Change In rCBV Research Articles

Improvement of cerebral blood flow after balloon angioplasty and stenting for symptomatic middle cerebral artery stenosis

Objective Although reports of endovascular treatment for intracranial arterial stenosis have been increasing recently, their efficacy remains to be elucidated. This study aimed to investigate the changes in cerebral hemodynamics of severe middle cerebral artery (MCA) stenosis patients by performing CT perfusion (CTP) after endovascular treatment. Methods Subjects were those who underwent balloon angioplasty and stenting for symptomatic MCA M1 stenosis refractory to medical therapy at our hospital between 2008 and 2022. We included 36 patients (mean age 63.69 ± 15.24 years, 20 males) who underwent CTP before and within three weeks after treatment. The CTP parameters such as relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) were calculated as ipsilateral values divided by contralateral value. Results Endovascular treatment consisted of 26 balloon angioplasty and 10 stenting procedures performed at an average of 1 month from onset. CTP was performed at an average of 5.5 days postoperatively. The mean overall stenosis rate decreased from 79.0% to 30.3%. In the balloon angioplasty group, it decreased from 77.6% to 35.3%, and in the stent group, it decreased from 82.7% to 17.5%. After treatment, rCBF and rMTT measured by CTP improved significantly (both p < 0.001), whereas there was no significant change in rCBV. The improvement rates of rCBF and rMTT were mild higher in the stent group, but not significantly so. Conclusion Balloon angioplasty and stenting for symptomatic MCA improved cerebral hemodynamics, resulting in significantly increased rCBF and decreased rMTT.

Early post-bevacizumab change in rCBV from DSC-MRI identifies pseudoresponse in recurrent glioblastoma: Results from ACRIN 6677/RTOG 0625.

Progressive enhancement predicted poor survival in ACRIN 6677/RTOG 0625, a multi-center trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma, but pseudoresponse likely limited enhancement-based survival prognostication in T1 non-progressors. We aimed to determine whether early change in cerebral blood volume from baseline (ΔCBV) could further stratify the T1 non-progressors according to overall (OS) and progression-free (PFS) survival. 37/123 enrolled patients had DSC-MRI, including 13, 15, and 8 patients without 2D-T1 progression at 2, 8, and 16 weeks post-treatment initiation, respectively. Mean CBV normalized to white matter (nRCBV) and mean standardized CBV (sRCBV) were extracted from enhancing tumor. ROC curves were derived for ΔCBV using six-month PFS and one-year OS as reference standards. Kaplan-Meier survival estimates and log-rank test compared PFS and OS for both ΔCBV (increase vs. decrease) and T1 response status (stable vs. decreasing enhancement). PFS and OS were significantly worse for increasing CBV at 2 weeks (p=0.003 and p=0.002 for nRCBV, and p=0.03 and p=0.03 for sRCBV, respectively), but not for 2D-T1 patients with stable vs. decreasing enhancement (p=0.44 and p=0.86, respectively). ΔCBV at week 2 was also a good prognostic marker for OS-1 and PFS-6 using ROC analysis. By contrast, 2D-T1 response status at weeks 2, 8, and 16 was not associated with PFS-6. ΔCBV at 16 weeks (p=0.008 for sRCBV) but not 8 weeks (p=0.74 for nRCBV and p=0.56 for sRCBV) was associated with significant difference in median survival, but no difference in survival was observed for 2D-T1 patients with stable vs. decreasing enhancement at 8 weeks (p=0.69) or 16 weeks (p=0.21). At 16 weeks, OS did not differ significantly between 2D-T1 progressors and 2D-T1 non-progressors with increasing CBV (median survival 3.3 months post week 16 scan vs. 9.2 months, respectively; p=0.13), suggesting that 2D-T1 non-progressors with increasing CBV may have a prognosis like that of 2D-T1 progressors. After 2 weeks of anti-angiogenic therapy, ΔCBV in 2D-T1 non-progressors significantly prognosticated PFS and OS, whereas 2D-T1 response status did not, identifying a subpopulation that benefits from bevacizumab. Combining 2D-T1 progression and ΔCBV may yield a response assessment paradigm with 3-tiered OS stratification.

