Publications by authors named "Andreas Stadlbauer"

68 Publications

Can we use the dynamic and complex interplay between pain and sleep to quantify neuromodulation responsiveness for chronic pain?

Expert Rev Neurother 2021 Feb 31;21(2):141-143. Epub 2020 Dec 31.

Institute of Molecular Bioimaging and Physiology, National Research Council , Catanzaro, Italy.

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http://dx.doi.org/10.1080/14737175.2021.1865805DOI Listing
February 2021

Burst Motor Cortex Stimulation Evokes Sustained Suppression of Thalamic Stroke Pain: A Narrative Review and Single-Case Overview.

Pain Ther 2020 Dec 16. Epub 2020 Dec 16.

Division of Functional Neurosurgery and Stereotaxy, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.

Chronic refractory central post-stroke pain (CPSP), one of the most disabling consequences of cerebral stroke, occurs in up to 10% of patients with CPSP. Because a considerable proportion of these patients with chronic pain remain resistant to pharmacological and behavioral therapies, adjunctive invasive and non-invasive brain stimulation therapies are needed. We performed a review of human studies applying burst and conventional motor cortex stimulation (burstMCS and cMCS, respectively) for chronic pain states, on the basis of data sources identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, as well as manual searches of the bibliographies of known primary and review articles. Our aim was to review and discuss clinical data on the indications of burstMCS for various chronic pain states originating from central stroke (excluding trigeminal facial pain). In addition, we assessed the efficacy and safety of burst versus cMCS for central post-stroke pain with an extended follow-up of 5 years in a 60-year-old man. According to our review, uncontrolled observational human cohort studies and one RCT using cMCS waveforms have revealed a meaningful clinical response; however, these studies lacked placebo groups and extended observation periods. In our case report, we found that 3 months of adjunctive cMCS reduced pain levels [visual analog scale (VAS) pre: 9/10 versus VAS post 7/10], whereas the pain decreased further under burstMCS (VAS pre: 7/10 versus VAS post: 2/10); the study involved a follow-up of 5 years and the following parameters: burst rate 40 Hz (500 Hz), 1-1.75 mA, 1 ms, bipolar configuration. To date, only limited evidence exists for the efficacy and safety of burst motor cortex stimulation for the treatment of refractory chronic pain. BurstMCS resulted in significantly decreased post-stroke pain observed after 5 years of cMCS. The available literature suggests similar efficacy as that of conventional (tonic) motor cortex stimulation, although the results are preliminary. Mechanistically, the precise mechanism of action is not fully understood. However, burstMCS may interact with the nociceptive thalamic-cingulate and descending spinal pain networks. To determine the potential utility of this treatment, large-scale sham-controlled trials comparing cMCS and burstMCS are highly recommended.
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http://dx.doi.org/10.1007/s40122-020-00221-0DOI Listing
December 2020

The Diagnostic and Therapeutic Role of Leptin and Its Receptor ObR in Glioblastoma Multiforme.

Cancers (Basel) 2020 Dec 9;12(12). Epub 2020 Dec 9.

Department of Basic Medical Sciences, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad 44000, Pakistan.

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients.
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http://dx.doi.org/10.3390/cancers12123691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764087PMC
December 2020

Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans.

Clin Cancer Res 2020 Dec 8. Epub 2020 Dec 8.

Department of Neurosurgery, University Clinic of St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria.

Purpose: Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches.

Experimental Design: Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence.

Results: Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence.

Conclusions: Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3580DOI Listing
December 2020

Quantitative sensory phenotyping in chronic neuropathic pain patients treated with unilateral L4-dorsal root ganglion stimulation.

J Transl Med 2020 10 21;18(1):403. Epub 2020 Oct 21.

Institute of Neurophysiology, Medical Faculty Mannheim, University Heidelberg, Heidelberg, Germany.

Background: In a previous study, we reported that selective dorsal root ganglion stimulation (DRG) at DRG level L4 promoted a favorable outcome for complex regional pain syndrome (CRPS) patients along with DRG-related changes of inflammatory biomarkers in blood and saliva. The impact on somatosensation is largely unknown. Herein, we assessed the quantitative sensory profile to quantify L4-DRG effects in CRPS patients.

Methods: Twelve refractory CRPS patients (4 female; 8 male; mean age 69 ± 9 years) received standardized quantitative sensory testing (QST) protocol at baseline and after 3 months of unilateral L4-DRG assessing nociceptive and non-nociceptive thermal and mechanical sensitivity of the knee affected by CRPS and the contralateral non-painful knee area.

Results: At baseline, CRPS subjects showed significantly increased thresholds for warmth, tactile and vibration detection (WDT, MDT and VDT) and exaggerated pain summation (WUR). After 3 months of unilateral L4-DRG all pain parameters exhibited trends towards normalization of sensitivity accumulating to a significant overall normalization for pain sensitivity (effect size: 0.91, p < 0.01), while with the one exception of WDT all non-nociceptive QST parameters remained unchanged. Overall change of non-nociceptive detection was negligible (effect size: 0.25, p > 0.40). Notably, reduction of pain summation (WUR) correlated significantly with pain reduction after 3 months of L4-DRG.

Conclusions: Selective L4-DRG lowered ongoing pain in CRPS patients and evoked significant normalization in the pain domain of the somatosensory profile. Thermoreception and mechanoreception remained unchanged. However, larger randomized, sham-controlled trials are highly warranted to shed more light on effects and mechanisms of dorsal root ganglion stimulation on quantitative sensory characteristics. The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.
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http://dx.doi.org/10.1186/s12967-020-02566-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579938PMC
October 2020

Association between tissue hypoxia, perfusion restrictions, and microvascular architecture alterations with lesion-induced impairment of neurovascular coupling.

J Cereb Blood Flow Metab 2020 Aug 12:271678X20947546. Epub 2020 Aug 12.

Department of Neurosurgery, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.

