Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now ...recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas.
Summary Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this ...technique only reflects biological activity of the tumour indirectly by detecting the breakdown of the blood–brain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in diffusivity through the interstitial space (diffusion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice.
Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography ...(SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT.
Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer 18F-FET and the nucleoside PET tracer 18F-FLT in high-grade gliomas (HGG).
MRI, 18F-FET and ...18F-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for 18F-FET and 18F-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman's rank correlation coefficient and the Mann-Whitney U test.
18F-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, 18F-FLT uptake was mainly restricted to cT1 tumor areas on MRI and 18F-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, 18F-FET PET detected 22 of 23 (96%) HGG. 18F-FET uptake beyond areas of cT1 was found in 61% of cases and 18F-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for 18F-FET compared to 18F-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001).
In HGG 18F-FET but not 18F-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to 18F-FET, blood-brain barrier breakdown seems to be a prerequisite for 18F-FLT tracer uptake.
Imaging of the glioma microenvironment by TSPO PET Zinnhardt, Bastian; Roncaroli, Federico; Foray, Claudia ...
European journal of nuclear medicine and molecular imaging,
12/2021, Letnik:
49, Številka:
1
Journal Article
Recenzirano
Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from ...intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein (TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.
The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and ...invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with
FDPA-714 (TSPO) and
FBR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume (
FFET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with
FFET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of
FDPA-714 (14%) and
FBR-351 (11%) volumes along the tumor rim could be identified.
FDPA-714 (TSPO) and
FBR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages.
.
In vivo positron emission tomography (PET) and magnetic resonance imaging (MRI) support non-invasive assessment of the spatiotemporal expression of proteins of interest and functional/structural ...changes. Our work promotes the use of a volumetric analysis on multimodal imaging datasets to assess the spatio-temporal dynamics and interaction of two imaging biomarkers, with a special focus on two neuroinflammation-related biomarkers, the translocator protein (TSPO) and matrix metalloproteinases (MMPs), in the acute and chronic post-ischemic phase.
To improve our understating of the neuroinflammatory reaction and tissue heterogeneity during the post ischemic phase, we aimed (i) to assess the spatio-temporal distribution of two radiotracers, 18FDPA-714 (TSPO) and 18FBR-351 (MMPs), (ii) to investigate their spatial interaction, including exclusive and overlapping areas, and (iii) their relationship with the T2w-MRI ischemic lesion in a transient middle cerebral artery occlusion (tMCAo) mouse model using an atlas-based volumetric analysis.
As described by Zinnhardt et al. (2015), a total of N = 30 C57BL/6 mice underwent 18FDPA-714 and 18FBR-351 PET-CT and subsequent MR imaging 24–48 h (n = 8), 7 ± 1 days (n = 8), 14 ± 1 days (n = 7), and 21 ± 1 days (n = 7) after 30 min transient middle cerebral artery occlusion (tMCAo). To further investigate the spatio-temporal distribution of 18FDPA-714 and 18FBR-351, an atlas-based ipsilesional volume of interest (VOI) was applied to co-registered PET-CT images and thresholded by the mean uptake + 2.5*standard deviation of a contralateral striatal control VOI. Mean lesion-to-contralateral ratios (L/C), volume extension (V in voxel), percentages of overlap and exclusive tracer uptake areas were determined. Both tracer volumes were also compared to the lesion extent depicted by T2w-MR imaging.
Both imaging biomarkers showed a constant small percentage of overlap across all time points (14.0 ± 14.2%). 18FDPA-714 reached its maximum extent and uptake at day 14 post ischemia (V = 12,143 ± 6262 voxels, L/C = 2.32 ± 0.48). The majority of 18FDPA-714 volume (82.4 ± 16.1%) was exclusive for 18FDPA-714 and showed limited overlap with 18FBR-351 and T2w-MRI lesion volumes. On the other hand, 18FBR-351 reached its maximum extent already 24–48 h after tMCAo (V = 7279 ± 4518 voxels) and significantly decreased at day 14 (V = 1706 ± 1202 voxels). Focal spots of residual activity were still observed at day 21 post ischemia (L/C = 2.10 ± 0.37).
The majority of 18FBR-351 volume was exclusive for 18FBR-351 (81.50 ± 25.07%) at 24–48 h and showed 64.84 ± 28.29% of overlap with 18FDPA-714 from day 14 post ischemia while only 9.28 ± 13.45% of the 18FBR-351 volume were overlapping the T2w-MRI lesion.
The percentage of exclusive area of 18FDPA-714 and 18FBR-351 uptakes regarding T2w-MR lesion increased over time, suggesting that TSPO and MMPs are mostly localized in the peri‑infarct region at latter time points.
This study promotes the use of an unbiased volumetric analyses of multi-modal imaging data sets to improve the characterization of pathological tissue heterogeneity. This approach improves our understanding of (i) the dynamics of disease-related multi-modal imaging biomarkers, (ii) their spatiotemporal interactions and (iii) the post-ischemic tissue heterogeneity. Our results indicate acute MMPs activation after tMCAo preceding TSPO-dependent (micro-)gliosis. The spatial distribution of MMPs and gliosis is regionally independent with only minor (< 20%) overlapping areas in peri‑infarct regions.
Immunomodulatory therapies have fueled interest in targeting microglial cells as part of the innate immune response after infection or injury. In this context, the colony-stimulating factor 1 (CSF-1) ...and its receptor (CSF-1R) have gained attention in various neurological conditions to deplete and reprogram the microglia/macrophages compartment. Published data in physiological conditions support the use of small-molecule inhibitors to study microglia/macrophages dynamics under inflammatory conditions and as a therapeutic strategy in pathologies where those cells support disease progression. However, preclinical and clinical data highlighted that the complexity of the spatiotemporal inflammatory response could limit their efficiency due to compensatory mechanisms, ultimately leading to therapy resistance. We review the current state-of-art in the field of CSF-1R inhibition in glioma and stroke and provide an overview of the fundamentals, ongoing research, potential developments of this promising therapeutic strategy and further application toward molecular imaging.
Positron emission tomography (PET) with both 2'-deoxy-2'-(18)Ffluoro-D-glucose (FDG) and 3'-(18)Ffluoro-3'-deoxy-L-thymidine (FLT) was evaluated with respect to the accuracy of early prediction of ...nonprogression following erlotinib therapy, independent from epidermal growth factor receptor (EGFR) mutational status, in patients with previously untreated advanced non-small-cell lung cancer (NSCLC).
Thirty-four patients with untreated stage IV NSCLC were evaluated in this phase II trial. Changes in FDG and FLT uptake after 1 (early) and 6 (late) weeks of erlotinib treatment were compared with nonprogression measured by computed tomography after 6 weeks of treatment, progression-free survival (PFS), and overall survival (OS).
Changes in FDG uptake after 1 week of therapy predicted nonprogression after 6 weeks of therapy with an area under the receiver operating characteristic curve of 0.75 (P = .02). Furthermore, patients with an early metabolic FDG response (cutoff value: 30% reduction in the peak standardized uptake value) had significantly longer PFS (hazard ratio HR, 0.23; 95% CI, 0.09 to 0.59; P = .002) and OS (HR, 0.36; 95% CI, 0.13 to 0.96; P = .04). Early FLT response also predicted significantly longer PFS (HR, 0.31; 95% CI, 0.10 to 0.95; P = .04) but not OS and was not predictive for nonprogression after 6 weeks of therapy.
Early FDG-PET predicts PFS, OS, and nonprogression after 6 weeks of therapy with erlotinib in unselected, previously untreated patients with advanced NSCLC independent from EGFR mutational status.
PDF