Paradoxical Association Between Relative Cerebral Blood Volume Dynamics Following Chemoradiation and Increased Progression-Free Survival in Newly Diagnosed IDH Wild-Type MGMT Promoter Methylated Glioblastoma With Measurable Disease.

Background and PurposeWhile relative cerebral blood volume (rCBV) may be diagnostic and prognostic for survival in glioblastoma (GBM), changes in rCBV during chemoradiation in the subset of newly diagnosed GBM with subtotal resection and the impact of MGMT promoter methylation status on survival have not been explored. This study aimed to investigate the association between rCBV response, MGMT methylation status, and progression-free (PFS) and overall survival (OS) in newly diagnosed GBM with measurable enhancing lesions.Methods1,153 newly diagnosed IDH wild-type GBM patients were screened and 53 patients (4.6%) had measurable post-surgical tumor (>1mL). rCBV was measured before and after patients underwent chemoradiation. Patients with a decrease in rCBV >10% were considered rCBV Responders, while patients with an increase or a decrease in rCBV <10% were considered rCBV Non-Responders. The association between change in enhancing tumor volume, change in rCBV, MGMT promotor methylation status, and PFS or OS were explored.ResultsA decrease in tumor volume following chemoradiation trended towards longer OS (p=0.12; median OS=26.8 vs. 16.3 months). Paradoxically, rCBV Non-Responders had a significantly improved PFS compared to Responders (p=0.047; median PFS=9.6 vs. 7.2 months). MGMT methylated rCBV Non-Responders exhibited a significantly longer PFS compared to MGMT unmethylated rCBV Non-Responders (p<0.001; median PFS=0.5 vs. 7.1 months), and MGMT methylated rCBV Non-Responders trended towards longer PFS compared to methylated rCBV Responders (p=0.089; median PFS=20.5 vs. 13.8 months).ConclusionsThis preliminary report demonstrates that in newly diagnosed IDH wild-type GBM with measurable enhancing disease after surgery (5% of patients), an enigmatic non-response in rCBV was associated with longer PFS, particularly in MGMT methylated patients.

Multiparametric MRI for early identification of therapeutic response in recurrent glioblastoma treated with immune checkpoint inhibitors.

Physiologic changes quantified by diffusion and perfusion MRI have shown utility in predicting treatment response in glioblastoma (GBM) patients treated with cytotoxic therapies. We aimed to investigate whether quantitative changes in diffusion and perfusion after treatment by immune checkpoint inhibitors (ICIs) would determine 6-month progression-free survival (PFS6) in patients with recurrent GBM. Inclusion criteria for this retrospective study were: (i) diagnosis of recurrent GBM treated with ICIs and (ii) availability of diffusion and perfusion in pre and post ICI MRI (iii) at ≥6 months follow-up from treatment. After co-registration, mean values of the relative apparent diffusion coefficient (rADC), Ktrans (volume transfer constant), Ve (extravascular extracellular space volume) and Vp (plasma volume), and relative cerebral blood volume (rCBV) were calculated from a volume-of-interest of the enhancing tumor. Final assignment of stable/improved versus progressive disease was determined on 6-month follow-up using modified Response Assessment in Neuro-Oncology criteria. Out of 19 patients who met inclusion criteria and follow-up (mean ± SD: 7.8 ± 1.4 mo), 12 were determined to have tumor progression, while 7 had treatment response after 6 months of ICI treatment. Only interval change of rADC was suggestive of treatment response. Patients with treatment response (6/7: 86%) had interval increased rADC, while 11/12 (92%) with tumor progression had decreased rADC (P = 0.001). Interval change in rCBV, Ktrans, Vp, and Ve were not indicative of treatment response within 6 months. In patients with recurrent GBM, interval change in rADC is promising in assessing treatment response versus progression within the first 6 months following ICI treatment. • In recurrent GBM treated with ICIs, interval change in rADC suggests early treatment response.• Interval change in rADC can be used as an imaging biomarker to determine PFS6.• Interval change in MR perfusion and permeability measures do not suggest ICI treatment response.

Assessment of Cerebral Vasodilatory Capacity as Part of Catheter-Based Cerebral Angiography.