Functional magnetic resonance imaging (fMRI) has been mainly utilized for the preoperative localization of eloquent cortical areas. However, lesion-induced impairment of neurovascular coupling (NVC) in the lesion border zone may lead to false-negative fMRI results. The purpose of this study was to determine physiological factors impacting the NVC. Twenty patients suffering from brain lesions were preoperatively examined using multimodal neuroimaging including fMRI, magnetoencephalography (MEG) during language or sensorimotor tasks (depending on lesion location), and a novel physiologic MRI approach for the combined quantification of oxygen metabolism, perfusion state, and microvascular architecture. Congruence of brain activity patterns between fMRI and MEG were found in 13 patients. In contrast, we observed missing fMRI activity in perilesional cortex that demonstrated MEG activity in seven patients, which was interpreted as lesion-induced impairment of NVC. In these brain regions with impaired NVC, physiologic MRI revealed significant brain tissue hypoxia, as well as significantly decreased macro- and microvascular perfusion and microvascular architecture. We demonstrated that perilesional hypoxia with reduced vascular perfusion and architecture is associated with lesion-induced impairment of NVC. Our physiologic MRI approach is a clinically applicable method for preoperative risk assessment for the presence of false-negative fMRI results and may prevent severe postoperative functional deficits.
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http://dx.doi.org/10.1177/0271678X20947546DOI Listing
August 2020

Non-Invasive Assessment of Hypoxia and Neovascularization with MRI for Identification of Aggressive Breast Cancer.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Department of Neurosurgery, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.

The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) for a non-invasive synergistic assessment of tumor microenvironment (TME) hypoxia and induced neovascularization for the identification of aggressive breast cancer. Fifty-three female patients with breast cancer underwent multiparametric breast MRI including quantitative blood-oxygen-level-dependent (qBOLD) imaging for hypoxia and vascular architecture mapping for neovascularization. Quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), mitochondrial oxygen tension (mitoPO2), microvessel radius (VSI), microvessel density (MVD), and microvessel type indicator (MTI) were calculated. Histopathology was the standard of reference. Histopathological markers (vascular endothelial growth factor receptor 1 (FLT1), podoplanin, hypoxia-inducible factor 1-alpha (HIF-1alpha), carbonic anhydrase 9 (CA IX), vascular endothelial growth factor C (VEGF-C)) were used to confirm imaging biomarker findings. Univariate and multivariate regression analyses were performed to differentiate less aggressive luminal from aggressive non-luminal (HER2-positive, triple negative) malignancies and assess the interplay between hypoxia and neoangiogenesis markers. Aggressive non-luminal cancers ( = 40) presented with significantly higher MRO2 (i.e., oxygen consumption), lower mitoPO2 values (i.e., hypoxia), lower MTI, and higher MVD than less aggressive cancers ( = 13). Data suggest that a model derived from OEF, mitoPO2, and MVD can predict tumor proliferation rate. This novel MRI approach, which can be easily implemented in routine breast MRI exams, aids in the non-invasive identification of aggressive breast cancer.
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http://dx.doi.org/10.3390/cancers12082024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464174PMC
July 2020

Incisionless MR-guided focused ultrasound: technical considerations and current therapeutic approaches in psychiatric disorders.

Expert Rev Neurother 2020 07 21;20(7):687-696. Epub 2020 Jun 21.

Department of Neurosurgery, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg , Germany.

Introduction: MR-guided focused ultrasound operating at higher intensities have been reported to effectively and precisely ablate deeper brain structures like the basal ganglia or the thalamic nuclei for the treatment of refractory movement disorders, neuropathic pain and most recently neuropsychiatric disorders, while low-intensity focused ultrasound represents an approach promoting mechanical blood-brain-barrier opening and neuromodulation. This narrative review summarizes the technical development and the therapeutic potential of incisionless MRgFUS in order to treat neuropsychiatric disorders.

Areas Covered: A narrative review of clinical trials assessing the safety and efficacy of MRgFUS. A literature review was performed using the following search terms: MR-guided focused ultrasound, psychiatric disorders, noninvasive and invasive brain modulation/stimulation techniques.

Expert Opinion: MRgFUS ablation is under clinical investigation (unblinded study design) for obsessive-compulsive disorders (OCDs) [capsulotomy; ALIC] and depression/anxiety disorders [capsulotomy] and has demonstrated an improvement in OCD and depression, although of preliminary character. Low-intensity ultrasound applications have been explored in Alzheimer´s disease (phase 1 study) and healthy subjects. Currently, limited evidence hinders comparison and selection between MRgFUS and noninvasive/invasive brain modulation therapies. However, comparative, sham-controlled trials are needed to reexamine the preliminary findings for the treatment of psychiatric disorders.
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http://dx.doi.org/10.1080/14737175.2020.1779590DOI Listing
July 2020

Vascular architecture mapping for early detection of glioblastoma recurrence.

Neurosurg Focus 2019 12;47(6):E14

4Department of Neurology, University Clinic of St. Pölten, St. Pölten, Austria.

Objective: Treatment failure and inevitable tumor recurrence are the main reasons for the poor prognosis of glioblastoma (GB). Gross-total resection at repeat craniotomy for GB recurrence improves patient overall survival but requires early and reliable detection. It is known, however, that even advanced MRI approaches have limited diagnostic performance for distinguishing tumor progression from pseudoprogression. The novel MRI technique of vascular architectural mapping (VAM) provides deeper insight into tumor microvascularity and neovascularization. In this study the authors evaluated the usefulness of VAM for the monitoring of GB patients and quantitatively analyzed the features of neovascularization of early- and progressed-stage GB recurrence.

Methods: In total, a group of 115 GB patients who received overall 374 follow-up MRI examinations after standard treatment were retrospectively evaluated in this study. The clinical routine MRI (cMRI) protocol at 3 Tesla was extended with the authors' experimental VAM approach, requiring 2 minutes of extra time for data acquisition. Custom-made MATLAB software was used for calculation of imaging biomarker maps of macrovascular perfusion from perfusion cMRI as well as of microvascular perfusion and architecture from VAM data. Additionally, cMRI data were analyzed by two board-certified radiologists in consensus. Statistical procedures included receiver operating characteristic (ROC) analysis to determine diagnostic performances for GB recurrence detection.

Results: Overall, cMRI showed GB recurrence in 89 patients, and in 28 of these patients recurrence was detected earlier with VAM data, by 1 (20 patients) or 2 (8 patients) follow-up examinations, than with cMRI data. The mean time difference between recurrence detection with VAM and cMRI data was 147 days. During this time period the mean tumor volume increased significantly (p < 0.001) from 9.7 to 26.8 cm3. Quantitative analysis of imaging biomarkers demonstrated microvascular but no macrovascular hyperperfusion in early GB recurrence. Therefore, ROC analysis revealed superior diagnostic performance for VAM compared with cMRI.

