Rules-based Volumetric Segmentation of Multiparametric MRI for Response Assessment in Recurrent High-Grade Glioma.

We report domain knowledge-based rules for assigning voxels in brain multiparametric MRI (mpMRI) to distinct tissuetypes based on their appearance on Apparent Diffusion Coefficient of water (ADC) maps, T1-weighted unenhanced and contrast-enhanced, T2-weighted, and Fluid-Attenuated Inversion Recovery images. The development dataset comprised mpMRI of 18 participants with preoperative high-grade glioma (HGG), recurrent HGG (rHGG), and brain metastases. External validation was performed on mpMRI of 235 HGG participants in the BraTS 2020 training dataset. The treatment dataset comprised serial mpMRI of 32 participants (total 231 scan dates) in a clinical trial of immunoradiotherapy in rHGG (NCT02313272). Pixel intensity-based rules for segmenting contrast-enhancing tumor (CE), hemorrhage, Fluid, non-enhancing tumor (Edema1), and leukoaraiosis (Edema2) were identified on calibrated, co-registered mpMRI images in the development dataset. On validation, rule-based CE and High FLAIR (Edema1 + Edema2) volumes were significantly correlated with ground truth volumes of enhancing tumor (R = 0.85;p < 0.001) and peritumoral edema (R = 0.87;p < 0.001), respectively. In the treatment dataset, a model combining time-on-treatment and rule-based volumes of CE and intratumoral Fluid was 82.5% accurate for predicting progression within 30 days of the scan date. An explainable decision tree applied to brain mpMRI yields validated, consistent, intratumoral tissuetype volumes suitable for quantitative response assessment in clinical trials of rHGG.

Pretherapy Ferumoxytol-enhanced MRI to Predict Response to Liposomal Irinotecan in Metastatic Breast Cancer.

Purpose To investigate ferumoxytol (FMX)-enhanced MRI as a pretreatment predictor of response to liposomal irinotecan (nal-IRI) for thoracoabdominal and brain metastases in women with metastatic breast cancer (mBC). Materials and Methods In this phase 1 expansion trial (ClinicalTrials.gov identifier, NCT01770353; 27 participants), 49 thoracoabdominal (19 participants; mean age, 48 years ± 11 [SD]) and 19 brain (seven participants; mean age, 54 years ± 8) metastases were analyzed on MR images acquired before, 1-4 hours after, and 16-24 hours after FMX administration. In thoracoabdominal metastases, tumor transverse relaxation rate (R*2) was normalized to the mean R*2 in the spleen (rR*2), and the tumor histogram metric rR*2,N, representing the average of rR*2 in voxels above the nth percentile, was computed. In brain metastases, a novel compartmentation index was derived by applying the MRI signal equation to phantom-calibrated coregistered FMX-enhanced MRI brain scans acquired before, 1-4 hours after, and 16-24 hours after FMX administration. The fraction of voxels with an FMX compartmentation index greater than 1 was computed over the whole tumor (FCIGT1) and from voxels above the 90th percentile R*2 (FCIGT1 R*2,90). Results rR*2,90 computed from pretherapy MRI performed 16-24 hours after FMX administration, without reference to calibration phantoms, predicted response to nal-IRI in thoracoabdominal metastases (accuracy, 74%). rR*2,90 performance was robust to the inclusion of some peritumoral tissue within the tumor region of interest. FCIGT1 R*2,90 provided 79% accuracy on cross-validation in prediction of response in brain metastases. Conclusion This first in-human study focused on mBC suggests that FMX-enhanced MRI biologic markers can be useful for pretherapy prediction of response to nal-IRI in patients with mBC. Keywords: MRI Contrast Agent, MRI, Breast, Head/Neck, Tumor Response, Experimental Investigations, Brain/Brain Stem Clinical trial registration no. NCT01770353 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Daldrup-Link in this issue.

Joint total variation-based reconstruction of multiparametric magnetic resonance images for mapping tissue types.

