Cerebral Blood Volume Measurements Research Articles

Exploratory Assessment of the Relationship Between Hemoglobin Volume Phase Index, Magnetic Resonance Imaging, and Functional Outcome in Neonates with Hypoxic-Ischemic Encephalopathy.

Near-infrared spectroscopy (NIRS)-based measures of cerebral autoregulation (CAR) can potentially identify neonates with hypoxic-ischemic encephalopathy (HIE) who are at greatest risk of irreversible brain injury. However, modest predictive abilities have precluded previously described metrics from entering clinical care. We previously validated a novel autoregulation metric in a piglet model of induced hypotension called the hemoglobin volume phase index (HVP). The objective of this study was to evaluate the clinical ability of the HVP to predict adverse outcomes neonates with HIE. This is a prospective study of neonates with HIE who underwent therapeutic hypothermia (TH) at a level 4 neonatal intensive care unit (NICU). Continuous cerebral NIRS and mean arterial blood pressure (MAP) from indwelling arterial catheters were measured during TH and through rewarming. Multivariate autoregressive process was used to calculate the coherence between MAP and the sum total of the oxy- and deoxygenated Hb densities (HbT), a surrogate measure of cerebral blood volume (CBV). The HVP was calculated as the cosine-transformed phase shift at the frequency of maximal MAP-HbT coherence. Brain injury was assessed by neonatal magnetic resonance imaging (MRI), and developmental outcomes were assessed by the Bayley Scales of Infant Development (BSID-III) at 15-30months. The ability of the HVP to predict (a) death or severe brain injury by MRI and (b) death or significant developmental delay was assessed using logistic regression analyses. In total, 50 neonates with moderate or severe HIE were monitored. Median HVP was higher, representing more dysfunctional autoregulation, in infants who had adverse outcomes. After adjusting for sex and encephalopathy grade at presentation, HVP at 21-24 and 24-27h of life predicted death or brain injury by MRI (21-24h: OR 8.8, p = 0.037; 24-27h: OR 31, p = 0.011) and death or developmental delay at 15-30months (21-24h: OR 11.8, p = 0.05; 24-27h: OR 15, p = 0.035). Based on this pilot study of neonates with HIE, HVP merits further study as an indicator of death or severe brain injury on neonatal MRI and neurodevelopmental delay in early childhood. Larger studies are warranted for further clinical validation of the HVP to evaluate cerebral autoregulation following HIE.

Large-scale functional ultrasound imaging of the spinal cord reveals in-depth spatiotemporal responses of spinal nociceptive circuits in both normal and inflammatory states.

Despite a century of research on the physiology/pathophysiology of the spinal cord in chronic pain condition, the properties of the spinal cord were rarely studied at the large-scale level from a neurovascular point of view. This is mostly due to the limited spatial and/or temporal resolution of the available techniques. Functional ultrasound imaging (fUS) is an emerging neuroimaging approach that allows, through the measurement of cerebral blood volume, the study of brain functional connectivity or functional activations with excellent spatial (100 μm) and temporal (1 msec) resolutions and a high sensitivity. The aim of this study was to increase our understanding of the spinal cord physiology through the study of the properties of spinal hemodynamic response to the natural or electrical stimulation of afferent fibers. Using a combination of fUS and ultrasound localization microscopy, the first step of this study was the fine description of the vascular structures in the rat spinal cord. Then, using either natural or electrical stimulations of different categories of afferent fibers (Aβ, Aδ, and C fibers), we could define the characteristics of the typical hemodynamic response of the rat spinal cord experimentally. We showed that the responses are fiber-specific, located ipsilaterally in the dorsal horn, and that they follow the somatotopy of afferent fiber entries in the dorsal horn and that the C-fiber response is an N-methyl-D-aspartate receptor-dependent mechanism. Finally, fUS imaging of the mesoscopic hemodynamic response induced by natural tactile stimulations revealed a potentiated response in inflammatory condition, suggesting an enhanced response to allodynic stimulations.

Impaired Frontal Brain Activity in Patients With Heart Failure Assessed by Near-Infrared Spectroscopy.