Conclusions: This study demonstrated that the targeted assessment of microvascular features using the VAM technique provided valuable information about early neovascularization activity in recurrent GB that is complementary to perfusion cMRI and may be helpful for earlier and more precise monitoring of patients suffering from GB. This VAM approach is compatible with existing cMRI protocols. Prospective clinical trials are necessary to investigate the clinical usefulness and potential benefit of increased overall survival with the use of VAM in patients with recurrent GB.
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http://dx.doi.org/10.3171/2019.9.FOCUS19613DOI Listing
December 2019

Refined Functional Magnetic Resonance Imaging and Magnetoencephalography Mapping Reveals Reorganization in Language-Relevant Areas of Lesioned Brains.

World Neurosurg 2020 Apr 10;136:e41-e59. Epub 2019 Oct 10.

Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany; Institute of Medical Radiology, University Clinic of St. Pölten, St. Pölten, Austria.

Background: Neurosurgical decisions regarding interventions close to brain areas with language-related functions remain highly challenging because of the risk of postoperative dysfunction. To minimize these risks, improvements in the preoperative mapping of language-related regions are required, especially as space-occupying lesions often lead to altered cortical topography and language area reorganization.

Methods: The degree of deviation and language area reorganization were investigated in 26 functional magnetic resonance imaging- and magnetoencephalography-dissociable cortical sub-areas displaying language-related activations in each of 18 patients with brain lesions and 3 healthy volunteers (during visual language tasks).

Results: Both modalities showed good congruency of the language areas. The mean spatial distance of the centroids and maxima was 9.06 mm and 10.58 mm, respectively, allowing us to define more specific anatomical positions. Postoperatively, language abilities increased in 11% (2 of 18) of the patients, remained unchanged in 83% (15 of 18) of the patients, and decreased in 6% (1 of 18) of the patients, respectively. Signs of language function reorganization detected on both functional magnetic resonance imaging and magnetoencephalography were present in 29% (5 of 17) of the patients. Attenuation of neurovascular coupling was found postoperatively in 17% (3 of 18) of the patients. Monohemispheric language processing cannot be assumed always in patients with brain lesions.

Conclusions: The more detailed subdivision of language-relevant brain areas shown in this study can help to achieve more radical tumor resection without postoperative language deficits.
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http://dx.doi.org/10.1016/j.wneu.2019.10.014DOI Listing
April 2020

Advanced MRI in neuro-oncology: can we proceed without inclusion of energy metabolism?

Oncotarget 2019 Jun 18;10(40):3994-3995. Epub 2019 Jun 18.

Institute of Medical Radiology, University Clinic of St. Pölten, St. Pölten, Austria; Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

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http://dx.doi.org/10.18632/oncotarget.27015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592286PMC
June 2019

Comparative fMRI and MEG localization of cortical sensorimotor function: Bimodal mapping supports motor area reorganization in glioma patients.

PLoS One 2019 7;14(3):e0213371. Epub 2019 Mar 7.

Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

Introduction: Preoperative functional mapping in the vicinity of brain lesion is of high importance for avoiding complications in surgical management. However, space-occupying lesions may lead to functional reorganization or decreased BOLD activity.

Methods: Therefore in 13 patients with cerebral gliomas or brain arterio-venous malformations/ hemangioma fMRI- and MEG-based cortical localizations of motor and somatosensory cortical activation pattern were compared in order to investigate their congruency.

Results: Localization of cortical sensorimotor areas with fMRI and MEG showed good congruency with a mean spatial distance of around 10 mm, with differences depending on the localization method. The smallest mean differences for the centroids were found for MEF with MNE 8 mm and SEF with sLORETA 8 mm. Primary motor area (M1) reorganization was found in 5 of 12 patients in fMRI and confirmed with MEG data. In these 5 patients with M1-reorganization the distance between the border of the fMRI-based cortical M1-localization and the tumor border on T1w MR images varied between 0-4 mm, which was significant (P = 0.025) different to the distance in glioma patients without M1-reorganization (5-26 mm).

Conclusion: Our multimodal preoperative mapping approach combining fMRI and MEG reveals a high degree of spatial congruence and provided high evidence for the presence of motor cortex reorganization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213371PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405066PMC
December 2019

Physiologic MR imaging of the tumor microenvironment revealed switching of metabolic phenotype upon recurrence of glioblastoma in humans.

J Cereb Blood Flow Metab 2020 03 7;40(3):528-538. Epub 2019 Feb 7.

Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

Treating recurrent glioblastoma (GB) is one of the challenges in modern neurooncology. Hypoxia, neovascularization, and energy metabolism are of crucial importance for therapy failure and recurrence. Twenty-one patients with initially untreated GB who developed recurrence were examined with a novel MRI approach for noninvasive visualization of the tumor microenvironment (TME). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of five different TME compartments: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation, and glycolysis. Volume percentages of these TME compartments were compared between untreated and recurrent GB. At initial diagnosis, all 21 GB showed either the features of a glycolytic dominant phenotype with a high percentage of functional neovasculature (N = 12) or those of a necrotic/hypoxic dominant phenotype with a high percentage of defective tumor neovasculature (N = 9). At recurrence, all 21 GB revealed switching of the initial metabolic phenotype: either from the glycolytic to the necrotic/hypoxic dominant phenotype or vice-versa. A necrotic/hypoxic phenotype at recurrence was associated with a higher rate of multifocality of the recurrent lesions. Our MRI approach may be helpful for a better understanding of treatment-induced metabolic phenotype switching and for future studies developing targeted therapeutic strategies for recurrent GB.
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http://dx.doi.org/10.1177/0271678X19827885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026844PMC
March 2020

Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results.

Mol Imaging Biol 2019 08;21(4):758-770

Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Purpose: To develop a novel magnetic resonance imaging (MRI) approach for the noninvasive assessment of hypoxia and neovascularization in breast tumors.

Procedures: In this IRB-approved prospective study, 20 patients with suspicious breast lesions (BI-RADS 4/5) underwent multiparametric breast MRI including quantitative BOLD (qBOLD) and vascular architecture mapping (VAM). Custom-made in-house MatLab software was used for qBOLD and VAM data postprocessing and calculation of quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO), and mitochondrial oxygen tension (mitoPO) to measure tissue hypoxia and neovascularization including vascular architecture including microvessel radius (VSI), density (MVD), and type (MTI). Histopathology was used as standard of reference. Appropriate statistics were performed to assess and compare correlations between MRI biomarkers for hypoxia and neovascularization.

