Jörg Mauler

Mobile sensor for high resolution NMR spectroscopy and imaging

In this work we describe the construction of a mobile NMR tomograph with a highly homogeneous magnetic field. Fast MRI techniques as well as NMR spectroscopy measurements were carried out. The magnet is based on a Halbach array built from identical permanent magnet blocks generating a magnetic field of 0.22T. To shim the field inhomogeneities inherent to magnet arrays constructed from these materials, a shim strategy based on the use of movable magnet blocks is employed. With this approach a reduction of the line-width from approximately 20kHz to less than 0.1kHz was achieved, that is by more than two orders of magnitude, in a volume of 21cm(3). Implementing a RARE sequence, 3D images of different objects placed in this volume were obtained in short experimental times. Moreover, by reducing the sample size to 1cm(3), sub ppm resolution is obtained in (1)H NMR spectra.

Comparison of cerebral blood flow acquired by simultaneous [15O]water positron emission tomography and arterial spin labeling magnetic resonance imaging.

Until recently, no direct comparison between [15O]water positron emission tomography (PET) and arterial spin labeling (ASL) for measuring cerebral blood flow (CBF) was possible. With the introduction of integrated, hybrid magnetic resonance (MR)-PET scanners, such a comparison becomes feasible. This study presents results of CBF measurements recorded simultaneously with [15O]water and ASL. A 3T MR-BrainPET scanner was used for the simultaneous acquisition of pseudo-continuous ASL (pCASL) magnetic resonance imaging (MRI) and [15O]water PET. Quantitative CBF values were compared in 10 young healthy male volunteers at baseline conditions. A statistically significant (P<0.05) correlation was observed between the two modalities; the whole-brain CBF values determined with PET and pCASL were 43.3 ±6.1 mL and 51.9 ± 7.1 mL per 100 g per minute, respectively. The gray/white matter (GM/WM) ratio of CBF was 3.0 for PET and 3.4 for pCASL. A paired t-test revealed differences in regional CBF between ASL and PET with higher ASL-CBF than PET-CBF values in cortical areas. Using an integrated, hybrid MR-PET a direct simultaneous comparison between ASL and [15O]water PET became possible for the first time so that temporal, physiologic, and functional variations were avoided. Regional and individual differences were found despite the overall similarity between ASL and PET, requiring further detailed investigations.

Advances in multimodal neuroimaging: hybrid MR-PET and MR-PET-EEG at 3 T and 9.4 T.

Multi-modal MR-PET-EEG data acquisition in simultaneous mode confers a number of advantages at 3 T and 9.4 T. The three modalities complement each other well; structural-functional imaging being the domain of MRI, molecular imaging with specific tracers is the strength of PET, and EEG provides a temporal dimension where the other two modalities are weak. The utility of hybrid MR-PET at 3 T in a clinical setting is presented and critically discussed. The potential problems and the putative gains to be accrued from hybrid imaging at 9.4 T, with examples from the human brain, are outlined. Steps on the road to 9.4 T multi-modal MR-PET-EEG are also illustrated. From an MR perspective, the potential for ultra-high resolution structural imaging is discussed and example images of the cerebellum with an isotropic resolution of 320 μm are presented, setting the stage for hybrid imaging at ultra-high field. Further, metabolic imaging is discussed and high-resolution images of the sodium distribution are presented. Examples of tumour imaging on a 3 T MR-PET system are presented and discussed. Finally, the perspectives for multi-modal imaging are discussed based on two on-going studies, the first comparing MR and PET methods for the measurement of perfusion and the second which looks at tumour delineation based on MRI contrasts but the knowledge of tumour extent is based on simultaneously acquired PET data.

Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer´s Disease

Targeting toxic amyloid beta (Aβ) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer´s disease. Using mirror-image phage display against Aβ1-42, we have previously identified the fully D-enantiomeric peptide D3, which is able to eliminate Aβ oligomers and has proven therapeutic potential in transgenic Alzheimer´s disease animal models. However, there is little information on the pharmacokinetic behaviour of D-enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half-life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer´s disease treatment.

Multimodal Fingerprints of Resting State Networks as assessed by Simultaneous Trimodal MR-PET-EEG Imaging

Simultaneous MR-PET-EEG (magnetic resonance imaging - positron emission tomography – electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here for the first time. It enables the assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. Here, we characterize the brain’s default mode network (DMN) in healthy male subjects using multimodal fingerprinting by quantifying energy metabolism via 2- [18F]fluoro-2-desoxy-D-glucose PET (FDG-PET), the inhibition – excitation balance of neuronal activation via magnetic resonance spectroscopy (MRS), its functional connectivity via fMRI and its electrophysiological signature via EEG. The trimodal approach reveals a complementary fingerprint. Neuronal activation within the DMN as assessed with fMRI is positively correlated with the mean standard uptake value of FDG. Electrical source localization of EEG signals shows a significant difference between the dorsal DMN and sensorimotor network in the frequency range of δ, θ, α and β–1, but not with β–2 and β–3. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.

Simultaneous trimodal PET-MR-EEG imaging: Do EEG caps generate artefacts in PET images?

