Cerebrovascular reactivity delay measured by blood oxygen level dependent magnetic resonance imaging and gas challenges: A systematic review.

Cerebrovascular reactivity (CVR), a promising marker of neurovascular responsiveness, is commonly measured using blood-oxygenation-level-dependent magnetic resonance imaging (BOLD-MRI) during a vasoactive gas challenge. While CVR magnitude (vascular response strength) has been widely studied, CVR delay (response time) is comparatively underexplored yet may provide valuable insight into vascular dysfunction across several neurological conditions. We systematically reviewed publications assessing delay using gas-challenge BOLD-MRI up to October 2025, identifying 200 relevant papers. Only 44 (22%) papers investigated delay in detail; the remainder only applied delay correction to improve CVR magnitude accuracy. Findings in disease were mixed and often limited by small sample sizes and methodological differences. Hypercapnic stimuli, typically delivered via fixed-inspired or fixed-expired methods, were most commonly used. While cross-correlation was the most popular delay estimation method, several alternatives, including haemodynamic response function fitting and Fourier analysis, have been proposed, but systematic comparisons against standard delay estimation methods remain limited, especially in clinical populations. Our review highlights inconsistencies in delay measurement and interpretation, with delay mostly treated as a confounder rather than a meaningful physiological parameter. Greater methodological validation and harmonisation are needed to realise the potential of CVR delay as a novel biomarker of brain health and disease.