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1.  Multimodality Imaging of Abnormal Vascular Perfusion and Morphology in Preclinical 9L Gliosarcoma Model 
PLoS ONE  2011;6(1):e16621.
Background
This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.
Methodology/Principal Findings
One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65±.13) as compared to the fifth day during treatment (1.26±.19, p<0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89±.13, 1.00±.21, 1.13±.23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32±2.34 branches/mm3, p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29±3.51 branches/mm3). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45±1.36 µm2) as compared to saline treated tumor regions (30.83±4.31 µm2, p<0.001) and non-tumor regions (22.80±1.11 µm2, p<0.01).
Conclusions/Significance
Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment.
doi:10.1371/journal.pone.0016621
PMCID: PMC3031600  PMID: 21305001
2.  Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models 
Neuro-Oncology  2010;13(1):51-60.
We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting αV-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4–6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting αV-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.
doi:10.1093/neuonc/noq150
PMCID: PMC3018910  PMID: 21123368
bevacizumab; blood–brain barrier; dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging; intetumumab
3.  Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence 
Journal of Neurology  2009;256(6):878-887.
To assess the capability of perfusion MRI to differentiate between necrosis and tumor recurrence in patients showing radiological progression of cerebral metastases treated with stereotactic radiosurgery (SRS). From 2004 to 2006 dynamic susceptibility-weighted contrast-enhanced perfusion MRI scans were performed on patients with cerebral metastasis showing radiological progression after SRS during follow-up. Several perfusion MRI characteristics were examined: a subjective visual score of the relative cerebral blood volume (rCBV) map and quantitative rCBV measurements of the contrast-enhanced areas of maximal perfusion. For a total of 34 lesions in 31 patients a perfusion MRI was performed. Diagnoses were based on histology, definite radiological decrease or a combination of radiological and clinical follow-up. The diagnosis of tumor recurrence was obtained in 20 of 34 lesions, and tumor necrosis in 14 of 34. Regression analyses for all measures proved statistically significant (χ2 = 11.6–21.6, P < 0.001–0.0001). Visual inspection of the rCBV map yielded a sensitivity and specificity of 70.0 respectively 92.9%. The optimal cutoff point for maximal tumor rCBV relative to white matter was 2.00 (improving the sensibility to 85.0%) and 1.85 relative to grey matter (GM), improving the specificity to 100%, with a corresponding sensitivity of 70.0%. Perfusion MRI seems to be a useful tool in the differentiation of necrosis and tumor recurrence after SRS. For the patients displaying a rCBV-GM greater than 1.85, the diagnosis of necrosis was excluded. Salvage treatment can be initiated for these patients in an attempt to prolong survival.
doi:10.1007/s00415-009-5034-5
PMCID: PMC2698975  PMID: 19274425
Cerebral metastases; Stereotactic radiosurgery; Perfusion MRI; Necrosis; Recurrence
4.  The Role of Preload and Leakage Correction in Gadolinium-Based Cerebral Blood Volume Estimation Determined by Comparison with MION as a Criterion Standard 
BACKGROUND AND PURPOSE
Contrast extravasation in DSC-MRI potentiates inaccurate and imprecise estimates of glioma rCBV. We tested assertions that preload and postprocessing algorithms minimize this error by comparing Gd-rCBV using permutations of these 2 techniques with criterion standard rCBV using MION, an intravascular agent.
MATERIALS AND METHODS
We imaged 7 Fisher rats with 9L gliosarcomas, by using 3T gradient-echo DSC-MRI with MION (2.0 mg Fe/kg) and staged injection of Gd-diethylene triamine pentaacetic acid: a 0.1-mmol/kg bolus provided no preload (P−) data and served as preload (P+) for a subsequent 0.2-mmol/kg bolus. We computed MION-rCBV (steady-state ΔR2*, tumor versus normal brain) and Gd-rCBV ΔR2* [t] integration) without (C−) and with (C+) postprocessing correction, thereby testing 4 correction permutations: P−C−, P−C+, P+C−, and P+C+. We tested whether each permutation reduced bias and variance of the Gd/MION rCBV differences by using generalized estimating equations and Fmax statistics (P < .05 significant).
RESULTS
Gd-rCBV progressively better approximated MION-rCBV with increasing leakage correction. There was no statistically significant bias for the mean percentage deviation of Gd-rCBV from MION-rCBV for any correction permutation, but there was significantly reduced variance by using P+C− (22-fold), P−C+ (32-fold), and P+C+ (267-fold) compared with P−C−. P+C+ provided significant additional variance reduction compared with P+C− (12-fold) and P−C+ (8-fold). Linear regression of Gd-rCBV versus MION-rCBV revealed P+C+ to have the closest slope and intercept compared with the ideal, substantially better than P+C−.
