Arterial spin labeling-derived cerebral blood flow as a translational biomarker and candidate surrogate endpoint for cognitive impairment.

PURPOSE OF REVIEW: Arterial spin labeling (ASL) MRI noninvasively quantifies cerebral blood flow (CBF), but its role as a mechanistic biomarker and surrogate endpoint in trials of cognitive impairment remains undefined. This review evaluates evidence linking regional CBF to cognition across Alzheimer's disease, mild cognitive impairment (MCI), and cerebral small vessel disease (SVD), with particular emphasis on CADASIL as a mechanistically informative model. RECENT FINDINGS: Multipostlabeling-delay ASL, spatial coefficient of variation metrics, and harmonized processing pipelines have improved reproducibility. Cross-sectional and longitudinal studies consistently link reduced CBF to cognitive impairment, with baseline CBF predicting cognitive decline, MCI-to-Alzheimer's disease conversion, white matter hyperintensity progression, and vascular events. In CADASIL, CBF is independently associated with cognitive performance and predicts subcortical hyperintensity progression over 2 years. Interventional data from SPRINT MIND, PRESERVE, and pilot lecanemab studies indicate that ASL-CBF is responsive to therapy. SUMMARY: Within the FDA-NIH BEST framework, ASL-CBF appears to meet several criteria consistent with a reasonably likely surrogate endpoint, capturing upstream, potentially reversible hemodynamic dysfunction beyond established structural markers. CADASIL provides an optimal context for qualifications. Larger clinical trials linking treatment-induced CBF changes to clinical benefit, further protocol harmonization, and regulatory engagement are needed to translate ASL-CBF into a validated trial endpoint.