Cerebral vasodilatory capacity assessment for risk stratification in patients with extracranial arterial stenosis or occlusion may be useful. We describe a new method that assesses cerebral vasodilatory capacity as part of catheter-based cerebral angiography. We prospectively assessed regional cerebral blood volume (rCBV) in the arterial distribution of interest using a controlled contrast injection in the common carotid or the subclavian arteries. rCBV maps were created using a predefined algorithm based on contrast distribution in the venous phase (voxel size: .466 mm3 ). rCBV maps were acquired again after selective administration of intra-arterial nicardipine (2.0 mg) distal to the stenosis. Two independent observers graded the change in rCBV in 10 predefined anatomical regions within the tributaries of the artery of interest (0 = reduction, 1 = no change, 2 = increase) and total rCBV change scores were summated. Twenty-five patients with internal carotid artery stenosis (n = 18; 0-90% in severity) or extracranial vertebral artery stenosis (n = 7; 0-100% in severity) were assessed. There was an increase in rCBV in a tributary of the artery of interest in 18 of 25 after intra-arterial nicardipine (mean score: 11.98; range 0-19.5). There was no change or decrease in rCBV in 7 of 25 patients. The mean rCBV change score was similar in patients with an assessment of internal carotid artery or vertebral artery distributions (12.2 ± 5.3; 11.4 ± 2.5; P = .68). Selective vasodilatory response to intra-arterial nicardipine in the affected arterial distribution during catheter-based cerebral angiography may provide new data for risk stratification.

Abstract WP22: A New Technique for the Assessment of Cerebral Vasodilatory Capacity as Part of Catheter-Based Cerebral Angiography

Background: Cerebral vasodilatory capacity assessment for risk stratification in patients with extracranial arterial stenosis or occlusion may be useful. We describe a new method that assesses cerebral vasodilatory capacity as part of catheter-based cerebral angiography. Methods: We prospectively assessed regional cerebral blood volume (rCBV) in the arterial distribution of interest using a controlled contrast injection in the common carotid or the subclavian arteries. rCBV maps were created using a predefined algorithm based on contrast distribution in the venous phase (voxel size 0.466 mm 3 ). rCBV maps were acquired again after selective administration of intra-arterial nicardipine (2.5 mg) distal to the stenosis. Two independent observers graded the change in rCBV in 10 predefined anatomical regions within the tributaries of the artery of interest (0=reduction, 1=no change, 2=increase) and total rCBV change scores were summated. The rCBV score values were averaged between the two observers for each patient. Mean arterial pressure was monitored at baseline and at 1 minute intervals post nicardipine administration for 5 minutes. Results: Twenty-five patients with internal carotid artery stenosis (n=18; 0%-90% in severity) or extracranial vertebral artery stenosis (n=7; 0%-100% in severity) were assessed. There was an increase in rCBV in a tributary of the artery of interest in 18 of 25 after intra-arterial nicardipine (mean score 11.98; range 0-19.5). There was no change or decrease in rCBV in 7 of 25 patients. The mean rCBV change score was similar in patients with assessment of internal carotid artery or vertebral artery distributions (12.2 ± 5.3; 11.4 ± 2.5; p=0.68 by ANOVA). There was an average (±SD) reduction of mean arterial pressure of 14mmHg ± 7.5 after intra-arterial nicardipine. There was no correlation between the magnitude of mean arterial pressure reduction post nicardipine (regression coefficient -0.13; p=0.38) or between the severity of stenosis (regression coefficient -0.04; p=0.29) and rCBV change scores. Conclusions: We describe a new technique for selective assessment of cerebral vasodilatory response in the affected arterial distribution during catheter-based cerebral angiography.

