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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]

Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography (μPET) using [18F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [18F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of critical parameters of poststroke inflammation. This allows further evaluation of novel treatment paradigms targeting the postischemic inflammation. [ABSTRACT FROM AUTHOR]

Simple Summary: Defining glioma heterogeneity represents a promising strategy to unravel the mechanisms behind therapy resistance and tumor recurrence. The current review provides a comprehensive overview of experimental and clinical data concerning the visualization and quantification of the tumor microenvironment heterogeneity using molecular imaging, with a special emphasis on positron emission tomography (PET). Glioblastoma is the most common primary brain tumor, highly aggressive by being proliferative, neovascularized and invasive, heavily infiltrated by immunosuppressive glioma-associated myeloid cells (GAMs), including glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSCs). Quantifying GAMs by molecular imaging could support patient selection for GAMs-targeting immunotherapy, drug target engagement and further assessment of clinical response. Magnetic resonance imaging (MRI) and amino acid positron emission tomography (PET) are clinically established imaging methods informing on tumor size, localization and secondary phenomena but remain quite limited in defining tumor heterogeneity, a key feature of glioma resistance mechanisms. The combination of different imaging modalities improved the in vivo characterization of the tumor mass by defining functionally distinct tissues probably linked to tumor regression, progression and infiltration. In-depth image validation on tracer specificity, biological function and quantification is critical for clinical decision making. The current review provides a comprehensive overview of the relevant experimental and clinical data concerning the spatiotemporal relationship between tumor cells and GAMs using PET imaging, with a special interest in the combination of amino acid and translocator protein (TSPO) PET imaging to define heterogeneity and as therapy readouts. [ABSTRACT FROM AUTHOR]

This document, published in the Journal of Neurology, explores the use of [18F]DPA-714-PET-MRI as a diagnostic tool for autoimmune limbic encephalitis (ALE) with specific autoantibodies. The study involved two patients with these autoantibodies, and the results showed increased tracer uptake in certain areas of the brain. The study suggests that [18F]DPA-714-PET-MRI could be a valuable tool for diagnosing ALE and assessing the immune response in the brain. However, further research is needed to fully understand its potential for clinical use in ALE. [Extracted from the article]

Abstract: Stroke can affect females very differently from males, and therefore preclinical research on underlying mechanisms and the effects of interventions should not be restricted to male subjects, and treatment strategies for stroke should be tailored to benefit both sexes. Previously, we demonstrated that a multinutrient intervention (Fortasyn) improved impairments after ischemic stroke induction in male C57Bl/6 mice, but the therapeutic potential of this dietary treatment remained to be investigated in females. We now induced a transient middle cerebral artery occlusion (tMCAo) in C57Bl/6 female mice and immediately after surgery switched to either Fortasyn or an isocaloric Control diet. The stroke females performed several behavioral and motor tasks before and after tMCAo and were scanned in an 11.7 Tesla magnetic resonance imaging (MRI) scanner to assess brain perfusion, integrity, and functional connectivity. To assess brain plasticity, inflammation, and vascular integrity, immunohistochemistry was performed after killing of the mice. We found that the multinutrient intervention had diverse effects on the stroke‐induced impairments in females. Similar to previous observations in male stroke mice, brain integrity, sensorimotor integration and neurogenesis benefitted from Fortasyn, but impairments in activity and motor skills were not improved in female stroke mice. Overall, Fortasyn effects in the female stroke mice seem more modest in comparison to previously investigated male stroke mice. We suggest that with further optimization of treatment protocols more information on the efficacy of specific interventions in stroked females can be gathered. This in turn will help with the development of (gender‐specific) treatment regimens for cerebrovascular diseases such as stroke. This article is part of the Special Issue “Vascular Dementia”. [ABSTRACT FROM AUTHOR]

Bioluminescence imaging in transgenic mice expressing firefly luciferase in Doublecortin+ (Dcx) neuroblasts might serve as a powerful tool to study the role of neurogenesis in models of brain injury and neurodegeneration using non-invasive, longitudinal in vivo imaging. Therefore, we aimed to use BLI in B6(Cg)-Tyrc-2J/J Dcx-Luc (Doublecortin-Luciferase, Dcx-Luc) mice to investigate its suitability to assess neurogenesis in a unilateral injection model of Parkinson's disease. We further aimed to assess the blood brain barrier leakage associated with the intranigral 6- OHDA injection to evaluate its impact on substrate delivery and bioluminescence signal intensity. Two weeks after lesion, we observed an increase in bioluminescence signal in the ipsilateral hippocampal region in both, 6- OHDA and vehicle injected Dcx-Luc mice. At the same time, no corresponding increase in Dcx+ neuroblast numbers could be observed in the dentate gyrus of C57Bl6 mice. Blood brain barrier leakage was observed in the hippocampal region and in the degenerating substantia nigra of C57Bl6 mice in vivo using T1 weighted Magnetic Resonance Imaging with Gadovist® and ex vivo using Evans Blue Fluorescence Reflectance Imaging and mouse Immunoglobulin G staining. Our data suggests a BLI signal dependency on blood brain barrier permeability, underlining a major pitfall of substrate/tracer dependent imaging in invasive disease models. [ABSTRACT FROM AUTHOR]

