Jonathan McConathy

Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between β-Amyloid and Tauopathy

IMPORTANCEnIn vivo tau imaging may become a diagnostic marker for Alzheimer disease (AD) and provides insights into the pathophysiology of AD.nnnOBJECTIVEnTo evaluate the usefulness of [18F]-AV-1451 positron emission tomography (PET) imaging to stage AD and assess the associations among β-amyloid (Aβ), tau, and volume loss.nnnDESIGN, SETTING, AND PARTICIPANTSnAn imaging study conducted at Knight Alzheimer Disease Research Center at Washington University in St Louis, Missouri. A total of 59 participants who were cognitively normal (CN) (Clinical Dementia Rating [CDR] score, 0) or had AD dementia (CDR score, >0) were included.nnnMAIN OUTCOMES AND MEASURESnStandardized uptake value ratio (SUVR) of [18F]-AV-1451 in the hippocampus and a priori-defined AD cortical signature regions, cerebrospinal fluid Aβ42, hippocampal volume, and AD signature cortical thickness.nnnRESULTSnOf the 59 participants, 38 (64%) were male; mean (SD) age was 74 (6) years. The [18F]-AV-1451 SUVR in the hippocampus and AD cortical signature regions distinguished AD from CN participants (area under the receiver operating characteristic curve range [95% CI], 0.89 [0.73-1.00] to 0.98 [0.92-1.00]). An [18F]-AV-1451 SUVR cutoff value of 1.19 (sensitivity, 100%; specificity, 86%) from AD cortical signature regions best separated cerebrospinal fluid Aβ42-positive (Aβ+) AD from cerebrospinal fluid Aβ42-negative (Aβ-) CN participants. This same cutoff also divided Aβ+ CN participants into low vs high tau groups. Moreover, the presence of Aβ+ was associated with an elevated [18F]-AV-1451 SUVR in AD cortical signature regions (Aβ+ participants: mean [SD], 1.3 [0.3]; Aβ- participants: 1.1 [0.1]; Fu2009=u20094.3, Pu2009=u2009.04) but not in the hippocampus. The presence of Aβ+ alone was not related to hippocampal volume or AD signature cortical thickness. An elevated [18F]-AV-1451 SUVR was associated with volumetric loss in both the hippocampus and AD cortical signature regions. The observed [18F]-AV-1451 SUVR volumetric association was modified by Aβ status in the hippocampus but not in AD cortical signature regions. An inverse association between hippocampal [18F]-AV-1451 SUVR and volume was seen in Aβ+ participants (R2u2009=u20090.55; Pu2009<u2009.001) but not Aβ- (R2u2009=u20090; Pu2009=u2009.97) participants.nnnCONCLUSIONS AND RELEVANCEnUse of [18F]-AV-1451 has a potential for staging of the preclinical and clinical phases of AD. β-Amyloid interacts with hippocampal and cortical tauopathy to affect neurodegeneration. In the absence of Aβ, hippocampal tau deposition may be insufficient for the neurodegenerative process that leads to AD.

PET/MR Imaging in Head and Neck Cancer: Current Applications and Future Directions

Clinical PET/MR imaging is being implemented at institutions worldwide as part of the standard-of-care imaging for select oncology patients. This article focuses on oncologic applications of PET/MR imaging in cancers of the head and neck. Although current published literature is relatively sparse, the potential benefits of a hybrid modality of PET/MR imaging are discussed along with several possible areas of research. With the increasing number of PET/MR imaging scanners in clinical use and ongoing research, the role of PET/MR imaging in the management of head and neck cancer is likely to become more evident in the near future.

18F-Fluciclovine (FACBC) and Its Potential Use for Breast Cancer Imaging

Radiolabeled amino acids have been in use for oncologic imaging for more than 2 decades, and several amino acids have proven utility in neurooncology. More recently, a major focus in this field has been the development of 18F-labeled amino acids targeting distinct transporter systems with different biologic and imaging properties and the assessment of these tracers in other solid tumors (1). The nonnatural amino acid anti-1-amino-318F-fluorocyclobutane-1-carboxylic acid (FACBC, fluciclovine) has recently received U.S. Food and Drug Administration (FDA) approval for the detection and localization of biochemically recurrent prostate cancer. Because amino acid transport is upregulated in many types of cancer, 18F-fluciclovine has potential application in multiple types of cancer. In this issue of The Journal of Nuclear Medicine, 2 groups report promising preliminary results for FACBC in women with breast cancer naı̈ve to therapy (2,3). These studies demonstrated substantially higher uptake of 18F-fluciclovine in primary and metastatic breast cancers than in benign breast lesions and normal breast tissue. Additionally, higher 18F-fluciclovine uptake occurred in more aggressive

Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with 18F-FDOPA and 18F-FDG PET

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein–expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic 18F-FDG and 18F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUVmax, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with an increase in 18F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. Conclusion: 18F-FDOPA PET/CT complemented 18F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.

Practical Considerations for Clinical PET/MR Imaging

Clinical PET/MR imaging is currently performed at a number of centers around the world as part of routine standard of care. This article focuses on issues and considerations for a clinical PET/MR imaging program, focusing on routine standard-of-care studies. Although local factors influence how clinical PET/MR imaging is implemented, the approaches and considerations described here intend to apply to most clinical programs. PET/MR imaging provides many more options than PET/computed tomography with diagnostic advantages for certain clinical applications but with added complexity. A recurring theme is matching the PET/MR imaging protocol to the clinical application to balance diagnostic accuracy with efficiency.

