Longitudinal Assessment of Cerebral Blood Volume Variation in Human Neonates Using Ultrafast Power Doppler and Diverging Waves.

Longitudinal assessment of brain perfusion is a critical parameter for neurodevelopmental outcome of neonates undergoing cardiopulmonary bypass procedure. In this study, we aim to measure the variations of cerebral blood volume (CBV) in human neonates during cardiac surgery, using Ultrafast Power Doppler and freehand scanning. To be clinically relevant, this method must satisfy three criteria: being able to image a wide field of view in the brain, show significant longitudinal CBV variations, and present reproducible results. To address the first point, we performed for the first time transfontanellar Ultrafast Power Doppler using a hand-held phased-array transducer with diverging waves. This increased the field of view more than threefold compared to previous studies using linear transducers and plane waves. We were able to image vessels in the cortical areas as well as the deep grey matter and temporal lobes. Second, we measured the longitudinal variations of CBV on human neonates undergoing cardiopulmonary bypass. When compared to a pre-operative baseline acquisition, the CBV exhibited significant variation during bypass: on average, + 20±3 % in the mid-sagittal full sector ( [Formula: see text]), - 11±3 % in the cortical regions ( [Formula: see text]) and - 10±4 % in the basal ganglia ( [Formula: see text]). Third, a trained operator performing identical scans was able to reproduce CBV estimates with a variability of 4% to 7.5% depending on the regions considered. We also investigated whether vessel segmentation could further improve reproducibility, but found that it actually introduced greater variability in the results. Overall, this study demonstrates the clinical translation of ultrafast power Doppler with diverging-waves and freehand scanning.

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

Characterizing white matter fiber orientation effects on multi-parametric quantitative BOLD assessment of oxygen extraction fraction.

Relative oxygen extraction fraction (rOEF) is a fundamental indicator of cerebral metabolic function. An easily applicable method for magnetic resonance imaging (MRI) based rOEF mapping is the multi-parametric quantitative blood oxygenation level dependent (mq-BOLD) approach with separate acquisitions of transverse relaxation times T2* and T2 and dynamic susceptibility contrast (DSC) based relative cerebral blood volume (rCBV). Given that transverse relaxation and rCBV in white matter (WM) strongly depend on nerve fiber orientation, mq-BOLD derived rOEF is expected to be affected as well. To investigate fiber orientation related rOEF artefacts, we present a methodological study characterizing anisotropy effects of WM as measured by diffusion tensor imaging (DTI) on mq-BOLD in 30 healthy volunteers. Using a 3T clinical MRI-scanner, we performed a comprehensive correlation of all parameters ( T2*, T2, R2', rCBV, rOEF, where R2'=1/ T2*-1/T2) with DTI-derived fiber orientation towards the main magnetic field (B0). Our results confirm strong dependencies of transverse relaxation and rCBV on the nerve fiber orientation towards B0, with anisotropy-driven variations up to 37%. Comparably weak orientation-dependent variations of mq-BOLD derived rOEF (3.8%) demonstrate partially counteracting influences of R2' and rCBV effects, possibly suggesting applicability of rOEF as an oxygenation sensitive biomarker. However, unresolved issues warrant caution when applying mq-BOLD to WM.

Systematic assessment of multi-echo dynamic susceptibility contrast MRI using a digital reference object.

