Synopsis

Blood-brain-barrier (BBB) permeability has been shown to be disrupted in many diseases. Current study proposes a non-invasive method to measure the extraction fraction and BBB permeability of water. Studies were performed to provide proof-of-principle and a new sequence was developed to improve efficiency. These methods provided consistent results with previous literature. CO₂ effect on permeability was explored and increased measurement sensitivity was demonstrated.

Purpose

Theory

BBB-permeability can be represented as permeability-surface-area-product (PS): $$$PS=-ln(1-E)·f$$$, where E is the extraction fraction of water, and f is cerebral blood flow (CBF)³. f is relatively easy to measure. For E, we reason that water molecules labeled arterially will be partially extracted to tissue, whereas non-extracted spins will be drained into the venous system (Fig. 1). In this study, we will focus on a large vein: the superior sagittal sinus (SSS). By labeling incoming arterial water by pCASL and measure the signal at SSS, we will be able to assess E and thereby PS. Assuming little dispersion, the pCASL signal at SSS can be written as:

$$\triangle M=\begin{cases}0 & t < \delta\\2\alpha(1-E)M_{0}exp(-\delta/T_{1,blood}) & \delta < t < \delta+\tau\\0 & t > \delta+\tau\end{cases}$$

where δ is bolus arrival time (BAT), α is labeling efficiency and τ is labeling duration.

Materials and Methods

All subjects provided informed consent and the study was approved by the local IRB.

Study One – Proof-of-principle with conventional multi-delay pCASL sequence

A Philips 3T was used. A conventional pCASL sequence with six (long) post-labeling delays (PLD=2000, 2500, 3000, 3500, 4000, 4500 ms) was used (labeling duration=2s) (Fig. 2a). Images were acquired at mid-sagittal plane (N=6, Male/Female: 3/3, Age: 27±6.4 yrs; single slice, voxel size = 3.13*3.13 mm²). ASL-signal at SSS was fitted to the model above. Scan time=40m42s.

Study Two – Improving efficiency by using a background-suppressed multi-acquisition pCASL sequence

We devised a new sequence that is similar to Look-Locker but has optimal background suppression for all readouts (Fig. 2b). This allows nine PLD acquisitions in one TR (N=6, Male/Female: 2/4, Age: 25±5.7 yrs; flip angle = 90°, single, coronal slice, voxel size = 2.34*2.34 mm²). Scan time=3m55s.

Study Three – Enhancing sensitivity by CO₂ inhalation

We examined the effect of hypercapnia on ΔM. We reasoned that 1) CO₂ reduces BAT; 2) CO₂ increases CBF which should increase (1-E), both of which should augment the targeted signal ΔM. Both Study 1 and Study 2 sequences were performed under room-air and CO₂ inhalation periods (N=5, Male/Female: 1/4, Age: 21±3.8 yrs).

Results and Discussion

Study 1: Representative sagittal ASL-images acquired with conventional multi-delay pCASL method are shown in Fig. 3a. Venous ASL-signal can be seen at SSS starting at PLD=2500ms, reaching a peak around PLD=3000-3500ms and decaying afterwards. Quantitative analysis of SSS-signal in Fig. 3b indicates that, from anterior to posterior SSS, the BAT increases and that the peak signal decreases due to T1-related decay of label. Average E was 96.5±1.7% (N=6). Assuming CBF of 57ml/100g/min, this corresponds to PS=191.3±26.5ml/100g/min.

In study 2, coronal images were acquired with background-suppressed multi-acquisition pCASL (Fig. 4a). It can be seen that data from short PLDs contained substantial tissue perfusion, which contaminated venous ASL-signal. Thus, only data from PLD=1500ms and above were used in the fitting analysis (Fig. 4b). Average E was 97.3±2.1%. Assuming CBF=57ml/100g/min, this corresponds to PS=218.7±46.0ml/100g/min. The E and PS results measured from Study 1 and Study 2 were not significantly different (p=0.38), and are in general agreement with literature values from PET ^4,5.

As shown in Fig. 5, CO₂ inhalation induced an increase in the SSS-signal compared to room air, and the labeled spins arrived earlier. Quantitative analysis showed an increase in CBF and decrease in E (Table 1). Paired t-test showed significant differences in CBF and E (p=0.005 and 0.03), but not a significant change in PS (p>0.05).

Conclusion

Acknowledgements

References

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