BackgroundThe prevalence of depression and/or anxiety disorders is reported to be higher in patients with heart failure (HF) than in the general population, and patients with HF also have coexisting cognitive problems. Recently, the development of near‐infrared spectroscopy (NIRS) has enabled noninvasive measurements of regional cerebral blood volume and brain activity, in terms of cerebral oxyhemoglobin in the cerebral cortex, with a high time resolution. The aim of the current study was to determine the associations between frontal brain activity and depressive symptoms, anxiety status, and cognitive function in patients with HF.Methods and ResultsWe measured and compared frontal brain activity determined by NIRS during a verbal fluency task in patients with HF (n=35) and control subjects (n=28). The Center for Epidemiologic Studies Depression Scale for assessment of depressive symptoms, State‐Trait Anxiety Inventory for assessment of anxiety status, Mini‐Mental State Examination for assessment of cognitive function, and NIRS were simultaneously conducted. NIRS showed that frontal brain activity was significantly lower in the HF group than in the control subjects (28.5 versus 88.0 mM·mm; P<0.001). Next, we examined the associations between frontal brain activity and the findings of Center for Epidemiologic Studies Depression Scale, State‐Trait Anxiety Inventory, Mini‐Mental State Examination, and verbal fluency task. There were significant correlations between frontal brain activity and State‐Trait Anxiety Inventory (R=−0.228, P=0.046), Mini‐Mental State Examination (R=0.414, P=0.017), and verbal fluency task (R=0.338, P=0.007), but not with Center for Epidemiologic Studies Depression Scale (R=−0.160, P=0.233).ConclusionsFrontal brain activity assessed by NIRS is reduced and is associated with high anxiety status and low cognitive function in patients with HF.

Exploring Two Methods of CBV Estimation in Two Groups of Grade III Gliomas with Different Appearance on Post-Contrast T1 Images.

Background: Many studies have used Cerebral Blood Volume (CBV) for gliomas grading and there has been in good agreement between CBV and tumor grade. Almost all of those studies have emphasized the importance of leakage correction due to the underestimation/overestimation of CBV caused by T1/T2* leakage effect in enhanced cases of tumors, especially high grade ones.Objectives: The aim of this study is to investigate two methods of CBV estimation in two groups of gliomas with the same grade and different appearance on post contrast T1 images (Enhanced vs. Non-enhanced ones).Material and Methods: In this retrospective study, eight glioma patients with histopatologically confirmed grade III were equally divided into two groups (with enhancement (group 1) and without enhancement (group 2)), and retrospectively studied. Imaging was performed on a 3 tesla MR Scanner and included gradient-echo DSC, 3D T1-weighted dataset and FLAIR images. The conventional method of CBV measurement (Integration over the whole curve of CTC- method 1) and the GVF fitting (method 2) was done using Matlab. Results: The observed mean rCBV in the tumor ROI was 2.85 and 2.12 for group 1 with method 1 and 2, respectively. Mean rCBV in the tumor ROI for group 2 was 1.24 and 1.11 with method 1 and 2, respectively.Conclusion: In conclusion, this pilot study demonstrated that with combined use of pre-bolus and accounting for T2* effect, CBV could be considered as a criterion for the categorization of glioma tumors.

NIMG-28. VALIDATION OF SINGLE-DOSE DSC-MRI PROTOCOLS FOR ROBUST PERFUSION ASSESSMENT IN BRAIN TUMORS

Abstract Dynamic susceptibility contrast (DSC) MRI measures of brain tumor cerebral blood volume (CBV) are able to predict grade, overall survival and response to treatment. Wide-spread acceptance of DSC-MRI has been challenged by the need to balance contrast agent dose and CBV accuracy. The goal of this study was to identify and validate single-dose, BTIP compliant, DSC-MRI protocols. Using a validated, patient-based DRO, we evaluated CBV accuracy across a range of acquisition parameters (field strength, TR, TE, flip angle, multi-echo acquisitions, dosing protocols) and post-processing steps. To validate the optimal protocols, we next collected DSC-MRI data following ASFNR’s recommended “double – dose” approach, where a single-dose preload (to minimize T1 effects) is given prior to a second bolus injection (for DSC-MRI data acquisition). The single-dose DSC-MRI data was collected during the preload bolus injection. Consistency of the derived CBV data, visual agreement and data characteristics (e.g. CNR) was statistically evaluated. When using a single-dose and routine single-echo pulse sequence, the DRO analysis found that a low flip angle (LFA = 30o) and 30ms TE provided the highest CBV accuracy (concordance correlation coefficient (CCC) = 0.92) and precision (coefficient of variation (CV) = 8.2%)). For comparison, the maximum accuracy found with the DRO utilizes a double-dose injection protocol and yielded a CCC of 0.98 and CV of 6.8%. Single-dose, multi-echo acquisitions provided higher accuracy than the LFA data and matched that found with the double-dose approach. In patients (data collection ongoing), the agreement between single-dose LFA (n &gt; 40) or multi-echo (n &gt; 40) based CBV values and the reference double-dose approach was very high (CCC &gt; 0.94) and were statistically equivalent. Optimized single-dose DSC-MRI protocols provide highly accurate CBV data, use lower doses of contrast agent, and simplify scan procedures, indicating their potential for robust use in clinical practice and trials.