Imaging biomarkers guided anti-angiogenic therapy for malignant gliomas

Antiangiogenic therapy is a universal approach to the treatment of malignant gliomas but fails to prolong the overall survival of newly diagnosed or recurrent glioblastoma patients. Imaging biomarkers are quantitative imaging parameters capable of objectively describing biological processes, pathological changes and treatment responses in some situations and have been utilized for outcome predictions of malignant gliomas in anti-angiogenic therapy. Advanced magnetic resonance imaging techniques (including perfusion-weighted imaging and diffusion-weighted imaging), positron emission computed tomography and magnetic resonance spectroscopy are imaging techniques that can be used to acquire imaging biomarkers, including the relative cerebral blood volume (rCBV), Ktrans, and the apparent diffusion coefficient (ADC). Imaging indicators for a better prognosis when treating malignant gliomas with antiangiogenic therapy include the following: a lower pre- or post-treatment rCBV, less change in rCBV during treatment, a lower pre-treatment Ktrans, a higher vascular normalization index during treatment, less change in arterio-venous overlap during treatment, lower pre-treatment ADC values for the lower peak, smaller ADC volume changes during treatment, and metabolic changes in glucose and phenylalanine. The investigation and utilization of these imaging markers may confront challenges, but may also promote further development of anti-angiogenic therapy. Despite considerable evidence, future prospective studies are critically needed to consolidate the current data and identify novel biomarkers.

Longitudinal DSC-MRI for Distinguishing Tumor Recurrence From Pseudoprogression in Patients With a High-grade Glioma.

For patients with high-grade glioma on clinical trials it is important to accurately assess time of disease progression. However, differentiation between pseudoprogression (PsP) and progressive disease (PD) is unreliable with standard magnetic resonance imaging (MRI) techniques. Dynamic susceptibility contrast perfusion MRI (DSC-MRI) can measure relative cerebral blood volume (rCBV) and may help distinguish PsP from PD. A subset of patients with high-grade glioma on a phase II clinical trial with temozolomide, paclitaxel poliglumex, and concurrent radiation were assessed. Nine patients (3 grade III, 6 grade IV), with a total of 19 enhancing lesions demonstrating progressive enhancement (≥25% increase from nadir) on postchemoradiation conventional contrast-enhanced MRI, had serial DSC-MRI. Mean leakage-corrected rCBV within enhancing lesions was computed for all postchemoradiation time points. Of the 19 progressively enhancing lesions, 10 were classified as PsP and 9 as PD by biopsy/surgery or serial enhancement patterns during interval follow-up MRI. Mean rCBV at initial progressive enhancement did not differ significantly between PsP and PD (2.35 vs. 2.17; P=0.67). However, change in rCBV at first subsequent follow-up (-0.84 vs. 0.84; P=0.001) and the overall linear trend in rCBV after initial progressive enhancement (negative vs. positive slope; P=0.04) differed significantly between PsP and PD. Longitudinal trends in rCBV may be more useful than absolute rCBV in distinguishing PsP from PD in chemoradiation-treated high-grade gliomas with DSC-MRI. Further studies of DSC-MRI in high-grade glioma as a potential technique for distinguishing PsP from PD are indicated.

Early Cerebral Blood Volume Changes Predict Progression After Convection-Enhanced Delivery of Topotecan for Recurrent Malignant Glioma

To assess whether early changes in enhancing tumor volume (eTV) and relative cerebral blood volume (rCBV) 1 month after convection-enhanced delivery of topotecan in patients with recurrent malignant glioma correlated with 6-month disease progression status. Sixteen patients were enrolled in a Phase Ib trial of convection-enhanced delivery of topotecan for recurrent malignant glioma. Each patient was evaluated with serial follow-up magnetic resonance imaging at baseline and at 4- to 8-week intervals. Changes at 1 month compared with baseline in eTV and rCBV were evaluated as potential predictors of 6-month progression status, classified as either progressive disease or nonprogressive disease. Relationships between percent changes in eTV and rCBV at 1 month with the probability of progressive disease at 6 months were estimated by the use of logistic regression analysis. Receiver operating characteristic curves for varying percent change thresholds in eTV and rCBV were evaluated by the use of 6-month progressive disease as the reference. There was a significant difference in the percent change in rCBV at 1 month in patients with progressive disease compared with those with nonprogressive disease at 6 months (+12% vs. -29%, P = 0.02). Logistic regression analysis demonstrated on average that a 10% increase in rCBV at 1 month after convection-enhanced delivery of topotecan was associated with 1.7 times the odds of developing progressive disease at 6 months (95% confidence interval [CI] 1.0-2.9 P = 0.05). Receiver operating characteristic analysis for determining progressive disease at 6 months showed a greater area under the curve with rCBV (0.867; 95% CI 0.66-1.00) than with change in enhancing tumor volume (0.767; 95% CI 0.51-1.00). In this selected population of patients with recurrent malignant glioma treated with convection-enhanced delivery of topotecan, early changes in rCBV at 4 weeks after therapy may help predict progression status at 6 months.

