Chemical exchange saturation transfer MRI in central nervous system tumours on a 1.5 T MR-Linac

Purpose: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. Methods: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. Results: The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. Conclusion: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols

Imaging Microvascular Changes Associated with Neurological Diseases

Microvascular lesions of the brain are observed in numerous pathological conditions including Alzheimer's disease (AD). Regional patterns of microvascular abnormality can be characterized using current neuroimaging technologies. When applied to mouse models of human disease, these technologies reveal cerebral vascular patterns and help uncover genotype-to-phenotype relationships. This thesis focuses on the development and testing of techniques for measuring two perfusion-related metrics in mouse brain regions, namely, cerebral blood volume (CBV) and cerebral blood flow (CBF) using micro-computed tomography (micro-CT) and arterial spin labeling (ASL), respectively. The main developments for measurement of CBV have included: refinements to micro-CT specimen preparation; registration of micro-CT images to an MRI anatomical brain atlas; and masking of major vessels to calculate small-vessel CBV (sv-CBV). The development of this micro-CT technique provided reference values of CBV over neuroanatomical brain regions in wildtype mice. A separate study was conducted to assess regional sv-CBV in a mouse model of AD; this study was motivated by the prevalence of microvascular lesions in patients who suffer from AD. Significant regional differences in sv-CBV were found between AD-afflicted mice and controls. The main developments for measurement of CBF have included: design and implementation of accurate ASL slice positioning and optimization of inversion efficiency parameters. The development of this ASL technique provided reference values of CBF over neuroanatomical brain regions in wildtype mice. These techniques for measuring CBV and CBF over mouse brain regions could lead to improved characterization of vascularity in models of neurological diseases.Ph

Investigation of irradiated volume in linac-based brain hypo-fractionated stereotactic radiotherapy

Abstract Background Emerging techniques such as brain hypo-fractionated radiotherapy (HF-RT) involve complex cases with limited guidelines for plan quality and normal tissue tolerances. The purpose of the present study was to statistically parameterize irradiated volume independently of dose prescription, or margin to determine what spread in achievable irradiated volume one may expect for a given case. Methods We defined EXT as the total tissue within the external contour of the patient (including the target) and we defined BMP as the contour of the brain minus PTV. Irradiated volumes of EXT and BMP at specific doses (i.e. 50, 60%, etc., of the prescribed dose) were extracted from 135 single-target HF-RT clinical cases, each planned with a single-arc, homogeneous (SAHO) approach in which target maximum dose (Dmax) was constrained to 3 targets (N = 10) to investigate the effect of target number. We also examined the effect of shape complexity. A series of best fit curves with confidence and prediction intervals were generated for irradiated volume versus total target volume and the resulting model was subsequently validated on a subsequent set of 23 consecutive prospective cases not originally used in curve-fitting. A subset of 30 HF-RT cases were re-planned with a well-published four-arc, heterogeneous (FAHE) radiosurgery planning approach (Dmax could exceed 130%) to demonstrate how technique affects irradiated volume. Results For SAHO, strong correlation (R2 > 0.98) was found for predicting irradiated volumes. For a given total target volume, irradiated-volume increased by a range of 1.4–2.9× for >3 versus single-targets depending on isodose level. Shape complexity had minor impact on irradiated volume. There was no statistical difference in irradiated volumes between validation and input data (p > 0.2). The FAHE-generated irradiated volumes yielded curves and prediction and confidence bands that agreed well with published data indicating that the proposed approach is feasible for cross-institutional comparisons. Conclusions A description of irradiated volume for linac-based HF-RT is proposed based on population data. We have demonstrated that the proposed approach is feasible for inter and intra-institutional comparisons

Measurement of cerebral blood volume in mouse brain regions using micro-computed tomography

