast cancer. As many of these patients have inoperable tumors, there is a need to identify imaging metrics that can characterize response to tucatinib. Positron emission tomography (PET) imaging can quantify changes in the tumor microenvironment that precede changes in tumor size through imaging with radiopharmaceuticals that target proliferation (fluorothymidine, [18F]-FLT), hypoxia (fluoromisonidazole, [18F]-FMISO) and HER2 expression ([89Zr]-Pertuzumab). The goal of this study is to use advanced PET imaging to non-invasively monitor response to tucatinib in HER2+ primary breast cancer and quantify the subsequent tumor microenvironment modulation. Methods: HER2+ cell line (BT474) and patient derived xenograft (BCM 3472) tumor models were engrafted and developed to 270 ± 166.4 mm3 before being enrolled into experiments. Mice were treated with 50 mg/kg tucatinib via PO and were imaged with [18F]-FLT PET (N = 8) on days 0, 3 and 7, [18F]-FMISO PET (N = 6) on days 0, 3 and 7, or [89Zr]-Pertuzumab PET (N = 5) on days 0 and 14. Intratumoral proliferation, hypoxia and HER2 expression were quantified with standardized uptake value (SUV). Following the final imaging timepoint, tumors were excised for immunohistochemistry against Ki-67 (proliferation), pimonidazole (hypoxia), and HER2. A non-parametric T-test was used to assess for significance. Results: Tucatinib treated BT474 and BCM3472 tumors had a 2.07 and 2.63 fold decrease in tumor volume, respectively (p<0.01). Tucatinib treated BT474 and BCM3472 tumors had significantly decreased hypoxia and proliferation, relative to control tumors (p<0.05). Tucatinib treated BT474 tumors had significantly decreased HER2 expression (p<0.05); however, no significant change in HER2 expression was observed in tucatinib treated BCM3472 tumors. Conclusion: Tucatinib significantly decreases tumor volume and decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2+ breast cancer. Our data suggests molecular imaging may drive understanding of and predict response to tucatinib therapy. Acknowledgements: Tucatinib was provided by Seagen Inc. Bothell, Washington, USA. Citation Format: Patrick Song, Ameer Mansur, Anna Sorace. Imaging molecular alterations during tucatinib response in preclinical models of HER2+ breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3990.

Bayesian penalized likelihood PET reconstruction impact on quantitative metrics in diffuse large B-cell lymphoma.

Evaluate the quantitative, subjective (Deauville score [DS]) and reader agreement differences between standard ordered subset expectation maximization (OSEM) and Bayesian penalized likelihood (BPL) positron emission tomography (PET) reconstruction methods. A retrospective review of 104 F-18 fluorodeoxyglucose PET/computed tomography (CT) exams among 52 patients with diffuse large B-cell lymphoma. An unblinded radiologist moderator reviewed both BPL and OSEM PET/CT exams. Four blinded radiologists then reviewed the annotated cases to provide a visual DS for each annotated lesion. Significant (P < .001) differences in BPL and OSEM PET methods were identified with greater standard uptake value (SUV) maximum and SUV mean for BPL. The DS was altered in 25% of cases when BPL and OSEM were reviewed by the same radiologist. Interobserver DS agreement was higher for OSEM (>1 cm lesion = 0.89 and ≤1 cm lesion = 0.84) compared to BPL (>1 cm lesion = 0.85 and ≤1 cm lesion = 0.81). Among the 4 readers, average intraobserver visual DS agreement between OSEM and BPL was 0.67 for lesions >1cm and 0.4 for lesions ≤1 cm. F-18 Fluorodeoxyglucose PET/CT of diffuse large B-cell lymphoma reconstructed with BPL has higher SUV values, altered DSs and reader agreement when compared to OSEM. This report finds volumetric PET measurements such as metabolic tumor volume to be similar between BPL and OSEM PET reconstructions. Efforts such as adoption of European Association Research Ltd accreditation should be made to harmonize PET data with an aim at balancing the need for harmonization and sensitivity for lesion detection.

Chronic Neuroinflammation and Cognitive Decline in Patients with Cardiac Disease: Evidence, Relevance, and Therapeutic Implications

Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target.

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.