CONCLUSIONS
Preload and postprocessing correction significantly reduced the variance of Gd-rCBV estimates, and bias reduction approached significance. Postprocessing correction provide significant benefit beyond preload alone.
doi:10.3174/ajnr.A2934
PMCID: PMC4331024  PMID: 22322605
5.  Cerebral blood volume, genotype and chemosensitivity in oligodendroglial tumours 
Neuroradiology  2006;48(10):703-713.
Introduction
The biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy.
Methods
Pretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33).
Results
1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss.
Conclusion
rCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.
doi:10.1007/s00234-006-0122-z
PMCID: PMC1592467  PMID: 16937145
Oligodendroglial tumour; rCBV; Chemosensitivity; Outcome
6.  High-resolution steady-state cerebral blood volume maps in patients with central nervous system neoplasms using ferumoxytol, a superparamagnetic iron oxide nanoparticle 
Cerebral blood volume (CBV) measurement complements conventional magnetic resonance imaging (MRI) to indicate pathologies in the central nervous system (CNS). Dynamic susceptibility contrast (DSC) perfusion imaging is limited by low resolution and distortion. Steady-state (SS) imaging may provide higher resolution CBV maps but was not previously possible in patients. We tested the feasibility of clinical SS-CBV measurement using ferumoxytol, a nanoparticle blood pool contrast agent. SS-CBV measurement was analyzed at various ferumoxytol doses and compared with DSC-CBV using gadoteridol. Ninety nine two-day MRI studies were acquired in 65 patients with CNS pathologies. The SS-CBV maps showed improved contrast to noise ratios, decreased motion artifacts at increasing ferumoxytol doses. Relative CBV (rCBV) values obtained in the thalamus and tumor regions indicated good consistency between the DSC and SS techniques when the higher dose (510 mg) ferumoxytol was used. The SS-CBV maps are feasible using ferumoxytol in a clinical dose of 510 mg, providing higher resolution images with comparable rCBV values to the DSC technique. Physiologic imaging using nanoparticles will be beneficial in visualizing CNS pathologies with high vascularity that may or may not correspond with blood–brain barrier abnormalities.
doi:10.1038/jcbfm.2013.36
PMCID: PMC3653563  PMID: 23486297
dynamic MR; ferumoxytol; relative cerebral blood volume; steady state
7.  Parametric Response Maps of Perfusion MRI May Identify Recurrent Glioblastomas Responsive to Bevacizumab and Irinotecan 
PLoS ONE  2014;9(3):e90535.
Background
Perfusion weighted imaging (PWI) can be used to measure key aspects of tumor vascularity in vivo and recent studies suggest that perfusion imaging may be useful in the early assessment of response to angiogenesis inhibitors. Aim of this work is to compare Parametric Response Maps (PRMs) with the Region Of Interest (ROI) approach in the analysis of tumor changes induced by bevacizumab and irinotecan in recurrent glioblastomas (rGBM), and to evaluate if changes in tumor blood volume measured by perfusion MRI may predict clinical outcome.
Methods
42 rGBM patients with KPS ≥50 were treated until progression, as defined by MRI with RANO criteria. Relative cerebral blood volume (rCBV) variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. Alternatively, rCBV variations with respect to baseline were calculated into the evolving tumor region using a voxel-by-voxel difference. PRMs were created showing where rCBV significantly increased, decreased or remained unchanged.
Results
An increased blood volume in PRM (PRMCBV+) higher than 18% (first quartile) after 8 weeks of treatment was associated with increased progression free survival (PFS; 24 versus 13 weeks, p = 0.045) and overall survival (OS; 38 versus 25 weeks, p = 0.016). After 8 weeks of treatment ROI analysis showed that mean rCBV remained elevated in non responsive patients (4.8±0.9 versus 5.1±1.2, p = 0.38), whereas decreased in responsive patients (4.2±1.3 versus 3.8±1.6 p = 0.04), and re-increased progressively when patients approached tumor progression.
Conclusions
Our data suggest that PRMs can provide an early marker of response to antiangiogenic treatment and warrant further confirmation in a larger cohort of GBM patients.
doi:10.1371/journal.pone.0090535
PMCID: PMC3968002  PMID: 24675671
8.  Ferumoxytol Enhanced resting state fMRI and Relative Cerebral Blood Volume mapping in Normal Human Brain 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.06.066.
