Altered glymphatic function and cerebrovascular reactivity in white matter hyperintensities: Insights into cognitive...

White matter hyperintensities (WMH) are linked to cognitive impairment and an increased risk of cerebrovascular and neurodegenerative disorders. While the glymphatic system plays a key role in WMH pathophysiology, the relationship between glymphatic function and cerebrovascular reactivity (CVR) in WMH remains unclear. This study aimed to investigate glymphatic function and CVR in WMH patients with varying lesion severity and cognitive status and to explore their relationship with cognitive performance.

A total of 124 participants were categorized into three groups based on Fazekas grade and cognitive function: controls (no/mild WMH), moderate-severe WMH without cognitive impairment, and moderate-severe WMH with cognitive impairment no dementia (WMH-CIND). Glymphatic function was assessed using diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) and global blood oxygen level-dependent cerebrospinal fluid (gBOLD-CSF) coupling from resting-state functional MRI (rs-fMRI). CVR mapping was derived from rs-fMRI, and cognitive performance was evaluated using a comprehensive battery.

The ALPS-index showed a stepwise decline with increasing WMH severity and cognitive impairment (p < 0.001). WMH-CIND participants exhibited lower gBOLD-CSF coupling compared with controls (p < 0.05). CVR alterations were localized to frontal and occipital regions. Significant associations were observed between glymphatic indices, region-specific CVR, and cognitive performance across multiple domains.

These findings highlight the complex interplay between glymphatic dysfunction, localized CVR impairments, and cognitive decline in WMH. Preserving vascular health and optimizing glymphatic clearance may represent promising approaches for controlling WMH progression and its associated cognitive deficits.