PET tracer SMBT‐1 discriminates between BU99008 and Deprenyl binding sites on reactive astrocytes in Alzheimer's disease brains

AbstractBackgroundAstrocytes are the homeostatic cells of the mammalian brain. We recently proposed a “two‐wave” hypothetical model in which reactive astrocytes (RA) are early‐responders to Alzheimer’s disease (AD) pathology and may support a perpetual brain inflammatory state1. Advances in positron emission tomography (PET) imaging biomarkers allow for detecting RA in the early stages of AD (e.g., [11C]‐L‐Deprenyl and [11C]BU99008, which target MAO‐B and the imidazole binding sites 2 – I2Bs, respectively). However, RA assume multiple states, thus, a very heterogenous population of RA exist. Based on a recent consensus, the development of novel PET‐tracers targeting different RA populations is a priority in the field. [18F]‐SMBT‐1, a selective MAO‐B PET‐tracer, was recently designed as an alternative to detect RA in the human brain. However, further studies using [18F]‐SMBT‐1 are needed to evaluate its sensitivity to image RA in AD. We aimed at evaluating the binding properties of SMBT‐1 versus two PET‐tracers targeting RA ‐ [3H]‐L‐Deprenyl and [3H]‐BU99008 ‐ using in vitro human brain techniques.MethodCompetition binding assays for [3H]‐L‐Deprenyl and [3H]‐BU99008 versus SMBT‐1 were performed in postmortem temporal cortex brain homogenate. The number of binding sites and their affinities (IC50 ; half‐maximal inhibitory concentration) as well as percentage were calculated in AD and control brainsResultOur competition binding assays in temporal cortex tissue revealed that SMBT‐1 competes for a single binding site versus [3H]‐L‐Deprenyl in AD (IC50 = 1.141 x 10‐8) and control (IC50 = 1.93 x 10‐8) human brains. Remarkably, SMBT‐1 also competes for [3H]‐BU99008 binding sites in both AD (IC50 = 1.09 x 10‐13 and IC50 = 3.36 x 10‐8, 31% in the high fraction) and control (IC50 = 3.51 x 10‐13 and IC50 = 1.06 x 10‐6, 30% in the high fraction) cases.ConclusionSMBT‐1 competes with [3H]‐L‐Deprenyl for the high affinity MAO‐B binding site and displaces [3H]‐BU99008 binding to the I2Bs. The presence of I2Bs in the entrance channel of MAO‐B may explain this behavior, as SMBT‐1 potentially causes steric hinderance, affecting the availability of this binding site.

Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced [18F]flortaucipir PET visual patterns across the Alzheimer's disease spectrum

AbstractBackgroundThe advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.MethodWe included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.ResultA total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.ConclusionOur large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.

Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced 18F‐flortaucipir PET visual patterns in aging and Alzheimer’s disease

AbstractBackgroundThe advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.MethodWe included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.ResultA total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.ConclusionOur large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.

PET imaging in animal models of Parkinson’s disease

Alpha-synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, are characterized by aberrant accumulation of alpha-synuclein and synaptic dysfunction leading to motor and cognitive deficits. Animal models of alpha-synucleinopathy have greatly facilitated the mechanistic understanding of the disease and the development of therapeutics. Various transgenic, alpha-synuclein fibril-injected, and toxin-injected animal models of Parkinson’s disease and multiple system atrophy that recapitulate the disease pathology have been developed and widely used. Recent advances in positron emission tomography have allowed the noninvasive visualization of molecular alterations, underpinning behavioral dysfunctions in the brains of animal models and the longitudinal monitoring of treatment effects. Imaging studies in these disease animal models have employed multi-tracer PET designs to reveal dopaminergic deficits together with other molecular alterations. This review focuses on the development of new positron emission tomography tracers and studies of alpha-synuclein, synaptic vesicle glycoprotein 2A neurotransmitter receptor deficits such as dopaminergic receptor, dopaminergic transporter, serotonergic receptor, vesicular monoamine transporter 2, hypometabolism, neuroinflammation, mitochondrial dysfunction and leucine rich repeat kinase 2 in animal models of Parkinson’s disease. The outstanding challenges and emerging applications are outlined, such as investigating the gut-brain-axis by using positron emission tomography in animal models, and provide a future outlook.