The brain demonstrates spontaneous low-frequency (< 0.1 Hz) cerebral blood flow (CBF) fluctuations, measurable by resting-state functional MRI (rs-fMRI). Ultra small superparamagnetic iron oxide particles have been shown to enhance task-based fMRI signals (cerebral blood volume fMRI or CBV-fMRI), compared to the BOLD effect, by a factor of ≈ 2.5 at 3T in primates and humans. We evaluated the use of ferumoxytol for steady state,resting state FMRI (CBV-rs-fMRI) and relative cerebral blood volume (rCBV) mapping, at 3 Tesla, in healthy volunteers. All standard resting state networks (RSNs) were identified in all subjects.On average the RSN Z-statistics(Melodic independent components)and volumes of the Visual and default mode (DMN)networks were comparable rCBV values were averaged forthe visual (Vis) and DMN networks and correlated with the corresponding DMN and Visual network Z statistics. There was a negative correlation between the rCBV and the Z-statisticsforthe DMN, for both BOLD and CBVrs-fMRI contrast (R2= 0.63, 0.76).A similar correlation was not found for the visual network. Short repetition time rs-fMRI data were Fourier transformed to evaluate the effect of ferumoxytol on cardiac and respiratory fluctuations in the brain rs-BOLD, CBV signals. Cardiac and respiratory fluctuations decreased to baseline within large vessels post ferumoxytol.Robust rs-fMRI and CBV mapping is possible in normal human brain.
doi:10.1016/j.neuroimage.2013.06.066
PMCID: PMC3815982  PMID: 23831413
9.  Dopaminergic response to graded dopamine concentration elicited by four amphetamine doses 
Synapse (New York, N.Y.)  2009;63(9):764-772.
We studied the metabolic responses to different dopamine (DA) concentrations elicited by four doses of D-amphetamine (AMPH, 0, 0.25, 0.5, 1.0, or 3.0 mg/kg). We compared the degree of DA release (via microdialysis) to striatal cAMP activity and whole brain maps of cerebral blood volume (rCBV) changes (via pharmacological MRI, phMRI). Results: AMPH increased DA release in the caudate/putamen (CPu) and cAMP activity in the CPu, nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) in a linear dose-dependent manner (p<0.0001). The cAMP data suggests that, postsynaptically, signal transduction induced by D1 receptor is stronger than that of D2 receptor at the higher doses (1–3mg/kg). phMRI showed that, while higher doses of AMPH (3mg/kg (n=7) and 1mg/kg (n=6)) induced significant rCBV increases in the CPu and NAc, the degree of rCBV increase was much smaller with AMPH of 0.5mg/kg (n=6). In contrast, AMPH of 0.25mg/kg (n=8) induced significant rCBV decreases in the anteromedial CPu and NAc. The sign switch of rCBV in response to AMPH from low to high doses likely reflects the switching in the balance of D2/D3 stimulation versus D1/D5 stimulation. In conclusion, degree of postsynaptic signal transduction is linearly correlated to the extracellular DA concentration. However, the presynaptic binding may dominate the overall DA innervation at the lower range of DA concentration.
doi:10.1002/syn.20659
PMCID: PMC2758079  PMID: 19484725
dopamine; fMRI; phMRI; rCBV
10.  Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol versus gadoteridol: A pilot study 
Purpose
We evaluated dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI) using gadoteridol in comparison to the iron oxide nanoparticle blood pool agent, ferumoxytol in patients with glioblastoma multiforme (GBM) who received standard radiochemotherapy (RCT).
Methods and Materials
Fourteen patients with GBM received standard RCT and underwent 19 MRI sessions that included DSC-MRI acquisitions with gadoteridol on day 1 and ferumoxytol on day 2. Relative cerebral blood volume (rCBV) values were calculated from DSC data obtained from each contrast agent. T1-weighted acquisition post-gadoteridol administration was used to identify enhancing regions.
Results
In 7 MRI sessions of clinically presumptive active tumor, gadoteridol-DSC showed low rCBV in 3 and high rCBV in 4, while ferumoxytol-DSC showed high rCBV in all 7 sessions (p=0.002). After RCT, 7 MRI sessions showed increased gadoteridol contrast enhancement on T1-weighted scans coupled with low rCBV without significant differences between contrast agents (p=0.9). Based on post-gadoteridol T1-weighted scans, DSC-MRI, and clinical presentation four patterns of response to RCT were observed: 1) regression, 2) pseudoprogression, 3) true progression, and 4) mixed response.
Conclusion
We conclude that DSC-MRI with a blood-pool agent such as ferumoxytol may provide a better monitor of tumor rCBV than DSC-MRI with gadoteridol. Lesions demonstrating increased enhancement on T1-weighted MRI coupled with low ferumoxytol rCBV, are likely exhibiting pseudoprogression, while high rCBV with ferumoxytol is a better marker than gadoteridol for determining active tumor. These interesting pilot observations suggest that ferumoxytol may differentiate tumor progression from pseudoprogression, and warrant further investigation.
doi:10.1016/j.ijrobp.2009.10.072
PMCID: PMC3111452  PMID: 20395065
Blood-brain barrier; dynamic susceptibility- weighted contrast-enhanced magnetic resonance imaging; glioblastoma multiforme; pseudoprogression; radiochemotherapy
11.  Perfusion MR imaging for differentiation of benign and malignant meningiomas 
Neuroradiology  2008;50(6):525-530.
