Non-contrast assessment of blood-brain barrier permeability to water in mice: An arterial spin labeling study at cerebral veins.

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.

Water-exchange MRI detects subtle blood-brain barrier breakdown in Alzheimer's disease rats.

Blood-brain barrier (BBB) breakdown has been hypothesized to play a key role in the onset and progression of Alzheimer's disease (AD). However, the question of whether AD itself contributes to loss of BBB integrity is still uncertain, as many in-vivo studies have failed to detect signs of AD-related BBB breakdown. We hypothesize AD-related BBB damage is subtle, and that these negative results arise from a lack of measurement sensitivity. With the aim of developing a more sensitive measure of BBB breakdown, we have designed a novel MRI scanning protocol to quantify the trans-BBB exchange of endogenous water. Using this method, we detect increased BBB water permeability in a rat model of AD that is associated with reduced expression of the tight junction protein occludin. BBB permeability to MRI contrast agent, assessed using dynamic contrast-enhanced (DCE)-MRI, did not differ between transgenic and wild-type animals and was uncorrelated with occludin expression. Our data supports the occurrence of AD-related BBB breakdown, and indicates that such BBB pathology is subtle and may be undetectable using existing 'tracer leakage' methods. Our validated water-exchange MRI method provides a new powerful tool with which to study BBB damage in-vivo.

3D MRI of whole-brain water permeability with intrinsic diffusivity encoding of arterial labeled spin (IDEALS).

This work proposes a novel MRI method - Intrinsic Diffusivity Encoding of Arterial Labeled Spin (IDEALS) - for the whole-brain mapping of water permeability in the human brain without an exogenous contrast agent. Quantitative separation of the intravascular and extravascular labeled water MRI signal was achieved in arterial spin labeling experiments with segmented 3D-GRASE acquisition by modulating the relative sensitivity between relaxation, true diffusion, and pseudodiffusion. The intrinsic diffusivity encoding in k-space created different broadening of the image-domain point spread functions for intravascular and extravascular labeled spins, from which blood-brain barrier (BBB) water extraction fraction (Ew) and water permeability surface area product (PSw) were estimated. The feasibility and sensitivity of this method was evaluated in healthy subjects at baseline and after caffeine challenge. The estimated baseline Ew and PSw maps showed contrast among gray matter (GM) and white matter (WM). GM Ew was significantly lower than that of WM (78.8% ±â€¯3.3% in GM vs. 83.9% ±â€¯4.6% in WM; p < 0.05) and GM PSw was significantly higher than that of WM (131.7 ±â€¯29.5 mL/100  g/min in GM vs. 76.2 ±â€¯18.4 mL/100  g/min in WM; p < 0.05). BBB Ew was significantly lower for females than males (74.9% ±â€¯3.7% for females vs. 81.3% ±â€¯3.3% for males in GM; 80.5% ±â€¯4.7% for females vs. 86.1 ±â€¯3.0 for males in WM; p < 0.05 for both), while significant PSw differences were only observed in WM (143.8 ±â€¯34.4 mL/100  g/min for females vs. 123.6 ±â€¯24.4 mL/100  g/min for males in GM; 91.6 ±â€¯15.0 mL/100  g/min for females vs. 65.9 ±â€¯12.5 mL/100  g/min for males in WM; p = 0.20 and p < 0.05 for GM and WM respectively). Significant correlations between Ew and CBF (r = -0.32, p < 0.05) and between PSw and CBF (r = 0.89, p < 0.05) were observed, consistent with 15O-H2O PET findings. After caffeine challenge, reduced CBF, Ew and PSw were observed, demonstrating the sensitivity of IDEALS approach.

Anti-angiogenic therapy affects the relationship between tumor vascular structure and function: A correlation study between micro-computed tomography angiography and dynamic contrast enhanced MRI.