Micro-computed tomography (micro-CT) is an X-ray imaging technique that can produce detailed 3D images of cerebral vasculature. This paper describes the development of a novel method for using micro-CT to measure cerebral blood volume (CBV) in the mouse brain. As an application of the methodology, we test the hypotheses that differences in CBV exist over anatomical brain regions and that high energy demanding primary sensory regions of the cortex have locally elevated CBV, which may reflect a vascular specialization. CBV was measured as the percentage of tissue space occupied by a radio-opaque silicon rubber that fills the vasculature. To ensure accuracy of the CBV measurements, several innovative refinements were made to standard micro-CT specimen preparation and analysis procedures. Key features of the described method are vascular perfusion under controlled pressure, registration of the micro-CT images to an MRI anatomical brain atlas and re-scaling of micro-CT intensities to CBV units with selectable exclusion of major vessels. Histological validation of the vascular perfusion showed that the average percentage of vessels filled was 93 ± 3%. Comparison of thirteen brain regions in nine mice revealed significant differences in CBV between regions (p b 0.0001) while cortical maps showed that primary visual and auditory areas have higher CBV than primary somatosensory areas

MRI commissioning of 1.5T MR-linac systems – a multi-institutional study

Background: Magnetic Resonance linear accelerator (MR-linac) systems represent a new type of technology that allows for online MR-guidance for high precision radiotherapy (RT). Currently, the first MR-linac installations are being introduced clinically. Since the imaging performance of these integrated MR-linac systems is critical for their application, a thorough commissioning of the MRI performance is essential. However, guidelines on the commissioning of MR-guided RT systems are not yet defined and data on the performance of MR-linacs are not yet available. Materials & methods: Here we describe a comprehensive commissioning protocol, which contains standard MRI performance measurements as well as dedicated hybrid tests that specifically assess the interactions between the Linac and the MRI system. The commissioning results of four MR-linac systems are presented in a multi-center study. Results: Although the four systems showed similar performance in all the standard MRI performance tests, some differences were observed relating to the hybrid character of the systems. Field homogeneity measurements identified differences in the gantry shim configuration, which was later confirmed by the vendor. Conclusion: Our results highlight the importance of dedicated hybrid commissioning tests and the ability to compare the machines between institutes at this very early stage of clinical introduction. Until formal guidelines and tolerances are defined the tests described in this study may be used as a practical guideline. Moreover, the multi-center results provide initial bench mark data for future MR-linac installations

MRI commissioning of 1.5T MR-linac systems – a multi-institutional study

Background: Magnetic Resonance linear accelerator (MR-linac) systems represent a new type of technology that allows for online MR-guidance for high precision radiotherapy (RT). Currently, the first MR-linac installations are being introduced clinically. Since the imaging performance of these integrated MR-linac systems is critical for their application, a thorough commissioning of the MRI performance is essential. However, guidelines on the commissioning of MR-guided RT systems are not yet defined and data on the performance of MR-linacs are not yet available. Materials & methods: Here we describe a comprehensive commissioning protocol, which contains standard MRI performance measurements as well as dedicated hybrid tests that specifically assess the interactions between the Linac and the MRI system. The commissioning results of four MR-linac systems are presented in a multi-center study. Results: Although the four systems showed similar performance in all the standard MRI performance tests, some differences were observed relating to the hybrid character of the systems. Field homogeneity measurements identified differences in the gantry shim configuration, which was later confirmed by the vendor. Conclusion: Our results highlight the importance of dedicated hybrid commissioning tests and the ability to compare the machines between institutes at this very early stage of clinical introduction. Until formal guidelines and tolerances are defined the tests described in this study may be used as a practical guideline. Moreover, the multi-center results provide initial bench mark data for future MR-linac installations

Accuracy and precision of apparent diffusion coefficient measurements on a 1.5 T MR-Linac in central nervous system tumour patients

Background and purpose: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner. Materials and methods: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans. Results: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: –0.05 ± 0.03, –0.08 ± 0.05, –0.1 ± 0.1, –0.08 ± 0.07 μm2/ms). ADC differed substantially in CSF (bias: –0.5 ± 0.3 μm2/ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable. Conclusions: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes