Imaging brain fluid dynamics and waste clearance involving perivascular spaces in cerebral small vessel disease

Abstract Cerebral small vessel disease (SVD) is recognized as a major vascular contributor to cognitive decline, ultimately leading to dementia and stroke. While the pathogenesis of SVD remains unclear, emerging evidence suggests that waste clearance involving perivascular space (PVS) – also known as the glymphatic system – dysfunction may play a role. Among SVD radiological markers, the increased presence of dilated PVS is recognized as a marker of waste clearance disruption. Recently developed neuroimaging methods have been proposed as indirect measures of brain fluid dynamics, but they currently lack formal validation. Here, we provide a comprehensive overview of the latest neuroimaging advancements for assessing brain fluid dynamics, including waste clearance involving PVS function in SVD. We review the mechanisms by which clearance dysfunction might contribute to SVD. Finally, we argue that robust, multimodal, and longitudinal studies are essential for understanding the waste clearance (involving PVS) function and for establishing a diagnostic gold standard. Highlights The majority of PVS are not visible on MRI, making it crucial to understand how and why they become dilated. The origin of waste clearance involving PVS disruption in SVD may be multifactorial. The BBB and waste clearance (involving PVS) dysfunction likely affect each other, forming a vicious cycle, promoting further amyloid beta accumulation. Yet their direct association in humans over time remains to be studied. Comparative studies can aid in the standardization of methods for assessing waste clearance involving PVS function.