Abstract 2482: Evaluating immune checkpoint blockade treatment efficacy via [89Zr]-CD4 and [89Zr]-CD8 PET imaging in breast cancer mouse models

Abstract Objective: Immune checkpoint blockades have shown a great promise in cancer therapy. However, as the overall response rate varies, there is a profound unmet need to monitor the treatment efficacy and predict therapeutic responders. Methods: In vivo blocking and biodistribution studies were performed to validate the specificity of [89Zr]-mouse-CD4 and [89Zr]-mouse-CD8. 4T1 and MMTV-HER2 mouse models of breast cancer (N=80 per model) were imaged on Days 0, 2, and 6 during treatment (saline, anti-PD1, anti-CTLA4, or combinational therapies) and evaluated for long-term changes in tumor response. Therapeutic responders were determined through the thresholding of tumor mass at the end of study. Intratumoral and splenic CD4+ and CD8+ cells were characterized in vivo via [89Zr]-mouse-CD4 and [89Zr]-mouse-CD8 positron emission tomography (PET) imaging during immunotherapy treatment. An additional of mice (N=16) were euthanized on day 7 post treatment for biological validation studies. Autoradiography and immunofluorescence staining (CD8 and CD4) were performed to validate the biological accuracy of [89Zr]-mouse-CD4 and [89Zr]-mouse-CD8 PET imaging. Results: Splenic CD4 and CD8 signal showed three-fold and two-fold decreased in the blocking group compared to non-blocking group, respectively (p&amp;lt;0.01). In 4T1 model, the changes of intratumoral CD4 SUVmean (the mean value of standard uptake value) from day 0 to day 6 significantly increased in responder group with anti-PD1 treatment (p&amp;lt;0.01). The baseline intratumoral CD8 SUVmean showed no significant difference between responders and non-responders; inversely, the changes from day 0 to day 6 increased in MMTV-HER2 (p=0.02) and 4T1 model (p=0.07) with combinational therapies. Spleen masses of responders decreased with anti-CTLA4 treatment (p&amp;lt;0.05) and for all treatments (p=0.06), in 4T1 model only. Terminal tumor mass and spleen mass were positively correlated in 4T1 model (r=0.26, p=0.02). In 4T1 model, splenic CD4 SUVmean on day 6 was negatively correlated with terminal spleen mass (r=-0.36, p=0.02) and tumor mass (r=0.33, p=0.04). PET, autoradiography, and immunofluorescence staining showed strong correlations when comparing in vivo imaging to ex vivo validations (r&amp;gt;0.75, p&amp;lt;0.01). Conclusion: [89Zr]-CD4 and [89Zr]-CD8 PET imaging can accurately evaluate CD4+ and CD8+ cell populations in vivo. Biomarkers for predicting immunotherapy response varies with different targeted drugs and tumor models. Characterizing immune cell population during immune checkpoint blockade treatment via advanced PET imaging can provide understanding of immunological alterations, monitor immunotherapy response and may potentially help in clinical decision making. Citation Format: Yun Lu, Hailey Houson, Alessandro Mascioni, Fang Jia, Patrick N. Song, Tiara Napier, Amer M. Mansur, Carlos A. Gallegos, Benjamin M. Larimer, Suzanne E. Lapi, Anna G. Sorace. Evaluating immune checkpoint blockade treatment efficacy via [89Zr]-CD4 and [89Zr]-CD8 PET imaging in breast cancer mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2482.

68Ga-DOTATATE PET-Based Radiation Contouring Creates More Precise Radiation Volumes for Patients With Meningioma

Radiation treatment planning for meningiomas traditionally involves magnetic resonance imaging (MRI) contrast enhanced images to define residual tumor. However, the gross tumor volume may be difficult to delineate for patients with a meningioma in the skull base sagittal sinus or after resection. Advanced positron emission tomography (PET) imaging using 68Ga-DOTATATE, which has been shown to be more sensitive and specific than MRI imaging, can be used for target volume delineation in these circumstances. We hypothesized that 68Ga-DOTATATE PET scan-based treatment planning would lead to smaller radiation volumes and would detect additional areas of disease compared with standard MRI alone. Our data evaluated retrospective, deidentified, and blinded gross tumor volume contour delineation with 7 central nervous system (CNS) specialists (4 CNS radiation oncologists and 3 neuroradiologists) for 25 patients with a meningioma diagnosis who received both a 68Ga-DOTATATE PET and an MRI for radiation treatment planning. Both the MRI and the PET were nonsequentially contoured by each physician for each patient. The median MRI volume for each physician ranged from 16.94-25.53 cm3. The median PET volume for each physician ranged from 2.09 to 8.36 cm3. The median PET volume was smaller for each physician. In addition, 7 of the 25 patients (28%) hadnew nonadjacent areas contoured on PET by at least 6 of the 7 physicians that were not contoured by these physicians on the corresponding MRI. These new areas would not have been in the traditional MRI-based volumes. Our study supports that 68Ga-DOTATATE PET imaging may help radiation oncologists create more precise radiation treatment volumes through finding undetected areas of disease not seen on MRI. Treatment planning guided by 68Ga-DOTATATE PET should be studied prospectively.