Introduction
Our purpose was to determine whether perfusion MR imaging can be used to differentiate benign and malignant meningiomas on the basis of the differences in perfusion of tumor parenchyma and/or peritumoral edema.
Methods
A total of 33 patients with preoperative meningiomas (25 benign and 8 malignant) underwent conventional and dynamic susceptibility contrast perfusion MR imaging. Maximal relative cerebral blood volume (rCBV) and the corresponding relative mean time to enhance (rMTE) (relative to the contralateral normal white matter) in both tumor parenchyma and peritumoral edema were measured. The independent samples t-test was used to determine whether there was a statistically significant difference in the mean rCBV and rMTE ratios between benign and malignant meningiomas.
Results
The mean maximal rCBV values of benign and malignant meningiomas were 7.16±4.08 (mean±SD) and 5.89±3.86, respectively, in the parenchyma, and 1.05±0.96 and 3.82±1.39, respectively, in the peritumoral edema. The mean rMTE values were 1.16±0.24 and 1.30±0.32, respectively, in the parenchyma, and 0.91±0.25 and 1.24±0.35, respectively, in the peritumoral edema. The differences in rCBV and rMTE values between benign and malignant meningiomas were not statistically significant (P>0.05) in the parenchyma, but both were statistically significant (P<0.05) in the peritumoral edema.
Conclusion
Perfusion MR imaging can provide useful information on meningioma vascularity which is not available from conventional MRI. Measurement of maximal rCBV and corresponding rMTE values in the peritumoral edema is useful in the preoperative differentiation between benign and malignant meningiomas.
doi:10.1007/s00234-008-0373-y
PMCID: PMC2440923  PMID: 18379768
Meningioma; Cerebral neoplasm; Magnetic resonance imaging; Perfusion-weighted imaging; Brain
12.  Facing Contrast-Enhancing Gliomas: Perfusion MRI in Grade III and Grade IV Gliomas according to Tumor Area 
BioMed Research International  2014;2014:154350.
Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV), calculated with Dynamic Susceptibility Contrast (DSC) Perfusion-Weighted Imaging (PWI), allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI) approach in three tumor areas—the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map—in patients affected by contrast-enhancing glioma (grades III and IV). Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp.), the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P = 0.036). In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading.
doi:10.1155/2014/154350
PMCID: PMC3996293  PMID: 24800207
13.  Feasibility Study of Perfusion Imaging Using Flat Detector CT with an Intra-Arterial Injection Protocol Compared to Conventional Multi-Slice Perfusion CT with an Intravenous Injection Protocol 
Interventional Neuroradiology  null;19(4):409-415.
Summary
This study investigated the feasibility of using intra-arterial injection-based cerebral blood volume (CBV) imaging with flat detector computed tomography (CT, IAFD-CBV). It is proven that this new method could provide comparable physiologic information as standard intravenous injection-based multi-slice computed tomography CBV imaging (IVCT-CBV).
Twelve patients were examined using both IAFD-CBV and IVCT-CBV. An experienced neuroradiologist read both sets of generated CBV maps. If a physiologic perfusion disorder was detected in standard IVCT-CBV, the focus was to check whether IAFD-CBV indicated the same disorder or not. Otherwise, if no disorder was detected, relative CBV (rCBV) values at different basal ganglia regions were measured for both CBV maps and then compared.
For three patients with lesions, IAFD-CBV and IVCT-CBV showed similar perfusion disorders in the corresponding regions. For nine patients without lesions, both CBV maps showed good symmetry of contrast agent (CA) distribution for left/right hemisphere, the total average of rCBV was found to be 0.94 −/+0.18 and 1.01 −/+0.14 (1.0 for perfect symmetry) in IAFD-CBV and IVCT-CBV, respectively. However, compared to IVCT-CBV, IAFD-CBV imaging required 70% less contrast agent (CA).
In general, a good correlation between IAFD-CBV and IVCT-CBV was found for all 12 patients. Minor deviations of IAFD-CBV were only detected at regions supplied by the middle cerebral artery. IAFD-CBV imaging, which can be directly performed in a catheterization laboratory, was proven to be technically feasible for real-time CBV assessment of the whole brain with good accuracy, and minimized CA usage.
PMCID: PMC3902738  PMID: 24355143
flat detector CT; cerebral blood volume; perfusion
14.  Regulation of oxygen transport during brain activation: stimulus-induced hemodynamic responses in human and animal cortices 
Background
The correlation between regional changes in neuronal activity and changes in hemodynamics is a major issue for noninvasive neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and near-infrared optical imaging (NIOI). A tight coupling of these changes has been assumed to elucidate brain function from data obtained with those techniques. In the present study, we investigated the relationship between neuronal activity and hemodynamic responses in the occipital cortex of humans during visual stimulation and in the somatosensory cortex of rats during peripheral nerve stimulation.
