Glymphatic dysfunction in moyamoya disease: the influence of arterial stenosis and ventricular enlargement

The glymphatic system is a vascular-dependent network, involving cerebrospinal fluid circulation, that facilitates waste clearance from the brain. Although glymphatic dysfunction has been implicated in various neurologic diseases, its influencing factors are still not fully understood. We aimed to evaluate glymphatic clearance in moyamoya disease (MMD) and explore its associations with arterial stenosis and ventricular size. Patients with MMD and healthy controls were prospectively recruited to undergo multi-modal MRI scans. Patients were divided into three subgroups based on initial symptoms: hemorrhagic, ischemic, and other. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, magnetic resonance angiography, 3D T1-weighted images to evaluate glymphatic clearance, arterial stenosis and ventricular size. The relationships between arterial stenosis, ventricular size, and ALPS index were analyzed using multivariable linear regression analyses. Compared to controls (n=39), patients (n=55) exhibited reduced ALPS index (p<0.001) and increased volumes of the lateral ventricles (p<0.001), third ventricle (p<0.001) and fourth ventricle (p=0.013). In MMD, arterial stenosis (standardized β=-0.283, p=0.013), lateral ventricular volume (standardized β=-0.504, p<0.001), and their interaction (standardized β=-0.606, p<0.001) were all significantly associated with the ALPS index in multivariable analysis. Among the three subgroups, hemorrhagic subgroup had the lowest ALPS index (p=0.085) and the largest lateral ventricular volume (p=0.013). Our findings demonstrated that enlarged lateral ventricles were associated with decreased ALPS index, both alone and synergistically with arterial stenosis, and the reduced ALPS index and ventricular enlargement would be exacerbated in hemorrhagic MMD. This evidence provides new insights into the mechanisms underlying glymphatic impairment in MMD.