Arterial spin labeling MRI in CADASIL: Implications for cerebral small vessel disease and therapeutic trials

Cerebral small vessel disease (CSVD) is a major cause of lacunar stroke, vascular cognitive impairment, and gait disturbance, yet the development of disease-modifying therapies is limited by the lack of robust, non-invasive biomarkers of microvascular pathology. Arterial spin labeling (ASL) MRI enables quantitative, non-invasive, contrast-free measurement of cerebral blood flow (CBF) and is well suited for longitudinal studies. In routine clinical and research practice, single-delay three-dimensional pseudo-continuous ASL (pCASL) with an appropriately long post-labeling delay is the workhorse implementation and has already been applied in several CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and hereditary CSVD cohorts, while more advanced approaches such as multi-delay ASL and diffusion-prepared pCASL can additionally probe arterial transit time (ATT) and blood-brain barrier (BBB) water exchange. CADASIL, caused by pathogenic NOTCH3 variants, is a prototypical monogenic CSVD with relatively low etiologic heterogeneity, providing a powerful clinical model in which to study microvascular dysfunction and trial-ready imaging markers. In this review, we synthesize data on ASL in CADASIL, including relationships between CBF, cognition, and lesion burden, evidence from acute encephalopathic episodes, and emerging work on ATT and BBB water exchange. We further compare perfusion profiles across monogenic (HTRA1-related CSVD, Fabry disease) and sporadic CSVD, and discuss how ASL-derived measures-CBF, ATT, and BBB water exchange rate-can be incorporated as imaging endpoints in CADASIL therapeutic trials. In particular, standardized single-delay three-dimensional pCASL provides a practical, scalable method to quantify regional CBF as a primary perfusion endpoint.