PURPOSE: To compare the effects of two anti-angiogenic drugs, bevacizumab and a cytosolic phospholipase A2-α inhibitor (AVX235), on the relationship between vascular structure and dynamic contrast enhanced (DCE)-MRI measurements in a patient-derived breast cancer xenograft model. METHODS: Mice bearing MAS98.12 tumors were randomized into three groups: bevacizumab-treated (n = 9), AVX235-treated (n = 9), and control (n = 8). DCE-MRI was performed pre- and post-treatment. Median initial area under the concentration-time curve (IAUC60 ) and volume transfer constant (Ktrans ) were computed for each tumor. Tumors were excised for ex vivo micro-CT (computed tomography) angiography, from which the vascular surface area (VSA) and fractional blood volume (FBV) were computed. Spearman correlation coefficients (ρ) were computed to evaluate the associations between the DCE-MRI and micro-CT parameters. RESULTS: With the groups pooled, IAUC60 and Ktrans correlated significantly with VSA (ρ = 0.475 and 0.527; P = 0.019 and 0.008). There were no significant correlations within the control group. There were various significant correlations within the treatment groups, but the correlations in the bevacizumab group were of opposite sign, for example, Ktrans versus FBV: AVX235, ρ = 0.800 (P = 0.014); bevacizumab, ρ = -0.786 (P = 0.023). CONCLUSION: DCE-MRI measurements can highly depend on vascular structure. The relationship between vascular structure and function changed markedly after anti-angiogenic treatment. Magn Reson Med 78:1513-1522, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Temporal Evolution of Perihematomal Blood-Brain Barrier Compromise and Edema Growth After Intracerebral Hemorrhage.

PURPOSE: The aim of this study was to investigate the temporal evolution of perihematomal blood-brain barrier (BBB) compromise and edema growth and to determine the role of BBB compromise in edema growth. METHODS: Spontaneous intracerebral hemorrhage patients who underwent computed tomography perfusion (CTP) were divided into five groups according to the time interval from symptom onset to CTP examination. Permeability-surface area product (PS) maps were generated using CTP source images. Ipsilateral and contralateral mean PS values were computed in the perihematomal and contralateral mirror regions. The relative PS (rPS) value was calculated as a ratio of ipsilateral to contralateral PS value. Hematoma and perihematomal edema volume were determined on non-contrast CT images. RESULTS: In the total of 101 intracerebral hemorrhage patients, the ipsilateral mean PS value was significantly higher than that in contralateral region (z = -8.284, p < 0.001). The perihematomal BBB permeability showed a course of dynamic changes including an increase in the hyperacute and acute phases, a decrease in the early subacute phase and a second increase in the late subacute phase and chronic phase. Perihematomal edema increased gradually until the late subacute phase and then slightly increased. There was a relationship between rPS value and edema volume (ß = 0.254, p = 0.006). CONCLUSION: The perihematomal BBB permeability is dynamic changes, and edema growth is gradually increased in patients following intracerebral hemorrhage. BBB compromise plays an essential role in edema growth. The quantitative assessment of BBB compromise may provide valuable information in therapeutic interventions of intracerebral hemorrhage patients.

Abnormal blood-brain barrier water exchange in chronic multiple sclerosis lesions: A preliminary study.

Relapsing-remitting multiple sclerosis (RRMS) is associated with persistent blood-brain barrier (BBB) dysfunction. The impact of this persistent dysfunction in both active and chronic MS lesions has yet to be investigated due to technological challenges associated with invasive assessment of BBB water transportation (e.g. 15O-PET). The purpose of this study was to test if persistent BBB dysfunction in RRMS manifests as lower BBB water exchange in chronic lesions using a recently developed noninvasive MRI paradigm. Patients with relapsing-remitting MS and healthy subjects were recruited for this prospective study. The novel Intrinsic Diffusivity Encoding of Arterial Labeled Spins (IDEALS) MRI method was used to map BBB water extraction fraction (Ew) and water permeability surface area product (PSw), as well as cerebral blood flow (CBF). Regional differences in BBB water exchange were evaluated between MS patients (normal appearing white matter [NAWM] and normal appearing gray matter [NAGM]) and healthy subjects (white matter [WM] and gray matter [GM]) and within MS subjects in non gadolinium-based contrast-agent (GBCA) enhancing chronic lesions, perilesional areas, and NAWM. Significantly lower PSw and Ew were observed in NAWM compared to WM (ΔPSw: -11.9 mL/100 g/min, p < .05; ΔEw: -4.3%, p < .01). Significantly lower Ew was observed in NAGM compared to GM (ΔEw: -12.1%, p < .01). Significantly lower PSw and CBF were observed in non-GBCA contrast enhancing lesions compared to NAWM (ΔPSw = -11.5 mL/100 g/min, p < .05; ΔCBF = -8.1 mL/100 g/min, p < .05). Ew was significantly higher in non-GBCA enhancing chronic MS lesions compared to NAWM (ΔEw = 1.6%, p < .05). The lower BBB water exchange in chronic MS lesions is consistent with previously reported observations and may demonstrate metabolic changes associated with MS.

Permeability Surface Area Product Using Perfusion Computed Tomography Is a Valuable Prognostic Factor in Glioblastomas Treated with Radiotherapy Plus Concomitant and Adjuvant Temozolomide.

OBJECTIVE: The current standard treatment protocol for patients with newly diagnosed glioblastoma (GBM) includes surgery, radiotherapy, and concomitant and adjuvant temozolomide (TMZ). We hypothesized that the permeability surface area product (PS) from a perfusion computed tomography (PCT) study is associated with sensitivity to TMZ. The aim of this study was to determine whether PS values were correlated with prognosis of GBM patients who received the standard treatment protocol. METHODS: This study included 36 patients with GBM that were newly diagnosed between October 2005 and September 2014 and who underwent preoperative PCT study and the standard treatment protocol. We measured the maximum value of relative cerebral blood volume (rCBVmax) and the maximum PS value (PSmax). We statistically examined the relationship between PSmax and prognosis using survival analysis, including other clinicopathologic factors (age, Karnofsky performance status [KPS], extent of resection, O6-methylguanine-DNA methyltransferase [MGMT] status, second-line use of bevacizumab, and rCBVmax). RESULTS: Log-rank tests revealed that age, KPS, MGMT status, and PSmax were significantly correlated with overall survival. Multivariate analysis using the Cox regression model showed that PSmax was the most significant prognostic factor. Receiver operating characteristic curve analysis showed that PSmax had the highest accuracy in differentiating longtime survivors (LTSs) (surviving more than 2 years) from non-LTSs. At a cutoff point of 8.26 mL/100 g/min, sensitivity and specificity were 90% and 70%, respectively. CONCLUSIONS: PSmax from PCT study can help predict survival time in patients with GBM receiving the standard treatment protocol. Survival may be related to sensitivity to TMZ.

Permeability surface area product analysis in malignant brain edema prediction - A pilot study.

BACKGROUND AND PURPOSE: Using an extended CT perfusion acquisition (150s), we sought to determine the association between perfusion parameters and malignant edema after ischemic stroke. METHODS: Patients (from prospective study PROVE-IT, NCT02184936) with terminal internal carotid artery±proximal middle cerebral occlusion were involved. CTA was assessed for clot location and status of leptomeningeal collaterals. The following CTP parameters were calculated within the ischemic territory and contralaterally: permeability surface area product (PS), cerebral blood flow (CBF) and cerebral blood volume (CBV). PS was calculated using the adiabatic approximation to the Johnson and Wilson model. Outcome was evaluated by midline shift and infarction volume on follow-up imaging. RESULTS: Of 200 patients enrolled, 7 patients (3.5%) had midline shift≥5mm (2 excluded for poor-quality scans). Five patients with midline shift and 5 matched controls were analysed. There was no significant difference in mean PS, CBF and CBV within the ischemic territory between the two groups. A CBV threshold of 1.7ml/100g had the highest AUC=0.72, 95% CI=0.54-0.90 for early midline shift prediction, sensitivity and specificity were 0.83 and 0.67 respectively. CONCLUSION: Our preliminary results did not show significant differences in permeability surface area analysis if analysed for complete ischemic region. CBV parameter had the highest accuracy and there was a trend for the mean PS values for midline shift prediction.

Is Adapted APD Theoretically More Efficient than Conventional APD?

