Jörg Mauler

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. ¹⁸F-FET uptake and the MRSI signals choline (Cho), N-acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with ¹⁸F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, ¹⁸F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81–0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71–0.88; threshold, 2.2). The combination of ¹⁸F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by ¹⁸F-FET PET. Visual Abstract

Introduction: The fMRI BOLD response to emotional stimuli highlighting the role of the medial prefrontal cortex (MPFC) has been thoroughly investigated. Recently, the relationship between emotion processing and GABA levels has been studied using MPFC proton magnetic resonance spectroscopy (1H-MRS). However, the role of GABAA receptors in the MPFC during emotion processing remains unexplored.Methods: Using [11C]flumazenil PET, we investigated the relationship between the binding potential of GABAA receptors and emotion processing as measured using simultaneous fMRI BOLD. We hypothesized a correlation between the percent signal change in the BOLD signal and the binding potential of GABAA receptors in the MPFC. In a combined simultaneous fMRI and [11C]flumazenil-PET study, we analyzed the data from 15 healthy subjects using visual emotional stimuli. Our task comprised two types of emotional processing: passive viewing and appraisal. Following the administration of a bolus plus infusion protocol, PET and fMRI data were simultaneously acquired in a hybrid 3 T MR-BrainPET.Results: We found a differential correlation of BOLD percent signal change with [11C]flumazenil binding potential in the MPFC. Specifically, [11C]flumazenil binding potential in the ventromedial prefrontal cortex (vMPFC) correlated with passive viewing of emotionally valenced pictures. In contrast, the [11C]flumazenil binding potential and the BOLD signal induced by picture appraisal did show a correlation in the paracingulate gyrus.Conclusion: Our data deliver first evidence for a relationship between MPFC GABAA receptors and emotion processing in the same region. Moreover, we observed that GABAA receptors appear to play different roles in emotion processing in the vMPFC (passive viewing) and paracingulate gyrus (appraisal).

Advanced MRI methods and PET using radiolabelled amino acids provide valuable information, in addition to conventional MR imaging, for brain tumour diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumour progression from treatment-related changes, and the early assessment of responses to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing, and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other, leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods, but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumours. PET is only required in equivocal situations, and the spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumours compared with a single modality. This review focuses on studies investigating the diagnostic value of combined amino acid PET and ‘advanced’ MRI in patients with cerebral gliomas. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterisation of newly diagnosed tumours. Few data are available concerning the delineation of tumour extent. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumour recurrence from treatment-related changes. Here, the PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of cerebral gliomas, for which hybrid PET/MRI offers optimal conditions.

Advanced MRI methods and PET using radiolabeled amino acids provide valuable information in addition to conventional MR imaging for brain tumor diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumor progression from treatment-related changes, and the early assessment of response to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumors. PET is only required in equivocal situations, and spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumors compared with a single modality. This systematic review focuses on studies that were able to demonstrate the additive value of amino acid PET and ‘advanced’ MRI in the diagnosis of brain tumors. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterization of newly diagnosed tumors. However, data concerning the delineation of tumor extent and biopsy guidance are of limited value. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumor recurrence from treatment-related changes. Here, PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of brain tumors, for which hybrid PET/MRI offers optimal conditions.

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians’ rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [¹¹C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BP_ND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BP_ND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall’s W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BP_ND changes. There was a significant ΔBP_ND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBP_ND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and γ-aminobutyric acid (GABA) and the receptor availability (RA) of GABA_A and mGluR5, remains unexplored. This research investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. The trimodal data were acquired from three studies using different radio-tracers such as, [¹¹C]ABP688 (ABP) (N = 9), [¹¹C]Flumazenil (FMZ) (N = 10) and 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) (N = 10) targeted to study the mGluR5, GABA_A receptors and glucose metabolism respectively. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BP_ND)) of GABA_A and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BP_ND of GABA_A relative to mGluR5 BP_ND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest. Changes in the neuroreceptors leading to an altered coupling with glucose metabolism may render the RSNs vulnerable to psychiatric conditions. The paradigm employed here will likely help identify the precise neurobiological mechanisms behind these alterations in fMRI functional connectivity and EEG oscillations, potentially benefitting individualised healthcare treatment measures.

Radiological differentiation of tumor progression (TPR) from treatment-related changes (TRC) in pretreated glioblastoma is crucial. This study aimed to explore the diagnostic value of diffusion kurtosis MRI combined with information derived from O-(2-[¹⁸F]-fluoroethyl)-l-tyrosine (¹⁸F-FET) PET for the differentiation of TPR from TRC in patients with pretreated glioblastoma. Thirty-two patients with histomolecularly defined and pretreated glioblastoma suspected of having TPR were included in this retrospective study. Twenty-one patients were included in the TPR group, and 11 patients in the TRC group, as assessed by neuropathology or clinicoradiological follow-up. Three-dimensional (3D) regions of interest were generated based on increased ¹⁸F-FET uptake using a tumor-to-brain ratio of 1.6. Furthermore, diffusion MRI kurtosis maps were obtained from the same regions of interest using co-registered ¹⁸F-FET PET images, and advanced histogram analysis of diffusion kurtosis map parameters was applied to generated 3D regions of interest. Diagnostic accuracy was analyzed by receiver operating characteristic curve analysis and combinations of PET and MRI parameters using multivariate logistic regression. Parameters derived from diffusion MRI kurtosis maps show high diagnostic accuracy, up to 88%, for differentiating between TPR and TRC. Logistic regression revealed that the highest diagnostic accuracy of 94% (area under the curve, 0.97; sensitivity, 94%; specificity, 91%) was achieved by combining the maximum tumor-to-brain ratio of ¹⁸F-FET uptake and diffusion MRI kurtosis metrics. The combined use of ¹⁸F-FET PET and MRI diffusion kurtosis maps appears to be a promising approach to improve the differentiation of TPR from TRC in pretreated glioblastoma and warrants further investigation.

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and GABA (γ -aminobutyric acid) and the receptor availability (RA) of GABA _A and mGluR5, remains unexplored. This study investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BP _ND )) of GABA _A and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BP _ND of GABA _A relative to mGluR5 BP _ND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest.