Non-contrast assessment of blood-brain-barrier permeability with water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI
Zixuan Lin1, Yang Li1, Pan Su1, Deng Mao1, Zhiliang Wei1, Jay Pillai1, Abhay Moghekar2, Matthias van Osch3, Yulin Ge4, and Hanzhang Lu1

1Department of Radiology, Johns Hopkins University, Baltimore, MD, United States, 2Department of Neurology, Johns Hopkins University, Baltimore, MD, United States, 3Department of Radiology, Leiden University Medical Center, Leiden, Netherlands, 4Department of Radiology, New York University Langone Medical Center, New York, NY, United States


A new method for non-contrast assessment of blood-brain-barrier (BBB) permeability to water has been proposed: water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, which allows selective imaging of venous ASL signal. Studies were performed to show proof-of-principle and Look-Locker readout were applied to expedite data acquisition. The results were consistent with previous literature. Mild hypercapnia was also shown to enhance the sensitivity of the technique significantly.


Disruption of Blood-brain barrier (BBB) permeability has been associated with many neurological diseases. Current methods using contrast-agent are primarily sensitive to major leakage of BBB to macromolecules, but may not detect subtle changes of BBB at early stage of diseases1. In this study, we aimed to measure global BBB permeability to water, without using any exogenous agent. We first developed a new sequence, water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, to selectively measure venous ASL signals, from which water permeability of BBB can be quantified. Next, to accelerate the acquisition, we developed a background-suppressed Look-Locker version of WEPCAST, and the results were compared to conventional WEPCAST. Finally, the benefit of hypercapnia and hyperoxia in enhancing the sensitivity of the technique was evaluated.


BBB permeability can be characterized by permeability-surface-area product (PS): $$$PS=-ln(1-E)·f$$$, where $$$E$$$ is the extraction fraction of water in its first-pass and $$$f$$$ is cerebral-blood-flow (CBF)2. To measure E, we can use pCASL to label the water molecules in arterial blood. At capillary-tissue interface, most labeled spins are extracted to tissue (Fig.1a, red), whereas non-extracted spins are drained directly to venous system (blue). Additionally, a small amount of labeled spins that are extracted to tissue will re-exchange back into venous system (yellow). Then ASL signal at superior-sagittal-sinus (SSS) can be written as $$$ΔM = ΔM_{1}+ΔM_{2}$$$, where $$$ΔM_{1}=2α(1-E)M_{0,blood}e^{-\frac{δ_{v}}{T_{1,blood}}}c(t)$$$ represents non-extracted spins and $$$ΔM_{2}=2αf/λEM_{0,blood}e^{-\frac{δ_{v}}{T_{1,blood}}}c(t)\bigotimes [r(t)m(t)]$$$ represents extracted spins that were re-exchanged into vessel. $$$λ$$$ is blood-brain partition coefficient, $$$α$$$ is labeling efficiency, $$$δ_{v}$$$ is bolus arrival time (BAT) to SSS, $$$\bigotimes $$$ denotes convolution, $$$c(t)=\left\{\begin{matrix}1, & if δ_{t}<t<δ_{t}\\ 0, & otherwise\end{matrix}\right.$$$ is arterial input function, $$$r(t)=e^{-ft/λ}$$$ is residue function and $$$m(t)=e^{-t/T_{1,tissue} }$$$ represents T1 relaxation3. Numerical simulation of SSS signal is shown in Fig.1b.


Study I – Selective imaging of venous ASL signal by WEPCAST MRI

To reduce the confounding contribution of tissue perfusion signal, we devised a new sequence, WEPCAST MRI, by adding a phase-contrast velocity-encoding gradient during acquisition of pCASL sequence (Fig.2a-b). The velocity-encoding gradient modifies the venous signal as $$$ΔM=2(ΔM_{1}+ΔM_{2})|sin(\frac{πv}{2V_{enc}})|$$$, where $$$v$$$ is the velocity of blood and $$$V_{enc}$$$ is encoding velocity. Images were acquired in mid-sagittal plane (N=6, age:23±3 years, male/female:3/3) with four long post-labeling-delays (PLD): 3000, 3500, 4000, 4500ms and $$$V_{enc}$$$=15cm/s. Scan duration=19min47s.

Study II – Expediting data acquisition using a background-suppressed Look-Locker WEPCAST sequence

The purpose of this study was to expedite the acquisition by applying a background-suppressed Look-Locker readout (Fig.2c), which allows 8-PLD acquisitions in one TR. Coronal images were acquired (N=6, age:28±8 years, male/female:3/3). Scan duration=5min3s. Multiple single-PLD WEPCAST sequence in Study I were also conducted for comparison.