Multispectral analysis of coregistered multiparametric magnetic resonance (MR) images provides a powerful method for tissue phenotyping and segmentation. Acquisition of a sufficiently varied set of multicontrast MR images and parameter maps to objectively define multiple normal and pathologic tissue types can require long scan times. Accelerated MRI on clinical scanners with multichannel receivers exploits techniques such as parallel imaging, while accelerated preclinical MRI scanning must rely on alternate approaches. In this work, tumor-bearing mice were imaged at 7 T to acquire k-space data corresponding to a series of images with varying T1-, T2- and T2*-weighting. A joint reconstruction framework is proposed to reconstruct a series of T1-weighted images and corresponding T1 maps simultaneously from undersampled Cartesian k-space data. The ambiguity introduced by undersampling was resolved by using model-based constraints and structural information from a reference fully sampled image as the joint total variation prior. This process was repeated to reconstruct T2-weighted and T2*-weighted images and corresponding maps of T2 and T2* from undersampled Cartesian k-space data. Validation of the reconstructed images and parameter maps was carried out by computing tissue-type maps, as well as maps of the proton density fat fraction (PDFF), proton density water fraction (PDwF), fat relaxation rate ( R2f*) and water relaxation rate ( R2w*) from the reconstructed data, and comparing them with ground truth (GT) equivalents. Tissue-type maps computed using 18% k-space data were visually similar to GT tissue-type maps, with dice coefficients ranging from 0.43 to 0.73 for tumor, fluid adipose and muscle tissue types. The mean T1 and T2 values within each tissue type computed using only 18% k-space data were within 8%-10% of the GT values from fully sampled data. The PDFF and PDwF maps computed using 27% k-space data were within 3%-15% of GT values and showed good agreement with the expected values for the four tissue types.

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

The association between BOLD-based cerebrovascular reactivity (CVR) and end-tidal CO2 in healthy subjects.

Cerebrovascular reactivity (CVR) mapping using CO2-inhalation can provide important insight into vascular health. At present, blood-oxygenation-level-dependent (BOLD) MRI acquisition is the most commonly used CVR method due to its high sensitivity, high spatial resolution, and relatively straightforward processing. However, large variations in CVR across subjects and across different sessions of the same subject are often observed, which can cloud the ability of this promising measure in detecting diseases or monitoring treatment responses. The present work aims to identify the physiological components underlying the observed variability in CVR data. When studying the association between CVR value and the subject's CO2 levels in a total of N = 253 healthy participants, we found that CVR was lower in individuals with a higher basal end-tidal CO2, EtCO2 (slope = -0.0036 ±â€¯0.0008%/mmHg2, p < 0.001), or with a greater EtCO2 change (ΔEtCO2) with hypercapnic condition (slope = -0.0072 ±â€¯0.0018%/mmHg2, p < 0.001). In a within-subject setting, when studying the CVR difference between two repeated scans (with repositioning) in relation to the corresponding differences in basal EtCO2 and ΔEtCO2 (n = 11), it was found that CVR values were lower if the basal EtCO2 or ΔEtCO2 during that particular scan session was greater. The present work suggests that basal physiological state and the level of hypercapnic stimulus intensity should be considered in application studies of CVR in order to reduce inter-subject and intra-subject variations in the data. Potential approaches to use these findings to reduce noise and augment sensitivity are proposed.

Spatial distribution of flow and oxygenation in the cerebral venous drainage system.

PURPOSE: To investigate the venous oxygenation and flow in the brain, and determine how they might change under challenged states. MATERIALS AND METHODS: Eight healthy human subjects (24-37 years) were studied. T2 -relaxation under spin tagging (TRUST) magnetic resonance imaging (MRI) and phase-contrast MRI were performed to measure venous oxygenation and venous blood flow, respectively, in the superior sagittal sinus (SSS), the straight sinus (SS), and the internal jugular veins (IJVs). Venous oxygenation was assessed at room air (0.03%CO2 , 21%O2 ) and under hyperoxia (O%CO2 , 95%O2 , and 5%N2 ) conditions. Venous blood flow was assessed at room air and under hypercapnia (5%CO2 , 21%O2 , and 74%N2 ) conditions. Whole-brain blood flow was also measured at the four feeding arteries of the brain using phase-contrast MRI. The changes in venous oxygenation and blood flow from room air to hyperoxia or hypercapnia conditions were tested using paired t-tests. RESULTS: Venous oxygenation in the SSS, the SS, and the IJVs was 61 ± 4%, 64 ± 4%, and 62 ± 4%, respectively, at room air, and increased to 70 ± 3% (P < 0.01 compared to room air), 71 ± 5% (P = 0.59), and 68 ± 5% (P < 0.05) under hyperoxic condition. The SSS, SS, and IJV drained 46 ± 9%, 16 ± 4%, and 79 ± 1% of whole-brain blood flow, respectively, and this flow distribution did not change under hypercapnic condition (P > 0.5). CONCLUSION: The results found in this study provide insight into the venous oxygenation and venous flow distribution and its heterogeneity among different venous structures. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1091-1098.

Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. OBJECTIVE: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. METHODS: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. RESULTS: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. CONCLUSION: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

Searching for a truly "iso-metabolic" gas challenge in physiological MRI.