♦ BACKGROUND: A modified version of automated peritoneal dialysis (APD) using not only variable dwell times but also variable fill volumes has been tested against conventional APD (cAPD) with fixed dwell volumes in a randomized controlled clinical study. The results have indicated that the modified schedule for APD, denoted adapted APD (aAPD), can lead to improved small solute clearances, and, above all, a markedly increased sodium removal (NaR). To theoretically test these results, we have modeled aAPD vs cAPD in computer simulations using the 3-pore model (TPM). ♦ METHODS: The TPM, modified by including a transient, initial inflation of small solute mass transfer area coefficients (PS values), was employed. For simulations of osmotic ultrafiltration (UF), the TPM uses a constantly inflated value for PS for glucose and also a reduced value for PS for Na+, setting the peritoneal lymphatic reabsorption term at 0.3 mL/min. The simulations were performed by assuming that increases in intraperitoneal hydrostatic pressure (IPP) are transmitted to the capillary level (via vein compression) and therefore do not significantly affect the Starling balance. Furthermore, the effective peritoneal surface area (A) was set to be variable as a function of intraperitoneal volume (IPV). ♦ RESULTS: The simulations demonstrated a minor improvement of small solute clearances (~0.7 - 1.6%) and a very small improvement of UF and NaR in aAPD compared to cAPD. ♦ CONCLUSIONS: Due mainly to the increased fill volumes in 3 out of 5 dwells in aAPD, this modality caused minor increases in small solute clearances and marginal effects on UF and NaR. The computer simulations point to a need for accurate sodium determinations in aAPD, considering all the methodological problems and pitfalls relevant to determining dialysate Na+ concentrations and peritoneal sodium mass balance.

Perfusion computed tomography of intracranial meningiomas: In vivo correlation of cerebral blood volume and vascular permeability.

BACKGROUND: A noninvasive method to predict the grade of a meningioma would be desirable since it would anticipate information about tumour nature, recurrence and improve tumour management and outcomes. The aim of the present study was to assess the ability of perfusion computed tomography (PCT) technique in predicting the meningioma grade before surgery. Data from PCT, such as cerebral blood volume (CBV) and permeability surface (PS), were correlated with immunohistolopathological information. METHODS: Twenty-three patients with a diagnosis of intracranial meningioma underwent PCT for pre-surgical evaluation of CBV and PS. During surgery, samples from the centre and periphery of the tumour were obtained. Two correspondent regions of interest (ROIs) were drawn on CBV and PS maps. Central and peripheral CBV and PS mean values were calculated. PCT parameters were correlated to CD-34 and endoglin. RESULTS: There was a positive correlation between PS and CD-34. No correlation was found between PS values and endoglin, CBV values and CD-34 and endoglin values. CONCLUSION: Our findings suggest that PCT may support conventional morphological imaging in predicting meningioma grading before surgery.

Dynamic contrast-enhanced magnetic resonance imaging in Head and Neck Cancer: differentiation of new H&N cancer, recurrent disease, and benign post-treatment changes.

PURPOSE: To determine if dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) parameters such as permeability surface area (PS) and blood volume (BV) allow differentiating between new head and neck (HN) cancer, recurrent HN cancer, and post-treatment benign changes. METHOD: A total of 35 patients with newly diagnosed, recurrent, and benign post-treatment benign changes underwent DCE-MRI. PS and BV were calculated. RESULTS: PS values of the lesion were 2.3×10(4)±5.8×10(4) for the newly diagnosed cancer group, 3.3×10(4)±1.7×10(4) for the recurrent cancer group, and 4.8×10(4)±8.1×10(4) for the post-treatment benign change group (P=.031). CONCLUSION: Post-treatment benign changes in the HN region had significantly high permeability property than newly diagnosed or previously treated recurrent tumor.

Dynamic perfusion CT in brain tumors.

Dynamic perfusion CT (PCT) is an imaging technique for assessing the vascular supply and hemodynamics of brain tumors by measuring blood flow, blood volume, and permeability-surface area product. These PCT parameters provide information complementary to histopathologic assessments and have been used for grading brain tumors, distinguishing high-grade gliomas from other brain lesions, differentiating true progression from post-treatment effects, and predicting prognosis after treatments. In this review, the basic principles of PCT are described, and applications of PCT of brain tumors are discussed. The advantages and current challenges, along with possible solutions, of PCT are presented.

Volumetric CT perfusion assessment of treatment response in head and neck squamous cell carcinoma: Comparison of CT perfusion parameters before and after chemoradiation therapy.

