Mapping the vessel architecture of brain cancer by advanced perfusion MRI

An important part of our understanding of brain tumours relies on our ability to assess the vascular function of the tumours. Dynamic susceptibility contrast (DSC), and the novel method Vessel Architectural Imaging (VAI), are MRI techniques that potentially can provide valuable information about the vascular properties of the brain. This thesis investigates the behaviour of DSC and VAI under a range of different conditions using an advanced simulation model. The simulations show that the derived parameters from DSC and VAI are dependent on a complex interaction between underlying vascular properties and the noise in the signal. Moreover, results from the simulations suggest that previous findings regarding these techniques are not always valid. This thesis also demonstrates a clinical application of DSC and VAI. By examining vascular function of brain tumours receiving high-dose radiotherapy, we found that brain tumours with poor vascular function were more prone to radiation-induced tissue damage than tumours with normal vascular function. The results from this work suggest that DSC and VAI can be clinically valuable, but must be used with caution. In addition, the results are highly relevant for further use and development of these techniques

Kartlegging av interferenser ved kvantitativ bestemmelse av et utvalg grunnstoffer målt med trippel kvadrupol ICP-MS

Grunnstoffanalyser er nødvendige innenfor en rekke industrier, blant annet matvareproduksjon, oljeindustri, bilproduksjon og medisinsk forskning. Grunnstoffsammensetningen i et produkt har mye å si for kvaliteten. En teknikk for å bestemme grunnstoffkonsentrasjon er ICP-MS. Ved bruk av teknologier som plasma (ionisert gass) kombinert med trippel kvadrupol massespektrometri er ICP-MS svært effektiv og nøyaktig. En utfordring med ICP-MS er at grunnstoffer i en prøve kan interferere på andre grunnstoffer i matriksen som kan føre til falske forhøyede konsentrasjoner. Interferens av grunnstoffene Al, Si, Ca, Mn, Fe, Ni, Cu, Sr og Mo har blitt undersøkt på et utvalg isotoper av Mg, Al, Si, Ca, Ti, Mn, Fe, Co, Cu, Ni, Sr, Ge og Cd. To tilleggsanalyser av Ca har blitt gjennomført for å undersøke effekten Si og Sr som interferenser har på Ca. I tillegg har interferens av de sjeldne jordartene La, Ce, Pr og Nd blitt undersøkt på et utvalg isotoper av La, Ce, Pr, Nd, Gd, Dy og Er. For å undersøke interferens og for å finne måter å effektivt unngå interferenser for hvert grunnstoff, har det blitt tatt i bruk flere metoder, i form av gassmoduser: «No Gas», «He-gass», «O2 On-mass» og «O2 Mass-shift». I de ulike gassmodusene tilsettes gasser som vil gi ulike betingelser for ionene som analyseres, slik at spesifikke interferenser kan unngås. Al, Mn, Fe, Ni og Cu førte ikke til problematiske interferenser på andre grunnstoff. Si og Sr ble funnet å interferere på Ca, mens Ca interfererte på Fe og Mo på Cd. I undersøkelsen mellom Si og Ca ble det funnet at Si ikke var en så stor interferens på Ca som antatt etter den første analysen. Da Sr og Ca deretter ble målt ble det derimot funnet at Sr var en svært sterk interferens på Ca. Prøven med en kjent Ca-konsentrasjon på 200 ng/mL ble i He-gassmodus målt til over 900 ng/mL ved tilstedeværelse av 200 ng/mL Sr. Ved bruk av O2 mass-shift-modus ble målt Ca-konsentrasjon redusert til 220 ng/mL. Blant de sjeldne jordartene var La en interferens på Gd, Ce på La og Gd, Pr var en spesielt kraftig interferens på Gd og Nd interfererte på Er

A theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast MRI

Mapping the complex heterogeneity of vascular tissue in the brain is important for understanding cerebrovascular disease. In this translational study, we build on previous work using vessel architectural imaging (VAI) and present a theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast magnetic resonance imaging (MRI). Our tissue model covers realistic structural architectures for vessel branching and orientations, as well as a range of hemodynamic scenarios for blood flow, capillary transit times and oxygenation. In a typical image voxel, our findings show that the apparent MRI relaxation rates are independent of the mean vessel orientation and that the vortex area, a VAI-based parameter, is determined by the relative oxygen saturation level and the vessel branching of the tissue. Finally, in both simulated and patient data, we show that the relative distributions of the vortex area parameter as a function of capillary transit times show unique characteristics in normal-appearing white and gray matter tissue, whereas tumour-voxels in comparison display a heterogeneous distribution. Collectively, our study presents a comprehensive framework that may serve as a roadmap for in vivo and per-voxel determination of vascular status and heterogeneity in cerebral tissue

Responses in the diffusivity and vascular function of the irradiated normal brain are seen up until 18 months following SRS of brain metastases