Trimodal simultaneous acquisition of positron emission tomography (PET), magnetic resonance imaging (MRI), and electroencephalography (EEG) has become feasible due to the development of hybrid PET-MR scanners. To capture the temporal dynamics of neuronal activation on a millisecond-by-millisecond basis, an EEG system is appended to the quantitative high resolution PET-MR imaging modality already established in our institute. One of the major difficulties associated with the development of simultaneous trimodal acquisition is that the components traditionally used in each modality can cause interferences in its counterpart. The mutual interferences of MRI components and PET components on PET and MR images, and the influence of EEG electrodes on functional MRI images have been studied and reported on. Building on this, this study aims to investigate the influence of the EEG cap on the quality and quantification of PET images acquired during simultaneous PET-MR measurements. A preliminary transmission scan study on the ECAT HR+ scanner, using an Iida phantom, showed visible attenuation effect due to the EEG cap. The BrainPET-MR emission images of the Iida phantom with [18F]Fluordeoxyglucose, as well as of human subjects with the EEG cap, did not show significant effects of the EEG cap, even though the applied attenuation correction did not take into account the attenuation of the EEG cap itself.

Congruency of tumour volume delineated by FET PET and MRSI.

In addition to MR imaging, PET imaging of O-(2-[18F]Fluorethyl)-L-Tyrosine (FET) uptake provides information on brain tumour extent and metabolic activity. Similarly, MRS has been shown to be of value for distinguishing high- from low-grade gliomas. Based on 2D spatially resolved MRSI, an overlap between 18FET uptake and the choline/N-acetyl-aspartate (Cho/NAA) ratio of more than 75 % has been reported.

Dissociated Crossed Speech Areas in a Tumour Patient

In the past, the eloquent areas could be deliberately localised by the invasive Wada test. The very rare cases of dissociated crossed speech areas were accidentally found based on the clinical symptomatology. Today functional magnetic resonance imaging (fMRI)-based imaging can be employed to non-invasively localise the eloquent areas in brain tumour patients for therapy planning. A 41-year-old, left-handed man with a low-grade glioma in the left frontal operculum extending to the insular cortex, tension headaches, and anomic aphasia over 5 months underwent a pre-operative speech area localisation fMRI measurement, which revealed the evidence of the transhemispheric disposition, where the dominant Wernicke speech area is located on the left and the Broca’s area is strongly lateralised to the right hemisphere. The outcome of the Wada test and the intraoperative cortico-subcortical stimulation mapping were congruent with this finding. After tumour removal, language area function was fully preserved. Upon the occurrence of brain tumours with a risk of impaired speech function, the rare dissociate crossed speech areas disposition may gain a clinically relevant meaning by allowing for more extended tumour removal. Hence, for its identification, diagnostics which take into account both brain hemispheres, such as fMRI, are recommended.

Comparison of EEG microstates with resting state fMRI and FDG-PET measures in the default mode network via simultaneously recorded trimodal (PET/MR/EEG) data

Simultaneous trimodal positron emission tomography/magnetic resonance imaging/electroencephalography (PET/MRI/EEG) resting state (rs) brain data were acquired from 10 healthy male volunteers. The rs-functional MRI (fMRI) metrics, such as regional homogeneity (ReHo), degree centrality (DC) and fractional amplitude of low-frequency fluctuations (fALFFs), as well as 2-[18F]fluoro-2-desoxy-d-glucose (FDG)-PET standardised uptake value (SUV), were calculated and the measures were extracted from the default mode network (DMN) regions of the brain. Similarly, four microstates for each subject, showing the diverse functional states of the whole brain via topographical variations due to global field power (GFP), were estimated from artefact-corrected EEG signals. In this exploratory analysis, the GFP of microstates was nonparametrically compared to rs-fMRI metrics and FDG-PET SUV measured in the DMN of the brain. The rs-fMRI metrics (ReHO, fALFF) and FDG-PET SUV did not show any significant correlations with any of the microstates. The DC metric showed a significant positive correlation with microstate C (r s = 0.73, p = .01). FDG-PET SUVs indicate a trend for a negative correlation with microstates A, B and C. The positive correlation of microstate C with DC metrics suggests a functional relationship between cortical hubs in the frontal and occipital lobes. The results of this study suggest further exploration of this method in a larger sample and in patients with neuropsychiatric disorders. The aim of this exploratory pilot study is to lay the foundation for the development of such multimodal measures to be applied as biomarkers for diagnosis, disease staging, treatment response and monitoring of neuropsychiatric disorders.

Spatial Relationship of Glioma Volume Derived from FET PET and Volumetric MRSI: a hybrid PET-MRI study

PET imaging of amino acid transport using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) and proton MR spectroscopy (MRS) imaging of cell turnover measured by the ratio of choline to N-acetyl-aspartate (Cho/NAA) may provide additional information on tumor extent of cerebral gliomas compared with anatomic imaging; however, comparative studies are rare. Methods: In this prospective study, 41 patients (16 women, 25 men; mean age ± SD, 48 ± 14 y) with cerebral gliomas (World Health Organization [WHO] grade II: 10 [including 1 patient with 2 lesions], WHO III: 17, WHO IV: 13, without biopsy low-grade: 1, high-grade: 1) were investigated with a hybrid PET/MR scanner. Tumor extent, spatial overlap, and the distance between the corresponding centers of mass in 18F-FET PET and MRS imaging of Cho/NAA, determined by simultaneously acquired, 3-dimensional spatially resolved MRS imaging data, were compared. Results: The average tumor volumes for 18F-FET uptake and increased Cho/NAA were 19 ± 20 cm3 (mean ± SD) and 22 ± 24 cm3, respectively, with an overlap of 40% ± 25% and separation of the centers of mass by 9 ± 8 mm. None of the parameters showed a significant correlation with tumor grade. Conclusion: 18F-FET uptake and increased Cho/NAA ratio are not always congruent and may represent different properties of glioma metabolism. The relationship to histologic tumor extent needs to be further analyzed.