Overview of Positron-Emission Tomography Tracers for Metabolic Imaging

Positron-emission tomography (PET) is a cross-sectional imaging technique that uses compounds labeled with positron-emitting radionuclides to measure the concentration and location of the radiolabeled compounds over time. PET has been used for a broad range of biomedical research and is used routinely in clinical patient care for oncologic, neurologic, and cardiac applications. PET has several properties that make this technique particularly well-suited for metabolic imaging as well as some important limitations. This chapter discusses key principles and applications of PET tracers for metabolic imaging in mammalian systems. Many of the first PET tracers developed for metabolic imaging were radiolabeled forms of naturally occurring products such as glucose and amino acids [1, 2]. Due to the wide range of metabolic PET tracers that have been developed, it is not possible to comprehensively cover this field in a single chapter. We focus primarily on small molecule PET tracers that participate in metabolic pathways and/or serve as markers for the activity of specific metabolic pathways that have been used in human imaging studies.

PET/MRI for Clinical Pediatric Oncologic Imaging

PET/MRI has significant potential advantages over PET/CT for use in pediatric populations including decreasing radiation dose, reducing exposure to sedation and anesthesia, reducing the need for gadolinium-based MR contrast agents, and increasing convenience to children and their families through combining PET and MRI acquisition into a single imaging session. PET/MRI is a clinical reality and is in routine use at a number of academic centers as well as in a few private practices with some centers performing pediatric imaging. Although promising, PET/MRI for pediatric oncology faces significant challenges including the high cost and relatively limited availability of PET/MRI systems, the lack of standardization across centers, limited evidence demonstrating the superiority of PET/MRI compared to PET/CT and other imaging modalities, and variable institutional utilization of PET and whole-body MR imaging in the diagnostic evaluation of children with cancer.

Role of PET imaging for biochemical recurrence following primary treatment for prostate cancer

Prostate cancer is one of the most common cancers in men worldwide, and primary prostate cancer is typically treated with surgery, radiation, androgen deprivation, or a combination of these therapeutic modalities. Despite technical advances, approximately 30% of men will experience biochemical recurrent within 10 years of definitive treatment. Upon detection of a rise in serum prostate specific antigen (PSA), there is great need to accurately stage these patients to help guide further therapy. As a result, there are considerable efforts underway to establish the role of positron emission tomography (PET) in the diagnostic algorithm of biochemically recurrent prostate cancer. This manuscript provides an overview of PET tracers used for the detection and localization of prostate cancer in the setting of biochemical recurrence with a focus on PET tracers that are currently being used in clinical practice in the United States.

Lymph node imaging in initial staging of prostate cancer: An overview and update

Accurate nodal staging at the time of diagnosis of prostate cancer is crucial in determining a treatment plan for the patient. Pelvic lymph node dissection is the most reliable method, but is less than perfect and has increased morbidity. Cross sectional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) are non-invasive tools that rely on morphologic characteristics such as shape and size of the lymph nodes. However, lymph nodes harboring metastatic disease may be normal sized and non-metastatic lymph nodes may be enlarged due to reactive hyperplasia. The optimal strategy for preoperative staging remains a topic of ongoing research. Advanced imaging techniques to assess lymph nodes in the setting of prostate cancer utilizing novel MRI contrast agents as well as positron emission tomography (PET) tracers have been developed and continue to be studied. Magnetic resonance lymphography utilizing ultra-small super paramagnetic iron oxide has shown promising results in detection of metastatic lymph nodes. Combining MRL with diffusion-weighted imaging may also improve accuracy. Considerable efforts are being made to develop effective PET radiotracers that are performed using hybrid-imaging systems that combine PET with CT or MRI. PET tracers that will be reviewed in this article include [18F]fluoro-D-glucose, sodium [18F]fluoride, [18F]choline, [11C]choline, prostate specific membrane antigen binding ligands, [11C]acetate, [18F]fluciclovine, gastrin releasing peptide receptor ligands, and androgen binding receptors. This article will review these advanced imaging modalities and ability to detect prostate cancer metastasis to lymph nodes. While more research is needed, these novel techniques to image lymph nodes in the setting of prostate cancer show a promising future in improving initial lymph node staging.

RELATING PET AND CSF MEASURE OF TAU PATHOLOGY

analyses to compare the three participant groups to each other within each PET modality. All results were reported at a FDR corrected threshold p <0.05. Results: Both Flutametamol and PiB showed greater signal throughout grey matter (GM) structures in AD vs. eCN or yCN as expected. (Figure) In all intragroup comparisons (yCN, eCN, and AD), greater white matter (WM) uptake was seen with Flutametamol vs. PiB. In yCN and eCN greater diffuse GM uptake was also seen with Flutametamol vs. PiB (although not as uniform and with a lower T-statistic (5) vs white matter (15)). Greater scalp and parotid uptake was seen in Flutametamol vs. PiB. Greater venous sinus signal was seen with PiB vs Flutametamol. When comparing yCN to eCN for each imaging drug, greater WM uptake was seen in eCN vs yCN. Conclusions: Flutametamol and PiB show similar GM uptake distributions in AD dementia vs CN participants. Differences in WM accumulation between the two amyloid tracers suggest quantitative differences will be apparent when using WM as a reference region. Both imaging drugs demonstrate an age dependent increase in WM binding.