Study III – Enhancing sensitivity by CO2 inhalation

We examined the benefit of mild hypercapnia (2.5%CO2) on enhancing WEPCAST signal because we reasoned that 1) CO2 increases CBF, which decreases E; 2) CO2 reduces BAT; 3) CO2 increases T2* of blood, all of which should augment the targeted signal. We also tested the benefit of hyperoxia challenge (on top of hypercapnia), as an increase in venous oxygenation may further enhance the signal via an increase in T2*. Sequence in Study II were performed under normocapnia, hypercapnia and hyperoxic-hypercapnia periods (N=5, age:28±5 years, male/female:2/3).

Results and Discussion

Study I: Fig.3a shows representative control, label, and difference images of WEPCAST MRI at PLD=4000ms. Venous signal can be seen at SSS and tissue signal is well suppressed. Fig.3b displays WEPCAST difference images for all PLD values. Quantitative analysis of posterior SSS revealed a signal curve shown in Fig.3c. Model fitting gave the average E of 95.5±1.1% and PS of 188.9±13.4mL/100g/min, which were consistent with previous literatures1,4-6.

Study II: Fig.4a displays difference images acquired with LL-WEPCAST. Averaged signal curves acquired with the LL- and conventional WEPCAST sequences are shown in Fig.4b. The two curves manifest similar signal intensities and temporal characteristics. Scatter plots of E and PS obtained from two methods are shown in Fig.4c, suggesting a good agreement between them (correlation-coefficient E:0.87; PS:0.92). Average E calculated from multiple single-PLD sequence and LL sequence was 96.4±0.6% and 97.0±0.7%, respectively. The average PS was 198.0±7.2mL/100g/min and 214.2.6±13.9mL/100g/min, respectively. Paired t-test did not show a significant difference.

Study III: As shown in Fig.5, hypercapnia challenge induced a considerable increase in signal intensity. CoV was reduced (P=0.028). Hyperoxic-hypercapnia, however, did not further increase the signal.


In this study, we developed a new sequence, WEPCAST MRI, for assessment of BBB permeability of water without using any exogenous contrast agent. The estimated permeability was in good agreement with prior literature. We also demonstrated that mild hypercapnia can significantly enhance the sensitivity of this technique without causing discomfort.


No acknowledgement found.


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Figure 1: Concept and simulations of the proposed method. (a) Illustration of the conceptual model used to describe water extraction around BBB in capillary. Most of incoming labeled spins are extracted by tissue (red arrow) while a small fraction is drained to the vein (blue). Additionally, some of the labeled spins that were extracted to tissue are re-exchanged back to the vein (yellow arrow). (b) Simulation results of ASL signal at SSS. Non-extracted spins contributed most of the signal compared with re-exchanged spins. Simulation parameters: T1, blood=1841ms , T1, tissue=1165ms, α=0.86 and λ=0.9mL/g.

Figure 2: Schematics of pulse sequences used in this study. (a) A conventional ASL sequence with a five-inversion background-suppression. (b) WEPCAST MRI sequence with flow-sensitive bipolar gradient added in the acquisition module. (c) Look-Locker WEPCAST MRI with background-suppression at all PLDs.

Figure 3: Venous ASL signal measured with WEPCAST MRI. (a) Representative images using the WEPCAST sequence (at PLD of 4000ms). Due to the flow-encoding, the control and label images show only large vessels without partial voluming of tissue signal. (b) WEPCAST difference images as a function of PLD. The M0 image that is used to normalize the difference images is also shown. (c) ROI results of posterior SSS signal. Error bar denotes the standard error across participants (N=6). Note that different participants have peak signals at different PLDs, resulting in a relatively large error bar.

Figure 4: Look-Locker WEPCAST results. (a) LL-WEPCAST: Imaging position and representative difference images at different PLDs. (b) Averaged signal curves (N=6) obtained from multiple single-PLD WEPCAST and LL-WEPCAST. Error bar denotes the standard error across participants. (c) Scatter plots of E and PS measured with the two methods. Each symbol represents data from one subject.

Figure 5: LL-WEPCAST MRI signal with physiological challenges. Averaged signal curve from SSS ROI (N=5) under normocapnia, hypercapnia (2.5% CO2), and hyperoxic-hypercapnia (2.5%CO2 and 58% O2). Hypercapnia dramatically increased the signal while hyperoxic-hypercapnia only showed a modest benefit.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)