Methods
The temporal frequency dependence of macroscopic hemodynamic responses on visual stimuli was investigated in the occipital cortex of humans by simultaneous measurements made using fMRI and NIOI. The stimulus-intensity dependence of both microscopic hemodynamic changes and changes in neuronal activity in response to peripheral nerve stimulation was investigated in animal models by analyzing membrane potential (fluorescence), hemodynamic parameters (visible spectra and laser-Doppler flowmetry), and vessel diameter (image analyzer).
Results
Above a certain level of stimulus-intensity, increases in regional cerebral blood flow (rCBF) were accompanied by a decrease in regional cerebral blood volume (rCBV), i.e., dissociation of rCBF and rCBV responses occurred in both the human and animal experiments. Furthermore, the animal experiments revealed that the distribution of increased rCBF and O2 spread well beyond the area of neuronal activation, and that the increases showed saturation in the activated area.
Conclusions
These results suggest that above a certain level of neuronal activity, a regulatory mechanism between regional cerebral blood flow (rCBF) and rCBV acts to prevent excess O2 inflow into the focally activated area.
doi:10.1186/1476-5918-2-6
PMCID: PMC341458  PMID: 14687423
15.  Value of Perfusion-Weighted MR Imaging in the Assessment of Early Cerebral Alterations in Neurologically Asymptomatic HIV-1-Positive and HCV-Positive Patients 
PLoS ONE  2014;9(7):e102214.
Background and Purpose
Asymptomatic central nervous system (CNS) involvement occurs in the early stage of the human immunodeficiency virus (HIV) infection. It has been documented that the hepatitis C virus (HCV) can replicate in the CNS. The aim of the study was to evaluate early disturbances in cerebral microcirculation using magnetic resonance (MR) perfusion-weighted imaging (PWI) in asymptomatic HIV-1-positive and HCV-positive patients, as well as to assess the correlation between PWI measurements and the clinical data.
Materials and Methods
Fifty-six patients: 17 HIV-1-positive non-treated, 18 HIV-1-positive treated with combination antiretroviral therapy (cART), 7 HIV-1/HCV-positive non-treated, 14 HCV-positive before antiviral therapy and 18 control subjects were enrolled in the study. PWI was performed with a 1.5T MR unit using dynamic susceptibility contrast (DSC) method. Cerebral blood volume (CBV) measurements relative to cerebellum (rCBV) were evaluated in the posterior cingulated region (PCG), basal ganglia (BG), temporoparietal (TPC) and frontal cortices (FC), as well as in white matter of frontoparietal areas. Correlations of rCBV values with immunologic data and liver histology activity index (HAI) were analyzed.
Results
Significantly lower rCBV values were found in the right TPC and left FC as well as in PCG in HIV-1-positive naïve (p = 0.009; p = 0.020; p = 0.012), HIV-1 cART treated (p = 0.007; p = 0.009; p = 0.033), HIV-1/HCV-positive (p = 0.007; p = 0.027; p = 0.045) and HCV-positive patients (p = 0.010; p = 0.005; p = 0.045) compared to controls. HIV-1-positive cART treated and HIV-1/HCV-positive patients demonstrated lower rCBV values in the right FC (p = 0.009; p = 0.032, respectively) and the left TPC (p = 0.036; p = 0.005, respectively), while HCV-positive subjects revealed lower rCBV values in the left TPC region (p = 0.003). We found significantly elevated rCBV values in BG in HCV-positive patients (p = 0.0002; p<0.0001) compared to controls as well as to all HIV-1-positive subjects. There were no significant correlations of rCBV values and CD4 T cell count or HAI score.
Conclusions
PWI examination enables the assessment of HIV-related as well as HCV-related early cerebral dysfunction in asymptomatic subjects. HCV-infected patients seem to reveal the most pronounced perfusion changes.
doi:10.1371/journal.pone.0102214
PMCID: PMC4094508  PMID: 25013963
16.  Pharmacologic Neuroimaging of the Ontogeny of Dopamine Receptor Function 
Developmental Neuroscience  2010;32(2):125-138.
Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.
doi:10.1159/000286215
PMCID: PMC2919511  PMID: 20523024
Ontogeny; Dopamine; D1 receptor; D2 receptor; Functional MRI; Pharmacological MRI
17.  Impact of Perfusion Map Analysis on Early Survival Prediction Accuracy in Glioma Patients1 
Translational Oncology  2013;6(6):766-774.
