Breakdown of the Blood-Brain Barrier (BBB) is implicated in many brain diseases such as MS, stroke and neurodegeneration¹. Gadolinium contrast agents and dynamic T₁-weighted imaging can be used to measure leakage of Gadolinium across the BBB. However, subtle breakdown is hard to detect², probably due to the relatively large molecular weight (~500 Da) of the agent. Measurements of endothelial water exchange may demonstrate greater and more reliable BBB differences between healthy brain and early disease. Several MRI sequences have been proposed to measure water exchange^3,4 but sensitivity is generally poor⁵. Here we propose an approach to increase the sensitivity of ASL to water exchange through the introduction of very small doses of Gadolinium contrast agent which alter the T₁ of blood. This will increase the sensitivity of the measurement to water exchange, but will reduce the signal to noise ratio due to signal decay during transit. This study investigates the feasibility of this approach using simulations and imaging. As a simple proof of principle, the Buxton model⁶ was adapted to allow the T₁ of the labelled water within the voxel to vary linearly between that of tissue and that of blood, as a function of the mean extraction fraction E (E=1 for complete exchange for which T₁ = T₁^tissue; E=0 for no exchange for which T₁ = T₁^blood). Model parameters were CBF=60 ml/min/100ml, arrival time=500ms, bolus duration=1000ms, T₁^tissue=1.3s, T₁^blood=1.6s, blood-brain partition coefficient=0.9. One person was scanned on a Philips 3T Achieva system using a Look-Locker ASL sequence⁷ with 17 inversion times (TI) 120ms apart. STAR labeling was employed with 15cm labelling slab and zero distance between label and imaging slab. Other parameters were: 80 control/label pairs, TR=2500 ms; TE=22ms; flip angle 40 degrees; 3.5 x3.5 x 7 mm voxels with 1mm gap between 3 axial slices. Bipolar ‘vascular crusher’ gradients were added to dephase fast flowing spins and so remove large vessel signal, increasing the sensitivity to exchanged water. A measurement of T₁^blood was made using the ‘Varela’ technique⁸ in a single slice through the sagittal sinus. Parameters were as described in the reference, with the collection of 20 averages to improve the precision of the estimate. Measurements were made at baseline and following consecutive contrast agent injections of 0.8ml, 1.6ml and 2.1ml of Dotarem. These were chosen to give a cumulative reduction of T₁^blood from 1.60s at baseline to 1.06s, 0.63s and 0.41s assuming relaxivity of 3.5 mM^-1s^-1 and total blood volume of 4.4L. One minute was left following injection before measurement to allow equilibration. Estimation of CBF and arrival time was made by fitting a single compartment model, adapted for Look-Locker readout⁹, to the global signal from the pre-contrast data, with bolus duration of 1.1s and T₁^blood of 1.6s. The post-contrast ASL data were fitted for T₁ using the values for CBF and arrival time estimated from the baseline data. Figure 1 shows the simulated ASL signal difference in the case of no contrast agent (a) and contrast agent that reduces T₁^blood to 0.7 s(b). In the latter case it can be seen that there is a large dependence on E, however the signal is more than halved compared to the no-contrast signal. T₁ measurements (the mean from a small region over the sagittal sinus) were 1.33s, 1.18s, 0.51s and 0.45s, in approximate agreement with the predicted signal change according to dose. Figure 2 shows the ASL signal difference for the 4 measurements along with the fitted curves. T₁ was estimated as 1.6s (fixed), 1.39s, 1.20s and 1.08s. It is clear that signal has not decayed as much as would be expected according to the known blood T₁, suggesting that there is substantial exchange of water into the extravascular space where T₁ is higher. This is supported by the subtraction images (Figure 3) which show reasonably high signal at TI of 2s after even the highest contrast agent dose.Despite strong shortening of T₁ (from dose calculation and confirmed on T₁ measurements), ASL signal is maintained at a relatively high TI of 2s, suggesting that water is exchanging into tissue quickly after labelling. Future work will develop a 2-compartment model to estimate exchange. This approach could provide estimates of water exchange in vivo in a clinically acceptable time.