Results: qBOLD and VAM data with good quality were obtained from all patients with 13 invasive ductal carcinoma (IDC) and 7 benign breast tumors with a lesion diameter of at least 10 mm in all spatial directions. MRI biomarker maps of oxygen metabolism and neovascularization demonstrated intratumoral spatial heterogeneity with a broad range of biomarker values. Bulk tumor neovasculature consisted of draining venous microvasculature with slow flowing blood. High OEF and low mitoPO were associated with low MVD and vice versa. The heterogeneous pattern of MRO values showed spatial congruence with VSI. IDCs showed significantly higher MRO (P = 0.007), lower mitoPO (P = 0.021), higher MVD (P = 0.005), and lower (i.e., more pathologic) MTI (P = 0.001) compared with benign breast tumors. These results indicate that IDCs consume more oxygen and are more hypoxic and neovascularized than benign tumors.

Conclusions: We developed a novel MRI approach for the noninvasive assessment of hypoxia and neovascularization in benign and malignant breast tumors that can be easily integrated in a diagnostic MRI protocol and provides insight into intratumoral heterogeneity.
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http://dx.doi.org/10.1007/s11307-018-1298-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480075PMC
August 2019

Predicting Glioblastoma Response to Bevacizumab Through MRI Biomarkers of the Tumor Microenvironment.

Mol Imaging Biol 2019 08;21(4):747-757

Department of Neurology, University Clinic of St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria.

Purpose: Glioblastoma (GB) is one of the most vascularized of all solid tumors and, therefore, represents an attractive target for antiangiogenic therapies. Many lesions, however, quickly develop escape mechanisms associated with changes in the tumor microenvironment (TME) resulting in rapid treatment failure. To prevent patients from adverse effects of ineffective therapy, there is a strong need to better predict and monitor antiangiogenic treatment response.

Procedures: We utilized a novel physiological magnetic resonance imaging (MRI) method combining the visualization of oxygen metabolism and neovascularization for classification of five different TME compartments: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation, and aerobic glycolysis. This approach, termed TME mapping, was used to monitor changes in tumor biology and pathophysiology within the TME in response to bevacizumab treatment in 18 patients with recurrent GB.

Results: We detected dramatic changes in the TME by rearrangement of its compartments after the onset of bevacizumab treatment. All patients showed a decrease in active tumor volume and neovascularization as well as an increase in hypoxia and necrosis in the first follow-up after 3 months. We found that recurrent GB with a high percentage of neovascularization and active tumor before bevacizumab onset showed a poor or no treatment response.

Conclusions: TME mapping might be useful to develop strategies for patient stratification and response prediction before bevacizumab onset.
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http://dx.doi.org/10.1007/s11307-018-1289-5DOI Listing
August 2019

Intratumoral heterogeneity of oxygen metabolism and neovascularization uncovers 2 survival-relevant subgroups of IDH1 wild-type glioblastoma.

Neuro Oncol 2018 10;20(11):1536-1546

Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

Background: The intratumoral heterogeneity of oxygen metabolism in combination with variable patterns of neovascularization (NV) as well as reprogramming of energy metabolism affects the landscape of tumor microenvironments (TMEs) in glioblastoma. Knowledge of the hypoxic and perivascular niches within the TME is essential for understanding treatment failure.

Methods: Fifty-two patients with untreated glioblastoma (isocitrate dehydrogenase 1 wild type [IDH1wt]) were examined with a physiological MRI protocol including a multiparametric quantitative blood oxygen level dependent (qBOLD) approach and vascular architecture mapping (VAM). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of 6 different TMEs: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation (OxPhos), and glycolysis with/without neovascularization. Association of the different TME volume fractions with progression-free survival (PFS) was assessed using Kaplan-Meier analysis and Cox proportional hazards models.

Results: A common spatial structure of TMEs was detected: central necrosis surrounded by tumor hypoxia (with defective and functional neovasculature) and different TMEs with a predominance of OxPhos and glycolysis for energy production, respectively. The percentage of the different TMEs on the total tumor volume uncovered 2 clearly different subtypes of glioblastoma IDH1wt: a glycolytic dominated phenotype with predominantly functional neovasculature and a necrotic/hypoxic dominated phenotype with approximately 50% of defective neovasculature. Patients with a necrotic/hypoxic dominated phenotype showed significantly shorter PFS (P = 0.035).

Conclusions: Our non-invasive mapping approach allows for classification of the TME and detection of tumor-supportive niches in glioblastoma which may be helpful for both clinical patient management and research.
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http://dx.doi.org/10.1093/neuonc/noy066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176796PMC
October 2018

Dynamical Graph Theory Networks Methods for the Analysis of Sparse Functional Connectivity Networks and for Determining Pinning Observability in Brain Networks.

Front Comput Neurosci 2017 5;11:87. Epub 2017 Oct 5.

Department of Scientific Computing, Florida State University, Tallahassee, FL, United States.

Neuroimaging in combination with graph theory has been successful in analyzing the functional connectome. However almost all analysis are performed based on static graph theory. The derived quantitative graph measures can only describe a snap shot of the disease over time. Neurodegenerative disease evolution is poorly understood and treatment strategies are consequently only of limited efficiency. Fusing modern dynamic graph network theory techniques and modeling strategies at different time scales with pinning observability of complex brain networks will lay the foundation for a transformational paradigm in neurodegnerative diseases research regarding disease evolution at the patient level, treatment response evaluation and revealing some central mechanism in a network that drives alterations in these diseases. We model and analyze brain networks as two-time scale sparse dynamic graph networks with hubs (clusters) representing the fast sub-system and the interconnections between hubs the slow sub-system. Alterations in brain function as seen in dementia can be dynamically modeled by determining the clusters in which disturbance inputs have entered and the impact they have on the large-scale dementia dynamic system. Observing a small fraction of specific nodes in dementia networks such that the others can be recovered is accomplished by the novel concept of pinning observability. In addition, how to control this complex network seems to be crucial in understanding the progressive abnormal neural circuits in many neurodegenerative diseases. Detecting the controlling regions in the networks, which serve as key nodes to control the aberrant dynamics of the networks to a desired state and thus influence the progressive abnormal behavior, will have a huge impact in understanding and developing therapeutic solutions and also will provide useful information about the trajectory of the disease. In this paper, we present the theoretical framework and derive the necessary conditions for (1) area aggregation and time-scale modeling in brain networks and for (2) pinning observability of nodes in dynamic graph networks. Simulation examples are given to illustrate the theoretical concepts.
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http://dx.doi.org/10.3389/fncom.2017.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633615PMC
October 2017

Vascular Hysteresis Loops and Vascular Architecture Mapping in Patients with Glioblastoma treated with Antiangiogenic Therapy.