Hypercapnia challenge (e.g. inhalation of CO2) has been used in calibrated fMRI as well as in the mapping of vascular reactivity in cerebrovascular diseases. An important assumption underlying these measurements is that CO2 is a pure vascular challenge but does not alter neural activity. However, recent reports have suggested that CO2 inhalation may suppress neural activity and brain metabolic rate. Therefore, the goal of this study is to propose and test a gas challenge that is truly "iso-metabolic," by adding a hypoxic component to the hypercapnic challenge, since hypoxia has been shown to enhance cerebral metabolic rate of oxygen (CMRO2). Measurement of global CMRO2 under various gas challenge conditions revealed that, while hypercapnia (P = 0.002) and hypoxia (P = 0.002) individually altered CMRO2 (by -7.6 ± 1.7% and 16.7 ± 4.1%, respectively), inhalation of hypercapnic-hypoxia gas (5% CO2/13% O2) did not change brain metabolism (CMRO2 change: 1.5 ± 3.9%, P = 0.92). Moreover, cerebral blood flow response to the hypercapnic-hypoxia challenge (in terms of % change per mmHg CO2 change) was even greater than that to hypercapnia alone (P = 0.007). Findings in this study suggest that hypercapnic-hypoxia gas challenge may be a useful maneuver in physiological MRI as it preserves vasodilatory response yet does not alter brain metabolism.

Simultaneous multi-slice (SMS) acquisition enhances the sensitivity of hemodynamic mapping using gas challenges.

Hemodynamic mapping using gas inhalation has received increasing interest in recent years. Cerebrovascular reactivity (CVR), which reflects the ability of the brain vasculature to dilate in response to a vasoactive stimulus, can be measured by CO2 inhalation with continuous acquisition of blood oxygen level-dependent (BOLD) magnetic resonance images. Cerebral blood volume (CBV) can be measured by O2 inhalation. These hemodynamic mapping methods are appealing because of their absence of gadolinium contrast agent, their ability to assess both baseline perfusion and vascular reserve, and their utility in calibrating the functional magnetic resonance imaging (fMRI) signal. However, like other functional and physiological indices, a major drawback of these measurements is their poor sensitivity and reliability. Simultaneous multi-slice echo planar imaging (SMS EPI) is a fast imaging technology that allows the excitation and acquisition of multiple two-dimensional slices simultaneously, and has been shown to enhance the sensitivity of several MRI applications. To our knowledge, the benefit of SMS in gas inhalation imaging has not been investigated. In this work, we compared the sensitivity of CO2 and O2 inhalation data collected using SMS factor 2 (SMS2) and SMS factor 3 (SMS3) with those collected using conventional EPI (SMS1). We showed that the sensitivity of SMS scans was significantly (p = 0.01) higher than that of conventional EPI, although no difference was found between SMS2 and SMS3 (p = 0.3). On a voxel-wise level, approximately 20-30% of voxels in the brain showed a significant enhancement in sensitivity when using SMS compared with conventional EPI, with other voxels showing an increase, but not reaching statistical significance. When using SMS, the scan duration can be reduced by half, whilst maintaining the sensitivity of conventional EPI. The availability of a sensitive acquisition technique can further enhance the potential of gas inhalation MRI in clinical applications.

On the optimization of imaging protocol for the mapping of cerebrovascular reactivity.

BACKGROUND: To devise an improved blood-oxygen-level-dependent (BOLD) imaging protocol for cerebrovascular reactivity (CVR) measurement that can remove a known artifact of negative values. METHODS: Theoretical and simulation studies were first performed to understand the biophysical mechanism of the negative CVR signals, through which improved BOLD sequence parameters were proposed. This was achieved by equating signal intensities between cerebrospinal fluid and blood, by means of shortening the echo time (TE) of the BOLD sequence. Then, 10 healthy volunteers were recruited to participate in an experimental study, in which we compared the CVR results of two versions of the optimized ("Opt1" and "Opt2") protocols with that of the standard protocol at 3 Tesla. Two sessions were performed for each subject to test the reproducibility of all three protocols. RESULTS: Experimental results demonstrated that the optimized protocols resulted in elimination of negative-CVR voxels. Quantitative CVR results were compared across protocols, which show that the optimized protocols yielded smaller CVR values (Opt1: 0.16 ± 0.01 %BOLD/mmHg CO2 ; Opt2: 0.15 ± 0.01 %BOLD/mmHg CO2 ) than (P < 0.001) the standard protocol (0.21 ± 0.01 %BOLD/mmHg CO2 ), but the CNR was comparable (P = 0.1) to the standard protocol. The coefficient-of-variation between repetitions was found to be 5.6 ± 1.4%, 6.3 ± 1.6%, and 6.9 ± 0.9% for the three protocols, but there were no significant differences (P = 0.65). CONCLUSION: Based on the theoretical and experimental results obtained from this study, we suggest that the use of a TE shorter than those used in fMRI is necessary to minimize negative artifact in CVR results.