ATIM-30. COMBATING RECURRENT GLIOBLASTOMA WITH MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, THROUGH MRI-GUIDED CONVECTIVE DELIVERY

Abstract MDNA55, an IL4R-directed toxin, is being studied in a Phase 2b trial in recurrent GBM (rGBM) patients at first or second relapse. MDNA55 is co-infused with Gadolinium-based contrast agent and delivered as a single intratumoral infusion using Convection Enhanced Delivery (CED). Primary endpoint is median Overall Survival (mOS) and secondary endpoint is objective response rate (ORR) assessed by mRANO-based criteria incorporating advanced imaging modalities. Enrollment is complete (n=46). Current safety data show similar profile to previous MDNA55 trials with no systemic toxicities or drug related deaths. Current mOS in subjects treated with low doses of MDNA55 (median 63µg; n=21) is 11.8 months. When stratified by IL4R expression, a biomarker for more aggressive GBM, IL4R+ve subjects (mOS 15.2 months; n=8) show a survival advantage of 7 months compared to IL4R-ve subjects (mOS 8.1 months; n=10). Updated survival and response outcomes including subjects receiving the high dose (median 180µg; n=25) and stratification by IL4R expression will be reported. Review of serial imaging within 90 days following MDNA55 treatment demonstrated tumor shrinkage or stabilization from baseline in 19/42 evaluable subjects (disease control rate of 45%). To account for initial pseudo-progression in some subjects, tumor response was also assessed from nadir: 83% (35/42) showed disease control. Multi-parametric MRI biomarkers including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) measurements demonstrated distinct imaging phenotypes among different disease states (pseudo-progression vs true-progression, pseudo-response vs true-response) and improved response staging. This trial is advancing neurosurgical methods for CED, potential of IL4R expression as a biomarker to select GBM patients most likely to benefit from MDNA55 treatment, and optimal use of multi-parametric MRI as an adjunct to clinical decision making. The improved survival and disease control seen after only a single infusion of MDNA55, especially in IL4R+ve subjects, may provide promising clinical benefit for rGBM patients.

P04.11 Voxelwise correlation between vascular MRI parameters obtained with ASL and DSC is decreased in IDH-wt non-enhancing glioma

Abstract BACKGROUND Comparative studies of dynamic susceptibility contrast (DSC) based measurement of cerebral blood volume (CBV) or cerebral blood flow (CBF) and arterial spin labelling (ASL) based measurement of CBF have previously shown good correlation of these parameters in human glioma. However, these studies were mostly done before inclusion of the mutation status of the isocitrate dehydrogenase (IDH) encoding gene in brain tumour classification. In light of the call for gadolinium-free imaging, here we investigate the effect of IDH-mutation status on the correlation between ASL and DSC-based perfusion measurements in non-enhancing glioma. MATERIAL AND METHODS Twenty-two patients with non-enhancing glioma and confirmed IDH-mutation status (next generation sequencing, 6 IDH-wildtype and 16 IDH-mutated) underwent 3T MRI scanning (GE, Milwaukee, WI, USA). Image acquisition included a 3D spiral pseudocontinuous ASL with time-encoded labelling (7 effective label delays from 0.8 to 2 s, reconstruction matrix 128x128x42, resolution 1.9x1.9x3.5 mm3), and 2D DSC imaging (122 TRs, TR/TE 1500m/18.6ms, 15 slices, voxel size: 1.88x1.88x4 mm3) in which a bolus of 7.5ml of gadolinium-based contrast agent (Gadovist, Bayer, Leverkussen, GE) was injected. A pre-load bolus of equal size was given 5 minutes prior to DSC imaging. DSC and ASL images were motion corrected and linearly registered to high resolution FLAIR images (FSL, version 5.0.9, Oxford, UK). DSC-relative CBV (rCBV), DSC-relative CBF (rCBF), and ASL-CBF maps were calculated via previously described methods. The glioma region of interest (ROI) was determined via manual segmentation on the FLAIR images. Voxel-wise Pearson’s linear correlation coefficients (ρ) within this ROI were calculated between ASL-CBF and DSC-rCBV, and between ASL-CBF and DSC-rCBF. RESULTS Normalised histograms indicate that IDH-wt glioma has higher values for ASL-CBF, DSC-rCBV, and DSC-rCBF than IDH-mutated glioma. IDH-wildtype glioma has a significantly lower ρ ASL-CBF vs DSC-rCBV and ρ ASL-CBF vs DSC-rCBF than IDH-mutated glioma (two-sample t-tests p &lt; 0.05). CONCLUSION IDH-mutation status of non-enhancing glioma potentially affects the correlation between ASL-CBF and DSC-rCBF/rCBV and should be taken into account when moving towards ASL-only imaging. The decreased correlation between ASL and DSC-based vascular parameters in IDH-wt gliomas may be due to more aggressive vasculature in subtypes of IDH-wt tumours. Future work includes expansion of the current patient cohort (part of the ongoing iGENE study).