Studies investigating dynamic susceptibility contrast magnetic resonance imaging-determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. rCBV maps were acquired in patients with high-grade gliomas at 0, 1, and 3 weeks into chemoradiation therapy. Various analytical techniques were applied to the same cohort of serial rCBV data for early assessment of survival. Three different methodologies were investigated: 1) percentage change of whole tumor statistics (i.e., mean, median, and percentiles), 2) physiological segmentation (low rCBV, medium rCBV, or high rCBV), and 3) a voxel-based approach, parametric response mapping (PRM). All analyses were performed using the same tumor contours, which were determined using contrast-enhanced T1-weighted and fluid attenuated inversion recovery images. The predictive potential of each response metric was assessed at 1-year and overall survival. PRM was the only analytical approach found to generate a response metric significantly predictive of patient 1-year survival. Time of acquisition and contour volume were not found to alter the sensitivity of the PRM approach for predicting overall survival. We have demonstrated the importance of the analytical approach in early response assessment using serial rCBV maps. The PRM analysis shows promise as a unified early and robust imaging biomarker of treatment response in patients diagnosed with high-grade gliomas.
PMCID: PMC3890712  PMID: 24466380
18.  Magnetic resonance imaging of intracranial tumors: intra-patient comparison of gadoteridol and ferumoxytol 
Neuro-Oncology  2010;13(2):251-260.
This study aims to compare gadoteridol with ferumoxytol for contrast-enhanced and perfusion-weighted (PW) MRI of intracranial tumors. The final analysis included 26 patients, who underwent 3 consecutive days of 3T MRI. Day 1 consisted of anatomical pre- and postcontrast images, and PW MRI was acquired using gadoteridol (0.1 mmol/kg). On Day 2, the same MRI sequences were obtained with ferumoxytol (510 mg) and on Day 3, the anatomical images were repeated to detect delayed ferumoxytol-induced signal changes. The T1-weighted images were evaluated qualitatively and quantitatively for enhancement volume and signal intensity (SI) changes; PW data were used to estimate the relative cerebral blood volume (rCBV). All 26 lesions showed 24-hour T1-weighted ferumoxytol enhancement; 16 also had T2-weighted hypointensities. In 6 patients, ferumoxytol-induced signal changes were noted in areas with no gadoteridol enhancement. Significantly greater (P< .0001) SI changes were seen with gadoteridol, and qualitative analyses (lesion border delineation, internal morphology, contrast enhancement) also showed significant preferences (P= .0121; P = .0015; P < .0001, respectively) for this agent. There was no significant difference in lesion enhancement volumes between contrast materials. The ferumoxytol-rCBV values were significantly higher (P = .0016) compared with the gadoteridol-rCBV values. In conclusion, ferumoxytol provides important information about tumor biology that complements gadoteridol imaging. The rCBV measurements indicate areas of tumor undergoing rapid growth, whereas the 24-hour scans mark the presence of inflammatory cells. Both of these functions provide useful information about tumor response to treatment. We suggest that dynamic and anatomical imaging with ferumoxytol warrant further assessment in brain tumor therapy.
doi:10.1093/neuonc/noq172
PMCID: PMC3064624  PMID: 21163809
brain tumors; ferumoxytol; magnetic resonance imaging; ultrasmall superparamagnetic iron oxide nanoparticles
19.  Perfusion MR Imaging in Gliomas: Comparison with Histologic Tumor Grade 
Objective
To determine the usefulness of perfusion MR imaging in assessing the histologic grade of cerebral gliomas.
Materials and Methods
In order to determine relative cerebral blood volume (rCBV), 22 patients with pathologically proven gliomas (9 glioblastomas, 9 anaplastic gliomas and 4 low-grade gliomas) underwent dynamic contrast-enhanced T2*-weighted and conventional T1- and T2-weighted imaging. rCBV maps were obtained by fitting a gamma-variate function to the contrast material concentration versus time curve. rCBV ratios between tumor and normal white matter (maximum rCBV of tumor / rCBV of contralateral white matter) were calculated and compared between glioblastomas, anaplastic gliomas and low-grade gliomas.
Results
Mean rCBV ratios were 4.90°±1.01 for glioblastomas, 3.97°±0.56 for anaplastic gliomas and 1.75°±1.51 for low-grade gliomas, and were thus significantly different; p < .05 between glioblastomas and anaplastic gliomas, p < .05 between anaplastic gliomas and low-grade gliomas, p < .01 between glioblastomas and low-grade gliomas. The rCBV ratio cutoff value which permitted discrimination between high-grade (glioblastomas and anaplastic gliomas) and low-grade gliomas was 2.60, and the sensitivity and specificity of this value were 100% and 75%, respectively.
Conclusion
Perfusion MR imaging is a useful and reliable technique for estimating the histologic grade of gliomas.
doi:10.3348/kjr.2001.2.1.1
PMCID: PMC2718089  PMID: 11752962
Brain neoplasms, MR; Brain, blood flow; Cerebral blood vessels, flow dynamics; Magnetic resonance (MR), contrast enhancement
20.  Clinical utility of cerebrovascular reactivity mapping in patients with low grade gliomas 
AIM: To evaluate neurovascular uncoupling (NVU) associated with low grade gliomas (LGG) using blood oxygen level dependent (BOLD) cerebrovascular reactivity mapping.