Background MRI may provide insights into longitudinal responses in the diffusivity and vascular function of the irradiated normal-appearing brain following stereotactic radiosurgery (SRS) of brain metastases. Methods Forty patients with brain metastases from non-small cell lung cancer (N = 26) and malignant melanoma (N = 14) received SRS (15–25 Gy). Longitudinal MRI was performed pre-SRS and at 3, 6, 9, 12, and 18 months post-SRS. Measures of tissue diffusivity and vascularity were assessed by diffusion-weighted and perfusion MRI, respectively. All maps were normalized to white matter receiving less than 1 Gy. Longitudinal responses were assessed in normal-appearing brain, excluding tumor and edema, in the LowDose (1–10 Gy) and HighDose (>10 Gy) regions. The Eastern Cooperative Oncology Group (ECOG) performance status was recorded pre-SRS. Results Following SRS, the diffusivity in the LowDose region increased continuously for 1 year (105.1% ± 6.2%; P < .001), before reversing toward pre-SRS levels at 18 months. Transient reductions in microvascular cerebral blood volume (P < .05), blood flow (P < .05), and vessel densities (P < .05) were observed in LowDose at 6–9 months post-SRS. Correspondingly, vessel calibers in LowDose transiently increased at 3–9 months (P < .01). The responses in HighDose displayed similar trends as in LowDose, but with larger interpatient variations. Vascular responses followed pre-SRS ECOG status. Conclusions Our results imply that even low doses of radiation to normal-appearing brain following cerebral SRS induce increased diffusivity and reduced vascular function for up until 18 months. In particular, the vascular responses indicate the reduced ability of the normal-appearing brain tissue to form new capillaries. Assessing the potential long-term neurologic effects of SRS on the normal-appearing brain is warranted

Noise dependency in vascular parameters from combined gradient-echo and spin-echo DSC MRI

Dynamic susceptibility contrast (DSC) imaging is a widely used technique for assessment of cerebral blood volume (CBV). With combined gradient-echo and spin-echo DSC techniques, measures of the underlying vessel size and vessel architecture can be obtained from the vessel size index (VSI) and vortex area, respectively. However, how noise, and specifically the contrast-to-noise ratio (CNR), affect the estimations of these parameters has largely been overlooked. In order to address this issue, we have performed simulations to generate DSC signals with varying levels of CNR, defined by the peak of relaxation rate curve divided by the standard deviation of the baseline. Moreover, DSC data from 59 brain cancer patients were acquired at two different 3 T-scanners (N = 29 and N = 30, respectively), where CNR and relative parameter maps were obtained. Our simulations showed that the measured parameters were affected by CNR in different ways, where low CNR led to overestimations of CBV and underestimations of VSI and vortex area. In addition, a higher noise-sensitivity was found in vortex area than in CBV and VSI. Results from clinical data were consistent with simulations, and indicated that CNR < 4 gives highly unreliable measurements. Moreover, we have shown that the distribution of values in the tumour regions could change considerably when voxels with CNR below a given cut off are excluded when generating the relative parameter maps. The widespread use of CBV and attractive potential of VSI and vortex area, makes the noise-sensitivity of these parameters found in our study relevant for further use and development of the DSC imaging technique. Our results suggest that the CNR has considerable impact on the measured parameters, with the potential to affect the clinical interpretation of DSC-MRI, and should therefore be taken into account in the clinical decision-making process

Brain metastases with poor vascular function are susceptible to pseudoprogression after stereotactic radiation surgery

Purpose: This study aimed to investigate the hemodynamic status of cerebral metastases prior to and after stereotactic radiation surgery (SRS) and to identify the vascular characteristics that are associated with the development of pseudoprogression from radiation-induced damage with and without a radionecrotic component. Methods and materials: Twenty-four patients with 29 metastases from non-small cell lung cancer or malignant melanoma received SRS with dose of 15 Gy to 25 Gy. Magnetic resonance imaging (MRI) scans were acquired prior to SRS, every 3 months during the first year after SRS, and every 6 months thereafter. On the basis of the follow-up MRI scans or histology after SRS, metastases were classified as having response, tumor progression, or pseudoprogression. Advanced perfusion MRI enabled the estimation of vascular status in tumor regions including fractions of abnormal vessel architecture, underperfused tissue, and vessel pruning. Results: Prior to SRS, metastases that later developed pseudoprogression had a distinct poor vascular function in the peritumoral zone compared with responding metastases (P < .05; number of metastases = 15). In addition, differences were found between the peritumoral zone of pseudoprogressing metastases and normal-appearing brain tissue (P < .05). In contrast, for responding metastases, no differences in vascular status between peritumoral and normal-appearing brain tissue were observed. The dysfunctional peritumoral vasculature persisted in pseudoprogressing metastases after SRS. Conclusions: Our results suggest that the vascular status of peritumoral tissue prior to SRS plays a defining role in the development of pseudoprogression and that advanced perfusion MRI may provide new insights into patients' susceptibility to radiation-induced effects

The impact of EPI-based distortion correction of dynamic susceptibility contrast MRI on cerebral blood volume estimation in patients with glioblastoma

Relative cerebral blood volume (rCBV) from dynamic susceptibility contrast (DSC)-MRI is a valuable biomarker in patients with glioblastoma for assessing treatment response and predicting overall survival. DSC-MRI based on echo planar images (EPI) may possess severe geometric distortions from magnetic field inhomogeneities up to the order of centimeters. The aim of this study is to assess how much two readily available EPI-based geometric distortion correction methods, FSL TOPUP and EPIC, affect rCBV values from DSC-MRI in patients with confirmed glioblastoma