Design and modeling of a high resolution and high sensitivity PET brain scanner with double-ended readout

In the wake of recent advancements in scintillator, photodetector, and low-noise fast electronics technologies, as well as in fast reconstruction software, positron emission tomography (PET) scanners have seen considerable improvements in spatial resolution, time resolution, and absolute sensitivity. To continue this trend, we present a helmet type PET brain scanner design that combines high solid angle coverage and double-ended readout of 30 mm-thick scintillator crystals to achieve excellent absolute sensitivity, depth of interaction resolution, and time resolution. This scanner comprises 598 detector arrays, each with 8 × 8 Lu1.8Y0.2SiO5:Ce (LYSO:Ce) crystals with dimensions 3.005 × 3.005 × 30 mm3 one-to-one coupled on either end to silicon photomultipliers (SiPMs). Our Monte Carlo simulations based in the platform Geant4 predict that this scanner would attain an absolute sensitivity to a 35 cm line source placed at the center of the radial field of view of (17.1 ± 0.1)%, a depth of interaction resolution of (3.99 ± 0.05) mm, and a coincidence time resolution of (198 ± 5) ps. Our simulations also predict radial, tangential, and axial spatial resolutions at the center of the field of view of 3.3 mm, 3.1 mm, and 3.3 mm, respectively. As this set of simultaneous parameters compares favorably to today’s most advanced clinical PET scanners and other proposed designs, this scanner has a good chance of becoming a preferred tool for high quality brain imaging.

Preliminary evaluation of [11C]MAGL-0519 as a promising PET ligand for the diagnosis of Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent liver malignancy, which ranks third in the cancer-related cause of deaths in worldwide and ninth in the United States. Currently, HCC is typically diagnosed by ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scan at its late stage and the survival of HCC patients after diagnosis is usually very poor. Therefore, the development of novel and effective tool for early diagnosis, characterization and staging of HCC patients is of critical importance. Recent studies have demonstrated correlation of HCC with MAGL. In HCC cells, upregulation of MAGL activity enhanced cell invasiveness ability, while pharmacological blockade of MAGL led to significant inhibition of this trend. In this study, we aim to visualize the expression and activity of hepatic MAGL in different HCC cells and HCC patients’ samples by taking advantage of positron emission tomography (PET) imaging with our previously developed MAGL radioligand [11C]MAGL-0519. As a result, [11C]MAGL-0519 exhibited higher radioactivity accumulation in HepaG2 and Hepa 1–6 cell lines compared with that of normal liver cells (AML-12 and LX-2), indicating higher MAGL expression levels in these HCC cells. This rationale was then validated by Western blot and immunofluorescent staining analysis. Furthermore, HCC patients’ liver sections exhibited significantly increased uptake of [11C]MAGL-0519, which was consistent with the results in cell uptake assays. Taking together, these results provided a biological rationale and built a foundation to use [11C]MAGL-0519 as a potential and effective PET ligand for the diagnosis of HCC.

Positron Emission Tomography in Animal Models of Alzheimer's Disease Amyloidosis: Translational Implications.

Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models is essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models and in patients with Alzheimer’s disease. These tools have facilitated our understanding of disease mechanisms and provided longitudinal monitoring of treatment effects in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood–brain barrier impairment, and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes and discuss outstanding challenges in disease animal models and future outlook in the on-chip characterization of imaging biomarkers towards clinical translation.

Amyloid-Associated Depression—or Not?