Sci Rep 2017 08 17;7(1):8508. Epub 2017 Aug 17.

Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

In this study, we investigated the variability of vascular hysteresis loop (VHL) shapes and the spatial heterogeneity of neovascularization and microvascular alterations using vascular architecture mapping (VAM) in patients with recurrent glioblastoma during bevacizumab mono-therapy. VAM data were acquired in 13 patients suffering from recurrent glioblastoma prior to and 3 months after bevacizumab treatment onset using a dual contrast agent injections approach as part of routine MRI. Two patients were additionally examined after the first cycle of bevacizumab to check for early treatment response. VHLs were evaluated as biomarker maps of neovascularization activity: microvessel type indicator (MTI) and curvature (Curv) of the VHL-long-axis. Early response to bevacizumab was dominated by reduction of smaller microvasculature (around 10 µm). In the 3-month follow-up, responding tumors additionally showed a reduction in larger microvasculature (>20 µm). VAM biomarker images revealed spatially heterogeneous microvascular alterations during bevacizumab treatment. Responding, non-responding, progressive, and remote-progressive tumor areas were observed. MTI may be useful to predict responding and non-responding tumor regions, and Curv to assess severity of vasogenic edema. Analysis of VHLs in combination with VAM biomarkers may lead to a new perspective on investigating the spatial heterogeneity of neovascularization and microvascular alterations in glioblastoma during antiangiogenic therapy.
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http://dx.doi.org/10.1038/s41598-017-09048-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561153PMC
August 2017

Evaluation of a novel noninvasive ICP monitoring device in patients undergoing invasive ICP monitoring: preliminary results.

J Neurosurg 2018 06 8;128(6):1653-1660. Epub 2017 Aug 8.

2Department of Neurosurgery, University of Erlangen, Germany.

OBJECTIVE There is no established method of noninvasive intracranial pressure (NI-ICP) monitoring that can serve as an alternative to the gold standards of invasive monitoring with external ventricular drainage or intraparenchymal monitoring. In this study a new method of NI-ICP monitoring performed using algorithms to determine ICP based on acoustic properties of the brain was applied in patients undergoing invasive ICP (I-ICP) monitoring, and the results were analyzed. METHODS In patients with traumatic brain injury and subarachnoid hemorrhage who were undergoing treatment in a neurocritical intensive care unit, the authors recorded ICP using the gold standard method of invasive external ventricular drainage or intraparenchymal monitoring. In addition, the authors simultaneously measured the ICP noninvasively with a device (the HS-1000) that uses advanced signal analysis algorithms for acoustic signals propagating through the cranium. To assess the accuracy of the NI-ICP method, data obtained using both I-ICP and NI-ICP monitoring methods were analyzed with MATLAB to determine the statistical significance of the differences between the ICP measurements obtained using NI-ICP and I-ICP monitoring. RESULTS Data were collected in 14 patients, yielding 2543 data points of continuous parallel ICP values in recordings obtained from I-ICP and NI-ICP. Each of the 2 methods yielded the same number of data points. For measurements at the ≥ 17-mm Hg cutoff, which was arbitrarily chosen for this preliminary analysis, the sensitivity and specificity for the NI-ICP monitoring were found to be 0.7541 and 0.8887, respectively. Linear regression analysis indicated that there was a strong positive relationship between the measurements. Differential pressure between NI-ICP and I-ICP was within ± 3 mm Hg in 63% of data-paired readings and within ± 5 mm Hg in 85% of data-paired readings. The receiver operating characteristic-area under the curve analysis revealed that the area under the curve was 0.895, corresponding to the overall performance of NI-ICP monitoring in comparison with I-ICP monitoring. CONCLUSIONS This study provides the first clinical data on the accuracy of the HS-1000 NI-ICP monitor, which uses advanced signal analysis algorithms to evaluate properties of acoustic signals traveling through the brain in patients undergoing I-ICP monitoring. The findings of this study highlight the capability of this NI-ICP device to accurately measure ICP noninvasively. Further studies should focus on clinical validation for elevated ICP values.
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http://dx.doi.org/10.3171/2016.11.JNS152268DOI Listing
June 2018

Recurrence of glioblastoma is associated with elevated microvascular transit time heterogeneity and increased hypoxia.

J Cereb Blood Flow Metab 2018 03 24;38(3):422-432. Epub 2017 Feb 24.

1 Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

Dynamic susceptibility contrast (DSC) perfusion MRI provide information about differences in macro- and microvasculature when executed with gradient-echo (GE; sensitive to macrovasculature) and spin-echo (SE; sensitive to microvasculature) contrast. This study investigated whether there are differences between macro- and microvascular transit time heterogeneity (MVTH and µVTH) and tissue oxygen tension (PO2) in newly-diagnosed and recurrent glioblastoma. Fifty-seven patients with glioblastoma (25 newly-diagnosed/32 recurrent) were examined with GE- and SE-DSC perfusion sequences, and a quantitative blood-oxygen-level-dependent (qBOLD) approach. Maps of MVTH, µVTH and coefficient of variation (MCOV and µCOV) were calculated from GE- and SE-DSC data, respectively, using an extended flow-diffusion equation. PO2 maps were calculated from qBOLD data. Newly-diagnosed and recurrent glioblastoma showed significantly lower ( P ≤ 0.001) µCOV values compared to both normal brain and macrovasculature (MCOV) of the lesions. Recurrent glioblastoma had significantly higher µVTH ( P = 0.014) and µCOV ( P = 0.039) as well as significantly lower PO2 values ( P = 0.008) compared to newly-diagnosed glioblastoma. The macrovasculature, however, showed no significant differences. Our findings provide evidence of microvascular adaption in the disorganized tumor vasculature for retaining the metabolic demands in stress response of therapeutically-uncontrolled glioblastomas. Thus, µVTH and PO2 mapping gives insight into the tumor microenvironment (vascular and hypoxic niches) responsible for therapy resistance.
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http://dx.doi.org/10.1177/0271678X17694905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851132PMC
March 2018

Intraoperative Magnetic Resonance Imaging of Cerebral Oxygen Metabolism During Resection of Brain Lesions.