Multi-parametric MRI as supplement to mRANO criteria for response assessment to MDNA55 in adults with recurrent or progressive glioblastoma.

e13559 Background: Modified response assessment in neuro-oncology (mRANO) criteria are widely used in GBM but seem insufficient to capture Pseudoprogression (PsP), which occurs due to extensive inflammatory infiltration, increased vascular permeability, tumor necrosis and edema. mRANO criteria recommend volumetric response evaluation using contrast-enhanced T1 subtraction maps for identifying PsP. Our approach incorporates multi-parametric MRI biomarkers to unravel the true PsP from recurrence or distinguish Pseudo Response (PsR) - following anti-VEGF agents - from delayed (immuno)response. Methods: Multiple time-points MRI (18-24h after convection-enhance delivery of the anti-IL4-R agent MDNA55, then at 30-day intervals) was utilized to determine response. Multi-parametric MRI biomarkers analyzed included (1) 3D-FLAIR-T2-based tumor volume assessment reflecting edema, necrosis and tumor infiltration; (2) 3D-gadolinium-enhanced-based tumor volume estimation reflecting active tumor infiltration, neo-angiogenesis and disrupted blood brain barrier; (3) Dynamic susceptibility contrast-based relative cerebral blood volume (rCBV) measurements for estimation of the vascular tumour properties; and (4) Diffusion weighted imaging – Apparent diffusion coefficient measurements that assess interstitial edema, tumor cellularity and ischemic injury. Results: We demonstrate similar imaging phenotypes on conventional FLAIR-T2- and enhanced T1- MR images among different disease states (PsP vs true progression, PsR vs and immuno-response) and describe the perfusion and diffusion MRI biomarkers that improve response staging including PsP masking true progression, PsP masking clinical response, early progression with delayed response, and differentiation between true and PsR. The results are compared with the mRANO-based assessments for concurrence. Conclusions: Incorporating multi-parametric MRI measurements to determine the complex underlying tissue processes enables a better assessment of PsP, PsR and delayed tumour response, and can supplement mRANO-based response assessments in GBM patients undergoing novel immunotherapies.

Association between Tumor Acidity and Hypervascularity in Human Gliomas Using pH-Weighted Amine Chemical Exchange Saturation Transfer Echo-Planar Imaging and Dynamic Susceptibility Contrast Perfusion MRI at 3T.

Acidification of the tumor microenvironment from abnormal metabolism along with angiogenesis to meet metabolic demands are both hallmarks of malignant brain tumors; however, the interdependency of tumor acidity and vascularity has not been explored. Therefore, our aim was to investigate the association between pH-sensitive amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) and relative cerebral blood volume (CBV) measurements obtained from dynamic susceptibility contrast (DSC) perfusion MRI in patients with gliomas. In this retrospective study, 90 patients with histologically confirmed gliomas were scanned between 2015 and 2018 (median age, 50.3 years; male/female ratio = 59:31). pH-weighting was obtained using chemical exchange saturation transfer echo-planar imaging estimation of the magnetization transfer ratio asymmetry at 3 ppm, and CBV was estimated using DSC-MR imaging. The voxelwise correlation and patient-wise median value correlation between the magnetization transfer ratio asymmetry at 3 ppm and CBV within T2-hyperintense lesions and contrast-enhancing lesions were evaluated using the Pearson correlation analysis. General colocalization of elevated perfusion and high acidity was observed in tumors, with local intratumor heterogeneity. For patient-wise analysis, median CBV and magnetization transfer ratio asymmetry at 3 ppm within T2-hyperintense lesions were significantly correlated (R = 0.3180, P = .002), but not in areas of contrast enhancement (P = .52). The positive correlation in T2-hyperintense lesions remained within high-grade gliomas (R = 0.4128, P = .001) and in isocitrate dehydrogenase wild-type gliomas (R = 0.4300, P = .002), but not in World Health Organization II or in isocitrate dehydrogenase mutant tumors. Both magnetization transfer ratio asymmetry at 3 ppm and the voxelwise correlation between magnetization transfer ratio asymmetry and CBV were higher in high-grade gliomas compared with low-grade gliomas in T2-hyperintense tumors (magnetization transfer ratio asymmetry, P = .02; Pearson correlation, P = .01). The same trend held when comparing isocitrate dehydrogenase wild-type gliomas and isocitrate dehydrogenase mutant gliomas (magnetization transfer ratio asymmetry, P = .04; Pearson correlation, P = .01). A positive linear correlation between CBV and acidity in areas of T2-hyperintense, nonenhancing tumor, but not enhancing tumor, was observed across patients. Local heterogeneity was observed within individual tumors.