PURPOSE: Brain tumor dynamic susceptibility contrast (DSC) MRI is adversely impacted by T1 and T2∗ contrast agent leakage effects that result in inaccurate hemodynamic metrics. While multi-echo acquisitions remove T1 leakage effects, there is no consensus on the optimal set of acquisition parameters. Using a computational approach, we systematically evaluated a wide range of acquisition strategies to determine the optimal multi-echo DSC-MRI perfusion protocol. METHODS: Using a population-based DSC-MRI digital reference object (DRO), we assessed the influence of preload dosing (no preload and full dose preload), field strength (1.5 and 3T), pulse sequence parameters (echo time, repetition time, and flip angle), and leakage correction on relative cerebral blood volume (rCBV) and flow (rCBF) accuracy. We also compared multi-echo DSC-MRI protocols with standard single-echo protocols. RESULTS: Multi-echo DSC-MRI is highly consistent across all protocols, and multi-echo rCBV (with or without use of a preload dose) had higher accuracy than single-echo rCBV. Regression analysis showed that choice of repetition time and flip angle had minimal impact on multi-echo rCBV and rCBV, indicating the potential for significant flexibility in acquisition parameters. The echo time combination had minimal impact on rCBV, though longer echo times should be avoided, particularly at higher field strengths. Leakage correction improved rCBV accuracy in all cases. Multi-echo rCBF was less biased than single-echo rCBF, although rCBF accuracy was reduced overall relative to rCBV. CONCLUSIONS: Multi-echo acquisitions were more robust than single-echo, essentially decoupling both repetition time and flip angle from rCBV accuracy. Multi-echo acquisitions obviate the need for preload dosing, although leakage correction to remove residual T2∗ leakage effects remains compulsory for high rCBV accuracy.

Neurovascular coupling preserved in a chronic mouse model of Alzheimer's disease: Methodology is critical.

Impaired neurovascular coupling has been suggested as an early pathogenic factor in Alzheimer's disease (AD), which could serve as an early biomarker of cerebral pathology. We have established an anaesthetic regime to allow repeated measurements of neurovascular function over three months in the J20 mouse model of AD (J20-AD) and wild-type (WT) controls. Animals were 9-12 months old at the start of the experiment. Mice were chronically prepared with a cranial window through which 2-Dimensional optical imaging spectroscopy (2D-OIS) was used to generate functional maps of the cerebral blood volume and saturation changes evoked by whisker stimulation and vascular reactivity challenges. Unexpectedly, the hemodynamic responses were largely preserved in the J20-AD group. This result failed to confirm previous investigations using the J20-AD model. However, a final acute electrophysiology and 2D-OIS experiment was performed to measure both neural and hemodynamic responses concurrently. In this experiment, previously reported deficits in neurovascular coupling in the J20-AD model were observed. This suggests that J20-AD mice may be more susceptible to the physiologically stressing conditions of an acute experimental procedure compared to WT animals. These results therefore highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.

Real-Time Quantitative Assessment of Accuracy and Precision of Blood Volume Derived from DCE-MRI in Individual Patients During a Clinical Trial.

Accuracy and precision of quantitative imaging (QI) metrics should be assessed in real time in each patient during a clinical trial to support QI-based decision-making. We developed a framework for real-time quantitative assessment of QI metrics and evaluated accuracy and precision of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI)-derived blood volume (BV) in a clinical trial for head and neck cancers. Patients underwent DCE-MRI before and after 2 weeks of radiation therapy (2wkRT). A mean as a reference value and a repeatability coefficient (RC) of BV values established from n patients in cerebellum volumes of interest (VOIs), which were normal and affected little by therapy, served as accuracy and precision measurements. The BV maps of a new patient were called accurate and precise if the values in cerebellum VOIs and the difference between the 2 scans agreed with the respective mean and RC with 95% confidence. The new data could be used to update reference values. Otherwise, the data were flagged for further evaluation before use in the trial. BV maps from 62 patients enrolled on the trial were evaluated. Mean BV values were 2.21 (±0.14) mL/100 g pre-RT and 2.22 (±0.17) mL/100 g at 2wkRT; relative RC was 15.9%. The BV maps from 3 patients were identified to be inaccurate and imprecise before use in the clinical trial. Our framework of real-time quantitative assessment of QI metrics during a clinical trial can be translated to different QI metrics and organ-sites for supporting QI-based decision-making that warrants success of a clinical trial.

Non-invasive Cerebrovascular Autoregulation Assessment Using the Volumetric Reactivity Index: Prospective Study.