METHODS: Seven patients with low grade gliomas referred by neurosurgeons for presurgical mapping were included in this pilot study. Cerebrovascular reactivity (CVR) mapping was performed by acquiring BOLD images while patients performed a block-design breath-hold (BH) hypercapnia task. CVR mapping was expressed as BOLD percentage signal change (PSC) from baseline associated with performance of the BH hypercapnia task. Standard T2* Dynamic Susceptibility Contrast perfusion imaging was performed and relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) maps were generated. Structural T1 weighted MR images were also acquired. A correlation analysis between intratumoral normalized (via ratio with contralateral homologous regions) BOLD BH PSC [referred to as (nCVR)] and intratumoral normalized resting state rCBV (rCBF) values (i.e., nCBV and nCBF, respectively) was performed.
RESULTS: No significant correlation was seen between the normalized BOLD BH PSC (i.e., nCBV) and nCBV or nCBF. However, the average nCVR (median = 0.50, z = -2.28, P = 0.01) was significantly less than 1.0, indicating abnormally reduced vascular responses in the tumor regions relative to normal contralesional homologous regions, whereas the average nCBV (median = 0.94, z = -0.92, P = 0.375) and nCBF (median = 0.93, z = -1.16, P = 0.25) were not significantly higher or lower than 1.0, indicating iso-perfusion in the tumor regions relative to normal contralesional homologous regions. These findings suggest that in LGG, hyperperfusion that is seen in high grade gliomas is not present, but, nevertheless, abnormally decreased regional CVR is present within and adjacent to LGG. Since the patients all demonstrated at least some residual function attributable to the cortical regions of impaired CVR, but were incapable of producing a BOLD response in these regions regardless of the tasks performed, such regionally decreased CVR is indicative of NVU. The low nCVR ratios indicate high prevalence of NVU in this LGG cohort, which is an important consideration in the interpretation of clinical presurgical mapping with functional magnetic resonance (MR) imaging.
CONCLUSION: Our preliminary study shows that BH CVR mapping is clinically feasible and demonstrates an unexpectedly high prevalence of NVU in patients with LGG.
doi:10.5306/wjco.v2.i12.397
PMCID: PMC3235658  PMID: 22171282
Blood oxygen level dependent; Brain tumor; Cerebrovascular reactivity; Functional MRI; Neurovascular uncoupling; Presurgical mapping
21.  Standardization of Relative Cerebral Blood Volume (rCBV) Image Maps for Ease of Both Inter- and Intrapatient Comparisons 
Relative cerebral blood volume (rCBV) measured using dynamic susceptibility contrast MRI suffers from interpatient and interstudy variability for the same tissue type. Traditionally, when a more quantitative assessment of rCBV is required, as for comparison across studies and patients, the rCBV values are normalized to the rCBV in a reference region such as normal-appearing white matter. However, this technique of normalization is subjective and time consuming and introduces user-dependent variability. In this study, we demonstrate that a method called standardization, applied to rCBV maps, is an objective means of translating all rCBV values to a consistent scale. This approach reduces interpatient and interstudy variability for the same tissue type, thus enabling easy and accurate visual and quantitative comparison across studies. One caveat to this approach is that it is not appropriate for the evaluation of global changes in blood volume, since systematic differences are removed in the process of standardization.
doi:10.1002/mrm.22445
PMCID: PMC4323176  PMID: 20806381
rCBV; standardization; DSC; MRI; intrapatient comparisons
22.  Perfusion MR Imaging: Clinical Utility for the Differential Diagnosis of Various Brain Tumors 
Korean Journal of Radiology  2002;3(3):171-179.
Objective
To determine the utility of perfusion MR imaging in the differential diagnosis of brain tumors.
Materials and Methods
Fifty-seven patients with pathologically proven brain tumors (21 high-grade gliomas, 8 low-grade gliomas, 8 lymphomas, 6 hemangioblastomas, 7 metastases, and 7 various other tumors) were included in this study. Relative cerebral blood volume (rCBV) and time-to-peak (TTP) ratios were quantitatively analyzed and the rCBV grade of each tumor was also visually assessed on an rCBV map.
Results
The highest rCBV ratios were seen in hemangioblastomas, followed by high-grade gliomas, metastases, low-grade gliomas, and lymphomas. There was no significant difference in TTP ratios between each tumor group (p>0.05). At visual assessment, rCBV was high in 17 (81%) of 21 high-grade gliomas and in 4 (50%) of 8 low-grade gliomas. Hemangioblastomas showed the highest rCBV and lymphomas the lowest.