Repeatability and reproducibility of relative cerebral blood volume measurement of recurrent glioma in a multicentre trial setting

BackgroundMeasurement of relative cerebral blood volume (rCBV) with dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) is used extensively for brain tumour diagnosis and follow-up. The aim of this pilot study was to assess the robustness of rCBV measurement in patients with enhancing recurrent glioma in a European multicentre trial setting. MethodsWe included pre-treatment postcontrast T1 weighted (T1w) and DSC scans of 20 patients with recurrent glioma from 2 European Organisation for Research and Treatment of Cancer trials (26101 and 26091). Three reviewers independently placed a fixed circular region of interest of 70 mm2 in the tumour area of highest rCBV (rCBVmax). To calculate the normalised rCBVmax (nrCBVmax), three ROIs were placed in the anterior, middle and posterior centrum semiovale normal-appearing white matter of the contralateral hemisphere. After several months, each observer repeated the assessments blinded for initial findings. Repeatability and reproducibility were estimated with a mixed model. Each measurement was also classified according to 4 clinically meaningful categories. ResultsThree patients were post hoc excluded from analysis because of lack of enhancing tumour. The mean nrCBVmax repeatability was 49.5%, and reproducibility was 5.5%. In 14 of 17 patients, at least 2 reviewers classified the patient into the same category. ConclusionsOur results indicate that a well-established review process needs to be applied upfront to assess perfusion in a multicentre trial setting. While awaiting further validation, we propose as a strategy to measure rCBV in the context of recurrent glioma trials to use two central reviewers and an adjudicator in case of disagreement.

S202. T2-Relaxation Time in Prefrontal Regions and Cerebellar Lingula Size Prospectively Predict Degree of Substance Use in Maltreated Individuals

Childhood maltreatment accounts for 64% of the population attributable risk for addiction to illicit drugs. We previously reported that degree of drug use in maltreated individuals correlated with T2-relaxation time (T2-RT- an indirect measure of relative cerebral blood volume) in prefrontal regions and size of the lingula of the cerebellar vermis. A key question is whether there is a causal relation and if these measures could predict subsequent degree of use in a prospective longitudinal study.

Probabilistic independent component analysis of dynamic susceptibility contrast perfusion MRI in metastatic brain tumors

PurposeTo identify clinically relevant magnetic resonance imaging (MRI) features of different types of metastatic brain lesions, including standard anatomical, diffusion weighted imaging (DWI) and dynamic susceptibility contrast (DSC) perfusion MRI.MethodsMRI imaging was retrospectively assessed on one hundred and fourteen (N = 114) brain metastases including breast (n = 27), non-small cell lung cancer (NSCLC, n = 43) and ‘other’ primary tumors (n = 44). Based on 114 patient’s MRI scans, a total of 346 individual contrast enhancing tumors were manually segmented. In addition to tumor volume, apparent diffusion coefficients (ADC) and relative cerebral blood volume (rCBV) measurements, an independent component analysis (ICA) was performed with raw DSC data in order to assess arterio-venous components and the volume of overlap (AVOL) relative to tumor volume, as well as time to peak (TTP) of T2* signal from each component.ResultsResults suggests non-breast or non-NSCLC (‘other’) tumors had higher volume compare to breast and NSCLC patients (p = 0.0056 and p = 0.0003, respectively). No differences in median ADC or rCBV were observed across tumor types; however, breast and NSCLC tumors had a significantly higher “arterial” proportion of the tumor volume as indicated by ICA (p = 0.0062 and p = 0.0018, respectively), while a higher “venous” proportion were prominent in breast tumors compared with NSCLC (p = 0.0027) and ‘other’ lesions (p = 0.0011). The AVOL component was positively related to rCBV in all groups, but no correlation was found for arterial and venous components with respect to rCBV values. Median time to peak of arterial and venous components were 8.4 s and 12.6 s, respectively (p < 0.0001). No difference was found in arterial or venous TTP across groups.ConclusionsAdvanced ICA-derived component analysis demonstrates perfusion differences between metastatic brain tumor types that were not observable with classical ADC and rCBV measurements. These results highlight the complex relationship between brain tumor vasculature characteristics and the site of primary tumor diagnosis.

