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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. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [18F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [18F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro , MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival (bcl2) and pro-apoptotic (bax/bad) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo , MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [18F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [18F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals' survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects. [ABSTRACT FROM AUTHOR]

Purpose: Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. Methods: In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. Results: In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. Conclusions: [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease. [ABSTRACT FROM AUTHOR]

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, [18F]DPA-714 (TSPO) and [18F]BR-351 (MMPs), (ii) to investigate their spatial interaction, including exclusive and overlapping areas, and (iii) their relationship with the T 2 w-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 [18F]DPA-714 and [18F]BR-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 [18F]DPA-714 and [18F]BR-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 T 2 w-MR imaging. Both imaging biomarkers showed a constant small percentage of overlap across all time points (14.0 ± 14.2%). [18F]DPA-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 [18F]DPA-714 volume (82.4 ± 16.1%) was exclusive for [18F]DPA-714 and showed limited overlap with [18F]BR-351 and T 2 w-MRI lesion volumes. On the other hand, [18F]BR-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 [18F]BR-351 volume was exclusive for [18F]BR-351 (81.50 ± 25.07%) at 24–48 h and showed 64.84 ± 28.29% of overlap with [18F]DPA-714 from day 14 post ischemia while only 9.28 ± 13.45% of the [18F]BR-351 volume were overlapping the T 2 w-MRI lesion. The percentage of exclusive area of [18F]DPA-714 and [18F]BR-351 uptakes regarding T 2 w-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. [ABSTRACT FROM AUTHOR]