Changes in Relative Cerebral Blood Volume 1 Month after Radiation-Temozolomide Therapy Can Help Predict Overall Survival in Patients with Glioblastoma

To evaluate perfusion parameter changes in patients with glioblastoma multiforme by comparing the perfusion magnetic resonance (MR) imaging measurements obtained before combined radiation and temozolomide therapy (RT-TMZ) with the follow-up MR imaging measurements obtained 1 month after completion of this treatment. Institutional review board approval was obtained, and HIPAA guidelines were followed. The data of 36 patients (24 male [median age, 63 years]; 12 female [median age, 59 years]) with glioblastoma multiforme who were treated with RT-TMZ were retrospectively reviewed. The hypothesis was that a change in relative cerebral blood volume (rCBV) 1 month after RT-TMZ is predictive of overall survival. Linear regression analysis was performed to correlate changes in tumor size and perfusion parameters with overall survival. Receiver operating characteristic (ROC) curves were evaluated for 1-year survival. Overall survival was assessed with Kaplan-Meir survival curves and log-rank testing. Percentage change in rCBV at 1 month after RT-TMZ correlated with overall survival. Increased rCBV after treatment was a strong predictor of poor survival (median survival, 235 days versus 529 days with decreased rCBV) (P < .008, log-rank test). The ROC curves for 1-year survival showed a greater area under the curve (0.806; 95% confidence interval [CI]: 0.698, 0.970) (P = .005) with rCBV than with tumor size (0.556; 95% CI: 0.342, 0.729) (P = .382). The overall survival for patients with increased tumor size, based on Macdonald criteria, was shorter than that for patients who showed no progression (stable or partial response), but the difference was not significant (median survival, 442 days versus 598 days) (P = .761, log-rank test). Change in rCBV after RT-TMZ appears to correlate with overall survival.

The parametric response map is an imaging biomarker for early cancer treatment outcome

Here we describe the parametric response map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRM(rCBV) and PRM(rCBF)) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations made on the basis of PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRM(rCBV) proved more predictive of overall survival.

Relative changes of cerebral arterial and venous blood volumes during increased cerebral blood flow: implications for BOLD fMRI.

Measurement of cerebral arterial and venous blood volumes during increased cerebral blood flow can provide important information regarding hemodynamic regulation under normal, pathological, and neuronally active conditions. In particular, the change in venous blood volume induced by neural activity is one critical component of the blood oxygenation level-dependent (BOLD) signal because BOLD contrast is dependent only on venous blood, not arterial blood. Thus, relative venous and arterial blood volume (rCBV) and cerebral blood flow (rCBF) in alpha-chlorolase-anesthetized rats under hypercapnia were measured by novel diffusion-weighted (19)F NMR following an i.v. administration of intravascular tracer, perfluorocarbons, and continuous arterial spin labeling methods, respectively. The relationship between rCBF and total rCBV during hypercapnia was rCBV(total) = rCBF(0.40), which is consistent with previous PET measurement in monkeys. This relationship can be linearized in a CBF range of 50-130 ml/100 g/min as DeltarCBV(total)/ DeltarCBF = 0.31 where DeltarCBV and DeltarCBF represent rCBV and rCBF changes. The average arterial volume fraction was 0.25 at a basal condition with CBF of approximately 60 ml/100 g/min and increased up to 0.4 during hypercapnia. The change in venous rCBV was 2-fold smaller than that of total rCBV (DeltarCBV(vein)/DeltarCBF = 0.15), while the arterial rCBV change was 2.5 times larger than that of total rCBV (DeltarCBV(artery)/DeltarCBF = 0.79). These NMR results were confirmed by vessel diameter measurements with in vivo videomicroscopy. The absolute venous blood volume change contributes up to 36% of the total blood volume change during hypercapnia. Our findings provide a quantitative physiological model of BOLD contrast.