Frequency-resolved analysis of coherent oscillations of local cerebral blood volume, measured with near-infrared spectroscopy, and systemic arterial pressure in healthy human subjects.

We report a study on twenty-two healthy human subjects of the dynamic relationship between cerebral hemoglobin concentration ([HbT]), measured with near-infrared spectroscopy (NIRS) in the prefrontal cortex, and systemic arterial blood pressure (ABP), measured with finger plethysmography. [HbT] is a measure of local cerebral blood volume (CBV). We induced hemodynamic oscillations at discrete frequencies in the range 0.04–0.20 Hz with cyclic inflation and deflation of pneumatic cuffs wrapped around the subject’s thighs. We modeled the transfer function of ABP and [HbT] in terms of effective arterial (K(a)) and venous (K(v)) compliances, and a cerebral autoregulation time constant (τ(AR)). The mean values (± standard errors) of these parameters across the twenty-two subjects were K(a) = 0.01 ± 0.01 μM/mmHg, K(v) = 0.09 ± 0.05 μM/mmHg, and τ(AR) = 2.2 ± 1.3 s. Spatially resolved measurements in a subset of eight subjects reveal a spatial variability of these parameters that may exceed the inter-subject variability at a set location. This study sheds some light onto the role that ABP and cerebral blood flow (CBF) play in the dynamics of [HbT] measured with NIRS, and paves the way for new non-invasive optical studies of cerebral blood flow and cerebral autoregulation.

Measurement of microvascular cerebral blood volume changes over the cardiac cycle with ferumoxytol-enhanced T2* MRI.

This feasibility study investigates the non-invasive measurement of microvascular cerebral blood volume (BV) changes over the cardiac cycle using cardiac-gated, ferumoxytol-enhanced MRI. Institutional review board approval was obtained and all subjects provided written informed consent. Cardiac gated MR scans were prospectively acquired on a 3.0T scanner in 22 healthy subjects using -weighted sequences with 2D-EPI and 3D spiral trajectories. Images were collected before and after the intravenous administration of 2 doses of ferumoxytol (1 mg FE/kg and 4 mg FE/kg). Cardiac cycle-induced (1/ ) changes (Δ ) and BV changes (ΔBV) throughout the cardiac cycle in gray matter (GM) and white matter (WM) were quantified and differences assessed using ANOVA followed by post hoc analysis. Δ was found to increase in a dose-dependent fashion. A significantly larger increase was observed in GM compared to WM in both 2D and 3D acquisitions (P < 0.050). In addition, Δ increased significantly (P < 0.001) post versus pre-contrast injection in GM in both MRI acquisitions. Mean GM Δ derived from 2D-EPI images was 0.14 ± 0.06 s-1 pre-contrast and 0.33 ± 0.13 s-1 after 5 mg FE/kg. In WM, Δ was 0.19 ± 0.06 s-1 pre-contrast, and 0.23 ± 0.06 s-1 after 5 mg FE/kg. The fractional changes in BV throughout the cardiac cycle were 0.031 ± 0.019% in GM and 0.011 ± 0.008% in WM (P < 0.001) after 5 mg FE/kg. Cardiac-gated, ferumoxytol-enhanced MRI enables characterization of microvascular BV changes throughout the cardiac cycle in GM and WM tissue of healthy subjects.

Cerebral blood volume mapping using Fourier-transform-based velocity-selective saturation pulse trains.