BACKGROUND: This prospective study of an innovative non-invasive ultrasonic cerebrovascular autoregulation (CA) monitoring method is based on real-time measurements of intracranial blood volume (IBV) reactions following changes in arterial blood pressure. In this study, we aimed to determine the clinical applicability of a non-invasive CA monitoring method by performing a prospective comparative clinical study of simultaneous invasive and non-invasive CA monitoring on intensive care patients. METHODS: CA was monitored in 61 patients with severe traumatic brain injuries invasively by calculating the pressure reactivity index (PRx) and non-invasively by calculating the volumetric reactivity index (VRx) simultaneously. The PRx was calculated as a moving correlation coefficient between intracranial pressure and arterial blood pressure slow waves. The VRx was calculated as a moving correlation coefficient between arterial blood pressure and non-invasively-measured IBV slow waves. RESULTS: A linear regression between VRx and PRx averaged per patients' monitoring session showed a significant correlation (r = 0.843, p < 0.001; 95% confidence interval 0.751 - 0.903). The standard deviation of the difference between VRx and PRx was 0.192; bias was - 0.065. CONCLUSIONS: This prospective clinical study of the non-invasive ultrasonic volumetric reactivity index VRx monitoring, based on ultrasonic time-of-flight measurements of IBV dynamics, showed significant coincidence of non-invasive VRx index with invasive PRx index. The ultrasonic time-of-flight method reflects blood volume changes inside the acoustic path, which crosses both hemispheres of the brain. This method does not reflect locally and invasively-recorded intracranial pressure slow waves, but the autoregulatory reactions of both hemispheres of the brain. Therefore, VRx can be used as a non-invasive cerebrovascular autoregulation index in the same way as PRx and can also provide information about the CA status encompassing all intracranial hemodynamics.

Assessment of cerebral autoregulation using continuous-wave near-infrared spectroscopy during squat-stand maneuvers in subjects with symptoms of orthostatic intolerance.

Orthostatic lightheadedness in healthy young adults often leads to syncope in severe cases. One suggested underlying mechanism of orthostatic lightheadedness is a drop in transient blood pressure (BP); however, a decrease in BP does not always lead to a drop in cerebral blood flow (CBF) due to cerebral autoregulation (CA). We present a direct assessment method of CA using a multichannel continuous-wave near-infrared spectroscopy (CW-NIRS) device that measures the temporal changes in oxy- and deoxy-hemoglobin concentrations in the prefrontal cortex. Twenty healthy young adults were recruited. During the experiment, continuous beat-to-beat BP and heart rate were simultaneously measured during repetitive squat-stand maneuvers. We introduce a new metric termed 'time-derivative hemodynamic model (DHbT)', which is the time-derivative of total-hemoglobin concentration change that reflects the changes of cerebral blood volume and CBF. Although the absolute levels and the variations of systolic and diastolic BPs and mean arterial pressure showed no significant difference between the two groups, the proposed model showed a distinct difference in slope variation and response time of DHbT between the subjects with frequent symptom of orthostatic intolerance and the healthy control subjects. Thus, these results clearly demonstrate the feasibility of using CW-NIRS devices as a CA performance assessment tool.

A New Technique for the Assessment of Cerebral Vasodilatory Capacity as Part of Catheter-Based Cerebral Angiography.

BACKGROUND: Previous studies have demonstrated the value of cerebral vasodilatory capacity assessment for risk stratification in patients with extracranial arterial stenosis or occlusion. We describe a new method that assesses cerebral vasodilatory capacity as part of catheter-based cerebral angiography. METHODS: We assessed regional cerebral blood volume (rCBV) in the arterial distribution of interest using a controlled contrast injection through a diagnostic catheter placed in the common carotid or the subclavian artery. rCBV maps were created using predefined algorithm based on contrast distribution in the venous phase (voxel size 0.466 mm3) into high, intermediate, low, and no detectable rCBV regions. rCBV maps were acquired again after the administration of intra-arterial nicardipine (1.5-2.5 mg), and percentage increases of the area of various grades of rCBV were calculated. RESULTS: Three patients with internal carotid artery stenosis (32% - 64% in severity) and 1 patient with extracranial vertebral artery stenosis (46% in severity) were assessed. There was a variable but consistent increase in the area of high rCBV in the ipsilateral hemisphere in 3 patients with internal carotid artery flow (5.5%-24.5%) and the cerebellum (9.6%) in 1 patient with vertebral artery flow assessments. The increase in high rCBV was most prominent in the patient who received 2.5 mg (24.5%) and least prominent in a patient who received 1.5 mg (5.5%) of intra-arterial nicardipine. There was a concurrent reduction in areas of intermediate and low rCBV (shift) in 3 patients, and there was an increase in all areas of rCBV grades (addition) in 1 patient. CONCLUSIONS: Selective assessment of cerebral vasodilatory response in the affected arterial distribution is feasible during catheter-based cerebral angiography.