In the current issue of Biological Psychiatry, Mackin et al. ( 1 Mackin R.S. Insel P.S. Landau S. Bickford D. Morin R. Rhodes E. et al. Late-life depression is associated with reduced cortical amyloid burden: Findings from the Alzheimer’s Disease Neuroimaging Initiative Depression Project. Biol Psychiatry. 2021; 89: 757-765 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar ) throw new light on the relationship between amyloid-β (Aβ) and depression in older individuals without dementia. But they may also compel us to throw some of our previous assumptions about this emerging field out the window. Early evidence for a link between late-life depression (LLD) and elevated Aβ pathogenesis came from postmortem studies of patients with dementia revealing an association between Aβ plaques and a history of major depression ( 2 Rapp M.A. Schnaider-Beeri M. Grossman H.T. Sano M. Perl D.P. Purohit D.P. et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry. 2006; 63: 161-167 Crossref PubMed Scopus (294) Google Scholar ). The advent of positron emission tomography (PET) enabled the study of clinicopathologic associations in vivo and provided further support for Aβ pathogenesis as a possible mechanism underlying the connection between LLD and Alzheimer’s disease (AD). Elevated cortical Aβ deposition in older individuals with current or lifetime major depression has been observed in most PET studies ( 3 Kumar A. Kepe V. Barrio J.R. Siddarth P. Manoukian V. Elderkin-Thompson V. et al. Protein binding in patients with late-life depression. Arch Gen Psychiatry. 2011; 68: 1143-1150 Crossref PubMed Scopus (60) Google Scholar , 4 Wu K.Y. Hsiao I.T. Chen C.S. Chen C.H. Hsieh C.J. Wai Y.Y. et al. Increased brain amyloid deposition in patients with a lifetime history of major depression: Evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography. Eur J Nucl Med Mol Imaging. 2014; 41: 714-722 Crossref PubMed Scopus (76) Google Scholar ). Longitudinal cohort studies using PET imaging have also reported positive associations between Aβ pathology and subsyndromal depressive symptoms in cognitively normal older adults ( 5 Krell-Roesch J. Lowe V.J. Neureiter J. Pink A. Roberts R.O. Mielke M.M. et al. Depressive and anxiety symptoms and cortical amyloid deposition among cognitively normal elderly persons: The Mayo Clinic Study of Aging. Int Psychogeriatr. 2018; 30: 245-251 Crossref PubMed Scopus (34) Google Scholar , 6 Donovan N.J. Locascio J.J. Marshall G.A. Gatchel J. Hanseeuw B.J. Rentz D.M. et al. Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults. Am J Psychiatry. 2018; 175: 530-537 Crossref PubMed Scopus (106) Google Scholar ). Of note, also in this issue of Biological Psychiatry, Xu et al. ( 7 Xu W. Feng W. Shen X.-N. Bi Y.-L. Ma Y.-H. Li J.-Q. et al. Amyloid pathologies modulate the associations of minimal depressive symptoms with cognitive impairments in older adults without dementia. Biol Psychiatry. 2021; 89: 766-775 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ) corroborate these findings in older adults without dementia and use causal mediation analyses to explore the mediation effects of AD pathologies on cognition. These authors thus provide important new evidence that the influence of minimal depressive symptoms on cognition is partially mediated by Aβ pathology and that the causal relationship between depression and Aβ might be bidirectional. SEE CORRESPONDING ARTICLE ON PAGE 757 SEE CORRESPONDING ARTICLE ON PAGE 757 Late-Life Depression Is Associated With Reduced Cortical Amyloid Burden: Findings From the Alzheimer’s Disease Neuroimaging Initiative Depression ProjectBiological PsychiatryVol. 89Issue 8PreviewWe evaluated the role of cortical amyloid deposition as a factor contributing to memory dysfunction and increased risk of dementia associated with late-life depression (LLD). Full-Text PDF

Advanced Imaging Techniques for Radiotherapy Planning of Gliomas.

Simple SummaryConventional magnetic resonance imaging (MRI) sequences have known limitations in target delineation for radiation treatment (RT) planning of cerebral gliomas. Advanced physiology-based MRI techniques and radionuclide imaging techniques, including positron emission tomography (PET) with amino acid radiopharmaceuticals, may increase the specificity for glioma tissue characterization. Our work aims to provide a comprehensive review of the advanced MRI and PET imaging modalities that can complement conventional MRI for RT planning of gliomas. A detailed overview of their basic principles and clinical results is given based on the most updated literature.The accuracy of target delineation in radiation treatment (RT) planning of cerebral gliomas is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Conventional magnetic resonance imaging (MRI), including contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, represents the current standard imaging modality for target volume delineation of gliomas. However, conventional sequences have limited capability to discriminate treatment-related changes from viable tumors, owing to the low specificity of increased blood-brain barrier permeability and peritumoral edema. Advanced physiology-based MRI techniques, such as MR spectroscopy, diffusion MRI and perfusion MRI, have been developed for the biological characterization of gliomas and may circumvent these limitations, providing additional metabolic, structural, and hemodynamic information for treatment planning and monitoring. Radionuclide imaging techniques, such as positron emission tomography (PET) with amino acid radiopharmaceuticals, are also increasingly used in the workup of primary brain tumors, and their integration in RT planning is being evaluated in specialized centers. This review focuses on the basic principles and clinical results of advanced MRI and PET imaging techniques that have promise as a complement to RT planning of gliomas.