Velocity-selective saturation (VSS) pulse trains provide a viable alternative to the spatially selective methods for measuring cerebral blood volume (CBV) by reducing the sensitivity to arterial transit time. This study is to compare the Fourier-transform-based velocity-selective saturation (FT-VSS) pulse trains with the conventional flow-dephasing VSS techniques for CBV quantification. The proposed FT-VSS label and control modules were compared with VSS pulse trains utilizing double refocused hyperbolic tangent (DRHT) and 8-segment B1-insensitive rotation (BIR-8). This was done using both numerical simulations and phantom studies to evaluate their sensitivities to gradient imperfections such as eddy currents. DRHT, BIR-8, and FT-VSS prepared CBV mapping was further compared for velocity-encoding gradients along 3 orthogonal directions in healthy subjects at 3T. The phantom studies exhibited more consistent immunity to gradient imperfections for the utilized FT-VSS pulse trains. Compared to DRHT and BIR-8, FT-VSS delivered more robust CBV results across the 3 VS encoding directions with significantly reduced artifacts along the superior-inferior direction and improved temporal signal-to-noise ratio (SNR) values. Average CBV values obtained from FT-VSS based sequences were 5.3 mL/100 g for gray matter and 2.3 mL/100 g for white matter, comparable to literature expectations. Absolute CBV quantification utilizing advanced FT-VSS pulse trains had several advantages over the existing approaches using flow-dephasing VSS modules. A greater immunity to gradient imperfections and the concurrent tissue background suppression of FT-VSS pulse trains enabled more robust CBV measurements and higher SNR than the conventional VSS pulse trains.

Ensuring signal quality of cerebral near infrared spectroscopy during continuous longterm monitoring

BackgroundNear infrared spectroscopy (NIRS) derived hemoglobin difference (HbD: oxygenated [HbO2] – reduced hemoglobin [Hb]) and total hemoglobin (HbT: HbO2+Hb) have been used as surrogate measures of cerebral blood flow and volume, respectively. Statistically, a lack of HbD-blood pressure (BP) or negative HbT-BP association is regarded as a state of intact cerebral pressure autoregulation (CPA). In contrast, a co-variation of HbD/HbT and systemic blood pressure (BP) in the same direction is thought of as a failure of CPA. If the quality of one (NIRS/BP) or both signals is compromised, the reliability of the results may be adversely affected. In this work, we develop an analytic approach to assess the quality of the NIRS signals. New methodGiven that cardiac pulses cause hemodynamic changes that are transmitted through the peripheral vasculature, cerebral NIRS signals should exhibit cyclical changes at the pulse frequency. Therefore, we propose that an association between HbD/HbT and electrocardiogram (EKG) signals would be an indicator of NIRS quality. We demonstrate the application of this approach with data collected from six newborns undergoing therapeutic hypothermia for neonatal encephalopathy. ResultsWe observed an intermittent lack of association between NIRS signals and EKG data over the course of several hours of continuous records, indicating a loss in the strength in NIRS signals. Comparison with existing methodExisting CPA characterization suffers from Type-II error which the current preprocessing approach can mitigate. ConclusionsThe proposed approach will allow for real-time assessment of NIRS signal quality that is essential for accurate CPA monitoring.

Consistency of normalized cerebral blood volume values in glioblastoma using different leakage correction algorithms on dynamic susceptibility contrast magnetic resonance imaging data without and with preload

Background and purposeSeveral leakage correction algorithms for dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI)-based cerebral blood volume (CBV) measurement have been proposed, and combination with a preload of contrast agent is generally recommended. A single bolus application scheme would largely simplify and facilitate standardized clinical applications, while reducing contrast agent (CA) dose. The aim of this study was, therefore, to investigate whether appropriate leakage correction redundantizes prebolus application by comparing normalized DSC-based CBV (nCBV) measures of two consecutive CA boli. Materials and methodsTwenty-seven patients with suspected glioblastoma (WHO-grade-IV) underwent DSC-MRI during two consecutive boli of Gd-based CA. Four variants of two post-processing leakage correction techniques were compared with respect to nCBV in contrast enhancing tumor tissue. First, a reference curve approach with first pass and full integration of corrected ΔR2*(t), and second, a deconvolution-based approach using singular value decomposition (SVD) with a standard noise-dependent cutoff or Tikhonov regularization. ResultsCompared to respective uncorrected values, all leakage correction techniques increased nCBV for data acquired without prebolus, while there was no consistent trend for data acquired with prebolus. The best agreement between corrected nCBV values in contrast enhancing tumor, obtained in the same patients without and with prebolus, respectively, was obtained for the reference curve-based correction approach with either first pass or full integration. ConclusionThe reference curve-based leakage correction approach with integration-based nCBV calculation yielded a high accordance between nCBV values without and with prebolus, respectively. Thus, it appears possible to obtain valid nCBV in glioblastoma with a single CA injection.

Dynamic susceptibility contrast (DSC) perfusion MRI in differential diagnosis between radionecrosis and neoangiogenesis in cerebral metastases using rCBV, rCBF and K2.

