Triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in microglia activation and is being investigated as a potential therapeutic target for modulation of microglia in several neurological diseases. In this study, we present the development and preclinical evaluation of Cu-labeled antibody-based PET radiotracers as tools for non-invasive assessment of TREM2 expression. Furthermore, we tested the potential of an antibody transport vehicle (ATV) that binds human transferrin receptor to facilitate transcytosis of TREM2 antibody-based radiotracers to the CNS and improve target engagement.
View Article and Find Full Text PDFPurpose: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood.
Methods: Healthy wild-type mice of both sexes (2-21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons.
Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS.
View Article and Find Full Text PDFVarious cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels.
View Article and Find Full Text PDFTSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas.
View Article and Find Full Text PDFThe 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients.
View Article and Find Full Text PDFBackground: Encephalitis and myelitis have been linked to both COVID-19 vaccination and infection, causing symptoms such as reduced consciousness, mental state alterations and seizures. Remarkably, most cases do not show significant structural alterations on MRI scans, which poses a diagnostic challenge.
Methods: We present the diagnostic workup and clinical course of a patient who developed a progressive brainstem syndrome two weeks after COVID-19 vaccination and subsequent infection.
Aim: We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG-PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated.
View Article and Find Full Text PDFLoss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody.
View Article and Find Full Text PDFEur J Nucl Med Mol Imaging
February 2023
Purpose: Glioma patients, especially recurrent glioma, suffer from a poor prognosis. While advances to classify glioma on a molecular level improved prognostication at initial diagnosis, markers to prognosticate survival in the recurrent situation are still needed. As 18 kDa translocator protein (TSPO) was previously reported to be associated with aggressive histopathological glioma features, we correlated the TSPO positron emission tomography (PET) signal using [F]GE180 in a large cohort of recurrent glioma patients with their clinical outcome.
View Article and Find Full Text PDFIntroduction: The 18 kDa translocator protein (TSPO) receives growing interest as a biomarker in glioblastoma. Mouse models can serve as an important tool for the investigation of biomarkers in glioblastoma, but several glioblastoma models indicated only low TSPO-PET signals in contrast to high TSPO-PET signals of human glioblastoma. Thus, we aimed to investigate TSPO-PET imaging in the syngeneic immunocompetent SB28 mouse model, which is thought to closely represent the tumor microenvironment (TME) of human glioblastoma.
View Article and Find Full Text PDFPurpose: The aim of this study was to build and evaluate a prediction model which incorporates clinical parameters and radiomic features extracted from static as well as dynamic [F]FET PET for the survival stratification in patients with newly diagnosed IDH-wildtype glioblastoma.
Methods: A total of 141 patients with newly diagnosed IDH-wildtype glioblastoma and dynamic [F]FET PET prior to surgical intervention were included. Patients with a survival time ≤ 12 months were classified as short-term survivors.
With great interest, our independent groups of scientists located in Korea and Germany recognized the use of a very similar methodologic approach to quantify the uptake of radioactive glucose (F-FDG) at the cellular level. The focus of our investigations was to disentangle microglial F-FDG uptake. To do so, CD11b immunomagnetic cell sorting was applied to isolate microglia cells after in vivo F-FDG injection, to allow simple quantification via a γ-counter.
View Article and Find Full Text PDFThe 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging and autoradiography in the frequently used GL261 glioblastoma mouse model and aimed to generate insights into the temporal evolution of TSPO radioligand uptake in glioblastoma in a preclinical setting. We performed a longitudinal [18F]GE-180 PET imaging study from day 4 to 14 post inoculation in the orthotopic syngeneic GL261 GBM mouse model (n = 21 GBM mice, n = 3 sham mice).
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