BACKGROUND AND PURPOSE: World Health Organization estimated that there were 600,000 new cases of head and neck cancers and 300,000 deaths each year worldwide. Scientific modalities to predict the treatment outcomes are not available yet. We conducted this study to (1) compare CT perfusion parameters before and after chemoradiation among patients with head and neck squamous cell carcinoma and (2) to evaluate the prognostic value of each perfusion parameter in predicting the response to chemoradiation. MATERIALS AND METHODS: We conducted a prospective study among all patients with head and neck squamous cell carcinoma registered for chemoradiotherapy (CRT) at Regional Cancer Research Center, Shimla, Himachal Pradesh, India during the period June 2012 through June 2013. CTp data were acquired on a 64-slice CT scanner (Light speed VCT Xte; GE Healthcare) with 14 cm z-axis coverage using Volume Helical Shuttle (VHS) feature at baseline, on completion of 40 Gy and 66 Gy of chemoradiation. We dichotomised the treatment outcome as complete response and non-response (partial responders/stable disease/progressive disease) using RECIST 1.1 criteria. We compared all perfusion parameters at baseline, 40 Gy and 66 Gy of CRT between responders and non-responders. We dichotomised the perfusion parameters as high (>median value) and low (≤median value) to analyze association between perfusion parameters and treatment outcome. We calculated the sensitivity, specificity, predictive values, and likelihood ratios for each dichotomized perfusion parameter using Wilson Score method. RESULTS: We followed 24 patients (23 of them men) from start of the treatment till completion of it. All had Stage III or Stage IV of the disease. Blood flow (BF) and blood volume (BV) decreased and Mean Transit Time (MTT) increased significantly (p < 0.05) at 66 Gy among responders to CRT as compared to non-responders. Patients with high BF (>106 ml/100 g/min) at baseline were five times more likely (p = 0.004) to respond to treatment as compared to those with low BF. BF was found to be 83.3% predictive of complete response. Other perfusion parameters were not significantly predictive of outcome (p > 0.05) Combination of high BF (>106 ml/100 g/min) and low (≤47 ml/100 g/min) permeability surface (PS) was 100% predictive of response to CRT irrespective of the stage of tumor. CONCLUSIONS: High BF at baseline is the single best predictor of response to chemoradiaton. A combination of high BF and low PS was found to be 100% predictive of complete response irrespective of the stage of the tumor.

Blood-brain transfer of Pittsburgh compound B in humans.

In the labeled form, the Pittsburgh compound B (2-(4'-{N-methyl-[(11)C]}methyl-aminophenyl)-6-hydroxy-benzothiazole, [(11)C]PiB), is used as a biomarker for positron emission tomography (PET) of brain ß-amyloid deposition in Alzheimer's disease (AD). The permeability of [(11)C]PiB in the blood-brain barrier is held to be high but the permeability-surface area product and extraction fractions in patients or healthy volunteers are not known. We used PET to determine the clearance associated with the unidrectional blood-brain transfer of [(11)C]PiB and the corresponding cerebral blood flow rates in frontal lobe, whole cerebral cortex, and cerebellum of patients with Alzheimer's disease and healthy volunteers. Regional cerebral blood flow rates differed significantly between the two groups. Thus, regional and whole-brain permeability-surface area products were identical, in agreement with the observation that numerically, but insignificantly, unidirectional blood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchanged permeability-surface area products in the patients implies that blood flow changes can be deduced from the unidirectional blood-brain clearances of [(11)C]PiB in the patients.

Use of permeability surface area-product to differentiate intracranial tumours from abscess.

BACKGROUND AND PURPOSE: Clinical and radiological findings of intracranial abscesses may mimic the findings of brain tumours and vice versa. However, the discrimination is of great clinical importance in planning treatment and in following prognosis and response to therapy. This study evaluates the Computed Tomography (CT) perfusion parameters, especially the permeability index, with the aim of evaluating the usefulness of dynamic CT perfusion imaging as an alternative tool to differentiate necrotic brain tumours and intracerebral abscesses. MATERIALS AND METHODS: A total of 21 patients underwent perfusion CT study and were divided into 2 groups: Group 1, patients with necrotic brain tumours (n=13); and Group 2, patients with cerebral abscesses (n=8). The mean perfusion parameters were obtained from the enhancing part of the lesion. The relative ratios were then calculated by using the results from mirrored regions within the contralateral hemisphere as reference. RESULTS: The results of this study showed that there was significant difference in the relative permeability surface values between necrotic brain tumours and cerebral abscesses (p=0.005). By applying the ROC curve, a value of 25.1 for rPS was found to be the best estimate to distinguish necrotic brain tumours from cerebral abscesses with a specificity of 88 % and sensitivity of 70 %. CONCLUSION: CT perfusion, especially permeability surface, may allow for better differentiation of cerebral abscesses from brain tumours, making it a strong additional imaging modality in the early diagnosis of these two entities.