Distinction between treatment-related changes and tumour recurrence in patients who have received radiation treatment for brain metastases can be difficult on conventional MRI. In this study, we investigated the ability of dynamic susceptibility contrast (DSC) perfusion in differentiating necrotic changes from pathological angiogenesis and compared measurements of relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and K2, using a dedicated software. Twenty-nine patients with secondary brain tumors were included in this retrospective study and underwent DSC perfusion MRI with a 3-month follow-up imaging after chemo- or radiation-therapy. Region-of-interests were drawn around the contrast enhancing lesions and measurements of rCBV, rCBF and K2 were performed in all patients. Based on subsequent histological examination or clinico-radiological follow-up, the cohort was divided in two groups: recurrent disease and stable disease. Differences between the two groups were analyzed using the Student's t test. Sensitivity, specificity and diagnostic accuracy of rCBV measurements were analyzed considering three different cut-off values. Between patients with and without disease, only rCBV and rCBF values were significant (p<0.05). The only cut-off value giving the best diagnostic accuracy of 100% was rCBV=2.1 (sensitivity=100%; specificity=100%). Patients with tumor recurrence showed a higher mean value of rCBV (mean=4.28, standard deviation=2.09) than patients with necrotic-related changes (mean=0.77, standard deviation=0.44). DSC-MRI appears a clinically useful method to differentiate between tumor recurrence, tumor necrosis and pseudoprogression in patients treated for cerebral metastases. Relative CBV using a cut-off value of 2.1 proved to be the most accurate and reliable parameter.

In Vivo Molecular Profiling of Human Glioma

To assess the diagnostic performance of dynamic susceptibility contrast perfusion magnetic resonance perfusion imaging (DSC-MRI) for in vivohuman glioma molecular profiling. In this study 100 patients with histopathologically confirmed glioma who provided written informed consent were retrospectively assessed between January 2016 and February 2017 in two prospective trials that were approved by the local institutional review board. Cerebral blood volume (CBV) measurements from DSC-MRI were assessed, and histogram parameters of relative CBV (rCBV) results were compared among World Health Organization (WHO) 2016 based histological findings and molecular characteristics. Aclassification and regression tree (CART) algorithm with 10-fold cross-validation was used to calculate the diagnostic accuracy. The 90th percentile (C90) of rCBV was significantly lower in patients with the isocitrate dehydrogenase 1/2 (IDH1/2) mutation (2.86 ± 1.21; p < 0.001) and loss of alpha-thalassemia mental retardation syndrome X‑linked (ATRX) expression (2.23 ± 0.91; p < 0.001) than in those with the IDH1/2 wild type (4.78 ± 2.34) and maintained ATRX expression (4.30 ± 2.02). The standard deviation (SD) of rCBV was significantly higher in glioblastoma (GBM) with methylated O6-methylguanine DNA methyltransferase (MGMT; 1.99 ± 0.73; p = 0.001) than in those with unmethylated MGMT (1.20 ± 0.45). In CART analysis, rCBV predicted the molecular subgroup in 76.3% of astroglial tumors; however, the diagnostic performance was reduced to 48.1% by including oligodendrogliomas with chromosome 1p/19q co-deletion in the analysis due to substantial overlap of rCBV values between OD1p/19q-LOH and IDHwt GBM. The DSC-MRI procedure may provide insight into the IDH1/2 mutation and ATRX expression status and MGMT methylation profile of diffuse glioma; however, taking integrated oligodendroglioma into account limits the diagnostic performance of rCBV in non-invasively predicting the molecular subtype.

MRI techniques to measure arterial and venous cerebral blood volume

The measurement of cerebral blood volume (CBV) has been the topic of numerous neuroimaging studies. To date, however, most in vivo imaging approaches can only measure CBV summed over all types of blood vessels, including arterial, capillary and venous vessels in the microvasculature (i.e. total CBV or CBVtot). As different types of blood vessels have intrinsically different anatomy, function and physiology, the ability to quantify CBV in different segments of the microvascular tree may furnish information that is not obtainable from CBVtot, and may provide a more sensitive and specific measure for the underlying physiology. This review attempts to summarize major efforts in the development of MRI techniques to measure arterial (CBVa) and venous CBV (CBVv) separately. Advantages and disadvantages of each type of method are discussed. Applications of some of the methods in the investigation of flow-volume coupling in healthy brains, and in the detection of pathophysiological abnormalities in brain diseases such as arterial steno-occlusive disease, brain tumors, schizophrenia, Huntington's disease, Alzheimer's disease, and hypertension are demonstrated. We believe that the continual development of MRI approaches for the measurement of compartment-specific CBV will likely provide essential imaging tools for the advancement and refinement of our knowledge on the exquisite details of the microvasculature in healthy and diseased brains.