World Neurosurg 2017 Apr 27;100:388-394. Epub 2017 Jan 27.

Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

Objective: Tissue oxygen tension is an important parameter for brain tissue viability and its noninvasive intraoperative monitoring in the whole brain is of highly clinical relevance. The purpose of this study was the introduction of a multiparametric quantitative blood oxygenation dependent magnetic resonance imaging (MRI) approach for intraoperative examination of oxygen metabolism during the resection of brain lesions.

Methods: Sixteen patients suffering from brain lesions were examined intraoperatively twice (before craniotomy and after gross-total resection) via the quantitative blood oxygenation dependent technique and a 1.5-Tesla MRI scanner, which is installed in an operating room. The MRI protocol included T2*- and T2 mapping and dynamic susceptibility weighted perfusion. Data analysis was performed with a custom-made, in-house MatLab software for calculation of maps of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO) as well as of cerebral blood volume and cerebral blood flow.

Results: Perilesional edema showed a significant increase in both perfusion (cerebral blood volume +21%, cerebral blood flow +13%) and oxygen metabolism (OEF +32%, CMRO +16%) after resection of the lesions. In perilesional nonedematous tissue only, however, oxygen metabolism (OEF +19%, CMRO +11%) was significantly increased, but not perfusion. No changes were found in normal brain. Fortunately, no neurovascular adverse events were observed.

Conclusions: This approach for intraoperative examination of oxygen metabolism in the whole brain is a new application of intraoperative MRI additionally to resection control (residual tumor detection) and updating of neuronavigation (brain shift detection). It may help to detect neurovascular adverse events early during surgery.
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http://dx.doi.org/10.1016/j.wneu.2017.01.060DOI Listing
April 2017

Individually Stabilized, Superparamagnetic Nanoparticles with Controlled Shell and Size Leading to Exceptional Stealth Properties and High Relaxivities.

ACS Appl Mater Interfaces 2017 Feb 20;9(4):3343-3353. Epub 2017 Jan 20.

Department of Nanobiotechnology, Institute for Biologically Inspired Materials, University of Natural Resources and Life Sciences , Muthgasse 11, 1190 Vienna, Austria.

Superparamagnetic iron oxide nanoparticles (SPION) have received immense interest for biomedical applications, with the first clinical application as negative contrast agent in magnetic resonance imaging (MRI). However, the first generation MRI contrast agents with dextran-enwrapped, polydisperse iron oxide nanoparticle clusters are limited to imaging of the liver and spleen; this is related to their poor colloidal stability in biological media and inability to evade clearance by the reticuloendothelial system. We investigate the qualitatively different performance of a new generation of individually PEG-grafted core-shell SPION in terms of relaxivity and cell uptake and compare them to benchmark iron oxide contrast agents. These PEG-grafted SPION uniquely enable relaxivity measurements in aqueous suspension without aggregation even at 9.4 T magnetic fields due to their extraordinary colloidal stability. This allows for determination of the size-dependent scaling of relaxivity, which is shown to follow a d dependence for identical core-shell structures. The here introduced core-shell SPION with ∼15 nm core diameter yield a higher R relaxivity than previous clinically used contrast agents as well as previous generations of individually stabilized SPION. The colloidal stability extends to control over evasion of macrophage clearance and stimulated uptake by SPION functionalized with protein ligands, which is a key requirement for targeted MRI.
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http://dx.doi.org/10.1021/acsami.6b12932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290491PMC
February 2017

MR Imaging-derived Oxygen Metabolism and Neovascularization Characterization for Grading and IDH Gene Mutation Detection of Gliomas.

Radiology 2017 06 13;283(3):799-809. Epub 2016 Dec 13.

From the Institute of Medical Radiology (A.S., G.H.), Department of Pathology (M.K.), and Department of Neurology (S.O.), University Clinic of St Pölten, Propst Führer-Strasse 4, A-3100 St Pölten, Austria; and Departments of Neurosurgery (A.S., M.Z., K.R., M.B.) and Neuroradiology (A.D.), University of Erlangen-Nürnberg, Erlangen, Germany.

Purpose To explore the diagnostic performance of physiological magnetic resonance (MR) imaging of oxygen metabolism and neovascularization activity for grading and characterization of isocitrate dehydrogenase (IDH) gene mutation status of gliomas. Materials and Methods This retrospective study had institutional review board approval; written informed consent was obtained from all patients. Eighty-three patients with histopathologically proven glioma (World Health Organization [WHO] grade II-IV) were examined with quantitative blood oxygen level-dependent imaging and vascular architecture mapping. Biomarker maps of neovascularization activity (microvessel radius, microvessel density, and microvessel type indicator [MTI]) and oxygen metabolism (oxygen extraction fraction [OEF] and cerebral metabolic rate of oxygen [CMRO]) were calculated. Receiver operating characteristic analysis was used to determine diagnostic performance for grading and detection of IDH gene mutation status. Results Low-grade (WHO grade II) glioma showed areas with increased OEF (+18%, P < .001, n = 20), whereas anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV) showed decreased OEF when compared with normal brain tissue (-54% [P < .001, n = 21] and -49% [P < .001, n = 41], respectively). This allowed clear differentiation between low- and high-grade glioma (area under the receiver operating characteristic curve [AUC], 1) for the patient cohort. MTI had the highest diagnostic performance (AUC, 0.782) for differentiation between gliomas of grades III and IV among all biomarkers. CMRO was decreased (P = .037) in low-grade glioma with a mutated IDH gene, and MTI was significantly increased in glioma grade III with IDH mutation (P = .013) when compared with the IDH wild-type counterparts. CMRO showed the highest diagnostic performance for IDH gene mutation detection in low-grade glioma (AUC, 0.818) and MTI in high-grade glioma (AUC, 0.854) and for all WHO grades (AUC, 0.899) among all biomarkers. Conclusion MR imaging-derived oxygen metabolism and neovascularization characterization may be useful for grading and IDH mutation detection of gliomas and requires only 7 minutes of extra imaging time. RSNA, 2016 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016161422DOI Listing
June 2017

Spatiotemporal Pattern of Human Cortical and Subcortical Activity during Early-Stage Odor Processing.

Chem Senses 2016 Nov;41(9):783-794

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg , Krankenhausstr. 9, D-91054 Erlangen , Germany.