Quantitative magnetic resonance imaging in experimental hypercapnia: improvement in the relation between changes in brain R2 and the oxygen saturation of venous blood after correction for changes in cerebral blood volume.

Acute hypercapnia simultaneously induces increases in regional cerebral blood volume (rCBV) and the oxygen saturation of cerebral venous blood (Yv). Changes in both physiologic parameters may influence the changes in R2 (deltaR2) that can be measured in the brain with gradient echo magnetic resonance imaging. The authors examined the effect of incorporating independent measurements of the change in rCBV (deltarCBV) on the fidelity of the relation between deltaR2 and deltaYv in the setting of experimental hypercapnia. A two-dimensional T2-weighted gradient echo sequence was used to measure deltaR2 in the brain parenchyma of anesthetized rats in response to hypercapnia with respect to the control state. In parallel, estimates of rCBV were obtained using a three-dimensional steady-state approach in conjunction with a paramagnetic contrast agent during both control and hypercapnic states so that a deltarCBV could be calculated. Regional CBV values of 2.96 +/- 0.82% and 5.74 +/- 1.21% were obtained during the control and hypercapnic states, respectively, and linear relations between rCBV and CO2 tension in both arterial (r = 0.80) and jugular venous (r = 0.76) blood samples were obtained. When correlating deltaR2 directly with deltaYv, no clear relation was apparent, but a strong linear relation (r = 0.76) was observed when correction for deltarCBV was incorporated into the data analysis. These results are consistent with the current understanding of the mechanisms of blood oxygen level-dependent (BOLD) contrast and underscore the potential importance of taking into account deltarCBV when quantitative estimates of deltaYv from the "BOLD effect" are intended.

Cerebral blood volume is increased in dogs during administration of nitrous oxide or isoflurane.

Positron emission tomography was used to study the effects of nitrous oxide (N2O) and isoflurane on regional cerebral blood volume (rCBV) in dogs during normocapnia and hypocapnia. Regional cerebral blood volume was measured serially during the addition of 50% N2O to a background anesthetic of fentanyl in normocapnic (group 1) and hypocapnic (PaCO2 25 mmHg, group 2) dogs. In each group, after 15 min of N2O administration accompanied by rCBV measurement, elimination of N2O with 100% O2 was continued for 15 min. This was followed by introduction of 2% isoflurane (no N2O), again accompanied by serial measurements of rCBV. In the normocapnic animals, the addition of 50% N2O caused an 11% increase in rCBV (6.1 +/- 1.4 to 6.8 +/- 1.0 ml/100 g, P less than 0.02) while 2% isoflurane caused a 36% increase (6.1 +/- 1.3 to 8.0 +/- 1.7 ml/100 g, P less than 0.02). The initial induction of hypocapnia during infusion of fentanyl in group 2 animals was associated with a 17% decrease in rCBV. In the hypocapnic dogs, there was no change in rCBV when N2O was introduced; however, an increase of 15% occurred following the addition of isoflurane (3.9 +/- 0.6 to 4.5 +/- 0.7 ml/100 g, P less than 0.02). Isoflurane, even during hypocapnia, may increase cerebral blood volume which in some circumstances may lead to an increase in ICP.

The effects of arterial blood pressure on the regional cerebral blood volume by X-ray fluorescence.

Cerebral blood flow (CBF) remains constant over a wide range of arterial blood pressure. This is thought to be accomplished by changes in the diameter, and therefore the volume, of the cerebral resistance vessels. To test this hypothesis, regional cerebral blood volume (rCBV) was measured in vivo in Rhesus monkeys over a range of mean arterial blood pressures (MABP) of 35 to 200 torr. Multiple measurements were made in each animal by the method of stimulated x-ray fluorescence. A significant linear relationship of rCBV = 6.26 (±0.47 SD) -0.015 (±0.004 SD) MABP was found. For each one torr change in the MABP, there is a change in rCBV of 0.015 cc/100 gm of brain tissue over a range of MABP of 35 to 200 torr. An additional observation of this investigation was that autoregulation of the cerebral blood flow (CBF) is perturbed for a period lasting up to 15 minutes after the intravenous injection of Renografin 76 R .