Interleaved quantitative BOLD: Combining extravascular R2' - and intravascular R2-measurements for estimation of deoxygenated blood volume and hemoglobin oxygen saturation.

Quantitative BOLD (qBOLD), a non-invasive MRI method for assessment of hemodynamic and metabolic properties of the brain in the baseline state, provides spatial maps of deoxygenated blood volume fraction (DBV) and hemoglobin oxygen saturation (HbO2) by means of an analytical model for the temporal evolution of free-induction-decay signals in the extravascular compartment. However, mutual coupling between DBV and HbO2 in the signal model results in considerable estimation uncertainty precluding achievement of a unique set of solutions. To address this problem, we developed an interleaved qBOLD method (iqBOLD) that combines extravascular R2' and intravascular R2 mapping techniques so as to obtain prior knowledge for the two unknown parameters. To achieve these goals, asymmetric spin echo and velocity-selective spin-labeling (VSSL) modules were interleaved in a single pulse sequence. Prior to VSSL, arterial blood and CSF signals were suppressed to produce reliable estimates for cerebral venous blood volume fraction (CBVv) as well as venous blood R2 (to yield HbO2). Parameter maps derived from the VSSL module were employed to initialize DBV and HbO2 in the qBOLD processing. Numerical simulations and in vivo experiments at 3 T were performed to evaluate the performance of iqBOLD in comparison to the parent qBOLD method. Data obtained in eight healthy subjects yielded plausible values averaging 60.1 ±â€¯3.3% for HbO2 and 3.1 ±â€¯0.5 and 2.0 ±â€¯0.4% for DBV in gray and white matter, respectively. Furthermore, the results show that prior estimates of CBVv and HbO2 from the VSSL component enhance the solution stability in the qBOLD processing, and thus suggest the feasibility of iqBOLD as a promising alternative to the conventional technique for quantifying neurometabolic parameters.

Novel Noninvasive Method of Cerebrovascular Blood Volume Assessment Using Brain Bioimpedance.

Cerebrovascular autoregulation (CAR) is the ability of vessels to modulate their tone in response to changes in pressure. As an auto-protective mechanism, CAR is critical in preventing secondary brain injury post-trauma. Monitoring of changes in cerebral blood volume might be valuable in evaluating CAR and response to various therapies. In this study, we utilized an ocular-brain bioimpedance interface to assess real time changes in cerebral blood volume in response to a number of physiological challenges. We hypothesize that changes in brain bioimpedance (dz) would track changes in cerebral blood volume. Anesthetized animals were instrumented for monitoring of intracranial pressure (ICP), mean arterial blood pressure, cerebral perfusion pressure (CPP) and cerebral blood flow (CBF). Bioimpedance was monitored continuously through electrocardiographic electrodes placed over the eyelids. Interventions such as hyperventilation, vasopressor administration, creation of an epidural hematoma, and systemic hemorrhage were used to manipulate levels of ICP, CPP, and CBF. The dz correlated with changes in ICP, CPP, and CBF (r = -0.72 to -0.88, p < 0.0001). The receiver operating characteristic for dz at different thresholds of CPP and CBF showed high impedance performance with area under the curve between 0.80-1.00 (p < 0.003) and sensitivity and specificity varying between 83%-100% and 70%-100%, respectively. Our preliminary tests show that brain bioimpedance as measured through the ocular-brain interface tracks changes in CPP and CBF with high precision and may prove to be valuable in the future in assessing changes in cerebral blood volume and CAR.