The dynamics of early-stage cortical and subcortical responses in the human brain to odor stimulation are currently unknown. The objective of the present study was to analyze spatiotemporal patterns of human brain activity during odor perception using magnetoencephalography (MEG). In 12 normosmic healthy subjects, we investigated the onset of brain activity in relation to ipsilateral and contralateral stimulation with 2 odorants. Olfactory stimuli (200ms duration) were applied using an olfactometer, and brain activity was recorded with a 248-magnetometer whole-head MEG system. Olfactory responses were identified shortly (within 150ms) after stimulus onset in both hemispheres. Stimulation on the ipsilateral side yielded signals earlier (starting at 90ms) compared with contralateral stimulation in the primary olfactory cortex, hippocampus, parahippocampal gyrus, amygdala, and orbitofrontal cortex ( P < 0.001). The duration and peak amplitude of olfactory evoked magnetic fields were found to increase with increasing poststimulus time in the majority of the investigated cortical structures ( P ≤ 0.019 and P ≤ 0.021). The study showed the locations of early olfactory brain activity in humans within 150ms after the onset of stimuli. Olfactory activation is processed on the ipsilateral side of stimulation in early stages. After a short delay of 34ms a corresponding pattern of activation was also seen in the contralateral hemisphere, indicating the functional connectivity between the 2 hemispheres in the anterior commissure.
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http://dx.doi.org/10.1093/chemse/bjw074DOI Listing
November 2016

Visualization of CSF Flow with Time-resolved 3D MR Velocity Mapping in Aqueductal Stenosis Before and After Endoscopic Third Ventriculostomy : A Feasibility Study.

Clin Neuroradiol 2018 Mar 8;28(1):69-74. Epub 2016 Aug 8.

Department of Neurosurgery, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.

Purpose: The aim of this study was to evaluate timed-resolved three-dimensional (3D) magnetic resonance (MR) velocity mapping as a method for investigation of cerebrospinal fluid (CSF) flow changes in patients with aqueductal stenosis (AS) treated by endoscopic third ventriculostomy (ETV).

Methods: The MR velocity mapping was performed in 12 AS patients before and after ETV and in 10 healthy volunteers by using a 3-Tesla MR system. Time-resolved 3D MR velocity mapping data were acquired with a standard 3D phase contrast (PC) sequence with cardiac triggering. Values of mean (v) and maximum (v) velocity were measured at several ventricular structures using dedicated software.

Results: Of the patients 11 showed a satisfactory clinical improvement after ETV, whereas one patient needed subsequent shunt implantation. All AS patients showed significant hypomotile CSF flow dynamics in the third ventricle when compared to healthy subjects before surgery (p < 0.05). In contrast, CSF flow velocity was increased within the Foramen of Monro in AS patients. After ETV, all AS patients showed a decrease of CSF flow dynamics within the third ventricle. Mean and peak CSF flow velocities through the ventriculostomy were 1.72 ± 0.59 cm/s (v) and 3.53 ± 0.79 cm/s (v), respectively after ETV. The patient who needed shunt implantation after ETV had the lowest flow velocities through the ventriculostomy.

Conclusion: This study demonstrates that timed-resolved 3D MR velocity mapping is a useful imaging investigation for diagnostics and follow-up in patients with AS. This new technique provides an insight into the physiological CSF flow changes related with AS and its treatment.
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http://dx.doi.org/10.1007/s00062-016-0530-3DOI Listing
March 2018

Magnetic resonance imaging biomarkers for clinical routine assessment of microvascular architecture in glioma.

J Cereb Blood Flow Metab 2017 Feb 21;37(2):632-643. Epub 2016 Jul 21.

1 Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen, Germany.

Knowledge about the topological and structural heterogeneity of the microvasculature is important for diagnosis and monitoring of glioma. A vessel caliber and type-dependent temporal shift in the magnetic resonance imaging signal forms the basis for vascular architecture mapping. This study introduced a clinically feasible approach for assessment of vascular pathologies in gliomas using vascular architecture mapping. Sixty consecutive patients with known or suspected gliomas were examined using vascular architecture mapping as part of the routine magnetic resonance imaging protocol. Maps of microvessel radius and density, which adapted to the vasculature-dependent temporal shift phenomenon, were calculated using a costume-made software tool. Microvessel radius and density were moderately to severely elevated in a heterogeneous, inversely correlated pattern within high-grade gliomas. Additionally, three new imaging biomarkers were introduced: Microvessel type indicator allowing differentiation between supplying arterial and draining venous microvasculature in high-grade gliomas. Vascular-induced bolus peak time shift may presumably be sensitive for early neovascularization in the infiltration zone. Surprisingly, curvature showed significant changes in peritumoral vasogenic edema which correlated with neovascularization in the tumor core of high-grade gliomas. These new magnetic resonance imaging biomarkers give insights into complexity and heterogeneity of vascular changes in glioma; however, histological validations in more well-defined patient populations are required.
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http://dx.doi.org/10.1177/0271678X16655549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381464PMC
February 2017

Reproducibility of MRI Dixon-Based Attenuation Correction in Combined PET/MR with Applications for Lean Body Mass Estimation.

J Nucl Med 2016 07 25;57(7):1096-101. Epub 2016 Feb 25.

Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.

Unlabelled: The aim of this study was to assess the reproducibility of standard, Dixon-based attenuation correction (MR-AC) in PET/MR imaging. A further aim was to estimate a patient-specific lean body mass (LBM) from these MR-AC data.

Methods: Ten subjects were positioned in a fully integrated PET/MR system, and 3 consecutive multibed acquisitions of the standard MR-AC image data were acquired. For each subject and MR-AC map, the following compartmental volumes were calculated: total body, soft tissue (ST), fat, lung, and intermediate tissue (IT). Intrasubject differences in the total body and subcompartmental volumes (ST, fat, lung, and IT) were assessed by means of coefficients of variation (CVs) calculated across the 3 consecutive measurements and, again, across these measurements but excluding those affected by major artifacts. All subjects underwent a body composition measurement using air displacement plethysmography (ADP) that was used to calculate a reference LBMADP A second LBM estimate was derived from available MR-AC data using a formula incorporating the respective tissue volumes and densities as well as the subject-specific body weights. A third LBM estimate was obtained from a sex-specific formula (LBMFormula). Pearson correlation was calculated for LBMADP, LBMMR-AC, and LBMFormula Further, linear regression analysis was performed on LBMMR-AC and LBMADP.