Intrathecal inflammation plays a key role in the pathogenesis of multiple sclerosis (MS). To better elucidate its relationship with peripheral inflammation, we investigated the correlation between cerebrospinal fluid (CSF) and serum levels of 61 inflammatory proteins. Paired CSF and serum samples were collected from 143 treatment-naïve MS patients at diagnosis. A customized panel of 61 inflammatory molecules was analyzed by a multiplex immunoassay. Correlations between serum and CSF expression levels for each molecule were performed by Spearman's method. The expression of sixteen CSF proteins correlated with their serum expression (p-value < 0.001): only five molecules (CXCL9, sTNFR2, IFNα2, Pentraxin-3, and TSLP) showed a Rho value >0.40, suggesting moderate CSF/serum correlation. No correlation between inflammatory serum patterns and Qalb was observed. Correlation analysis of serum expression levels of these sixteen proteins with clinical and MRI parameters pinpointed a subset of five molecules (CXCL9, sTNFR2, IFNα2, IFNβ, and TSLP) negatively correlating with spinal cord lesion volume. However, following FDR correction, only the correlation of CXCL9 remained significant. Our data support the hypothesis that the intrathecal inflammation in MS only partially associates with the peripheral one, except for the expression of some immunomodulators that might have a key role in the initial MS immune response. [ABSTRACT FROM AUTHOR]

Introduction: Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo.Methods: Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo. Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry.Results: We prepared three new 99mTc-labeled MMP inhibitors, bearing either a glycine ([99mTc]MEA39), lysine ([99mTc]MEA61), or the ligand HYNIC with the ionic co-ligand TPPTS ([99mTc]MEA223) yielding gradually increasing hydrophilicity. [99mTc]MEA39 and [99mTc]MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [99mTc]MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [99mTc]MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images.Conclusion: Introduction of HYNIC/TPPTS into the barbiturate lead structure ([99mTc]MEA223) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model. [ABSTRACT FROM AUTHOR]

Surgical resection is the therapy of choice in head and neck paraganglioma but is associated with considerable morbidity. For treatment of inoperable or progressive disease, less aggressive adjuvant options are warranted. This study assessed effectiveness and safety of peptide receptor radionuclide therapy (PRRT) with lutetium-177–DOTATATE for head and neck paraganglioma with emphasis on response assessment. A retrospective analysis of 7 patients with head and neck paraganglioma treated with PPRT between May 2014 and October 2016 was performed. Three patients had jugulotympanic paraganglioma, 3 patients had carotid body tumors, and 1 patient had a combination of both. Patients underwent PRRT after discussion in the local tumor board regarding progressive disease, inoperability, or lack of other adjuvant options. All patients underwent 3–5 cycles of PRRT. Treatment response was evaluated by gallium-68–DOTATATE positron emission tomography/computed tomography and contrast-enhanced computed tomography or magnetic resonance imaging. Outcome measures were two-dimensional tumor diameters and total tumor volumes. Median patient age was 60 years (interquartile range: 14–84 years). All patients had stable disease at posttherapy assessment. Decreasing tumor volumes were found in 4 patients. Clinical symptoms improved in 2 patients. No progression or adverse events occurred during a median follow-up of 39 months (interquartile range: 35–47 months). Somatostatin receptor–targeted therapy using lutetium-177-DOTATATE shows promising effectiveness with a high safety profile. Patients in whom surgical morbidity outweighs oncologic benefit should be informed about PRRT as a treatment option. [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]

The value of combined L-(methyl-[11C])methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n = 65 patients with histologically verified brain lesions n = 70MET-PET andMRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software "visualization and analysis framework volume rendering engine (Voreen)" was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined byMET-PET (21.6±36.8 cm3), T1w-Gd-MRI (3.9±7.8 cm3), and FLAIR/T2-MRI (64.8±60.4 cm3; P < .001). The METPET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8± 35.0 cm3 and without changes in FLAIR/T2 10.3±25.7 cm3. FLAIR/T2-MRI visualized greatest tumor extent with differences to METPET being greater in posttherapy (64.6±62.7 cm3) than in newly diagnosed patients (20.5±52.6 cm3). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n=10 fromother gliomas n=16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management. [ABSTRACT FROM AUTHOR]

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. [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]