Conclusion
Perfusion MR imaging may be helpful in the differentiation of thevarious solid tumors found in the brain, and in assessing the grade of the various glial tumors occurring there.
doi:10.3348/kjr.2002.3.3.171
PMCID: PMC2713881  PMID: 12271162
Brain neoplasms, diagnosis; Brain neoplasms, MR; Brain, perfusion; Magnetic resonance (MR), perfusion study
23.  Physiological Imaging-Defined Response-Driven Subvolumes of a Tumor1 
Summary
Dose painting of the physiological imaging-defined subvolumes of the tumors by intensity-modulated radiotherapy is hypothesized to lead to a better outcome than distributing a uniform dose within a target volume defined by anatomic imaging. We developed a general method to delineate the subvolumes of a tumor based upon multiple physiological imaging and tested their complementary roles for assessment of therapy response.
Purpose
To develop an image analysis framework to delineate the physiological imaging-defined subvolumes of a tumor in relating to treatment response and outcome.
Materials and Methods
Our proposed approach delineates the subvolumes of a tumor based upon its heterogeneous distributions of physiological imaging parameters. The method assigns each voxel a probabilistic membership function belonging to the physiological parameter classes defined in a sample of tumors, and then calculates the related subvolumes in each tumor. We applied our approach to regional cerebral blood volume (rCBV) and Gd-DTPA transfer constant (Ktrans) images of patients who had brain metastases and were treated by whole brain radiotherapy (WBRT). Forty-five lesions were included in the analysis. Changes in the rCBV (or Ktrans)-defined subvolumes of the tumors from pre RT to 2 weeks (2W) after the start of WBRT were evaluated for differentiation of responsive, stable and progressive tumors using Mann-Whitney U test. Performance of the newly developed metrics for predicting tumor response to WBRT was evaluated by Receiver Operating Characteristic (ROC) analysis.
Results
The percentage decrease in the high-CBV defined subvolumes of the tumors from pre-RT to 2W was significantly greater in the group of responsive tumors than the group of stable and progressive ones (p<0.007). The change in the high-CBV defined subvolumes of the tumors from pre-RT to 2W was a predictor for post-RT response significantly better than change in the gross tumor volume observed during the same time interval (p=0.012), suggesting the physiological change occurs prior to the volumetric change. Also, Ktrans did not add significant discriminatory information for assessing response with respect to rCBV.
Conclusion
The physiological imaging-defined subvolumes of the tumors delineated by our method could be a candidate for boost target, for which further development and evaluation is warranted.
doi:10.1016/j.ijrobp.2012.10.036
PMCID: PMC3638951  PMID: 23257692
24.  Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging 
Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2β-carbomethoxy-3β-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates.
doi:10.1523/JNEUROSCI.1558-04.2004
PMCID: PMC2629666  PMID: 15509742
amphetamine; dopamine; MRI; macaque; Parkinson's disease; PET
25.  Gliomas: Application of Cumulative Histogram Analysis of Normalized Cerebral Blood Volume on 3 T MRI to Tumor Grading 
PLoS ONE  2013;8(5):e63462.
Background
Glioma grading assumes significant importance in that low- and high-grade gliomas display different prognoses and are treated with dissimilar therapeutic strategies. The objective of our study was to retrospectively assess the usefulness of a cumulative normalized cerebral blood volume (nCBV) histogram for glioma grading based on 3 T MRI.
Methods
From February 2010 to April 2012, 63 patients with astrocytic tumors underwent 3 T MRI with dynamic susceptibility contrast perfusion-weighted imaging. Regions of interest containing the entire tumor volume were drawn on every section of the co-registered relative CBV (rCBV) maps and T2-weighted images. The percentile values from the cumulative nCBV histograms and the other histogram parameters were correlated with tumor grades. Cochran’s Q test and the McNemar test were used to compare the diagnostic accuracies of the histogram parameters after the receiver operating characteristic curve analysis. Using the parameter offering the highest diagnostic accuracy, a validation process was performed with an independent test set of nine patients.
Results
The 99th percentile of the cumulative nCBV histogram (nCBV C99), mean and peak height differed significantly between low- and high-grade gliomas (P = <0.001, 0.014 and <0.001, respectively) and between grade III and IV gliomas (P = <0.001, 0.001 and <0.001, respectively). The diagnostic accuracy of nCBV C99 was significantly higher than that of the mean nCBV (P = 0.016) in distinguishing high- from low-grade gliomas and was comparable to that of the peak height (P = 1.000). Validation using the two cutoff values of nCBV C99 achieved a diagnostic accuracy of 66.7% (6/9) for the separation of all three glioma grades.
Conclusion
Cumulative histogram analysis of nCBV using 3 T MRI can be a useful method for preoperative glioma grading. The nCBV C99 value is helpful in distinguishing high- from low-grade gliomas and grade IV from III gliomas.
doi:10.1371/journal.pone.0063462
PMCID: PMC3660395  PMID: 23704910

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