Assessment of MRI contrast agent concentration by quantitative susceptibility mapping (QSM): application to estimation of cerebral blood volume during steady state.

OBJECTIVE: One major issue in dynamic susceptibility contrast MRI (DSC-MRI) is to accurately determine contrast agent (CA) concentration, since T2* relaxivity in vivo is generally unknown and varies between blood and tissue. In this study, quantitative susceptibility mapping (QSM) was used for quantification of CA concentration. MATERIALS AND METHODS: A DSC-MRI protocol, including phase data acquisition, was applied to 20 healthy volunteers in a test-retest study. By selecting a CSF reference region of interest (ROI), the values of all QSM images were shifted to show no CA-induced change in CSF. CA concentration and cerebral blood volume (CBV) were estimated using shifted QSM data. CSF reference ROI optimization was evaluated by investigation of CBV repeatability. The CBV age dependence was analysed and tissue T2* relaxivity was estimated. RESULTS: The best repeatability of CBV, using an optimal CSF reference ROI, showed test-versus-retest correlations of r = 0.81 and r = 0.91 for white and grey matter, respectively. A slight CBV decrease with age was observed, and the estimated in vivo T2* relaxivity was 85 mM-1s-1. CONCLUSION: Provided that a carefully selected CSF reference ROI is used to shift QSM image values, susceptibility information can be used to estimate concentration of contrast agent and to calculate CBV.

Simultaneous assessment of cerebral blood volume and diffusion heterogeneity using hybrid IVIM and DK MR imaging: initial experience with brain tumors.

OBJECTIVES: To investigate the feasibility of simultaneously assessing cerebral blood volume and diffusion heterogeneity using hybrid diffusion-kurtosis (DK) and intravoxel-incoherent-motion (IVIM) MR imaging. METHODS: Fifteen healthy volunteers and 30 patients with histologically proven brain tumours (25 WHO grade II-IV gliomas and five metastases) were recruited. On a 3-T system, diffusion-weighted imaging was performed with six b-values ranging from 0 to 1,700 s/mm2. Nonlinear least-squares fitting was employed to extract diffusion coefficient (D), diffusion kurtosis coefficient (K, a measure of the degree of non-Gaussian and heterogeneous diffusion) and intravascular volume fraction (f, a measure proportional to cerebral blood volume). Repeated-measures multivariate analysis of variance and receiver operating characteristic analysis were performed to assess the ability of D/K/f in differentiating contrast-enhanced tumour from peritumoral oedema and normal-appearing white matter. RESULTS: Based on our imaging setting (baseline signal-to-noise ratio = 32-128), coefficient of variation was 14-20 % for K, ~6 % for D and 26-44 % for f. The indexes were able to differentiate contrast-enhanced tumour (Wilks' λ = 0.026, p < 10-3), and performance was greatest with K, followed by f and D. CONCLUSIONS: Hybrid DK IVIM imaging is capable of simultaneously measuring cerebral perfusion and diffusion indexes that together may improve brain tumour diagnosis. KEY POINTS: • Hybrid DK-IVIM imaging allows simultaneous measurement of K, D and f. • Combined K/D/f better demarcates contrast-enhanced tumour than they do separately. • f correlates better with contrast-leakage-corrected CBV DSC than with uncorrected CBV DSC.

Assessment of early response to tumor-treating fields in newly diagnosed glioblastoma using physiologic and metabolic MRI: initial experience.

Tumor-treating fields (TTFields) is a novel antimitotic treatment modality for patients with glioblastoma. To assess response to TTFields, a newly diagnosed patient with glioblastoma underwent diffusion, perfusion and 3D echo-planar spectroscopic imaging prior to initiation of TTFields plus temozolamide (baseline) and at 1- and 2-month follow-up periods. Increased mean diffusivity along with decreased fractional anisotropy and maximum relative cerebral blood volume were noted at 2 months relative to baseline suggesting inhibition of tumor growth and angiogenesis. Additionally, a reduction in choline/creatine was also noted during this period. These preliminary data indicate the potential of physiologic and metabolic MRI in assessing early treatment response to TTFields in combination with temozolamide.