Results: The mean CV for all 30 scans was 2.1 ± 1.9% (TB). When missing tissue artifacts were excluded, the CV was reduced to 0.3 ± 0.2%. The mean CVs for the subcompartments before and after exclusion of artifacts were 0.9 ± 1.1% and 0.7 ± 0.7% for the ST, 2.9 ± 4.1% and 1.3 ± 1.0% for fat, and 3.6 ± 3.9% and 1.3 ± 0.7% for the IT, respectively. Correlation was highest for LBMMR-AC and LBMADP (r = 0.99). Linear regression of data excluding artifacts resulted in a scaling factor of 1.06 for LBMMR-AC CONCLUSION: LBMMR-AC is shown to correlate well with standard LBM measurements and thus offers routine LBM-based SUV quantification in PET/MR. However, MR-AC images must be controlled for systematic artifacts, including missing tissue and tissue swaps. Efforts to minimize these artifacts could help improve the reproducibility of MR-AC.
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http://dx.doi.org/10.2967/jnumed.115.168294DOI Listing
July 2016

Quantification of serial changes in cerebral blood volume and metabolism in patients with recurrent glioblastoma undergoing antiangiogenic therapy.

Eur J Radiol 2015 Jun 6;84(6):1128-36. Epub 2015 Mar 6.

Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten, Austria.

Objectives: To evaluate the usefulness of quantitative advanced magnetic resonance imaging (MRI) methods for assessment of antiangiogenic therapy (AAT) response in recurrent glioblastoma multiforme (GBM).

Methods: Eighteen patients with recurrent GBM received bevacizumab and 18 patients served as control group. Baseline MRI and two follow-up examinations were acquired every 3-5 months using dynamic susceptibility-weighted contrast (DSC) perfusion MRI and (1)H-MR spectroscopic imaging ((1)H-MRSI). Maps of absolute cerebral blood volume (aCBV) were coregistered with choline (Cho) and N-acetyl-aspartate (NAA) concentrations and compared to usually used relative parameters as well as controls.

Results: Perfusion significantly decreased in responding and pseudoresponding GBMs but also in normal appearing brain after AAT onset. Cho and NAA concentrations were superior to Cr-ratios in lesion differentiation and showed a clear gap between responding and pseudoresponding lesions. Responders to AAT exceptionally frequently (6 out of 8 patients) showed remote GBM progression.

Conclusions: Quantification of CBV reveals changes in normal brain perfusion due to AAT, which were not described so far. DSC perfusion MRI seems not to be suitable for differentiation between response and pseudoresponse to AAT. However, absolute quantification of brain metabolites may allow for distinction due to a clear gap at 6-9 months after therapy onset.
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http://dx.doi.org/10.1016/j.ejrad.2015.02.025DOI Listing
June 2015

Functional and quantitative magnetic resonance myelography of symptomatic stenoses of the lumbar spine.

Neuroradiology 2014 Dec 23;56(12):1069-78. Epub 2014 Sep 23.

MRI Center of Excellence, District Hospital Castle of Werneck, Balthasar-Neumann-Platz 1, D-97440, Werneck, Germany,

Introduction: The objective of this study was to demonstrate that functional, quantitative magnetic resonance myelography (MRM) allows standardized diagnosis of symptomatic lumbar spinal stenoses which show at least equal detectability compared to functional myelography and postmyelographic CT (pmCT) based on intra- and postoperative findings.

Methods: We investigated 43 volunteers and 47 patients with symptomatic lumbar spinal stenoses using MRM in normal position as well as in flexion and extension in a standard whole-body MR scanner. Twenty volunteers were additionally examined under axial loading. All patients were investigated by functional myelography and pmCT and 10 patients had a functional lumbar MRM postoperatively. Range of motion and cerebrospinal fluid (CSF) volumes in normal position, flexion, extension, and under axial loading (volunteers) were assessed for each segment. Detectability was determined by using intraoperative findings, and postoperative freedom of symptoms was correlated with CSF volume changes in MRM.

Results: The ranges of motion in a standard whole-body MR scanner provide adequate scope for investigations into function (flexion and extension) in both volunteers and patients. Axial loading was associated with a mechanism of extension, albeit to a far smaller extent. Detectability of lumbar stenoses was 100% for MRM, 58% for conventional myelography, and 68% for pmCT. Postoperative changes in CSF volume of levels with stenoses in MRM strongly correlated with freedom of symptoms (R = 0.772).

Conclusion: This MRM method allows for exact diagnosis and reproducible quantification of stenoses, motion-related changes, and spondylolistheses of the lumbar spine. It may be useful for early detection of alterations in order to avoid neuronal compression.
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http://dx.doi.org/10.1007/s00234-014-1433-0DOI Listing
December 2014

Physiological effects of cigarette smoking in the limbic system revealed by 3 tesla magnetic resonance spectroscopy.

J Neural Transm (Vienna) 2014 Oct 19;121(10):1211-9. Epub 2014 Mar 19.

Department of Neuroradiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany,

Several studies and recent models of effects of nicotine, the main addictive and psychoactive component in tobacco, point to action of the drug on the limbic system during maintenance of addiction, either direct or indirect via projections from the ventral tegmental area. The objective of this study was to demonstrate physiological effects of cigarette smoking on the hippocampus and the grey matter of the dorsal anterior cingulate cortex in the human brain with regard to addiction and withdrawal. This aim was achieved by group comparisons of results of magnetic resonance spectroscopy between non-smokers, smokers and smokers during withdrawal. 12 smokers and 12 non-smokers were measured with single voxel proton magnetic resonance spectroscopy for total N-acetyl aspartate, glutamate and glutamine, choline-containing compounds, myo-inositol and total creatine in the right and the left hippocampus and in the right and the left dorsal anterior cingulate cortex. Smokers were examined twice, first during regular cigarette smoking and second on the third day of nicotine withdrawal. The ratios to total creatine were used for better reliability. In our study, Glx/tCr was significantly increased and tCho/tCr was significantly decreased in the left cingulate cortex in smokers compared to non-smokers (p = 0.01, both). Six out of seven smokers showed normalization of the Glx/tCr in the left cingulate cortex during withdrawal. Although these results are preliminary due to the small sample size, our results confirm the assumption that cigarette smoking interferes directly or indirectly with the glutamate circuit in the dorsal anterior cingulate cortex.
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http://dx.doi.org/10.1007/s00702-014-1190-6DOI Listing
October 2014