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1. Abstract Arterial Spin Labelling (ASL) is a non-invasive, non-contrast, perfusion imaging technique which is inherently SNR limited. It is, therefore, important to carefully design scan protocols to ensure accurate measurements. Many pseudo-continuous ASL (PCASL) protocol designs have been proposed for measuring cerebral blood flow (CBF), but it has not yet been demonstrated which design offers the most accurate and repeatable CBF measurements. In this work, a wide range of literature PCASL protocols, including single-delay, sequential and time-encoded multi-timepoint protocols, and several novel protocol designs, which are hybrids of time-encoded and sequential multi-timepoint protocols, were first optimised using a Cramér-Rao Lower Bound framework and then compared for CBF accuracy and repeatability using Monte Carlo simulations and in vivo experiments. It was found that several multi-timepoint protocols produced more confident, accurate, and repeatable CBF estimates than the single-delay protocol, while also generating maps of arterial transit time. One of the novel hybrid protocols, Hybrid T1 -adj , was found to produce the most confident, accurate and repeatable CBF estimates of all protocols tested in both simulations and in vivo (24%, 47%, and 28% more confident, accurate, and repeatable than single-PLD in vivo). The Hybrid T1 -adj protocol makes use of the best aspects of both time-encoded and sequential multi-timepoint protocols and should be a useful tool for accurately and efficiently measuring CBF.

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